WYETH v. LEVINE


Syllabus

WYETH v. LEVINE (No. 06-1249)
___ Vt. ___, 944 A. 2d 179, affirmed.

WYETH v. LEVINE

certiorari to the supreme court of vermont


No. 06–1249.Argued November 3, 2008—Decided March 4, 2009

Petitioner Wyeth manufactures the antinausea drug Phenergan. After a clinician injected respondent Levine with Phenergan by the “IV-push” method, whereby a drug is injected directly into a patient’s vein, the drug entered Levine’s artery, she developed gangrene, and doctors amputated her forearm. Levine brought a state-law damages action, alleging, inter alia, that Wyeth had failed to provide an adequate warning about the significant risks of administering Phenergan by the IV-push method. The Vermont jury determined that Levine’s injury would not have occurred if Phenergan’s label included an adequate warning, and it awarded damages for her pain and suffering, substantial medical expenses, and loss of her livelihood as a professional musician. Declining to overturn the verdict, the trial court rejected Wyeth’s argument that Levine’s failure-to-warn claims were pre-empted by federal law because Phenergan’s labeling had been approved by the federal Food and Drug Administration (FDA). The Vermont Supreme Court affirmed.

Held: Federal law does not pre-empt Levine’s claim that Phenergan’s label did not contain an adequate warning about the IV-push method of administration. Pp. 6–25.

(a) The argument that Levine’s state-law claims are pre-empted because it is impossible for Wyeth to comply with both the state-law duties underlying those claims and its federal labeling duties is rejected. Although a manufacturer generally may change a drug label only after the FDA approves a supplemental application, the agency’s “changes being effected” (CBE) regulation permits certain preapproval labeling changes that add or strengthen a warning to improve drug safety. Pursuant to the CBE regulation, Wyeth could have unilaterally added a stronger warning about IV-push administration, and there is no evidence that the FDA would ultimately have rejected such a labeling change. Wyeth’s cramped reading of the CBE regulation and its broad assertion that unilaterally changing the Phenergan label would have violated federal law governing unauthorized distribution and misbranding of drugs are based on the fundamental misunderstanding that the FDA, rather than the manufacturer, bears primary responsibility for drug labeling. It is a central premise of the Food, Drug, and Cosmetic Act (FDCA) and the FDA’s regulations that the manufacturer bears responsibility for the content of its label at all times. Pp. 11–16.

(b) Wyeth’s argument that requiring it to comply with a state-law duty to provide a stronger warning would interfere with Congress’ purpose of entrusting an expert agency with drug labeling decisions is meritless because it relies on an untenable interpretation of congressional intent and an overbroad view of an agency’s power to pre-empt state law. The history of the FDCA shows that Congress did not intend to pre-empt state-law failure-to-warn actions. In advancing the argument that the FDA must be presumed to have established a specific labeling standard that leaves no room for different state-law judgments, Wyeth relies not on any statement by Congress but on the preamble to a 2006 FDA regulation declaring that state-law failure-to-warn claims threaten the FDA’s statutorily prescribed role. Although an agency regulation with the force of law can pre-empt conflicting state requirements, this case involves no such regulation but merely an agency’s assertion that state law is an obstacle to achieving its statutory objectives. Where, as here, Congress has not authorized a federal agency to pre-empt state law directly, the weight this Court accords the agency’s explanation of state law’s impact on the federal scheme depends on its thoroughness, consistency, and persuasiveness. Cf., e.g., Skidmore v. Swift & Co., 323 U. S. 134. Under this standard, the FDA’s 2006 preamble does not merit deference: It is inherently suspect in light of the FDA’s failure to offer interested parties notice or opportunity for comment on the pre-emption question; it is at odds with the available evidence of Congress’ purposes; and it reverses the FDA’s own longstanding position that state law is a complementary form of drug regulation without providing a reasoned explanation. Geier v. American Honda Motor Co., 529 U. S. 861, is distinguished. Pp. 17–25.

___ Vt. ___, 944 A. 2d 179, affirmed.

Stevens, J., delivered the opinion of the Court, in which Kennedy, Souter, Ginsburg, and Breyer, JJ., joined. Breyer, J., filed a concurring opinion. Thomas, J., filed an opinion concurring in the judgment. Alito, J., filed a dissenting opinion, in which Roberts, C. J., and Scalia, J., joined.


TOP

Opinion

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Stevens delivered the opinion of the Court.

Directly injecting the drug Phenergan into a patient’s vein creates a significant risk of catastrophic consequences. A Vermont jury found that petitioner Wyeth, the manufacturer of the drug, had failed to provide an adequate warning of that risk and awarded damages to respondent Diana Levine to compensate her for the amputation of her arm. The warnings on Phenergan’s label had been deemed sufficient by the federal Food and Drug Administration (FDA) when it approved Wyeth’s new drug application in 1955 and when it later approved changes in the drug’s labeling. The question we must decide is whether the FDA’s approvals provide Wyeth with a complete defense to Levine’s tort claims. We conclude that they do not.

I

Phenergan is Wyeth’s brand name for promethazine hydrochloride, an antihistamine used to treat nausea. The injectable form of Phenergan can be administered intramuscularly or intravenously, and it can be administered intravenously through either the “IV-push” method, whereby the drug is injected directly into a patient’s vein, or the “IV-drip” method, whereby the drug is introduced into a saline solution in a hanging intravenous bag and slowly descends through a catheter inserted in a patient’s vein. The drug is corrosive and causes irreversible gangrene if it enters a patient’s artery.

Levine’s injury resulted from an IV-push injection of Phenergan. On April 7, 2000, as on previous visits to her local clinic for treatment of a migraine headache, she received an intramuscular injection of Demerol for her headache and Phenergan for her nausea. Because the combination did not provide relief, she returned later that day and received a second injection of both drugs. This time, the physician assistant administered the drugs by the IV-push method, and Phenergan entered Levine’s artery, either because the needle penetrated an artery directly or because the drug escaped from the vein into surrounding tissue (a phenomenon called “perivascular extravasation”) where it came in contact with arterial blood. As a result, Levine developed gangrene, and doctors amputated first her right hand and then her entire forearm. In addition to her pain and suffering, Levine incurred substantial medical expenses and the loss of her livelihood as a professional musician.

After settling claims against the health center and clinician, Levine brought an action for damages against Wyeth, relying on common-law negligence and strict-liability theories. Although Phenergan’s labeling warned of the danger of gangrene and amputation following inadvertent intra-arterial injection, 1 Levine alleged that the labeling was defective because it failed to instruct clinicians to use the IV-drip method of intravenous administration instead of the higher risk IV-push method. More broadly, she alleged that Phenergan is not reasonably safe for intravenous administration because the foreseeable risks of gangrene and loss of limb are great in relation to the drug’s therapeutic benefits. App. 14–15.

Wyeth filed a motion for summary judgment, arguing that Levine’s failure-to-warn claims were pre-empted by federal law. The court found no merit in either Wyeth’s field pre-emption argument, which it has since abandoned, or its conflict pre-emption argument. With respect to the contention that there was an “actual conflict between a specific FDA order,” id., at 21, and Levine’s failure-to-warn action, the court reviewed the sparse correspondence between Wyeth and the FDA about Phenergan’s labeling and found no evidence that Wyeth had “earnestly attempted” to strengthen the intra-arterial injection warning or that the FDA had “specifically disallowed” stronger language, id., at 23. The record, as then developed, “lack[ed] any evidence that the FDA set a ceiling on this matter.” Ibid.

The evidence presented during the 5-day jury trial showed that the risk of intra-arterial injection or perivascular extravasation can be almost entirely eliminated through the use of IV-drip, rather than IV-push, administration. An IV drip is started with saline, which will not flow properly if the catheter is not in the vein and fluid is entering an artery or surrounding tissue. See id., at 50–51, 60, 66–68, 75. By contrast, even a careful and experienced clinician using the IV-push method will occasionally expose an artery to Phenergan. See id., at 73, 75–76. While Phenergan’s labeling warned against intra-arterial injection and perivascular extravasation and advised that “[w]hen administering any irritant drug intravenously it is usually preferable to inject it through the tubing of an intravenous infusion set that is known to be function-ing satisfactorily,” id., at 390, the labeling did not con-tain a specific warning about the risks of IV-pushadministration.

The trial record also contains correspondence between Wyeth and the FDA discussing Phenergan’s label. The FDA first approved injectable Phenergan in 1955. In 1973 and 1976, Wyeth submitted supplemental new drug applications, which the agency approved after proposing labeling changes. Wyeth submitted a third supplemental application in 1981 in response to a new FDA rule governing drug labels. Over the next 17 years, Wyeth and the FDA intermittently corresponded about Phenergan’s label. The most notable activity occurred in 1987, when the FDA suggested different warnings about the risk of arterial exposure, and in 1988, when Wyeth submitted revised labeling incorporating the proposed changes. The FDA did not respond. Instead, in 1996, it requested from Wyeth the labeling then in use and, without addressing Wyeth’s 1988 submission, instructed it to “[r]etain verbiage in current label” regarding intra-arterial injection. Id., at 359. After a few further changes to the labeling not related to intra-arterial injection, the FDA approved Wyeth’s 1981 application in 1998, instructing that Phenergan’s final printed label “must be identical” to the approved package insert. Id., at 382.

Based on this regulatory history, the trial judge instructed the jury that it could consider evidence of Wyeth’s compliance with FDA requirements but that such compliance did not establish that the warnings were adequate. He also instructed, without objection from Wyeth, that FDA regulations “permit a drug manufacturer to change a product label to add or strengthen a warning about its product without prior FDA approval so long as it later submits the revised warning for review and approval.” Id., at 228.

Answering questions on a special verdict form, the jury found that Wyeth was negligent, that Phenergan was a defective product as a result of inadequate warnings and instructions, and that no intervening cause had broken the causal connection between the product defects and the plaintiff’s injury. Id., at 233–235. It awarded total damages of $7,400,000, which the court reduced to account for Levine’s earlier settlement with the health center and clinician. Id., at 235–236.

On August 3, 2004, the trial court filed a comprehensive opinion denying Wyeth’s motion for judgment as a matter of law. After making findings of fact based on the trial record (supplemented by one letter that Wyeth found after the trial), the court rejected Wyeth’s pre-emption arguments. It determined that there was no direct conflict between FDA regulations and Levine’s state-law claims because those regulations permit strengthened warnings without FDA approval on an interim basis and the record contained evidence of at least 20 reports of amputations similar to Levine’s since the 1960’s. The court also found that state tort liability in this case would not obstruct the FDA’s work because the agency had paid no more than passing attention to the question whether to warn against IV-push administration of Phenergan. In addition, the court noted that state law serves a compensatory function distinct from federal regulation. Id., at 249–252.

The Vermont Supreme Court affirmed. It held that the jury’s verdict “did not conflict with FDA’s labeling requirements for Phenergan because [Wyeth] could have warned against IV-push administration without prior FDA approval, and because federal labeling requirements create a floor, not a ceiling, for state regulation.” ___ Vt. ___, ___ 944 A. 2d 179, 184 (2006). In dissent, Chief Justice Reiber argued that the jury’s verdict conflicted with federal law because it was inconsistent with the FDA’s conclusion that intravenous administration of Phenergan was safe and effective.

The importance of the pre-emption issue, coupled with the fact that the FDA has changed its position on state tort law and now endorses the views expressed in Chief Justice Reiber’s dissent, persuaded us to grant Wyeth’s petition for certiorari. 552 U. S. ___ (2008). The question presented by the petition is whether the FDA’s drug labeling judgments “preempt state law product liability claims premised on the theory that different labeling judgments were necessary to make drugs reasonably safe for use.” Pet. for Cert. i.

II

Wyeth makes two separate pre-emption arguments: first, that it would have been impossible for it to comply with the state-law duty to modify Phenergan’s labeling without violating federal law, see Fidelity Fed. Sav. & Loan Assn. v. De la Cuesta, 458 U. S. 141, 153 (1982) , and second, that recognition of Levine’s state tort action creates an unacceptable “obstacle to the accomplishment and execution of the full purposes and objectives of Congress,” Hines v. Davidowitz, 312 U. S. 52, 67 (1941) , because it substitutes a lay jury’s decision about drug labeling for the expert judgment of the FDA. As a preface to our evaluation of these arguments, we identify two factual propositions decided during the trial court proceedings, emphasize two legal principles that guide our analysis, and review the history of the controlling federal statute.

The trial court proceedings established that Levine’s injury would not have occurred if Phenergan’s label had included an adequate warning about the risks of the IV-push method of administering the drug. The record contains evidence that the physician assistant administered a greater dose than the label prescribed, that she may have inadvertently injected the drug into an artery rather than a vein, and that she continued to inject the drug after Levine complained of pain. Nevertheless, the jury rejected Wyeth’s argument that the clinician’s conduct was an intervening cause that absolved it of liability. See App. 234 (jury verdict), 252–254. In finding Wyeth negligent as well as strictly liable, the jury also determined that Levine’s injury was foreseeable. That the inadequate label was both a but-for and proximate cause of Levine’s injury is supported by the record and no longer challenged by Wyeth. 2

The trial court proceedings further established that the critical defect in Phenergan’s label was the lack of an adequate warning about the risks of IV-push administration. Levine also offered evidence that the IV-push method should be contraindicated and that Phenergan should never be administered intravenously, even by the IV-drip method. Perhaps for this reason, the dissent incorrectly assumes that the state-law duty at issue is the duty to contraindicate the IV-push method. See, e.g., post, at 8, 25. But, as the Vermont Supreme Court explained, the jury verdict established only that Phenergan’s warning was insufficient. It did not mandate a particular replacement warning, nor did it require contraindicating IV-push administration: “There may have been any number of ways for [Wyeth] to strengthen the Phenergan warning without completely eliminating IV-push administration.” ___ Vt., at ___, n. 2, 944 A. 2d, at 189, n. 2. We therefore need not decide whether a state rule proscribing intravenous administration would be pre-empted. The narrower question presented is whether federal law pre-empts Levine’s claim that Phenergan’s label did not contain an adequate warning about using the IV-push method of administration.

Our answer to that question must be guided by two cornerstones of our pre-emption jurisprudence. First, “the purpose of Congress is the ultimate touchstone in every pre-emption case.” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) (internal quotation marks omitted); see Retail Clerks v. Schermerhorn, 375 U. S. 96, 103 (1963) . Second, “[i]n all pre-emption cases, and particularly in those in which Congress has ‘legislated … in a field which the States have traditionally occupied,’ … we ‘start with the assumption that the historic police powers of the States were not to be superseded by the Federal Act unless that was the clear and manifest purpose of Congress.’ ” Lohr, 518 U. S., at 485 (quoting Rice v. Santa Fe Elevator Corp., 331 U. S. 218, 230 (1947) ). 3

In order to identify the “purpose of Congress,” it is appropriate to briefly review the history of federal regulation of drugs and drug labeling. In 1906, Congress enacted its first significant public health law, the Federal Food and Drugs Act, ch. 3915, 34Stat. 768. The Act, which prohibited the manufacture or interstate shipment of adulterated or misbranded drugs, supplemented the protection for consumers already provided by state regulation and common-law liability. In the 1930’s, Congress became increasingly concerned about unsafe drugs and fraudulent marketing, and it enacted the Federal Food, Drug, and Cosmetic Act (FDCA), ch. 675, 52Stat. 1040, as amended, 21 U. S. C. §301 et seq. The Act’s most substantial innovation was its provision for premarket approval of new drugs. It required every manufacturer to submit a new drug application, including reports of investigations and specimens of proposed labeling, to the FDA for review. Until its application became effective, a manufacturer was prohibited from distributing a drug. The FDA could reject an application if it determined that the drug was not safe for use as labeled, though if the agency failed to act, an application became effective 60 days after the filing. FDCA, §505(c), 52Stat. 1052.

In 1962, Congress amended the FDCA and shifted the burden of proof from the FDA to the manufacturer. Before 1962, the agency had to prove harm to keep a drug out of the market, but the amendments required the manufacturer to demonstrate that its drug was “safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling” before it could distribute the drug. §§102(d), 104(b), 76Stat. 781, 784. In addition, the amendments required the manufacturer to prove the drug’s effectiveness by introducing “substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling.” §102(d), id., at 781.

As it enlarged the FDA’s powers to “protect the public health” and “assure the safety, effectiveness, and reliability of drugs,” id., at 780, Congress took care to preserve state law. The 1962 amendments added a saving clause, indicating that a provision of state law would only be invalidated upon a “direct and positive conflict” with the FDCA. §202, id., at 793. Consistent with that provision, state common-law suits “continued unabated despite … FDA regulation.” Riegel v. Medtronic, Inc., 552 U. S. ___, ___ (2008) (slip op., at 8) (Ginsburg, J., dissenting); see ibid., n. 11 (collecting state cases). And when Congress enacted an express pre-emption provision for medical devices in 1976, see §521, 90Stat. 574 (codified at 21 U. S. C. §360k(a)), it declined to enact such a provision for prescription drugs.

In 2007, after Levine’s injury and lawsuit, Congress again amended the FDCA. 121Stat. 823. For the first time, it granted the FDA statutory authority to require a manufacturer to change its drug label based on safety information that becomes available after a drug’s initial approval. §901(a), id., at 924–926. In doing so, however, Congress did not enact a provision in the Senate bill that would have required the FDA to preapprove all changes to drug labels. See S. 1082, 110th Cong., 1st Sess., §208, pp. 107–114 (2007) (as passed) (proposing new §506D). Instead, it adopted a rule of construction to make it clear that manufacturers remain responsible for updating their labels. See 121Stat. 925–926.

III

Wyeth first argues that Levine’s state-law claims are pre-empted because it is impossible for it to comply with both the state-law duties underlying those claims and its federal labeling duties. See De la Cuesta, 458 U. S., at 153. The FDA’s premarket approval of a new drug application includes the approval of the exact text in the proposed label. See 21 U. S. C. §355; 21 CFR §314.105(b) (2008). Generally speaking, a manufacturer may only change a drug label after the FDA approves a supplemental application. There is, however, an FDA regulation that permits a manufacturer to make certain changes to its label before receiving the agency’s approval. Among other things, this “changes being effected” (CBE) regulation provides that if a manufacturer is changing a label to “add or strengthen a contraindication, warning, precaution, or adverse reaction” or to “add or strengthen an instruction about dosage and administration that is intended to increase the safe use of the drug product,” it may make the labeling change upon filing its supplemental application with the FDA; it need not wait for FDA approval. §§314.70(c)(6)(iii)(A), (C).

Wyeth argues that the CBE regulation is not implicated in this case because a 2008 amendment provides that a manufacturer may only change its label “to reflect newly acquired information.” 73 Fed. Reg. 49609. Resting on this language (which Wyeth argues simply reaffirmed the interpretation of the regulation in effect when this case was tried), Wyeth contends that it could have changed Phenergan’s label only in response to new information that the FDA had not considered. And it maintains that Levine has not pointed to any such information concerning the risks of IV-push administration. Thus, Wyeth insists, it was impossible for it to discharge its state-law obligation to provide a stronger warning about IV-push administration without violating federal law. Wyeth’s argument misapprehends both the federal drug regulatory scheme and its burden in establishing a pre-emption defense.

We need not decide whether the 2008 CBE regulation is consistent with the FDCA and the previous version of the regulation, as Wyeth and the United States urge, because Wyeth could have revised Phenergan’s label even in accordance with the amended regulation. As the FDA explained in its notice of the final rule, “ ‘newly acquired information’ ” is not limited to new data, but also encompasses “new analyses of previously submitted data.” Id., at 49604. The rule accounts for the fact that risk information accumulates over time and that the same data may take on a different meaning in light of subsequent developments: “[I]f the sponsor submits adverse event information to FDA, and then later conducts a new analysis of data showing risks of a different type or of greater severity or frequency than did reports previously submitted to FDA, the sponsor meets the requirement for ‘newly acquired information.’ ” Id., at 49607; see also id., at 49606.

The record is limited concerning what newly acquired information Wyeth had or should have had about the risks of IV-push administration of Phenergan because Wyeth did not argue before the trial court that such information was required for a CBE labeling change. Levine did, however, present evidence of at least 20 incidents prior to her injury in which a Phenergan injection resulted in gangrene and an amputation. See App. 74, 252. 4 After the first such incident came to Wyeth’s attention in 1967, it notified the FDA and worked with the agency to change Phenergan’s label. In later years, as amputations continued to occur, Wyeth could have analyzed the accumulating data and added a stronger warning about IV-push administration of the drug.

Wyeth argues that if it had unilaterally added such a warning, it would have violated federal law governing unauthorized distribution and misbranding. Its argument that a change in Phenergan’s labeling would have subjected it to liability for unauthorized distribution rests on the assumption that this labeling change would have rendered Phenergan a new drug lacking an effective application. But strengthening the warning about IV-push administration would not have made Phenergan a new drug. See 21 U. S. C. §321(p)(1) (defining “new drug”); 21 CFR §310.3(h). Nor would this warning have rendered Phenergan misbranded. The FDCA does not provide that a drug is misbranded simply because the manufacturer has altered an FDA-approved label; instead, the misbranding provision focuses on the substance of the label and, among other things, proscribes labels that fail to include “adequate warnings.” 21 U. S. C. §352(f). Moreover, because the statute contemplates that federal juries will resolve most misbranding claims, the FDA’s belief that a drug is misbranded is not conclusive. See §§331, 332, 334(a)–(b). And the very idea that the FDA would bring an enforcement action against a manufacturer for strengthening a warning pursuant to the CBE regulation is difficult to accept—neither Wyeth nor the United States has identified a case in which the FDA has done so.

Wyeth’s cramped reading of the CBE regulation and its broad reading of the FDCA’s misbranding and unauthorized distribution provisions are premised on a more fundamental misunderstanding. Wyeth suggests that the FDA, rather than the manufacturer, bears primary responsibility for drug labeling. Yet through many amendments to the FDCA and to FDA regulations, it has remained a central premise of federal drug regulation that the manufacturer bears responsibility for the content of its label at all times. It is charged both with crafting an adequate label and with ensuring that its warnings remain adequate as long as the drug is on the market. See, e.g., 21 CFR §201.80(e) (requiring a manufacturer to revise its label “to include a warning as soon as there is reasonable evidence of an association of a serious hazard with a drug”);§314.80(b) (placing responsibility for postmarketing surveillance on the manufacturer); 73 Fed. Reg. 49605 (“Manufacturers continue to have a responsibility under Federal law … to maintain their labeling and update the labeling with new safety information”).

Indeed, prior to 2007, the FDA lacked the authority to order manufacturers to revise their labels. See 121Stat. 924–926. When Congress granted the FDA this authority, it reaffirmed the manufacturer’s obligations and referred specifically to the CBE regulation, which both reflects the manufacturer’s ultimate responsibility for its label and provides a mechanism for adding safety information to the label prior to FDA approval. See id., at 925–926(stating that a manufacturer retains the responsibility “to maintain its label in accordance with existing requirements, including subpart B of part 201 and sections 314.70 and 601.12 of title 21, Code of Federal Regulations (or any successor regulations)” (emphasis added)). Thus, when the risk of gangrene from IV-push injection of Phenergan became apparent, Wyeth had a duty to provide a warning that adequately described that risk, and the CBE regulation permitted it to provide such a warning before receiving the FDA’s approval.

Of course, the FDA retains authority to reject labeling changes made pursuant to the CBE regulation in its review of the manufacturer’s supplemental application, just as it retains such authority in reviewing all supplemental applications. But absent clear evidence that the FDA would not have approved a change to Phenergan’s label, we will not conclude that it was impossible for Wyeth to comply with both federal and state requirements.

Wyeth has offered no such evidence. It does not argue that it attempted to give the kind of warning required by the Vermont jury but was prohibited from doing so by the FDA. See Tr. of Oral Arg. 12–13; see also Brief for United States as Amicus Curiae 25. And while it does suggest that the FDA intended to prohibit it from strengthening the warning about IV-push administration because the agency deemed such a warning inappropriate in reviewing Phenergan’s drug applications, both the trial court and the Vermont Supreme Court rejected this account as a matter of fact. In its decision on Wyeth’s motion for judgment as a matter of law, the trial court found “no evidence in this record that either the FDA or the manufacturer gave more than passing attention to the issue of” IV-push versus IV-drip administration. App. 249. The Vermont Supreme Court likewise concluded that the FDA had not made an affirmative decision to preserve the IV-push method or intended to prohibit Wyeth from strengthening its warning about IV-push administration. ___ Vt., at ___, 944 A. 2d, at 188–189. Moreover, Wyeth does not argue that it supplied the FDA with an evaluation or analysis concerning the specific dangers posed by the IV-push method.We accordingly cannot credit Wyeth’s contention that the FDA would have prevented it from adding a stronger warning about the IV-push method of intravenous administration. 6

Impossibility pre-emption is a demanding defense. On the record before us, Wyeth has failed to demonstrate that it was impossible for it to comply with both federal and state requirements. The CBE regulation permitted Wyeth to unilaterally strengthen its warning, and the mere fact that the FDA approved Phenergan’s label does not establish that it would have prohibited such a change.

IV

Wyeth also argues that requiring it to comply with a state-law duty to provide a stronger warning about IV-push administration would obstruct the purposes and objectives of federal drug labeling regulation. Levine’s tort claims, it maintains, are pre-empted because they interfere with “Congress’s purpose to entrust an expert agency to make drug labeling decisions that strike a balance between competing objectives.” Brief for Petitioner 46. We find no merit in this argument, which relies on an untenable interpretation of congressional intent and an overbroad view of an agency’s power to pre-empt state law.

Wyeth contends that the FDCA establishes both a floor and a ceiling for drug regulation: Once the FDA has approved a drug’s label, a state-law verdict may not deem the label inadequate, regardless of whether there is any evidence that the FDA has considered the stronger warning at issue. The most glaring problem with this argument is that all evidence of Congress’ purposes is to the contrary. Building on its 1906 Act, Congress enacted the FDCA to bolster consumer protection against harmful products. See Kordel v. United States, 335 U. S. 345, 349 (1948) ; United States v. Sullivan, 332 U. S. 689, 696 (1948) . Congress did not provide a federal remedy for consumers harmed by unsafe or ineffective drugs in the 1938 statute or in any subsequent amendment. Evidently, it determined that widely available state rights of action provided appropriate relief for injured consumers. 7 It may also have recognized that state-law remedies further consumer protection by motivating manufacturers to produce safe and effective drugs and to give adequate warnings.

If Congress thought state-law suits posed an obstacle to its objectives, it surely would have enacted an express pre-emption provision at some point during the FDCA’s 70-year history. But despite its 1976 enactment of an express pre-emption provision for medical devices, see §521, 90Stat. 574 (codified at 21 U. S. C. §360k(a)), Congress has not enacted such a provision for prescription drugs.See Riegel, 552 U. S., at ___ (slip op., at 14)(“Congress could have applied the pre-emption clause to the entire FDCA. It did not do so, but instead wrote a pre-emption clause that applies only to medical devices”). 8 Its silence on the issue, coupled with its certain awareness of the prevalence of state tort litigation, is powerful evidence that Congress did not intend FDA oversight to be the exclusive means of ensuring drug safety and effectiveness. As Justice O’Connor explained in her opinion for a unanimous Court: “The case for federal pre-emption is particularly weak where Congress has indicated its awareness of the operation of state law in a field of federal interest, and has nonetheless decided to stand by both concepts and to tolerate whatever tension there [is] between them.” Bonito Boats, Inc. v. Thunder Craft Boats, Inc., 489 U. S. 141, 166–167 (1989) (internal quotation marks omitted); see also supra,at 8 (discussing the presumption against pre-emption).

Despite this evidence that Congress did not regard state tort litigation as an obstacle to achieving its purposes, Wyeth nonetheless maintains that, because the FDCA requires the FDA to determine that a drug is safe and effective under the conditions set forth in its labeling, the agency must be presumed to have performed a precise balancing of risks and benefits and to have established a specific labeling standard that leaves no room for different state-law judgments. In advancing this argument, Wyeth relies not on any statement by Congress, but instead on the preamble to a 2006 FDA regulation governing the content and format of prescription drug labels. See Brief for Petitioner 8, 11, 42, 45, and 50 (citing 71Fed. Reg. 3922 (2006)). In that preamble, the FDA declared that the FDCA establishes “both a ‘floor’ and a ‘ceiling,’ ” so that “FDA approval of labeling … preempts conflicting or contrary State law.” Id., at 3934–3935. It further stated that certain state-law actions, such as those involving failure-to-warn claims, “threaten FDA’s statutorily prescribed role as the expert Federal agency responsible for evaluating and regulating drugs.” Id., at 3935.

This Court has recognized that an agency regulation with the force of law can pre-empt conflicting state requirements. See, e.g., Geier v. American Honda Motor Co., 529 U. S. 861 (2000) ; Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707, 713 (1985) . In such cases, the Court has performed its own conflict determination, relying on the substance of state and federal law and not on agency proclamations of pre-emption. We are faced with no such regulation in this case, but rather with an agency’s mere assertion that state law is an obstacle to achieving its statutory objectives. Because Congress has not authorized the FDA to pre-empt state law directly, cf. 21 U. S. C. §360k (authorizing the FDA to determine the scope of the Medical Devices Amendments’ pre-emption clause), 9 the question is what weight we should accord the FDA’s opinion.

In prior cases, we have given “some weight” to an agency’s views about the impact of tort law on federal objectives when “the subject matter is technica[l] and the relevant history and background are complex and extensive.” Geier, 529 U. S., at 883. Even in such cases, however, we have not deferred to an agency’s conclusion that state law is pre-empted. Rather, we have attended to an agency’s explanation of how state law affects the regulatory scheme. While agencies have no special authority to pronounce on pre-emption absent delegation by Congress, they do have a unique understanding of the statutes they administer and an attendant ability to make informed determinations about how state requirements may pose an “obstacle to the accomplishment and execution of the full purposes and objectives of Congress.” Hines, 312 U.S, at 67; see Geier, 529 U. S., at 883; Lohr, 518 U. S., at 495–496. The weight we accord the agency’s explanation of state law’s impact on the federal scheme depends on its thoroughness, consistency, and persuasiveness. Cf. United States v. Mead Corp., 533 U. S. 218, 234–235 (2001) ; Skidmore v. Swift & Co., 323 U. S. 134, 140 (1944) .

Under this standard, the FDA’s 2006 preamble does not merit deference. When the FDA issued its notice of proposed rulemaking in December 2000, it explained that the rule would “not contain policies that have federalism implications or that preempt State law.” 65 Fed. Reg. 81103; see also 71 id., at 3969 (noting that the “proposed rule did not propose to preempt state law”). In 2006, the agency finalized the rule and, without offering States or other interested parties notice or opportunity for comment, articulated a sweeping position on the FDCA’s pre-emptive effect in the regulatory preamble. The agency’s views on state law are inherently suspect in light of this procedural failure.

Further, the preamble is at odds with what evidence we have of Congress’ purposes, and it reverses the FDA’s own longstanding position without providing a reasoned explanation, including any discussion of how state law has interfered with the FDA’s regulation of drug labeling during decades of coexistence. The FDA’s 2006 position plainly does not reflect the agency’s own view at all times relevant to this litigation. Not once prior to Levine’s injury did the FDA suggest that state tort law stood as an obstacle to its statutory mission. To the contrary, it cast federal labeling standards as a floor upon which States could build and repeatedly disclaimed any attempt to pre-empt failure-to-warn claims. For instance, in 1998, the FDA stated that it did “not believe that the evolution of state tort law [would] cause the development of standards that would be at odds with the agency’s regulations.” 63 id., at 66384. It further noted that, in establishing “minimal standards” for drug labels, it did not intend “to preclude the states from imposing additional labeling requirements.” Ibid. 10

In keeping with Congress’ decision not to pre-empt common-law tort suits, it appears that the FDA traditionally regarded state law as a complementary form of drug regulation. The FDA has limited resources to monitor the 11,000 drugs on the market, 11 and manufacturers have superior access to information about their drugs, especially in the postmarketing phase as new risks emerge. State tort suits uncover unknown drug hazards and provide incentives for drug manufacturers to disclose safety risks promptly. They also serve a distinct compensatory function that may motivate injured persons to come forward with information. Failure-to-warn actions, in particular, lend force to the FDCA’s premise that manufacturers, not the FDA, bear primary responsibility for their drug labeling at all times. Thus, the FDA long maintained that state law offers an additional, and important, layer of consumer protection that complements FDA regulation. 12 The agency’s 2006 preamble represents a dramatic change in position.

Largely based on the FDA’s new position, Wyeth argues that this case presents a conflict between state and federal law analogous to the one at issue in Geier. There, we held that state tort claims premised on Honda’s failure to install airbags conflicted with a federal regulation that did not require airbags for all cars. The Department of Transportation (DOT) had promulgated a rule that provided car manufacturers with a range of choices among passive restraint devices. Geier, 529 U. S., at 875. Rejecting an “ ‘all airbag’ ” standard, the agency had called for a gradual phase-in of a mix of passive restraints in order to spur technological development and win consumer acceptance. Id., at 879. Because the plaintiff’s claim was that car manufacturers had a duty to install airbags, it presented an obstacle to achieving “the variety and mix of devices that the federal regulation sought.” Id., at 881.

Wyeth and the dissent contend that the regulatory scheme in this case is nearly identical, but, as we have described, it is quite different. In Geier, the DOT conducted a formal rulemaking and then adopted a plan to phase in a mix of passive restraint devices. Examining the rule itself and the DOT’s contemporaneous record, which revealed the factors the agency had weighed and the balance it had struck, we determined that state tort suits presented an obstacle to the federal scheme. After conducting our own pre-emption analysis, we considered the agency’s explanation of how state law interfered with its regulation, regarding it as further support for our independent conclusion that the plaintiff’s tort claim obstructed the federal regime.

By contrast, we have no occasion in this case to consider the pre-emptive effect of a specific agency regulation bearing the force of law. And the FDA’s newfound opinion, expressed in its 2006 preamble, that state law “frustrate[s] the agency’s implementation of its statutory mandate,” 71 Fed. Reg. 3934, does not merit deference for the reasons we have explained. 13 Indeed, the “complex and extensive” regulatory history and background relevant to this case, Geier, 529 U. S., at 883, undercut the FDA’s recent pronouncements of pre-emption, as they reveal the longstanding coexistence of state and federal law and the FDA’s traditional recognition of state-law remedies—a recognition in place each time the agency reviewed Wyeth’s Phenergan label. 14

In short, Wyeth has not persuaded us that failure-to-warn claims like Levine’s obstruct the federal regulation of drug labeling. Congress has repeatedly declined to pre-empt state law, and the FDA’s recently adopted position that state tort suits interfere with its statutory mandate is entitled to no weight. Although we recognize that some state-law claims might well frustrate the achievement of congressional objectives, this is not such a case.

V

We conclude that it is not impossible for Wyeth to comply with its state and federal law obligations and that Levine’s common-law claims do not stand as an obstacle to the accomplishment of Congress’ purposes in the FDCA. Accordingly, the judgment of the Vermont Supreme Court is affirmed.

It is so ordered.


Notes

1 The warning for “Inadvertent Intra-arterial Injection” stated: “Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or inadvertent intra-arterial injection. Reports compatible with inadvertent intra-arterial injection of Phenergan Injection, usually in conjunction with other drugs intended for intravenous use, suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances. Intravenous injection was intended in all the cases reported but perivascular extravasation or arterial placement of the needle is now suspect. There is no proven successful management of this condition after it occurs. . . . Aspiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with Phenergan Injection. Use of syringes with rigid plungers or of small bore needles might obscure typical arterial backflow if this is relied upon alone. When used intravenously, Phenergan Injection should be given in a concentration no greater than 25 mg per mL and at a rate not to exceed 25 mg per minute. When administering any irritant drug intravenously, it is usually preferable to inject it through the tubing of an intravenous infusion set that is known to be functioning satisfactorily. In the event that a patient complains of pain during intended intravenous injection of Phenergan Injection, the injection should be stopped immediately to provide for evaluation of possible arterial placement or perivascular extravasation.” App. 390.

2 The dissent nonetheless suggests that physician malpractice was the exclusive cause of Levine’s injury. See, e.g., post, at 1 (opinion of Alito, J.) (“[I]t is unclear how a ‘stronger’ warning could have helped respondent”); post, at 16–18 (suggesting that the physician assistant’s conduct was the sole cause of the injury). The dissent’s frustration with the jury’s verdict does not put the merits of Levine’s tort claim before us, nor does it change the question we must decide—whether federal law pre-empts Levine’s state-law claims.

3 Wyeth argues that the presumption against pre-emption should not apply to this case because the Federal Government has regulated drug labeling for more than a century. That argument misunderstands the principle: We rely on the presumption because respect for the States as “independent sovereigns in our federal system” leads us to assume that “Congress does not cavalierly pre-empt state-law causes of action.” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) . The presumption thus accounts for the historic presence of state law but does not rely on the absence of federal regulation. For its part, the dissent argues that the presumption against pre-emption should not apply to claims of implied conflict pre-emption at all, post, at 21, but this Court has long held to the contrary. See, e.g., California v. ARC America Corp., 490 U. S. 93, 101–102 (1989) ; Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707, 716 (1985) ; see also Rush Prudential HMO, Inc. v. Moran, 536 U. S. 355, 387 (2002) . The dissent’s reliance on Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341 (2001) , see post, at 21, and n. 14, is especially curious, as that case involved state-law fraud-on-the-agency claims, and the Court distinguished state regulation of health and safety as matters to which the presumption does apply. See 531 U. S., at 347–348.

4 Levine also introduced evidence that Pfizer had withdrawn Vistaril, another antinausea drug, from intravenous use several decades earlier because its intravenous injection had resulted in gangrene and amputations. See App. 79.

5 The record would not, in any event, support such an argument. In 1988, Wyeth did propose different language for Phenergan’s warning about intra-arterial injection, adapted from revisions the FDA proposed in 1987. See App. 339–341, 311–312. When the FDA approved Wyeth’s application, it instructed Wyeth to retain the wording in its current label. During the trial court proceedings, Levine indicated that the language proposed in 1988 would have more strongly warned against IV-push administration. But the trial court and the Vermont Supreme Court found that the 1988 warning did not differ in any material respect from the FDA-approved warning. See ___ Vt. ___, ___, 944 A. 2d 179, 189 (2006) (“Simply stated, the proposed warning was different, but not stronger. It was also no longer or more prominent than the original warning …”); App. 248–250. Indeed, the United States concedes that the FDA did not regard the proposed warning as substantively different: “[I]t appears the FDA viewed the change as non-substantive and rejected it for formatting reasons.” Brief for United States as Amicus Curiae 25; see also ___ Vt., at ___, 944 A. 2d, at 189.

6 The dissent’s suggestion that the FDA intended to prohibit Wyeth from strengthening its warning does not fairly reflect the record. The dissent creatively paraphrases a few FDA orders—for instance by conflating warnings about IV-push administration and intra-arterial injection, see, e.g., post, at 9, 11–12, 15–16—to suggest greater agency attention to the question, and it undertakes a study of Phenergan’s labeling that is more elaborate than any FDA order. But even the dissent’s account does not support the conclusion that the FDA would have prohibited Wyeth from adding a stronger warning pursuant to the CBE regulation.

7 Although the first version of the bill that became the FDCA would have provided a federal cause of action for damages for injured consumers, see H. R. 6110, 73d Cong., 1st Sess., §25 (1933) (as introduced), witnesses testified that such a right of action was unnecessary because common-law claims were already available under state law. See Hearings on S. 1944 before a Subcommittee of the Senate Committee on Commerce, 73d Cong., 2d Sess., 400 (1933) (statement of W. A. Hines); see id., at 403 (statement of J. A. Ladds) (“This act should not attempt to modify or restate the common law with respect to personal injuries”).

8 In 1997, Congress pre-empted certain state requirements concerning over-the-counter medications and cosmetics but expressly preserved product liability actions. See 21 U. S. C. §§379r(e) (“Nothing in this section shall be construed to modify or otherwise affect any action or the liability of any person under the product liability law of any State”).

9 For similar examples, see 47 U. S. C. §§253(a), (d) (2000 ed.) (authorizing the Federal Communications Commission to pre-empt “any [state] statute, regulation, or legal requirement” that “may prohibit or have the effect of prohibiting the ability of any entity to provide any interstate or intrastate telecommunications service”); 30 U. S. C. §1254(g) (2006 ed.) (pre-empting any statute that conflicts with “the purposes and the requirements of this chapter” and permitting the Secretary of the Interior to “set forth any State law or regulation which is preempted and superseded”); and 49 U. S. C. §5125(d) (2000 ed. and Supp. V) (authorizing the Secretary of Transportation to decide whether a state or local statute that conflicts with the regulation of hazardous waste transportation is pre-empted).

10 See also 44Fed. Reg. 37437 (1979) (“It is not the intent of the FDA to influence the civil tort liability of the manufacturer”); 59Fed. Reg. 3948 (1994) (“[P]roduct liability plays an important role in consumer protection”); Porter, The Lohr Decision: FDA Perspective and Position, 52 Food & Drug L. J. 7, 10 (1997) (former chief counsel to the FDA stating that the FDA regarded state law as complementing the agency’s mission of consumer protection).

11 In 1955, the same year that the agency approved Wyeth’s Phenergan application, an FDA advisory committee issued a report finding “conclusively” that “the budget and staff of the Food and Drug Administration are inadequate to permit the discharge of its existing responsibilities for the protection of the American public.” Citizens Advisory Committee on the FDA, Report to the Secretary of Health, Education, and Welfare, H. R. Doc. No. 227, 84th Cong., 1st Sess., 53. Three recent studies have reached similar conclusions. See FDA Science Board, Report of the Subcommittee on Science and Technology: FDA Science and Mission at Risk 2, 6 (2007), online at http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4329b_02_01_FDA Report on Science and Technology.pdf (all Internet materials as visited Feb. 23, 2009, and available in Clerk of Court’s case file) (“[T]he Agency suffers from serious scientific deficiencies and is not positioned to meet current or emerging regulatory responsibilities”); National Academies, Institute of Medicine, The Future of Drug Safety: Promoting and Protecting the Health of the Public 193–194 (2007) (“The [FDA] lacks the resources needed to accomplish its large and complex mission … . There is widespread agreement that resources for postmarketing drug safety work are especially inadequate and that resource limitations have hobbled the agency’s ability to improve and expand this essential component of its mission”); GAO, Drug Safety: Improvement Needed in FDA’s Postmarket Decision-making and Oversight Process 5 (GAO–06–402, 2006), http://www.gao.gov/new.items/d06402.pdf (“FDA lacks a clear and effective process for making decisions about, and providing management oversight of, postmarket safety issues”); see also House Committee on Oversight and Government Reform, Majority Staff Report, FDA Career Staff Objected to Agency Preemption Policies 4 (2008) (“[T]he Office of Chief Counsel ignored the warnings from FDA scientists and career officials that the preemption language [of the 2006 preamble] was based on erroneous assertions about the ability of the drug approval process to ensure accurate and up-to-date drug labels”).

12 See generally Brief for Former FDA Commissioners Drs. Donald Kennedy and David Kessler as Amici Curiae; see also Kessler & Vladeck, A Critical Examination of the FDA’s Efforts To Preempt Failure-To-Warn Claims, 96 Geo. L. J. 461, 463 (2008); Bates v. Dow Agrosciences LLC, 544 U. S. 431, 451 (2005) (noting that state tort suits “can serve as a catalyst” by aiding in the exposure of new dangers and prompting a manufacturer or the federal agency to decide that a revised label is required).

13 The United States’ amicus brief is similarly undeserving of deference. Unlike the Government’s brief in Geier v. American Honda Motor Co., 529 U. S. 861 (2000) , which explained the effects of state law on the DOT’s regulation in a manner consistent with the agency’s prior accounts, see id., at 861, the Government’s explanation of federal drug regulation departs markedly from the FDA’s understanding at all times relevant to this case.

14 Wyeth’s more specific contention—that this case resembles Geier because the FDA determined that no additional warning on IV-push administration was needed, thereby setting a ceiling on Phenergan’s label—is belied by the record. As we have discussed, the FDA did not consider and reject a stronger warning against IV-push injection of Phenergan. See also App. 249–250 (“[A] tort case is unlikely to obstruct the regulatory process when the record shows that the FDA has paid very little attention to the issues raised by the parties at trial”).


TOP

Opinion

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Stevens delivered the opinion of the Court.

Directly injecting the drug Phenergan into a patient’s vein creates a significant risk of catastrophic consequences. A Vermont jury found that petitioner Wyeth, the manufacturer of the drug, had failed to provide an adequate warning of that risk and awarded damages to respondent Diana Levine to compensate her for the amputation of her arm. The warnings on Phenergan’s label had been deemed sufficient by the federal Food and Drug Administration (FDA) when it approved Wyeth’s new drug application in 1955 and when it later approved changes in the drug’s labeling. The question we must decide is whether the FDA’s approvals provide Wyeth with a complete defense to Levine’s tort claims. We conclude that they do not.

I

Phenergan is Wyeth’s brand name for promethazine hydrochloride, an antihistamine used to treat nausea. The injectable form of Phenergan can be administered intramuscularly or intravenously, and it can be administered intravenously through either the “IV-push” method, whereby the drug is injected directly into a patient’s vein, or the “IV-drip” method, whereby the drug is introduced into a saline solution in a hanging intravenous bag and slowly descends through a catheter inserted in a patient’s vein. The drug is corrosive and causes irreversible gangrene if it enters a patient’s artery.

Levine’s injury resulted from an IV-push injection of Phenergan. On April 7, 2000, as on previous visits to her local clinic for treatment of a migraine headache, she received an intramuscular injection of Demerol for her headache and Phenergan for her nausea. Because the combination did not provide relief, she returned later that day and received a second injection of both drugs. This time, the physician assistant administered the drugs by the IV-push method, and Phenergan entered Levine’s artery, either because the needle penetrated an artery directly or because the drug escaped from the vein into surrounding tissue (a phenomenon called “perivascular extravasation”) where it came in contact with arterial blood. As a result, Levine developed gangrene, and doctors amputated first her right hand and then her entire forearm. In addition to her pain and suffering, Levine incurred substantial medical expenses and the loss of her livelihood as a professional musician.

After settling claims against the health center and clinician, Levine brought an action for damages against Wyeth, relying on common-law negligence and strict-liability theories. Although Phenergan’s labeling warned of the danger of gangrene and amputation following inadvertent intra-arterial injection, 1 Levine alleged that the labeling was defective because it failed to instruct clinicians to use the IV-drip method of intravenous administration instead of the higher risk IV-push method. More broadly, she alleged that Phenergan is not reasonably safe for intravenous administration because the foreseeable risks of gangrene and loss of limb are great in relation to the drug’s therapeutic benefits. App. 14–15.

Wyeth filed a motion for summary judgment, arguing that Levine’s failure-to-warn claims were pre-empted by federal law. The court found no merit in either Wyeth’s field pre-emption argument, which it has since abandoned, or its conflict pre-emption argument. With respect to the contention that there was an “actual conflict between a specific FDA order,” id., at 21, and Levine’s failure-to-warn action, the court reviewed the sparse correspondence between Wyeth and the FDA about Phenergan’s labeling and found no evidence that Wyeth had “earnestly attempted” to strengthen the intra-arterial injection warning or that the FDA had “specifically disallowed” stronger language, id., at 23. The record, as then developed, “lack[ed] any evidence that the FDA set a ceiling on this matter.” Ibid.

The evidence presented during the 5-day jury trial showed that the risk of intra-arterial injection or perivascular extravasation can be almost entirely eliminated through the use of IV-drip, rather than IV-push, administration. An IV drip is started with saline, which will not flow properly if the catheter is not in the vein and fluid is entering an artery or surrounding tissue. See id., at 50–51, 60, 66–68, 75. By contrast, even a careful and experienced clinician using the IV-push method will occasionally expose an artery to Phenergan. See id., at 73, 75–76. While Phenergan’s labeling warned against intra-arterial injection and perivascular extravasation and advised that “[w]hen administering any irritant drug intravenously it is usually preferable to inject it through the tubing of an intravenous infusion set that is known to be function-ing satisfactorily,” id., at 390, the labeling did not con-tain a specific warning about the risks of IV-pushadministration.

The trial record also contains correspondence between Wyeth and the FDA discussing Phenergan’s label. The FDA first approved injectable Phenergan in 1955. In 1973 and 1976, Wyeth submitted supplemental new drug applications, which the agency approved after proposing labeling changes. Wyeth submitted a third supplemental application in 1981 in response to a new FDA rule governing drug labels. Over the next 17 years, Wyeth and the FDA intermittently corresponded about Phenergan’s label. The most notable activity occurred in 1987, when the FDA suggested different warnings about the risk of arterial exposure, and in 1988, when Wyeth submitted revised labeling incorporating the proposed changes. The FDA did not respond. Instead, in 1996, it requested from Wyeth the labeling then in use and, without addressing Wyeth’s 1988 submission, instructed it to “[r]etain verbiage in current label” regarding intra-arterial injection. Id., at 359. After a few further changes to the labeling not related to intra-arterial injection, the FDA approved Wyeth’s 1981 application in 1998, instructing that Phenergan’s final printed label “must be identical” to the approved package insert. Id., at 382.

Based on this regulatory history, the trial judge instructed the jury that it could consider evidence of Wyeth’s compliance with FDA requirements but that such compliance did not establish that the warnings were adequate. He also instructed, without objection from Wyeth, that FDA regulations “permit a drug manufacturer to change a product label to add or strengthen a warning about its product without prior FDA approval so long as it later submits the revised warning for review and approval.” Id., at 228.

Answering questions on a special verdict form, the jury found that Wyeth was negligent, that Phenergan was a defective product as a result of inadequate warnings and instructions, and that no intervening cause had broken the causal connection between the product defects and the plaintiff’s injury. Id., at 233–235. It awarded total damages of $7,400,000, which the court reduced to account for Levine’s earlier settlement with the health center and clinician. Id., at 235–236.

On August 3, 2004, the trial court filed a comprehensive opinion denying Wyeth’s motion for judgment as a matter of law. After making findings of fact based on the trial record (supplemented by one letter that Wyeth found after the trial), the court rejected Wyeth’s pre-emption arguments. It determined that there was no direct conflict between FDA regulations and Levine’s state-law claims because those regulations permit strengthened warnings without FDA approval on an interim basis and the record contained evidence of at least 20 reports of amputations similar to Levine’s since the 1960’s. The court also found that state tort liability in this case would not obstruct the FDA’s work because the agency had paid no more than passing attention to the question whether to warn against IV-push administration of Phenergan. In addition, the court noted that state law serves a compensatory function distinct from federal regulation. Id., at 249–252.

The Vermont Supreme Court affirmed. It held that the jury’s verdict “did not conflict with FDA’s labeling requirements for Phenergan because [Wyeth] could have warned against IV-push administration without prior FDA approval, and because federal labeling requirements create a floor, not a ceiling, for state regulation.” ___ Vt. ___, ___ 944 A. 2d 179, 184 (2006). In dissent, Chief Justice Reiber argued that the jury’s verdict conflicted with federal law because it was inconsistent with the FDA’s conclusion that intravenous administration of Phenergan was safe and effective.

The importance of the pre-emption issue, coupled with the fact that the FDA has changed its position on state tort law and now endorses the views expressed in Chief Justice Reiber’s dissent, persuaded us to grant Wyeth’s petition for certiorari. 552 U. S. ___ (2008). The question presented by the petition is whether the FDA’s drug labeling judgments “preempt state law product liability claims premised on the theory that different labeling judgments were necessary to make drugs reasonably safe for use.” Pet. for Cert. i.

II

Wyeth makes two separate pre-emption arguments: first, that it would have been impossible for it to comply with the state-law duty to modify Phenergan’s labeling without violating federal law, see Fidelity Fed. Sav. & Loan Assn. v. De la Cuesta, 458 U. S. 141, 153 (1982) , and second, that recognition of Levine’s state tort action creates an unacceptable “obstacle to the accomplishment and execution of the full purposes and objectives of Congress,” Hines v. Davidowitz, 312 U. S. 52, 67 (1941) , because it substitutes a lay jury’s decision about drug labeling for the expert judgment of the FDA. As a preface to our evaluation of these arguments, we identify two factual propositions decided during the trial court proceedings, emphasize two legal principles that guide our analysis, and review the history of the controlling federal statute.

The trial court proceedings established that Levine’s injury would not have occurred if Phenergan’s label had included an adequate warning about the risks of the IV-push method of administering the drug. The record contains evidence that the physician assistant administered a greater dose than the label prescribed, that she may have inadvertently injected the drug into an artery rather than a vein, and that she continued to inject the drug after Levine complained of pain. Nevertheless, the jury rejected Wyeth’s argument that the clinician’s conduct was an intervening cause that absolved it of liability. See App. 234 (jury verdict), 252–254. In finding Wyeth negligent as well as strictly liable, the jury also determined that Levine’s injury was foreseeable. That the inadequate label was both a but-for and proximate cause of Levine’s injury is supported by the record and no longer challenged by Wyeth. 2

The trial court proceedings further established that the critical defect in Phenergan’s label was the lack of an adequate warning about the risks of IV-push administration. Levine also offered evidence that the IV-push method should be contraindicated and that Phenergan should never be administered intravenously, even by the IV-drip method. Perhaps for this reason, the dissent incorrectly assumes that the state-law duty at issue is the duty to contraindicate the IV-push method. See, e.g., post, at 8, 25. But, as the Vermont Supreme Court explained, the jury verdict established only that Phenergan’s warning was insufficient. It did not mandate a particular replacement warning, nor did it require contraindicating IV-push administration: “There may have been any number of ways for [Wyeth] to strengthen the Phenergan warning without completely eliminating IV-push administration.” ___ Vt., at ___, n. 2, 944 A. 2d, at 189, n. 2. We therefore need not decide whether a state rule proscribing intravenous administration would be pre-empted. The narrower question presented is whether federal law pre-empts Levine’s claim that Phenergan’s label did not contain an adequate warning about using the IV-push method of administration.

Our answer to that question must be guided by two cornerstones of our pre-emption jurisprudence. First, “the purpose of Congress is the ultimate touchstone in every pre-emption case.” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) (internal quotation marks omitted); see Retail Clerks v. Schermerhorn, 375 U. S. 96, 103 (1963) . Second, “[i]n all pre-emption cases, and particularly in those in which Congress has ‘legislated … in a field which the States have traditionally occupied,’ … we ‘start with the assumption that the historic police powers of the States were not to be superseded by the Federal Act unless that was the clear and manifest purpose of Congress.’ ” Lohr, 518 U. S., at 485 (quoting Rice v. Santa Fe Elevator Corp., 331 U. S. 218, 230 (1947) ). 3

In order to identify the “purpose of Congress,” it is appropriate to briefly review the history of federal regulation of drugs and drug labeling. In 1906, Congress enacted its first significant public health law, the Federal Food and Drugs Act, ch. 3915, 34Stat. 768. The Act, which prohibited the manufacture or interstate shipment of adulterated or misbranded drugs, supplemented the protection for consumers already provided by state regulation and common-law liability. In the 1930’s, Congress became increasingly concerned about unsafe drugs and fraudulent marketing, and it enacted the Federal Food, Drug, and Cosmetic Act (FDCA), ch. 675, 52Stat. 1040, as amended, 21 U. S. C. §301 et seq. The Act’s most substantial innovation was its provision for premarket approval of new drugs. It required every manufacturer to submit a new drug application, including reports of investigations and specimens of proposed labeling, to the FDA for review. Until its application became effective, a manufacturer was prohibited from distributing a drug. The FDA could reject an application if it determined that the drug was not safe for use as labeled, though if the agency failed to act, an application became effective 60 days after the filing. FDCA, §505(c), 52Stat. 1052.

In 1962, Congress amended the FDCA and shifted the burden of proof from the FDA to the manufacturer. Before 1962, the agency had to prove harm to keep a drug out of the market, but the amendments required the manufacturer to demonstrate that its drug was “safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling” before it could distribute the drug. §§102(d), 104(b), 76Stat. 781, 784. In addition, the amendments required the manufacturer to prove the drug’s effectiveness by introducing “substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling.” §102(d), id., at 781.

As it enlarged the FDA’s powers to “protect the public health” and “assure the safety, effectiveness, and reliability of drugs,” id., at 780, Congress took care to preserve state law. The 1962 amendments added a saving clause, indicating that a provision of state law would only be invalidated upon a “direct and positive conflict” with the FDCA. §202, id., at 793. Consistent with that provision, state common-law suits “continued unabated despite … FDA regulation.” Riegel v. Medtronic, Inc., 552 U. S. ___, ___ (2008) (slip op., at 8) (Ginsburg, J., dissenting); see ibid., n. 11 (collecting state cases). And when Congress enacted an express pre-emption provision for medical devices in 1976, see §521, 90Stat. 574 (codified at 21 U. S. C. §360k(a)), it declined to enact such a provision for prescription drugs.

In 2007, after Levine’s injury and lawsuit, Congress again amended the FDCA. 121Stat. 823. For the first time, it granted the FDA statutory authority to require a manufacturer to change its drug label based on safety information that becomes available after a drug’s initial approval. §901(a), id., at 924–926. In doing so, however, Congress did not enact a provision in the Senate bill that would have required the FDA to preapprove all changes to drug labels. See S. 1082, 110th Cong., 1st Sess., §208, pp. 107–114 (2007) (as passed) (proposing new §506D). Instead, it adopted a rule of construction to make it clear that manufacturers remain responsible for updating their labels. See 121Stat. 925–926.

III

Wyeth first argues that Levine’s state-law claims are pre-empted because it is impossible for it to comply with both the state-law duties underlying those claims and its federal labeling duties. See De la Cuesta, 458 U. S., at 153. The FDA’s premarket approval of a new drug application includes the approval of the exact text in the proposed label. See 21 U. S. C. §355; 21 CFR §314.105(b) (2008). Generally speaking, a manufacturer may only change a drug label after the FDA approves a supplemental application. There is, however, an FDA regulation that permits a manufacturer to make certain changes to its label before receiving the agency’s approval. Among other things, this “changes being effected” (CBE) regulation provides that if a manufacturer is changing a label to “add or strengthen a contraindication, warning, precaution, or adverse reaction” or to “add or strengthen an instruction about dosage and administration that is intended to increase the safe use of the drug product,” it may make the labeling change upon filing its supplemental application with the FDA; it need not wait for FDA approval. §§314.70(c)(6)(iii)(A), (C).

Wyeth argues that the CBE regulation is not implicated in this case because a 2008 amendment provides that a manufacturer may only change its label “to reflect newly acquired information.” 73 Fed. Reg. 49609. Resting on this language (which Wyeth argues simply reaffirmed the interpretation of the regulation in effect when this case was tried), Wyeth contends that it could have changed Phenergan’s label only in response to new information that the FDA had not considered. And it maintains that Levine has not pointed to any such information concerning the risks of IV-push administration. Thus, Wyeth insists, it was impossible for it to discharge its state-law obligation to provide a stronger warning about IV-push administration without violating federal law. Wyeth’s argument misapprehends both the federal drug regulatory scheme and its burden in establishing a pre-emption defense.

We need not decide whether the 2008 CBE regulation is consistent with the FDCA and the previous version of the regulation, as Wyeth and the United States urge, because Wyeth could have revised Phenergan’s label even in accordance with the amended regulation. As the FDA explained in its notice of the final rule, “ ‘newly acquired information’ ” is not limited to new data, but also encompasses “new analyses of previously submitted data.” Id., at 49604. The rule accounts for the fact that risk information accumulates over time and that the same data may take on a different meaning in light of subsequent developments: “[I]f the sponsor submits adverse event information to FDA, and then later conducts a new analysis of data showing risks of a different type or of greater severity or frequency than did reports previously submitted to FDA, the sponsor meets the requirement for ‘newly acquired information.’ ” Id., at 49607; see also id., at 49606.

The record is limited concerning what newly acquired information Wyeth had or should have had about the risks of IV-push administration of Phenergan because Wyeth did not argue before the trial court that such information was required for a CBE labeling change. Levine did, however, present evidence of at least 20 incidents prior to her injury in which a Phenergan injection resulted in gangrene and an amputation. See App. 74, 252. 4 After the first such incident came to Wyeth’s attention in 1967, it notified the FDA and worked with the agency to change Phenergan’s label. In later years, as amputations continued to occur, Wyeth could have analyzed the accumulating data and added a stronger warning about IV-push administration of the drug.

Wyeth argues that if it had unilaterally added such a warning, it would have violated federal law governing unauthorized distribution and misbranding. Its argument that a change in Phenergan’s labeling would have subjected it to liability for unauthorized distribution rests on the assumption that this labeling change would have rendered Phenergan a new drug lacking an effective application. But strengthening the warning about IV-push administration would not have made Phenergan a new drug. See 21 U. S. C. §321(p)(1) (defining “new drug”); 21 CFR §310.3(h). Nor would this warning have rendered Phenergan misbranded. The FDCA does not provide that a drug is misbranded simply because the manufacturer has altered an FDA-approved label; instead, the misbranding provision focuses on the substance of the label and, among other things, proscribes labels that fail to include “adequate warnings.” 21 U. S. C. §352(f). Moreover, because the statute contemplates that federal juries will resolve most misbranding claims, the FDA’s belief that a drug is misbranded is not conclusive. See §§331, 332, 334(a)–(b). And the very idea that the FDA would bring an enforcement action against a manufacturer for strengthening a warning pursuant to the CBE regulation is difficult to accept—neither Wyeth nor the United States has identified a case in which the FDA has done so.

Wyeth’s cramped reading of the CBE regulation and its broad reading of the FDCA’s misbranding and unauthorized distribution provisions are premised on a more fundamental misunderstanding. Wyeth suggests that the FDA, rather than the manufacturer, bears primary responsibility for drug labeling. Yet through many amendments to the FDCA and to FDA regulations, it has remained a central premise of federal drug regulation that the manufacturer bears responsibility for the content of its label at all times. It is charged both with crafting an adequate label and with ensuring that its warnings remain adequate as long as the drug is on the market. See, e.g., 21 CFR §201.80(e) (requiring a manufacturer to revise its label “to include a warning as soon as there is reasonable evidence of an association of a serious hazard with a drug”);§314.80(b) (placing responsibility for postmarketing surveillance on the manufacturer); 73 Fed. Reg. 49605 (“Manufacturers continue to have a responsibility under Federal law … to maintain their labeling and update the labeling with new safety information”).

Indeed, prior to 2007, the FDA lacked the authority to order manufacturers to revise their labels. See 121Stat. 924–926. When Congress granted the FDA this authority, it reaffirmed the manufacturer’s obligations and referred specifically to the CBE regulation, which both reflects the manufacturer’s ultimate responsibility for its label and provides a mechanism for adding safety information to the label prior to FDA approval. See id., at 925–926(stating that a manufacturer retains the responsibility “to maintain its label in accordance with existing requirements, including subpart B of part 201 and sections 314.70 and 601.12 of title 21, Code of Federal Regulations (or any successor regulations)” (emphasis added)). Thus, when the risk of gangrene from IV-push injection of Phenergan became apparent, Wyeth had a duty to provide a warning that adequately described that risk, and the CBE regulation permitted it to provide such a warning before receiving the FDA’s approval.

Of course, the FDA retains authority to reject labeling changes made pursuant to the CBE regulation in its review of the manufacturer’s supplemental application, just as it retains such authority in reviewing all supplemental applications. But absent clear evidence that the FDA would not have approved a change to Phenergan’s label, we will not conclude that it was impossible for Wyeth to comply with both federal and state requirements.

Wyeth has offered no such evidence. It does not argue that it attempted to give the kind of warning required by the Vermont jury but was prohibited from doing so by the FDA. See Tr. of Oral Arg. 12–13; see also Brief for United States as Amicus Curiae 25. And while it does suggest that the FDA intended to prohibit it from strengthening the warning about IV-push administration because the agency deemed such a warning inappropriate in reviewing Phenergan’s drug applications, both the trial court and the Vermont Supreme Court rejected this account as a matter of fact. In its decision on Wyeth’s motion for judgment as a matter of law, the trial court found “no evidence in this record that either the FDA or the manufacturer gave more than passing attention to the issue of” IV-push versus IV-drip administration. App. 249. The Vermont Supreme Court likewise concluded that the FDA had not made an affirmative decision to preserve the IV-push method or intended to prohibit Wyeth from strengthening its warning about IV-push administration. ___ Vt., at ___, 944 A. 2d, at 188–189. Moreover, Wyeth does not argue that it supplied the FDA with an evaluation or analysis concerning the specific dangers posed by the IV-push method.We accordingly cannot credit Wyeth’s contention that the FDA would have prevented it from adding a stronger warning about the IV-push method of intravenous administration. 6

Impossibility pre-emption is a demanding defense. On the record before us, Wyeth has failed to demonstrate that it was impossible for it to comply with both federal and state requirements. The CBE regulation permitted Wyeth to unilaterally strengthen its warning, and the mere fact that the FDA approved Phenergan’s label does not establish that it would have prohibited such a change.

IV

Wyeth also argues that requiring it to comply with a state-law duty to provide a stronger warning about IV-push administration would obstruct the purposes and objectives of federal drug labeling regulation. Levine’s tort claims, it maintains, are pre-empted because they interfere with “Congress’s purpose to entrust an expert agency to make drug labeling decisions that strike a balance between competing objectives.” Brief for Petitioner 46. We find no merit in this argument, which relies on an untenable interpretation of congressional intent and an overbroad view of an agency’s power to pre-empt state law.

Wyeth contends that the FDCA establishes both a floor and a ceiling for drug regulation: Once the FDA has approved a drug’s label, a state-law verdict may not deem the label inadequate, regardless of whether there is any evidence that the FDA has considered the stronger warning at issue. The most glaring problem with this argument is that all evidence of Congress’ purposes is to the contrary. Building on its 1906 Act, Congress enacted the FDCA to bolster consumer protection against harmful products. See Kordel v. United States, 335 U. S. 345, 349 (1948) ; United States v. Sullivan, 332 U. S. 689, 696 (1948) . Congress did not provide a federal remedy for consumers harmed by unsafe or ineffective drugs in the 1938 statute or in any subsequent amendment. Evidently, it determined that widely available state rights of action provided appropriate relief for injured consumers. 7 It may also have recognized that state-law remedies further consumer protection by motivating manufacturers to produce safe and effective drugs and to give adequate warnings.

If Congress thought state-law suits posed an obstacle to its objectives, it surely would have enacted an express pre-emption provision at some point during the FDCA’s 70-year history. But despite its 1976 enactment of an express pre-emption provision for medical devices, see §521, 90Stat. 574 (codified at 21 U. S. C. §360k(a)), Congress has not enacted such a provision for prescription drugs.See Riegel, 552 U. S., at ___ (slip op., at 14)(“Congress could have applied the pre-emption clause to the entire FDCA. It did not do so, but instead wrote a pre-emption clause that applies only to medical devices”). 8 Its silence on the issue, coupled with its certain awareness of the prevalence of state tort litigation, is powerful evidence that Congress did not intend FDA oversight to be the exclusive means of ensuring drug safety and effectiveness. As Justice O’Connor explained in her opinion for a unanimous Court: “The case for federal pre-emption is particularly weak where Congress has indicated its awareness of the operation of state law in a field of federal interest, and has nonetheless decided to stand by both concepts and to tolerate whatever tension there [is] between them.” Bonito Boats, Inc. v. Thunder Craft Boats, Inc., 489 U. S. 141, 166–167 (1989) (internal quotation marks omitted); see also supra,at 8 (discussing the presumption against pre-emption).

Despite this evidence that Congress did not regard state tort litigation as an obstacle to achieving its purposes, Wyeth nonetheless maintains that, because the FDCA requires the FDA to determine that a drug is safe and effective under the conditions set forth in its labeling, the agency must be presumed to have performed a precise balancing of risks and benefits and to have established a specific labeling standard that leaves no room for different state-law judgments. In advancing this argument, Wyeth relies not on any statement by Congress, but instead on the preamble to a 2006 FDA regulation governing the content and format of prescription drug labels. See Brief for Petitioner 8, 11, 42, 45, and 50 (citing 71Fed. Reg. 3922 (2006)). In that preamble, the FDA declared that the FDCA establishes “both a ‘floor’ and a ‘ceiling,’ ” so that “FDA approval of labeling … preempts conflicting or contrary State law.” Id., at 3934–3935. It further stated that certain state-law actions, such as those involving failure-to-warn claims, “threaten FDA’s statutorily prescribed role as the expert Federal agency responsible for evaluating and regulating drugs.” Id., at 3935.

This Court has recognized that an agency regulation with the force of law can pre-empt conflicting state requirements. See, e.g., Geier v. American Honda Motor Co., 529 U. S. 861 (2000) ; Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707, 713 (1985) . In such cases, the Court has performed its own conflict determination, relying on the substance of state and federal law and not on agency proclamations of pre-emption. We are faced with no such regulation in this case, but rather with an agency’s mere assertion that state law is an obstacle to achieving its statutory objectives. Because Congress has not authorized the FDA to pre-empt state law directly, cf. 21 U. S. C. §360k (authorizing the FDA to determine the scope of the Medical Devices Amendments’ pre-emption clause), 9 the question is what weight we should accord the FDA’s opinion.

In prior cases, we have given “some weight” to an agency’s views about the impact of tort law on federal objectives when “the subject matter is technica[l] and the relevant history and background are complex and extensive.” Geier, 529 U. S., at 883. Even in such cases, however, we have not deferred to an agency’s conclusion that state law is pre-empted. Rather, we have attended to an agency’s explanation of how state law affects the regulatory scheme. While agencies have no special authority to pronounce on pre-emption absent delegation by Congress, they do have a unique understanding of the statutes they administer and an attendant ability to make informed determinations about how state requirements may pose an “obstacle to the accomplishment and execution of the full purposes and objectives of Congress.” Hines, 312 U.S, at 67; see Geier, 529 U. S., at 883; Lohr, 518 U. S., at 495–496. The weight we accord the agency’s explanation of state law’s impact on the federal scheme depends on its thoroughness, consistency, and persuasiveness. Cf. United States v. Mead Corp., 533 U. S. 218, 234–235 (2001) ; Skidmore v. Swift & Co., 323 U. S. 134, 140 (1944) .

Under this standard, the FDA’s 2006 preamble does not merit deference. When the FDA issued its notice of proposed rulemaking in December 2000, it explained that the rule would “not contain policies that have federalism implications or that preempt State law.” 65 Fed. Reg. 81103; see also 71 id., at 3969 (noting that the “proposed rule did not propose to preempt state law”). In 2006, the agency finalized the rule and, without offering States or other interested parties notice or opportunity for comment, articulated a sweeping position on the FDCA’s pre-emptive effect in the regulatory preamble. The agency’s views on state law are inherently suspect in light of this procedural failure.

Further, the preamble is at odds with what evidence we have of Congress’ purposes, and it reverses the FDA’s own longstanding position without providing a reasoned explanation, including any discussion of how state law has interfered with the FDA’s regulation of drug labeling during decades of coexistence. The FDA’s 2006 position plainly does not reflect the agency’s own view at all times relevant to this litigation. Not once prior to Levine’s injury did the FDA suggest that state tort law stood as an obstacle to its statutory mission. To the contrary, it cast federal labeling standards as a floor upon which States could build and repeatedly disclaimed any attempt to pre-empt failure-to-warn claims. For instance, in 1998, the FDA stated that it did “not believe that the evolution of state tort law [would] cause the development of standards that would be at odds with the agency’s regulations.” 63 id., at 66384. It further noted that, in establishing “minimal standards” for drug labels, it did not intend “to preclude the states from imposing additional labeling requirements.” Ibid. 10

In keeping with Congress’ decision not to pre-empt common-law tort suits, it appears that the FDA traditionally regarded state law as a complementary form of drug regulation. The FDA has limited resources to monitor the 11,000 drugs on the market, 11 and manufacturers have superior access to information about their drugs, especially in the postmarketing phase as new risks emerge. State tort suits uncover unknown drug hazards and provide incentives for drug manufacturers to disclose safety risks promptly. They also serve a distinct compensatory function that may motivate injured persons to come forward with information. Failure-to-warn actions, in particular, lend force to the FDCA’s premise that manufacturers, not the FDA, bear primary responsibility for their drug labeling at all times. Thus, the FDA long maintained that state law offers an additional, and important, layer of consumer protection that complements FDA regulation. 12 The agency’s 2006 preamble represents a dramatic change in position.

Largely based on the FDA’s new position, Wyeth argues that this case presents a conflict between state and federal law analogous to the one at issue in Geier. There, we held that state tort claims premised on Honda’s failure to install airbags conflicted with a federal regulation that did not require airbags for all cars. The Department of Transportation (DOT) had promulgated a rule that provided car manufacturers with a range of choices among passive restraint devices. Geier, 529 U. S., at 875. Rejecting an “ ‘all airbag’ ” standard, the agency had called for a gradual phase-in of a mix of passive restraints in order to spur technological development and win consumer acceptance. Id., at 879. Because the plaintiff’s claim was that car manufacturers had a duty to install airbags, it presented an obstacle to achieving “the variety and mix of devices that the federal regulation sought.” Id., at 881.

Wyeth and the dissent contend that the regulatory scheme in this case is nearly identical, but, as we have described, it is quite different. In Geier, the DOT conducted a formal rulemaking and then adopted a plan to phase in a mix of passive restraint devices. Examining the rule itself and the DOT’s contemporaneous record, which revealed the factors the agency had weighed and the balance it had struck, we determined that state tort suits presented an obstacle to the federal scheme. After conducting our own pre-emption analysis, we considered the agency’s explanation of how state law interfered with its regulation, regarding it as further support for our independent conclusion that the plaintiff’s tort claim obstructed the federal regime.

By contrast, we have no occasion in this case to consider the pre-emptive effect of a specific agency regulation bearing the force of law. And the FDA’s newfound opinion, expressed in its 2006 preamble, that state law “frustrate[s] the agency’s implementation of its statutory mandate,” 71 Fed. Reg. 3934, does not merit deference for the reasons we have explained. 13 Indeed, the “complex and extensive” regulatory history and background relevant to this case, Geier, 529 U. S., at 883, undercut the FDA’s recent pronouncements of pre-emption, as they reveal the longstanding coexistence of state and federal law and the FDA’s traditional recognition of state-law remedies—a recognition in place each time the agency reviewed Wyeth’s Phenergan label. 14

In short, Wyeth has not persuaded us that failure-to-warn claims like Levine’s obstruct the federal regulation of drug labeling. Congress has repeatedly declined to pre-empt state law, and the FDA’s recently adopted position that state tort suits interfere with its statutory mandate is entitled to no weight. Although we recognize that some state-law claims might well frustrate the achievement of congressional objectives, this is not such a case.

V

We conclude that it is not impossible for Wyeth to comply with its state and federal law obligations and that Levine’s common-law claims do not stand as an obstacle to the accomplishment of Congress’ purposes in the FDCA. Accordingly, the judgment of the Vermont Supreme Court is affirmed.

It is so ordered.


Notes

1 The warning for “Inadvertent Intra-arterial Injection” stated: “Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or inadvertent intra-arterial injection. Reports compatible with inadvertent intra-arterial injection of Phenergan Injection, usually in conjunction with other drugs intended for intravenous use, suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances. Intravenous injection was intended in all the cases reported but perivascular extravasation or arterial placement of the needle is now suspect. There is no proven successful management of this condition after it occurs. . . . Aspiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with Phenergan Injection. Use of syringes with rigid plungers or of small bore needles might obscure typical arterial backflow if this is relied upon alone. When used intravenously, Phenergan Injection should be given in a concentration no greater than 25 mg per mL and at a rate not to exceed 25 mg per minute. When administering any irritant drug intravenously, it is usually preferable to inject it through the tubing of an intravenous infusion set that is known to be functioning satisfactorily. In the event that a patient complains of pain during intended intravenous injection of Phenergan Injection, the injection should be stopped immediately to provide for evaluation of possible arterial placement or perivascular extravasation.” App. 390.

2 The dissent nonetheless suggests that physician malpractice was the exclusive cause of Levine’s injury. See, e.g., post, at 1 (opinion of Alito, J.) (“[I]t is unclear how a ‘stronger’ warning could have helped respondent”); post, at 16–18 (suggesting that the physician assistant’s conduct was the sole cause of the injury). The dissent’s frustration with the jury’s verdict does not put the merits of Levine’s tort claim before us, nor does it change the question we must decide—whether federal law pre-empts Levine’s state-law claims.

3 Wyeth argues that the presumption against pre-emption should not apply to this case because the Federal Government has regulated drug labeling for more than a century. That argument misunderstands the principle: We rely on the presumption because respect for the States as “independent sovereigns in our federal system” leads us to assume that “Congress does not cavalierly pre-empt state-law causes of action.” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) . The presumption thus accounts for the historic presence of state law but does not rely on the absence of federal regulation. For its part, the dissent argues that the presumption against pre-emption should not apply to claims of implied conflict pre-emption at all, post, at 21, but this Court has long held to the contrary. See, e.g., California v. ARC America Corp., 490 U. S. 93, 101–102 (1989) ; Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707, 716 (1985) ; see also Rush Prudential HMO, Inc. v. Moran, 536 U. S. 355, 387 (2002) . The dissent’s reliance on Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341 (2001) , see post, at 21, and n. 14, is especially curious, as that case involved state-law fraud-on-the-agency claims, and the Court distinguished state regulation of health and safety as matters to which the presumption does apply. See 531 U. S., at 347–348.

4 Levine also introduced evidence that Pfizer had withdrawn Vistaril, another antinausea drug, from intravenous use several decades earlier because its intravenous injection had resulted in gangrene and amputations. See App. 79.

5 The record would not, in any event, support such an argument. In 1988, Wyeth did propose different language for Phenergan’s warning about intra-arterial injection, adapted from revisions the FDA proposed in 1987. See App. 339–341, 311–312. When the FDA approved Wyeth’s application, it instructed Wyeth to retain the wording in its current label. During the trial court proceedings, Levine indicated that the language proposed in 1988 would have more strongly warned against IV-push administration. But the trial court and the Vermont Supreme Court found that the 1988 warning did not differ in any material respect from the FDA-approved warning. See ___ Vt. ___, ___, 944 A. 2d 179, 189 (2006) (“Simply stated, the proposed warning was different, but not stronger. It was also no longer or more prominent than the original warning …”); App. 248–250. Indeed, the United States concedes that the FDA did not regard the proposed warning as substantively different: “[I]t appears the FDA viewed the change as non-substantive and rejected it for formatting reasons.” Brief for United States as Amicus Curiae 25; see also ___ Vt., at ___, 944 A. 2d, at 189.

6 The dissent’s suggestion that the FDA intended to prohibit Wyeth from strengthening its warning does not fairly reflect the record. The dissent creatively paraphrases a few FDA orders—for instance by conflating warnings about IV-push administration and intra-arterial injection, see, e.g., post, at 9, 11–12, 15–16—to suggest greater agency attention to the question, and it undertakes a study of Phenergan’s labeling that is more elaborate than any FDA order. But even the dissent’s account does not support the conclusion that the FDA would have prohibited Wyeth from adding a stronger warning pursuant to the CBE regulation.

7 Although the first version of the bill that became the FDCA would have provided a federal cause of action for damages for injured consumers, see H. R. 6110, 73d Cong., 1st Sess., §25 (1933) (as introduced), witnesses testified that such a right of action was unnecessary because common-law claims were already available under state law. See Hearings on S. 1944 before a Subcommittee of the Senate Committee on Commerce, 73d Cong., 2d Sess., 400 (1933) (statement of W. A. Hines); see id., at 403 (statement of J. A. Ladds) (“This act should not attempt to modify or restate the common law with respect to personal injuries”).

8 In 1997, Congress pre-empted certain state requirements concerning over-the-counter medications and cosmetics but expressly preserved product liability actions. See 21 U. S. C. §§379r(e) (“Nothing in this section shall be construed to modify or otherwise affect any action or the liability of any person under the product liability law of any State”).

9 For similar examples, see 47 U. S. C. §§253(a), (d) (2000 ed.) (authorizing the Federal Communications Commission to pre-empt “any [state] statute, regulation, or legal requirement” that “may prohibit or have the effect of prohibiting the ability of any entity to provide any interstate or intrastate telecommunications service”); 30 U. S. C. §1254(g) (2006 ed.) (pre-empting any statute that conflicts with “the purposes and the requirements of this chapter” and permitting the Secretary of the Interior to “set forth any State law or regulation which is preempted and superseded”); and 49 U. S. C. §5125(d) (2000 ed. and Supp. V) (authorizing the Secretary of Transportation to decide whether a state or local statute that conflicts with the regulation of hazardous waste transportation is pre-empted).

10 See also 44Fed. Reg. 37437 (1979) (“It is not the intent of the FDA to influence the civil tort liability of the manufacturer”); 59Fed. Reg. 3948 (1994) (“[P]roduct liability plays an important role in consumer protection”); Porter, The Lohr Decision: FDA Perspective and Position, 52 Food & Drug L. J. 7, 10 (1997) (former chief counsel to the FDA stating that the FDA regarded state law as complementing the agency’s mission of consumer protection).

11 In 1955, the same year that the agency approved Wyeth’s Phenergan application, an FDA advisory committee issued a report finding “conclusively” that “the budget and staff of the Food and Drug Administration are inadequate to permit the discharge of its existing responsibilities for the protection of the American public.” Citizens Advisory Committee on the FDA, Report to the Secretary of Health, Education, and Welfare, H. R. Doc. No. 227, 84th Cong., 1st Sess., 53. Three recent studies have reached similar conclusions. See FDA Science Board, Report of the Subcommittee on Science and Technology: FDA Science and Mission at Risk 2, 6 (2007), online at http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4329b_02_01_FDA Report on Science and Technology.pdf (all Internet materials as visited Feb. 23, 2009, and available in Clerk of Court’s case file) (“[T]he Agency suffers from serious scientific deficiencies and is not positioned to meet current or emerging regulatory responsibilities”); National Academies, Institute of Medicine, The Future of Drug Safety: Promoting and Protecting the Health of the Public 193–194 (2007) (“The [FDA] lacks the resources needed to accomplish its large and complex mission … . There is widespread agreement that resources for postmarketing drug safety work are especially inadequate and that resource limitations have hobbled the agency’s ability to improve and expand this essential component of its mission”); GAO, Drug Safety: Improvement Needed in FDA’s Postmarket Decision-making and Oversight Process 5 (GAO–06–402, 2006), http://www.gao.gov/new.items/d06402.pdf (“FDA lacks a clear and effective process for making decisions about, and providing management oversight of, postmarket safety issues”); see also House Committee on Oversight and Government Reform, Majority Staff Report, FDA Career Staff Objected to Agency Preemption Policies 4 (2008) (“[T]he Office of Chief Counsel ignored the warnings from FDA scientists and career officials that the preemption language [of the 2006 preamble] was based on erroneous assertions about the ability of the drug approval process to ensure accurate and up-to-date drug labels”).

12 See generally Brief for Former FDA Commissioners Drs. Donald Kennedy and David Kessler as Amici Curiae; see also Kessler & Vladeck, A Critical Examination of the FDA’s Efforts To Preempt Failure-To-Warn Claims, 96 Geo. L. J. 461, 463 (2008); Bates v. Dow Agrosciences LLC, 544 U. S. 431, 451 (2005) (noting that state tort suits “can serve as a catalyst” by aiding in the exposure of new dangers and prompting a manufacturer or the federal agency to decide that a revised label is required).

13 The United States’ amicus brief is similarly undeserving of deference. Unlike the Government’s brief in Geier v. American Honda Motor Co., 529 U. S. 861 (2000) , which explained the effects of state law on the DOT’s regulation in a manner consistent with the agency’s prior accounts, see id., at 861, the Government’s explanation of federal drug regulation departs markedly from the FDA’s understanding at all times relevant to this case.

14 Wyeth’s more specific contention—that this case resembles Geier because the FDA determined that no additional warning on IV-push administration was needed, thereby setting a ceiling on Phenergan’s label—is belied by the record. As we have discussed, the FDA did not consider and reject a stronger warning against IV-push injection of Phenergan. See also App. 249–250 (“[A] tort case is unlikely to obstruct the regulatory process when the record shows that the FDA has paid very little attention to the issues raised by the parties at trial”).


TOP

Opinion

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Stevens delivered the opinion of the Court.

Directly injecting the drug Phenergan into a patient’s vein creates a significant risk of catastrophic consequences. A Vermont jury found that petitioner Wyeth, the manufacturer of the drug, had failed to provide an adequate warning of that risk and awarded damages to respondent Diana Levine to compensate her for the amputation of her arm. The warnings on Phenergan’s label had been deemed sufficient by the federal Food and Drug Administration (FDA) when it approved Wyeth’s new drug application in 1955 and when it later approved changes in the drug’s labeling. The question we must decide is whether the FDA’s approvals provide Wyeth with a complete defense to Levine’s tort claims. We conclude that they do not.

I

Phenergan is Wyeth’s brand name for promethazine hydrochloride, an antihistamine used to treat nausea. The injectable form of Phenergan can be administered intramuscularly or intravenously, and it can be administered intravenously through either the “IV-push” method, whereby the drug is injected directly into a patient’s vein, or the “IV-drip” method, whereby the drug is introduced into a saline solution in a hanging intravenous bag and slowly descends through a catheter inserted in a patient’s vein. The drug is corrosive and causes irreversible gangrene if it enters a patient’s artery.

Levine’s injury resulted from an IV-push injection of Phenergan. On April 7, 2000, as on previous visits to her local clinic for treatment of a migraine headache, she received an intramuscular injection of Demerol for her headache and Phenergan for her nausea. Because the combination did not provide relief, she returned later that day and received a second injection of both drugs. This time, the physician assistant administered the drugs by the IV-push method, and Phenergan entered Levine’s artery, either because the needle penetrated an artery directly or because the drug escaped from the vein into surrounding tissue (a phenomenon called “perivascular extravasation”) where it came in contact with arterial blood. As a result, Levine developed gangrene, and doctors amputated first her right hand and then her entire forearm. In addition to her pain and suffering, Levine incurred substantial medical expenses and the loss of her livelihood as a professional musician.

After settling claims against the health center and clinician, Levine brought an action for damages against Wyeth, relying on common-law negligence and strict-liability theories. Although Phenergan’s labeling warned of the danger of gangrene and amputation following inadvertent intra-arterial injection, 1 Levine alleged that the labeling was defective because it failed to instruct clinicians to use the IV-drip method of intravenous administration instead of the higher risk IV-push method. More broadly, she alleged that Phenergan is not reasonably safe for intravenous administration because the foreseeable risks of gangrene and loss of limb are great in relation to the drug’s therapeutic benefits. App. 14–15.

Wyeth filed a motion for summary judgment, arguing that Levine’s failure-to-warn claims were pre-empted by federal law. The court found no merit in either Wyeth’s field pre-emption argument, which it has since abandoned, or its conflict pre-emption argument. With respect to the contention that there was an “actual conflict between a specific FDA order,” id., at 21, and Levine’s failure-to-warn action, the court reviewed the sparse correspondence between Wyeth and the FDA about Phenergan’s labeling and found no evidence that Wyeth had “earnestly attempted” to strengthen the intra-arterial injection warning or that the FDA had “specifically disallowed” stronger language, id., at 23. The record, as then developed, “lack[ed] any evidence that the FDA set a ceiling on this matter.” Ibid.

The evidence presented during the 5-day jury trial showed that the risk of intra-arterial injection or perivascular extravasation can be almost entirely eliminated through the use of IV-drip, rather than IV-push, administration. An IV drip is started with saline, which will not flow properly if the catheter is not in the vein and fluid is entering an artery or surrounding tissue. See id., at 50–51, 60, 66–68, 75. By contrast, even a careful and experienced clinician using the IV-push method will occasionally expose an artery to Phenergan. See id., at 73, 75–76. While Phenergan’s labeling warned against intra-arterial injection and perivascular extravasation and advised that “[w]hen administering any irritant drug intravenously it is usually preferable to inject it through the tubing of an intravenous infusion set that is known to be function-ing satisfactorily,” id., at 390, the labeling did not con-tain a specific warning about the risks of IV-pushadministration.

The trial record also contains correspondence between Wyeth and the FDA discussing Phenergan’s label. The FDA first approved injectable Phenergan in 1955. In 1973 and 1976, Wyeth submitted supplemental new drug applications, which the agency approved after proposing labeling changes. Wyeth submitted a third supplemental application in 1981 in response to a new FDA rule governing drug labels. Over the next 17 years, Wyeth and the FDA intermittently corresponded about Phenergan’s label. The most notable activity occurred in 1987, when the FDA suggested different warnings about the risk of arterial exposure, and in 1988, when Wyeth submitted revised labeling incorporating the proposed changes. The FDA did not respond. Instead, in 1996, it requested from Wyeth the labeling then in use and, without addressing Wyeth’s 1988 submission, instructed it to “[r]etain verbiage in current label” regarding intra-arterial injection. Id., at 359. After a few further changes to the labeling not related to intra-arterial injection, the FDA approved Wyeth’s 1981 application in 1998, instructing that Phenergan’s final printed label “must be identical” to the approved package insert. Id., at 382.

Based on this regulatory history, the trial judge instructed the jury that it could consider evidence of Wyeth’s compliance with FDA requirements but that such compliance did not establish that the warnings were adequate. He also instructed, without objection from Wyeth, that FDA regulations “permit a drug manufacturer to change a product label to add or strengthen a warning about its product without prior FDA approval so long as it later submits the revised warning for review and approval.” Id., at 228.

Answering questions on a special verdict form, the jury found that Wyeth was negligent, that Phenergan was a defective product as a result of inadequate warnings and instructions, and that no intervening cause had broken the causal connection between the product defects and the plaintiff’s injury. Id., at 233–235. It awarded total damages of $7,400,000, which the court reduced to account for Levine’s earlier settlement with the health center and clinician. Id., at 235–236.

On August 3, 2004, the trial court filed a comprehensive opinion denying Wyeth’s motion for judgment as a matter of law. After making findings of fact based on the trial record (supplemented by one letter that Wyeth found after the trial), the court rejected Wyeth’s pre-emption arguments. It determined that there was no direct conflict between FDA regulations and Levine’s state-law claims because those regulations permit strengthened warnings without FDA approval on an interim basis and the record contained evidence of at least 20 reports of amputations similar to Levine’s since the 1960’s. The court also found that state tort liability in this case would not obstruct the FDA’s work because the agency had paid no more than passing attention to the question whether to warn against IV-push administration of Phenergan. In addition, the court noted that state law serves a compensatory function distinct from federal regulation. Id., at 249–252.

The Vermont Supreme Court affirmed. It held that the jury’s verdict “did not conflict with FDA’s labeling requirements for Phenergan because [Wyeth] could have warned against IV-push administration without prior FDA approval, and because federal labeling requirements create a floor, not a ceiling, for state regulation.” ___ Vt. ___, ___ 944 A. 2d 179, 184 (2006). In dissent, Chief Justice Reiber argued that the jury’s verdict conflicted with federal law because it was inconsistent with the FDA’s conclusion that intravenous administration of Phenergan was safe and effective.

The importance of the pre-emption issue, coupled with the fact that the FDA has changed its position on state tort law and now endorses the views expressed in Chief Justice Reiber’s dissent, persuaded us to grant Wyeth’s petition for certiorari. 552 U. S. ___ (2008). The question presented by the petition is whether the FDA’s drug labeling judgments “preempt state law product liability claims premised on the theory that different labeling judgments were necessary to make drugs reasonably safe for use.” Pet. for Cert. i.

II

Wyeth makes two separate pre-emption arguments: first, that it would have been impossible for it to comply with the state-law duty to modify Phenergan’s labeling without violating federal law, see Fidelity Fed. Sav. & Loan Assn. v. De la Cuesta, 458 U. S. 141, 153 (1982) , and second, that recognition of Levine’s state tort action creates an unacceptable “obstacle to the accomplishment and execution of the full purposes and objectives of Congress,” Hines v. Davidowitz, 312 U. S. 52, 67 (1941) , because it substitutes a lay jury’s decision about drug labeling for the expert judgment of the FDA. As a preface to our evaluation of these arguments, we identify two factual propositions decided during the trial court proceedings, emphasize two legal principles that guide our analysis, and review the history of the controlling federal statute.

The trial court proceedings established that Levine’s injury would not have occurred if Phenergan’s label had included an adequate warning about the risks of the IV-push method of administering the drug. The record contains evidence that the physician assistant administered a greater dose than the label prescribed, that she may have inadvertently injected the drug into an artery rather than a vein, and that she continued to inject the drug after Levine complained of pain. Nevertheless, the jury rejected Wyeth’s argument that the clinician’s conduct was an intervening cause that absolved it of liability. See App. 234 (jury verdict), 252–254. In finding Wyeth negligent as well as strictly liable, the jury also determined that Levine’s injury was foreseeable. That the inadequate label was both a but-for and proximate cause of Levine’s injury is supported by the record and no longer challenged by Wyeth. 2

The trial court proceedings further established that the critical defect in Phenergan’s label was the lack of an adequate warning about the risks of IV-push administration. Levine also offered evidence that the IV-push method should be contraindicated and that Phenergan should never be administered intravenously, even by the IV-drip method. Perhaps for this reason, the dissent incorrectly assumes that the state-law duty at issue is the duty to contraindicate the IV-push method. See, e.g., post, at 8, 25. But, as the Vermont Supreme Court explained, the jury verdict established only that Phenergan’s warning was insufficient. It did not mandate a particular replacement warning, nor did it require contraindicating IV-push administration: “There may have been any number of ways for [Wyeth] to strengthen the Phenergan warning without completely eliminating IV-push administration.” ___ Vt., at ___, n. 2, 944 A. 2d, at 189, n. 2. We therefore need not decide whether a state rule proscribing intravenous administration would be pre-empted. The narrower question presented is whether federal law pre-empts Levine’s claim that Phenergan’s label did not contain an adequate warning about using the IV-push method of administration.

Our answer to that question must be guided by two cornerstones of our pre-emption jurisprudence. First, “the purpose of Congress is the ultimate touchstone in every pre-emption case.” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) (internal quotation marks omitted); see Retail Clerks v. Schermerhorn, 375 U. S. 96, 103 (1963) . Second, “[i]n all pre-emption cases, and particularly in those in which Congress has ‘legislated … in a field which the States have traditionally occupied,’ … we ‘start with the assumption that the historic police powers of the States were not to be superseded by the Federal Act unless that was the clear and manifest purpose of Congress.’ ” Lohr, 518 U. S., at 485 (quoting Rice v. Santa Fe Elevator Corp., 331 U. S. 218, 230 (1947) ). 3

In order to identify the “purpose of Congress,” it is appropriate to briefly review the history of federal regulation of drugs and drug labeling. In 1906, Congress enacted its first significant public health law, the Federal Food and Drugs Act, ch. 3915, 34Stat. 768. The Act, which prohibited the manufacture or interstate shipment of adulterated or misbranded drugs, supplemented the protection for consumers already provided by state regulation and common-law liability. In the 1930’s, Congress became increasingly concerned about unsafe drugs and fraudulent marketing, and it enacted the Federal Food, Drug, and Cosmetic Act (FDCA), ch. 675, 52Stat. 1040, as amended, 21 U. S. C. §301 et seq. The Act’s most substantial innovation was its provision for premarket approval of new drugs. It required every manufacturer to submit a new drug application, including reports of investigations and specimens of proposed labeling, to the FDA for review. Until its application became effective, a manufacturer was prohibited from distributing a drug. The FDA could reject an application if it determined that the drug was not safe for use as labeled, though if the agency failed to act, an application became effective 60 days after the filing. FDCA, §505(c), 52Stat. 1052.

In 1962, Congress amended the FDCA and shifted the burden of proof from the FDA to the manufacturer. Before 1962, the agency had to prove harm to keep a drug out of the market, but the amendments required the manufacturer to demonstrate that its drug was “safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling” before it could distribute the drug. §§102(d), 104(b), 76Stat. 781, 784. In addition, the amendments required the manufacturer to prove the drug’s effectiveness by introducing “substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling.” §102(d), id., at 781.

As it enlarged the FDA’s powers to “protect the public health” and “assure the safety, effectiveness, and reliability of drugs,” id., at 780, Congress took care to preserve state law. The 1962 amendments added a saving clause, indicating that a provision of state law would only be invalidated upon a “direct and positive conflict” with the FDCA. §202, id., at 793. Consistent with that provision, state common-law suits “continued unabated despite … FDA regulation.” Riegel v. Medtronic, Inc., 552 U. S. ___, ___ (2008) (slip op., at 8) (Ginsburg, J., dissenting); see ibid., n. 11 (collecting state cases). And when Congress enacted an express pre-emption provision for medical devices in 1976, see §521, 90Stat. 574 (codified at 21 U. S. C. §360k(a)), it declined to enact such a provision for prescription drugs.

In 2007, after Levine’s injury and lawsuit, Congress again amended the FDCA. 121Stat. 823. For the first time, it granted the FDA statutory authority to require a manufacturer to change its drug label based on safety information that becomes available after a drug’s initial approval. §901(a), id., at 924–926. In doing so, however, Congress did not enact a provision in the Senate bill that would have required the FDA to preapprove all changes to drug labels. See S. 1082, 110th Cong., 1st Sess., §208, pp. 107–114 (2007) (as passed) (proposing new §506D). Instead, it adopted a rule of construction to make it clear that manufacturers remain responsible for updating their labels. See 121Stat. 925–926.

III

Wyeth first argues that Levine’s state-law claims are pre-empted because it is impossible for it to comply with both the state-law duties underlying those claims and its federal labeling duties. See De la Cuesta, 458 U. S., at 153. The FDA’s premarket approval of a new drug application includes the approval of the exact text in the proposed label. See 21 U. S. C. §355; 21 CFR §314.105(b) (2008). Generally speaking, a manufacturer may only change a drug label after the FDA approves a supplemental application. There is, however, an FDA regulation that permits a manufacturer to make certain changes to its label before receiving the agency’s approval. Among other things, this “changes being effected” (CBE) regulation provides that if a manufacturer is changing a label to “add or strengthen a contraindication, warning, precaution, or adverse reaction” or to “add or strengthen an instruction about dosage and administration that is intended to increase the safe use of the drug product,” it may make the labeling change upon filing its supplemental application with the FDA; it need not wait for FDA approval. §§314.70(c)(6)(iii)(A), (C).

Wyeth argues that the CBE regulation is not implicated in this case because a 2008 amendment provides that a manufacturer may only change its label “to reflect newly acquired information.” 73 Fed. Reg. 49609. Resting on this language (which Wyeth argues simply reaffirmed the interpretation of the regulation in effect when this case was tried), Wyeth contends that it could have changed Phenergan’s label only in response to new information that the FDA had not considered. And it maintains that Levine has not pointed to any such information concerning the risks of IV-push administration. Thus, Wyeth insists, it was impossible for it to discharge its state-law obligation to provide a stronger warning about IV-push administration without violating federal law. Wyeth’s argument misapprehends both the federal drug regulatory scheme and its burden in establishing a pre-emption defense.

We need not decide whether the 2008 CBE regulation is consistent with the FDCA and the previous version of the regulation, as Wyeth and the United States urge, because Wyeth could have revised Phenergan’s label even in accordance with the amended regulation. As the FDA explained in its notice of the final rule, “ ‘newly acquired information’ ” is not limited to new data, but also encompasses “new analyses of previously submitted data.” Id., at 49604. The rule accounts for the fact that risk information accumulates over time and that the same data may take on a different meaning in light of subsequent developments: “[I]f the sponsor submits adverse event information to FDA, and then later conducts a new analysis of data showing risks of a different type or of greater severity or frequency than did reports previously submitted to FDA, the sponsor meets the requirement for ‘newly acquired information.’ ” Id., at 49607; see also id., at 49606.

The record is limited concerning what newly acquired information Wyeth had or should have had about the risks of IV-push administration of Phenergan because Wyeth did not argue before the trial court that such information was required for a CBE labeling change. Levine did, however, present evidence of at least 20 incidents prior to her injury in which a Phenergan injection resulted in gangrene and an amputation. See App. 74, 252. 4 After the first such incident came to Wyeth’s attention in 1967, it notified the FDA and worked with the agency to change Phenergan’s label. In later years, as amputations continued to occur, Wyeth could have analyzed the accumulating data and added a stronger warning about IV-push administration of the drug.

Wyeth argues that if it had unilaterally added such a warning, it would have violated federal law governing unauthorized distribution and misbranding. Its argument that a change in Phenergan’s labeling would have subjected it to liability for unauthorized distribution rests on the assumption that this labeling change would have rendered Phenergan a new drug lacking an effective application. But strengthening the warning about IV-push administration would not have made Phenergan a new drug. See 21 U. S. C. §321(p)(1) (defining “new drug”); 21 CFR §310.3(h). Nor would this warning have rendered Phenergan misbranded. The FDCA does not provide that a drug is misbranded simply because the manufacturer has altered an FDA-approved label; instead, the misbranding provision focuses on the substance of the label and, among other things, proscribes labels that fail to include “adequate warnings.” 21 U. S. C. §352(f). Moreover, because the statute contemplates that federal juries will resolve most misbranding claims, the FDA’s belief that a drug is misbranded is not conclusive. See §§331, 332, 334(a)–(b). And the very idea that the FDA would bring an enforcement action against a manufacturer for strengthening a warning pursuant to the CBE regulation is difficult to accept—neither Wyeth nor the United States has identified a case in which the FDA has done so.

Wyeth’s cramped reading of the CBE regulation and its broad reading of the FDCA’s misbranding and unauthorized distribution provisions are premised on a more fundamental misunderstanding. Wyeth suggests that the FDA, rather than the manufacturer, bears primary responsibility for drug labeling. Yet through many amendments to the FDCA and to FDA regulations, it has remained a central premise of federal drug regulation that the manufacturer bears responsibility for the content of its label at all times. It is charged both with crafting an adequate label and with ensuring that its warnings remain adequate as long as the drug is on the market. See, e.g., 21 CFR §201.80(e) (requiring a manufacturer to revise its label “to include a warning as soon as there is reasonable evidence of an association of a serious hazard with a drug”);§314.80(b) (placing responsibility for postmarketing surveillance on the manufacturer); 73 Fed. Reg. 49605 (“Manufacturers continue to have a responsibility under Federal law … to maintain their labeling and update the labeling with new safety information”).

Indeed, prior to 2007, the FDA lacked the authority to order manufacturers to revise their labels. See 121Stat. 924–926. When Congress granted the FDA this authority, it reaffirmed the manufacturer’s obligations and referred specifically to the CBE regulation, which both reflects the manufacturer’s ultimate responsibility for its label and provides a mechanism for adding safety information to the label prior to FDA approval. See id., at 925–926(stating that a manufacturer retains the responsibility “to maintain its label in accordance with existing requirements, including subpart B of part 201 and sections 314.70 and 601.12 of title 21, Code of Federal Regulations (or any successor regulations)” (emphasis added)). Thus, when the risk of gangrene from IV-push injection of Phenergan became apparent, Wyeth had a duty to provide a warning that adequately described that risk, and the CBE regulation permitted it to provide such a warning before receiving the FDA’s approval.

Of course, the FDA retains authority to reject labeling changes made pursuant to the CBE regulation in its review of the manufacturer’s supplemental application, just as it retains such authority in reviewing all supplemental applications. But absent clear evidence that the FDA would not have approved a change to Phenergan’s label, we will not conclude that it was impossible for Wyeth to comply with both federal and state requirements.

Wyeth has offered no such evidence. It does not argue that it attempted to give the kind of warning required by the Vermont jury but was prohibited from doing so by the FDA. See Tr. of Oral Arg. 12–13; see also Brief for United States as Amicus Curiae 25. And while it does suggest that the FDA intended to prohibit it from strengthening the warning about IV-push administration because the agency deemed such a warning inappropriate in reviewing Phenergan’s drug applications, both the trial court and the Vermont Supreme Court rejected this account as a matter of fact. In its decision on Wyeth’s motion for judgment as a matter of law, the trial court found “no evidence in this record that either the FDA or the manufacturer gave more than passing attention to the issue of” IV-push versus IV-drip administration. App. 249. The Vermont Supreme Court likewise concluded that the FDA had not made an affirmative decision to preserve the IV-push method or intended to prohibit Wyeth from strengthening its warning about IV-push administration. ___ Vt., at ___, 944 A. 2d, at 188–189. Moreover, Wyeth does not argue that it supplied the FDA with an evaluation or analysis concerning the specific dangers posed by the IV-push method.We accordingly cannot credit Wyeth’s contention that the FDA would have prevented it from adding a stronger warning about the IV-push method of intravenous administration. 6

Impossibility pre-emption is a demanding defense. On the record before us, Wyeth has failed to demonstrate that it was impossible for it to comply with both federal and state requirements. The CBE regulation permitted Wyeth to unilaterally strengthen its warning, and the mere fact that the FDA approved Phenergan’s label does not establish that it would have prohibited such a change.

IV

Wyeth also argues that requiring it to comply with a state-law duty to provide a stronger warning about IV-push administration would obstruct the purposes and objectives of federal drug labeling regulation. Levine’s tort claims, it maintains, are pre-empted because they interfere with “Congress’s purpose to entrust an expert agency to make drug labeling decisions that strike a balance between competing objectives.” Brief for Petitioner 46. We find no merit in this argument, which relies on an untenable interpretation of congressional intent and an overbroad view of an agency’s power to pre-empt state law.

Wyeth contends that the FDCA establishes both a floor and a ceiling for drug regulation: Once the FDA has approved a drug’s label, a state-law verdict may not deem the label inadequate, regardless of whether there is any evidence that the FDA has considered the stronger warning at issue. The most glaring problem with this argument is that all evidence of Congress’ purposes is to the contrary. Building on its 1906 Act, Congress enacted the FDCA to bolster consumer protection against harmful products. See Kordel v. United States, 335 U. S. 345, 349 (1948) ; United States v. Sullivan, 332 U. S. 689, 696 (1948) . Congress did not provide a federal remedy for consumers harmed by unsafe or ineffective drugs in the 1938 statute or in any subsequent amendment. Evidently, it determined that widely available state rights of action provided appropriate relief for injured consumers. 7 It may also have recognized that state-law remedies further consumer protection by motivating manufacturers to produce safe and effective drugs and to give adequate warnings.

If Congress thought state-law suits posed an obstacle to its objectives, it surely would have enacted an express pre-emption provision at some point during the FDCA’s 70-year history. But despite its 1976 enactment of an express pre-emption provision for medical devices, see §521, 90Stat. 574 (codified at 21 U. S. C. §360k(a)), Congress has not enacted such a provision for prescription drugs.See Riegel, 552 U. S., at ___ (slip op., at 14)(“Congress could have applied the pre-emption clause to the entire FDCA. It did not do so, but instead wrote a pre-emption clause that applies only to medical devices”). 8 Its silence on the issue, coupled with its certain awareness of the prevalence of state tort litigation, is powerful evidence that Congress did not intend FDA oversight to be the exclusive means of ensuring drug safety and effectiveness. As Justice O’Connor explained in her opinion for a unanimous Court: “The case for federal pre-emption is particularly weak where Congress has indicated its awareness of the operation of state law in a field of federal interest, and has nonetheless decided to stand by both concepts and to tolerate whatever tension there [is] between them.” Bonito Boats, Inc. v. Thunder Craft Boats, Inc., 489 U. S. 141, 166–167 (1989) (internal quotation marks omitted); see also supra,at 8 (discussing the presumption against pre-emption).

Despite this evidence that Congress did not regard state tort litigation as an obstacle to achieving its purposes, Wyeth nonetheless maintains that, because the FDCA requires the FDA to determine that a drug is safe and effective under the conditions set forth in its labeling, the agency must be presumed to have performed a precise balancing of risks and benefits and to have established a specific labeling standard that leaves no room for different state-law judgments. In advancing this argument, Wyeth relies not on any statement by Congress, but instead on the preamble to a 2006 FDA regulation governing the content and format of prescription drug labels. See Brief for Petitioner 8, 11, 42, 45, and 50 (citing 71Fed. Reg. 3922 (2006)). In that preamble, the FDA declared that the FDCA establishes “both a ‘floor’ and a ‘ceiling,’ ” so that “FDA approval of labeling … preempts conflicting or contrary State law.” Id., at 3934–3935. It further stated that certain state-law actions, such as those involving failure-to-warn claims, “threaten FDA’s statutorily prescribed role as the expert Federal agency responsible for evaluating and regulating drugs.” Id., at 3935.

This Court has recognized that an agency regulation with the force of law can pre-empt conflicting state requirements. See, e.g., Geier v. American Honda Motor Co., 529 U. S. 861 (2000) ; Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707, 713 (1985) . In such cases, the Court has performed its own conflict determination, relying on the substance of state and federal law and not on agency proclamations of pre-emption. We are faced with no such regulation in this case, but rather with an agency’s mere assertion that state law is an obstacle to achieving its statutory objectives. Because Congress has not authorized the FDA to pre-empt state law directly, cf. 21 U. S. C. §360k (authorizing the FDA to determine the scope of the Medical Devices Amendments’ pre-emption clause), 9 the question is what weight we should accord the FDA’s opinion.

In prior cases, we have given “some weight” to an agency’s views about the impact of tort law on federal objectives when “the subject matter is technica[l] and the relevant history and background are complex and extensive.” Geier, 529 U. S., at 883. Even in such cases, however, we have not deferred to an agency’s conclusion that state law is pre-empted. Rather, we have attended to an agency’s explanation of how state law affects the regulatory scheme. While agencies have no special authority to pronounce on pre-emption absent delegation by Congress, they do have a unique understanding of the statutes they administer and an attendant ability to make informed determinations about how state requirements may pose an “obstacle to the accomplishment and execution of the full purposes and objectives of Congress.” Hines, 312 U.S, at 67; see Geier, 529 U. S., at 883; Lohr, 518 U. S., at 495–496. The weight we accord the agency’s explanation of state law’s impact on the federal scheme depends on its thoroughness, consistency, and persuasiveness. Cf. United States v. Mead Corp., 533 U. S. 218, 234–235 (2001) ; Skidmore v. Swift & Co., 323 U. S. 134, 140 (1944) .

Under this standard, the FDA’s 2006 preamble does not merit deference. When the FDA issued its notice of proposed rulemaking in December 2000, it explained that the rule would “not contain policies that have federalism implications or that preempt State law.” 65 Fed. Reg. 81103; see also 71 id., at 3969 (noting that the “proposed rule did not propose to preempt state law”). In 2006, the agency finalized the rule and, without offering States or other interested parties notice or opportunity for comment, articulated a sweeping position on the FDCA’s pre-emptive effect in the regulatory preamble. The agency’s views on state law are inherently suspect in light of this procedural failure.

Further, the preamble is at odds with what evidence we have of Congress’ purposes, and it reverses the FDA’s own longstanding position without providing a reasoned explanation, including any discussion of how state law has interfered with the FDA’s regulation of drug labeling during decades of coexistence. The FDA’s 2006 position plainly does not reflect the agency’s own view at all times relevant to this litigation. Not once prior to Levine’s injury did the FDA suggest that state tort law stood as an obstacle to its statutory mission. To the contrary, it cast federal labeling standards as a floor upon which States could build and repeatedly disclaimed any attempt to pre-empt failure-to-warn claims. For instance, in 1998, the FDA stated that it did “not believe that the evolution of state tort law [would] cause the development of standards that would be at odds with the agency’s regulations.” 63 id., at 66384. It further noted that, in establishing “minimal standards” for drug labels, it did not intend “to preclude the states from imposing additional labeling requirements.” Ibid. 10

In keeping with Congress’ decision not to pre-empt common-law tort suits, it appears that the FDA traditionally regarded state law as a complementary form of drug regulation. The FDA has limited resources to monitor the 11,000 drugs on the market, 11 and manufacturers have superior access to information about their drugs, especially in the postmarketing phase as new risks emerge. State tort suits uncover unknown drug hazards and provide incentives for drug manufacturers to disclose safety risks promptly. They also serve a distinct compensatory function that may motivate injured persons to come forward with information. Failure-to-warn actions, in particular, lend force to the FDCA’s premise that manufacturers, not the FDA, bear primary responsibility for their drug labeling at all times. Thus, the FDA long maintained that state law offers an additional, and important, layer of consumer protection that complements FDA regulation. 12 The agency’s 2006 preamble represents a dramatic change in position.

Largely based on the FDA’s new position, Wyeth argues that this case presents a conflict between state and federal law analogous to the one at issue in Geier. There, we held that state tort claims premised on Honda’s failure to install airbags conflicted with a federal regulation that did not require airbags for all cars. The Department of Transportation (DOT) had promulgated a rule that provided car manufacturers with a range of choices among passive restraint devices. Geier, 529 U. S., at 875. Rejecting an “ ‘all airbag’ ” standard, the agency had called for a gradual phase-in of a mix of passive restraints in order to spur technological development and win consumer acceptance. Id., at 879. Because the plaintiff’s claim was that car manufacturers had a duty to install airbags, it presented an obstacle to achieving “the variety and mix of devices that the federal regulation sought.” Id., at 881.

Wyeth and the dissent contend that the regulatory scheme in this case is nearly identical, but, as we have described, it is quite different. In Geier, the DOT conducted a formal rulemaking and then adopted a plan to phase in a mix of passive restraint devices. Examining the rule itself and the DOT’s contemporaneous record, which revealed the factors the agency had weighed and the balance it had struck, we determined that state tort suits presented an obstacle to the federal scheme. After conducting our own pre-emption analysis, we considered the agency’s explanation of how state law interfered with its regulation, regarding it as further support for our independent conclusion that the plaintiff’s tort claim obstructed the federal regime.

By contrast, we have no occasion in this case to consider the pre-emptive effect of a specific agency regulation bearing the force of law. And the FDA’s newfound opinion, expressed in its 2006 preamble, that state law “frustrate[s] the agency’s implementation of its statutory mandate,” 71 Fed. Reg. 3934, does not merit deference for the reasons we have explained. 13 Indeed, the “complex and extensive” regulatory history and background relevant to this case, Geier, 529 U. S., at 883, undercut the FDA’s recent pronouncements of pre-emption, as they reveal the longstanding coexistence of state and federal law and the FDA’s traditional recognition of state-law remedies—a recognition in place each time the agency reviewed Wyeth’s Phenergan label. 14

In short, Wyeth has not persuaded us that failure-to-warn claims like Levine’s obstruct the federal regulation of drug labeling. Congress has repeatedly declined to pre-empt state law, and the FDA’s recently adopted position that state tort suits interfere with its statutory mandate is entitled to no weight. Although we recognize that some state-law claims might well frustrate the achievement of congressional objectives, this is not such a case.

V

We conclude that it is not impossible for Wyeth to comply with its state and federal law obligations and that Levine’s common-law claims do not stand as an obstacle to the accomplishment of Congress’ purposes in the FDCA. Accordingly, the judgment of the Vermont Supreme Court is affirmed.

It is so ordered.


Notes

1 The warning for “Inadvertent Intra-arterial Injection” stated: “Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or inadvertent intra-arterial injection. Reports compatible with inadvertent intra-arterial injection of Phenergan Injection, usually in conjunction with other drugs intended for intravenous use, suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances. Intravenous injection was intended in all the cases reported but perivascular extravasation or arterial placement of the needle is now suspect. There is no proven successful management of this condition after it occurs. . . . Aspiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with Phenergan Injection. Use of syringes with rigid plungers or of small bore needles might obscure typical arterial backflow if this is relied upon alone. When used intravenously, Phenergan Injection should be given in a concentration no greater than 25 mg per mL and at a rate not to exceed 25 mg per minute. When administering any irritant drug intravenously, it is usually preferable to inject it through the tubing of an intravenous infusion set that is known to be functioning satisfactorily. In the event that a patient complains of pain during intended intravenous injection of Phenergan Injection, the injection should be stopped immediately to provide for evaluation of possible arterial placement or perivascular extravasation.” App. 390.

2 The dissent nonetheless suggests that physician malpractice was the exclusive cause of Levine’s injury. See, e.g., post, at 1 (opinion of Alito, J.) (“[I]t is unclear how a ‘stronger’ warning could have helped respondent”); post, at 16–18 (suggesting that the physician assistant’s conduct was the sole cause of the injury). The dissent’s frustration with the jury’s verdict does not put the merits of Levine’s tort claim before us, nor does it change the question we must decide—whether federal law pre-empts Levine’s state-law claims.

3 Wyeth argues that the presumption against pre-emption should not apply to this case because the Federal Government has regulated drug labeling for more than a century. That argument misunderstands the principle: We rely on the presumption because respect for the States as “independent sovereigns in our federal system” leads us to assume that “Congress does not cavalierly pre-empt state-law causes of action.” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) . The presumption thus accounts for the historic presence of state law but does not rely on the absence of federal regulation. For its part, the dissent argues that the presumption against pre-emption should not apply to claims of implied conflict pre-emption at all, post, at 21, but this Court has long held to the contrary. See, e.g., California v. ARC America Corp., 490 U. S. 93, 101–102 (1989) ; Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707, 716 (1985) ; see also Rush Prudential HMO, Inc. v. Moran, 536 U. S. 355, 387 (2002) . The dissent’s reliance on Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341 (2001) , see post, at 21, and n. 14, is especially curious, as that case involved state-law fraud-on-the-agency claims, and the Court distinguished state regulation of health and safety as matters to which the presumption does apply. See 531 U. S., at 347–348.

4 Levine also introduced evidence that Pfizer had withdrawn Vistaril, another antinausea drug, from intravenous use several decades earlier because its intravenous injection had resulted in gangrene and amputations. See App. 79.

5 The record would not, in any event, support such an argument. In 1988, Wyeth did propose different language for Phenergan’s warning about intra-arterial injection, adapted from revisions the FDA proposed in 1987. See App. 339–341, 311–312. When the FDA approved Wyeth’s application, it instructed Wyeth to retain the wording in its current label. During the trial court proceedings, Levine indicated that the language proposed in 1988 would have more strongly warned against IV-push administration. But the trial court and the Vermont Supreme Court found that the 1988 warning did not differ in any material respect from the FDA-approved warning. See ___ Vt. ___, ___, 944 A. 2d 179, 189 (2006) (“Simply stated, the proposed warning was different, but not stronger. It was also no longer or more prominent than the original warning …”); App. 248–250. Indeed, the United States concedes that the FDA did not regard the proposed warning as substantively different: “[I]t appears the FDA viewed the change as non-substantive and rejected it for formatting reasons.” Brief for United States as Amicus Curiae 25; see also ___ Vt., at ___, 944 A. 2d, at 189.

6 The dissent’s suggestion that the FDA intended to prohibit Wyeth from strengthening its warning does not fairly reflect the record. The dissent creatively paraphrases a few FDA orders—for instance by conflating warnings about IV-push administration and intra-arterial injection, see, e.g., post, at 9, 11–12, 15–16—to suggest greater agency attention to the question, and it undertakes a study of Phenergan’s labeling that is more elaborate than any FDA order. But even the dissent’s account does not support the conclusion that the FDA would have prohibited Wyeth from adding a stronger warning pursuant to the CBE regulation.

7 Although the first version of the bill that became the FDCA would have provided a federal cause of action for damages for injured consumers, see H. R. 6110, 73d Cong., 1st Sess., §25 (1933) (as introduced), witnesses testified that such a right of action was unnecessary because common-law claims were already available under state law. See Hearings on S. 1944 before a Subcommittee of the Senate Committee on Commerce, 73d Cong., 2d Sess., 400 (1933) (statement of W. A. Hines); see id., at 403 (statement of J. A. Ladds) (“This act should not attempt to modify or restate the common law with respect to personal injuries”).

8 In 1997, Congress pre-empted certain state requirements concerning over-the-counter medications and cosmetics but expressly preserved product liability actions. See 21 U. S. C. §§379r(e) (“Nothing in this section shall be construed to modify or otherwise affect any action or the liability of any person under the product liability law of any State”).

9 For similar examples, see 47 U. S. C. §§253(a), (d) (2000 ed.) (authorizing the Federal Communications Commission to pre-empt “any [state] statute, regulation, or legal requirement” that “may prohibit or have the effect of prohibiting the ability of any entity to provide any interstate or intrastate telecommunications service”); 30 U. S. C. §1254(g) (2006 ed.) (pre-empting any statute that conflicts with “the purposes and the requirements of this chapter” and permitting the Secretary of the Interior to “set forth any State law or regulation which is preempted and superseded”); and 49 U. S. C. §5125(d) (2000 ed. and Supp. V) (authorizing the Secretary of Transportation to decide whether a state or local statute that conflicts with the regulation of hazardous waste transportation is pre-empted).

10 See also 44Fed. Reg. 37437 (1979) (“It is not the intent of the FDA to influence the civil tort liability of the manufacturer”); 59Fed. Reg. 3948 (1994) (“[P]roduct liability plays an important role in consumer protection”); Porter, The Lohr Decision: FDA Perspective and Position, 52 Food & Drug L. J. 7, 10 (1997) (former chief counsel to the FDA stating that the FDA regarded state law as complementing the agency’s mission of consumer protection).

11 In 1955, the same year that the agency approved Wyeth’s Phenergan application, an FDA advisory committee issued a report finding “conclusively” that “the budget and staff of the Food and Drug Administration are inadequate to permit the discharge of its existing responsibilities for the protection of the American public.” Citizens Advisory Committee on the FDA, Report to the Secretary of Health, Education, and Welfare, H. R. Doc. No. 227, 84th Cong., 1st Sess., 53. Three recent studies have reached similar conclusions. See FDA Science Board, Report of the Subcommittee on Science and Technology: FDA Science and Mission at Risk 2, 6 (2007), online at http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4329b_02_01_FDA Report on Science and Technology.pdf (all Internet materials as visited Feb. 23, 2009, and available in Clerk of Court’s case file) (“[T]he Agency suffers from serious scientific deficiencies and is not positioned to meet current or emerging regulatory responsibilities”); National Academies, Institute of Medicine, The Future of Drug Safety: Promoting and Protecting the Health of the Public 193–194 (2007) (“The [FDA] lacks the resources needed to accomplish its large and complex mission … . There is widespread agreement that resources for postmarketing drug safety work are especially inadequate and that resource limitations have hobbled the agency’s ability to improve and expand this essential component of its mission”); GAO, Drug Safety: Improvement Needed in FDA’s Postmarket Decision-making and Oversight Process 5 (GAO–06–402, 2006), http://www.gao.gov/new.items/d06402.pdf (“FDA lacks a clear and effective process for making decisions about, and providing management oversight of, postmarket safety issues”); see also House Committee on Oversight and Government Reform, Majority Staff Report, FDA Career Staff Objected to Agency Preemption Policies 4 (2008) (“[T]he Office of Chief Counsel ignored the warnings from FDA scientists and career officials that the preemption language [of the 2006 preamble] was based on erroneous assertions about the ability of the drug approval process to ensure accurate and up-to-date drug labels”).

12 See generally Brief for Former FDA Commissioners Drs. Donald Kennedy and David Kessler as Amici Curiae; see also Kessler & Vladeck, A Critical Examination of the FDA’s Efforts To Preempt Failure-To-Warn Claims, 96 Geo. L. J. 461, 463 (2008); Bates v. Dow Agrosciences LLC, 544 U. S. 431, 451 (2005) (noting that state tort suits “can serve as a catalyst” by aiding in the exposure of new dangers and prompting a manufacturer or the federal agency to decide that a revised label is required).

13 The United States’ amicus brief is similarly undeserving of deference. Unlike the Government’s brief in Geier v. American Honda Motor Co., 529 U. S. 861 (2000) , which explained the effects of state law on the DOT’s regulation in a manner consistent with the agency’s prior accounts, see id., at 861, the Government’s explanation of federal drug regulation departs markedly from the FDA’s understanding at all times relevant to this case.

14 Wyeth’s more specific contention—that this case resembles Geier because the FDA determined that no additional warning on IV-push administration was needed, thereby setting a ceiling on Phenergan’s label—is belied by the record. As we have discussed, the FDA did not consider and reject a stronger warning against IV-push injection of Phenergan. See also App. 249–250 (“[A] tort case is unlikely to obstruct the regulatory process when the record shows that the FDA has paid very little attention to the issues raised by the parties at trial”).


TOP

Opinion

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Stevens delivered the opinion of the Court.

Directly injecting the drug Phenergan into a patient’s vein creates a significant risk of catastrophic consequences. A Vermont jury found that petitioner Wyeth, the manufacturer of the drug, had failed to provide an adequate warning of that risk and awarded damages to respondent Diana Levine to compensate her for the amputation of her arm. The warnings on Phenergan’s label had been deemed sufficient by the federal Food and Drug Administration (FDA) when it approved Wyeth’s new drug application in 1955 and when it later approved changes in the drug’s labeling. The question we must decide is whether the FDA’s approvals provide Wyeth with a complete defense to Levine’s tort claims. We conclude that they do not.

I

Phenergan is Wyeth’s brand name for promethazine hydrochloride, an antihistamine used to treat nausea. The injectable form of Phenergan can be administered intramuscularly or intravenously, and it can be administered intravenously through either the “IV-push” method, whereby the drug is injected directly into a patient’s vein, or the “IV-drip” method, whereby the drug is introduced into a saline solution in a hanging intravenous bag and slowly descends through a catheter inserted in a patient’s vein. The drug is corrosive and causes irreversible gangrene if it enters a patient’s artery.

Levine’s injury resulted from an IV-push injection of Phenergan. On April 7, 2000, as on previous visits to her local clinic for treatment of a migraine headache, she received an intramuscular injection of Demerol for her headache and Phenergan for her nausea. Because the combination did not provide relief, she returned later that day and received a second injection of both drugs. This time, the physician assistant administered the drugs by the IV-push method, and Phenergan entered Levine’s artery, either because the needle penetrated an artery directly or because the drug escaped from the vein into surrounding tissue (a phenomenon called “perivascular extravasation”) where it came in contact with arterial blood. As a result, Levine developed gangrene, and doctors amputated first her right hand and then her entire forearm. In addition to her pain and suffering, Levine incurred substantial medical expenses and the loss of her livelihood as a professional musician.

After settling claims against the health center and clinician, Levine brought an action for damages against Wyeth, relying on common-law negligence and strict-liability theories. Although Phenergan’s labeling warned of the danger of gangrene and amputation following inadvertent intra-arterial injection, 1 Levine alleged that the labeling was defective because it failed to instruct clinicians to use the IV-drip method of intravenous administration instead of the higher risk IV-push method. More broadly, she alleged that Phenergan is not reasonably safe for intravenous administration because the foreseeable risks of gangrene and loss of limb are great in relation to the drug’s therapeutic benefits. App. 14–15.

Wyeth filed a motion for summary judgment, arguing that Levine’s failure-to-warn claims were pre-empted by federal law. The court found no merit in either Wyeth’s field pre-emption argument, which it has since abandoned, or its conflict pre-emption argument. With respect to the contention that there was an “actual conflict between a specific FDA order,” id., at 21, and Levine’s failure-to-warn action, the court reviewed the sparse correspondence between Wyeth and the FDA about Phenergan’s labeling and found no evidence that Wyeth had “earnestly attempted” to strengthen the intra-arterial injection warning or that the FDA had “specifically disallowed” stronger language, id., at 23. The record, as then developed, “lack[ed] any evidence that the FDA set a ceiling on this matter.” Ibid.

The evidence presented during the 5-day jury trial showed that the risk of intra-arterial injection or perivascular extravasation can be almost entirely eliminated through the use of IV-drip, rather than IV-push, administration. An IV drip is started with saline, which will not flow properly if the catheter is not in the vein and fluid is entering an artery or surrounding tissue. See id., at 50–51, 60, 66–68, 75. By contrast, even a careful and experienced clinician using the IV-push method will occasionally expose an artery to Phenergan. See id., at 73, 75–76. While Phenergan’s labeling warned against intra-arterial injection and perivascular extravasation and advised that “[w]hen administering any irritant drug intravenously it is usually preferable to inject it through the tubing of an intravenous infusion set that is known to be function-ing satisfactorily,” id., at 390, the labeling did not con-tain a specific warning about the risks of IV-pushadministration.

The trial record also contains correspondence between Wyeth and the FDA discussing Phenergan’s label. The FDA first approved injectable Phenergan in 1955. In 1973 and 1976, Wyeth submitted supplemental new drug applications, which the agency approved after proposing labeling changes. Wyeth submitted a third supplemental application in 1981 in response to a new FDA rule governing drug labels. Over the next 17 years, Wyeth and the FDA intermittently corresponded about Phenergan’s label. The most notable activity occurred in 1987, when the FDA suggested different warnings about the risk of arterial exposure, and in 1988, when Wyeth submitted revised labeling incorporating the proposed changes. The FDA did not respond. Instead, in 1996, it requested from Wyeth the labeling then in use and, without addressing Wyeth’s 1988 submission, instructed it to “[r]etain verbiage in current label” regarding intra-arterial injection. Id., at 359. After a few further changes to the labeling not related to intra-arterial injection, the FDA approved Wyeth’s 1981 application in 1998, instructing that Phenergan’s final printed label “must be identical” to the approved package insert. Id., at 382.

Based on this regulatory history, the trial judge instructed the jury that it could consider evidence of Wyeth’s compliance with FDA requirements but that such compliance did not establish that the warnings were adequate. He also instructed, without objection from Wyeth, that FDA regulations “permit a drug manufacturer to change a product label to add or strengthen a warning about its product without prior FDA approval so long as it later submits the revised warning for review and approval.” Id., at 228.

Answering questions on a special verdict form, the jury found that Wyeth was negligent, that Phenergan was a defective product as a result of inadequate warnings and instructions, and that no intervening cause had broken the causal connection between the product defects and the plaintiff’s injury. Id., at 233–235. It awarded total damages of $7,400,000, which the court reduced to account for Levine’s earlier settlement with the health center and clinician. Id., at 235–236.

On August 3, 2004, the trial court filed a comprehensive opinion denying Wyeth’s motion for judgment as a matter of law. After making findings of fact based on the trial record (supplemented by one letter that Wyeth found after the trial), the court rejected Wyeth’s pre-emption arguments. It determined that there was no direct conflict between FDA regulations and Levine’s state-law claims because those regulations permit strengthened warnings without FDA approval on an interim basis and the record contained evidence of at least 20 reports of amputations similar to Levine’s since the 1960’s. The court also found that state tort liability in this case would not obstruct the FDA’s work because the agency had paid no more than passing attention to the question whether to warn against IV-push administration of Phenergan. In addition, the court noted that state law serves a compensatory function distinct from federal regulation. Id., at 249–252.

The Vermont Supreme Court affirmed. It held that the jury’s verdict “did not conflict with FDA’s labeling requirements for Phenergan because [Wyeth] could have warned against IV-push administration without prior FDA approval, and because federal labeling requirements create a floor, not a ceiling, for state regulation.” ___ Vt. ___, ___ 944 A. 2d 179, 184 (2006). In dissent, Chief Justice Reiber argued that the jury’s verdict conflicted with federal law because it was inconsistent with the FDA’s conclusion that intravenous administration of Phenergan was safe and effective.

The importance of the pre-emption issue, coupled with the fact that the FDA has changed its position on state tort law and now endorses the views expressed in Chief Justice Reiber’s dissent, persuaded us to grant Wyeth’s petition for certiorari. 552 U. S. ___ (2008). The question presented by the petition is whether the FDA’s drug labeling judgments “preempt state law product liability claims premised on the theory that different labeling judgments were necessary to make drugs reasonably safe for use.” Pet. for Cert. i.

II

Wyeth makes two separate pre-emption arguments: first, that it would have been impossible for it to comply with the state-law duty to modify Phenergan’s labeling without violating federal law, see Fidelity Fed. Sav. & Loan Assn. v. De la Cuesta, 458 U. S. 141, 153 (1982) , and second, that recognition of Levine’s state tort action creates an unacceptable “obstacle to the accomplishment and execution of the full purposes and objectives of Congress,” Hines v. Davidowitz, 312 U. S. 52, 67 (1941) , because it substitutes a lay jury’s decision about drug labeling for the expert judgment of the FDA. As a preface to our evaluation of these arguments, we identify two factual propositions decided during the trial court proceedings, emphasize two legal principles that guide our analysis, and review the history of the controlling federal statute.

The trial court proceedings established that Levine’s injury would not have occurred if Phenergan’s label had included an adequate warning about the risks of the IV-push method of administering the drug. The record contains evidence that the physician assistant administered a greater dose than the label prescribed, that she may have inadvertently injected the drug into an artery rather than a vein, and that she continued to inject the drug after Levine complained of pain. Nevertheless, the jury rejected Wyeth’s argument that the clinician’s conduct was an intervening cause that absolved it of liability. See App. 234 (jury verdict), 252–254. In finding Wyeth negligent as well as strictly liable, the jury also determined that Levine’s injury was foreseeable. That the inadequate label was both a but-for and proximate cause of Levine’s injury is supported by the record and no longer challenged by Wyeth. 2

The trial court proceedings further established that the critical defect in Phenergan’s label was the lack of an adequate warning about the risks of IV-push administration. Levine also offered evidence that the IV-push method should be contraindicated and that Phenergan should never be administered intravenously, even by the IV-drip method. Perhaps for this reason, the dissent incorrectly assumes that the state-law duty at issue is the duty to contraindicate the IV-push method. See, e.g., post, at 8, 25. But, as the Vermont Supreme Court explained, the jury verdict established only that Phenergan’s warning was insufficient. It did not mandate a particular replacement warning, nor did it require contraindicating IV-push administration: “There may have been any number of ways for [Wyeth] to strengthen the Phenergan warning without completely eliminating IV-push administration.” ___ Vt., at ___, n. 2, 944 A. 2d, at 189, n. 2. We therefore need not decide whether a state rule proscribing intravenous administration would be pre-empted. The narrower question presented is whether federal law pre-empts Levine’s claim that Phenergan’s label did not contain an adequate warning about using the IV-push method of administration.

Our answer to that question must be guided by two cornerstones of our pre-emption jurisprudence. First, “the purpose of Congress is the ultimate touchstone in every pre-emption case.” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) (internal quotation marks omitted); see Retail Clerks v. Schermerhorn, 375 U. S. 96, 103 (1963) . Second, “[i]n all pre-emption cases, and particularly in those in which Congress has ‘legislated … in a field which the States have traditionally occupied,’ … we ‘start with the assumption that the historic police powers of the States were not to be superseded by the Federal Act unless that was the clear and manifest purpose of Congress.’ ” Lohr, 518 U. S., at 485 (quoting Rice v. Santa Fe Elevator Corp., 331 U. S. 218, 230 (1947) ). 3

In order to identify the “purpose of Congress,” it is appropriate to briefly review the history of federal regulation of drugs and drug labeling. In 1906, Congress enacted its first significant public health law, the Federal Food and Drugs Act, ch. 3915, 34Stat. 768. The Act, which prohibited the manufacture or interstate shipment of adulterated or misbranded drugs, supplemented the protection for consumers already provided by state regulation and common-law liability. In the 1930’s, Congress became increasingly concerned about unsafe drugs and fraudulent marketing, and it enacted the Federal Food, Drug, and Cosmetic Act (FDCA), ch. 675, 52Stat. 1040, as amended, 21 U. S. C. §301 et seq. The Act’s most substantial innovation was its provision for premarket approval of new drugs. It required every manufacturer to submit a new drug application, including reports of investigations and specimens of proposed labeling, to the FDA for review. Until its application became effective, a manufacturer was prohibited from distributing a drug. The FDA could reject an application if it determined that the drug was not safe for use as labeled, though if the agency failed to act, an application became effective 60 days after the filing. FDCA, §505(c), 52Stat. 1052.

In 1962, Congress amended the FDCA and shifted the burden of proof from the FDA to the manufacturer. Before 1962, the agency had to prove harm to keep a drug out of the market, but the amendments required the manufacturer to demonstrate that its drug was “safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling” before it could distribute the drug. §§102(d), 104(b), 76Stat. 781, 784. In addition, the amendments required the manufacturer to prove the drug’s effectiveness by introducing “substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling.” §102(d), id., at 781.

As it enlarged the FDA’s powers to “protect the public health” and “assure the safety, effectiveness, and reliability of drugs,” id., at 780, Congress took care to preserve state law. The 1962 amendments added a saving clause, indicating that a provision of state law would only be invalidated upon a “direct and positive conflict” with the FDCA. §202, id., at 793. Consistent with that provision, state common-law suits “continued unabated despite … FDA regulation.” Riegel v. Medtronic, Inc., 552 U. S. ___, ___ (2008) (slip op., at 8) (Ginsburg, J., dissenting); see ibid., n. 11 (collecting state cases). And when Congress enacted an express pre-emption provision for medical devices in 1976, see §521, 90Stat. 574 (codified at 21 U. S. C. §360k(a)), it declined to enact such a provision for prescription drugs.

In 2007, after Levine’s injury and lawsuit, Congress again amended the FDCA. 121Stat. 823. For the first time, it granted the FDA statutory authority to require a manufacturer to change its drug label based on safety information that becomes available after a drug’s initial approval. §901(a), id., at 924–926. In doing so, however, Congress did not enact a provision in the Senate bill that would have required the FDA to preapprove all changes to drug labels. See S. 1082, 110th Cong., 1st Sess., §208, pp. 107–114 (2007) (as passed) (proposing new §506D). Instead, it adopted a rule of construction to make it clear that manufacturers remain responsible for updating their labels. See 121Stat. 925–926.

III

Wyeth first argues that Levine’s state-law claims are pre-empted because it is impossible for it to comply with both the state-law duties underlying those claims and its federal labeling duties. See De la Cuesta, 458 U. S., at 153. The FDA’s premarket approval of a new drug application includes the approval of the exact text in the proposed label. See 21 U. S. C. §355; 21 CFR §314.105(b) (2008). Generally speaking, a manufacturer may only change a drug label after the FDA approves a supplemental application. There is, however, an FDA regulation that permits a manufacturer to make certain changes to its label before receiving the agency’s approval. Among other things, this “changes being effected” (CBE) regulation provides that if a manufacturer is changing a label to “add or strengthen a contraindication, warning, precaution, or adverse reaction” or to “add or strengthen an instruction about dosage and administration that is intended to increase the safe use of the drug product,” it may make the labeling change upon filing its supplemental application with the FDA; it need not wait for FDA approval. §§314.70(c)(6)(iii)(A), (C).

Wyeth argues that the CBE regulation is not implicated in this case because a 2008 amendment provides that a manufacturer may only change its label “to reflect newly acquired information.” 73 Fed. Reg. 49609. Resting on this language (which Wyeth argues simply reaffirmed the interpretation of the regulation in effect when this case was tried), Wyeth contends that it could have changed Phenergan’s label only in response to new information that the FDA had not considered. And it maintains that Levine has not pointed to any such information concerning the risks of IV-push administration. Thus, Wyeth insists, it was impossible for it to discharge its state-law obligation to provide a stronger warning about IV-push administration without violating federal law. Wyeth’s argument misapprehends both the federal drug regulatory scheme and its burden in establishing a pre-emption defense.

We need not decide whether the 2008 CBE regulation is consistent with the FDCA and the previous version of the regulation, as Wyeth and the United States urge, because Wyeth could have revised Phenergan’s label even in accordance with the amended regulation. As the FDA explained in its notice of the final rule, “ ‘newly acquired information’ ” is not limited to new data, but also encompasses “new analyses of previously submitted data.” Id., at 49604. The rule accounts for the fact that risk information accumulates over time and that the same data may take on a different meaning in light of subsequent developments: “[I]f the sponsor submits adverse event information to FDA, and then later conducts a new analysis of data showing risks of a different type or of greater severity or frequency than did reports previously submitted to FDA, the sponsor meets the requirement for ‘newly acquired information.’ ” Id., at 49607; see also id., at 49606.

The record is limited concerning what newly acquired information Wyeth had or should have had about the risks of IV-push administration of Phenergan because Wyeth did not argue before the trial court that such information was required for a CBE labeling change. Levine did, however, present evidence of at least 20 incidents prior to her injury in which a Phenergan injection resulted in gangrene and an amputation. See App. 74, 252. 4 After the first such incident came to Wyeth’s attention in 1967, it notified the FDA and worked with the agency to change Phenergan’s label. In later years, as amputations continued to occur, Wyeth could have analyzed the accumulating data and added a stronger warning about IV-push administration of the drug.

Wyeth argues that if it had unilaterally added such a warning, it would have violated federal law governing unauthorized distribution and misbranding. Its argument that a change in Phenergan’s labeling would have subjected it to liability for unauthorized distribution rests on the assumption that this labeling change would have rendered Phenergan a new drug lacking an effective application. But strengthening the warning about IV-push administration would not have made Phenergan a new drug. See 21 U. S. C. §321(p)(1) (defining “new drug”); 21 CFR §310.3(h). Nor would this warning have rendered Phenergan misbranded. The FDCA does not provide that a drug is misbranded simply because the manufacturer has altered an FDA-approved label; instead, the misbranding provision focuses on the substance of the label and, among other things, proscribes labels that fail to include “adequate warnings.” 21 U. S. C. §352(f). Moreover, because the statute contemplates that federal juries will resolve most misbranding claims, the FDA’s belief that a drug is misbranded is not conclusive. See §§331, 332, 334(a)–(b). And the very idea that the FDA would bring an enforcement action against a manufacturer for strengthening a warning pursuant to the CBE regulation is difficult to accept—neither Wyeth nor the United States has identified a case in which the FDA has done so.

Wyeth’s cramped reading of the CBE regulation and its broad reading of the FDCA’s misbranding and unauthorized distribution provisions are premised on a more fundamental misunderstanding. Wyeth suggests that the FDA, rather than the manufacturer, bears primary responsibility for drug labeling. Yet through many amendments to the FDCA and to FDA regulations, it has remained a central premise of federal drug regulation that the manufacturer bears responsibility for the content of its label at all times. It is charged both with crafting an adequate label and with ensuring that its warnings remain adequate as long as the drug is on the market. See, e.g., 21 CFR §201.80(e) (requiring a manufacturer to revise its label “to include a warning as soon as there is reasonable evidence of an association of a serious hazard with a drug”);§314.80(b) (placing responsibility for postmarketing surveillance on the manufacturer); 73 Fed. Reg. 49605 (“Manufacturers continue to have a responsibility under Federal law … to maintain their labeling and update the labeling with new safety information”).

Indeed, prior to 2007, the FDA lacked the authority to order manufacturers to revise their labels. See 121Stat. 924–926. When Congress granted the FDA this authority, it reaffirmed the manufacturer’s obligations and referred specifically to the CBE regulation, which both reflects the manufacturer’s ultimate responsibility for its label and provides a mechanism for adding safety information to the label prior to FDA approval. See id., at 925–926(stating that a manufacturer retains the responsibility “to maintain its label in accordance with existing requirements, including subpart B of part 201 and sections 314.70 and 601.12 of title 21, Code of Federal Regulations (or any successor regulations)” (emphasis added)). Thus, when the risk of gangrene from IV-push injection of Phenergan became apparent, Wyeth had a duty to provide a warning that adequately described that risk, and the CBE regulation permitted it to provide such a warning before receiving the FDA’s approval.

Of course, the FDA retains authority to reject labeling changes made pursuant to the CBE regulation in its review of the manufacturer’s supplemental application, just as it retains such authority in reviewing all supplemental applications. But absent clear evidence that the FDA would not have approved a change to Phenergan’s label, we will not conclude that it was impossible for Wyeth to comply with both federal and state requirements.

Wyeth has offered no such evidence. It does not argue that it attempted to give the kind of warning required by the Vermont jury but was prohibited from doing so by the FDA. See Tr. of Oral Arg. 12–13; see also Brief for United States as Amicus Curiae 25. And while it does suggest that the FDA intended to prohibit it from strengthening the warning about IV-push administration because the agency deemed such a warning inappropriate in reviewing Phenergan’s drug applications, both the trial court and the Vermont Supreme Court rejected this account as a matter of fact. In its decision on Wyeth’s motion for judgment as a matter of law, the trial court found “no evidence in this record that either the FDA or the manufacturer gave more than passing attention to the issue of” IV-push versus IV-drip administration. App. 249. The Vermont Supreme Court likewise concluded that the FDA had not made an affirmative decision to preserve the IV-push method or intended to prohibit Wyeth from strengthening its warning about IV-push administration. ___ Vt., at ___, 944 A. 2d, at 188–189. Moreover, Wyeth does not argue that it supplied the FDA with an evaluation or analysis concerning the specific dangers posed by the IV-push method.We accordingly cannot credit Wyeth’s contention that the FDA would have prevented it from adding a stronger warning about the IV-push method of intravenous administration. 6

Impossibility pre-emption is a demanding defense. On the record before us, Wyeth has failed to demonstrate that it was impossible for it to comply with both federal and state requirements. The CBE regulation permitted Wyeth to unilaterally strengthen its warning, and the mere fact that the FDA approved Phenergan’s label does not establish that it would have prohibited such a change.

IV

Wyeth also argues that requiring it to comply with a state-law duty to provide a stronger warning about IV-push administration would obstruct the purposes and objectives of federal drug labeling regulation. Levine’s tort claims, it maintains, are pre-empted because they interfere with “Congress’s purpose to entrust an expert agency to make drug labeling decisions that strike a balance between competing objectives.” Brief for Petitioner 46. We find no merit in this argument, which relies on an untenable interpretation of congressional intent and an overbroad view of an agency’s power to pre-empt state law.

Wyeth contends that the FDCA establishes both a floor and a ceiling for drug regulation: Once the FDA has approved a drug’s label, a state-law verdict may not deem the label inadequate, regardless of whether there is any evidence that the FDA has considered the stronger warning at issue. The most glaring problem with this argument is that all evidence of Congress’ purposes is to the contrary. Building on its 1906 Act, Congress enacted the FDCA to bolster consumer protection against harmful products. See Kordel v. United States, 335 U. S. 345, 349 (1948) ; United States v. Sullivan, 332 U. S. 689, 696 (1948) . Congress did not provide a federal remedy for consumers harmed by unsafe or ineffective drugs in the 1938 statute or in any subsequent amendment. Evidently, it determined that widely available state rights of action provided appropriate relief for injured consumers. 7 It may also have recognized that state-law remedies further consumer protection by motivating manufacturers to produce safe and effective drugs and to give adequate warnings.

If Congress thought state-law suits posed an obstacle to its objectives, it surely would have enacted an express pre-emption provision at some point during the FDCA’s 70-year history. But despite its 1976 enactment of an express pre-emption provision for medical devices, see §521, 90Stat. 574 (codified at 21 U. S. C. §360k(a)), Congress has not enacted such a provision for prescription drugs.See Riegel, 552 U. S., at ___ (slip op., at 14)(“Congress could have applied the pre-emption clause to the entire FDCA. It did not do so, but instead wrote a pre-emption clause that applies only to medical devices”). 8 Its silence on the issue, coupled with its certain awareness of the prevalence of state tort litigation, is powerful evidence that Congress did not intend FDA oversight to be the exclusive means of ensuring drug safety and effectiveness. As Justice O’Connor explained in her opinion for a unanimous Court: “The case for federal pre-emption is particularly weak where Congress has indicated its awareness of the operation of state law in a field of federal interest, and has nonetheless decided to stand by both concepts and to tolerate whatever tension there [is] between them.” Bonito Boats, Inc. v. Thunder Craft Boats, Inc., 489 U. S. 141, 166–167 (1989) (internal quotation marks omitted); see also supra,at 8 (discussing the presumption against pre-emption).

Despite this evidence that Congress did not regard state tort litigation as an obstacle to achieving its purposes, Wyeth nonetheless maintains that, because the FDCA requires the FDA to determine that a drug is safe and effective under the conditions set forth in its labeling, the agency must be presumed to have performed a precise balancing of risks and benefits and to have established a specific labeling standard that leaves no room for different state-law judgments. In advancing this argument, Wyeth relies not on any statement by Congress, but instead on the preamble to a 2006 FDA regulation governing the content and format of prescription drug labels. See Brief for Petitioner 8, 11, 42, 45, and 50 (citing 71Fed. Reg. 3922 (2006)). In that preamble, the FDA declared that the FDCA establishes “both a ‘floor’ and a ‘ceiling,’ ” so that “FDA approval of labeling … preempts conflicting or contrary State law.” Id., at 3934–3935. It further stated that certain state-law actions, such as those involving failure-to-warn claims, “threaten FDA’s statutorily prescribed role as the expert Federal agency responsible for evaluating and regulating drugs.” Id., at 3935.

This Court has recognized that an agency regulation with the force of law can pre-empt conflicting state requirements. See, e.g., Geier v. American Honda Motor Co., 529 U. S. 861 (2000) ; Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707, 713 (1985) . In such cases, the Court has performed its own conflict determination, relying on the substance of state and federal law and not on agency proclamations of pre-emption. We are faced with no such regulation in this case, but rather with an agency’s mere assertion that state law is an obstacle to achieving its statutory objectives. Because Congress has not authorized the FDA to pre-empt state law directly, cf. 21 U. S. C. §360k (authorizing the FDA to determine the scope of the Medical Devices Amendments’ pre-emption clause), 9 the question is what weight we should accord the FDA’s opinion.

In prior cases, we have given “some weight” to an agency’s views about the impact of tort law on federal objectives when “the subject matter is technica[l] and the relevant history and background are complex and extensive.” Geier, 529 U. S., at 883. Even in such cases, however, we have not deferred to an agency’s conclusion that state law is pre-empted. Rather, we have attended to an agency’s explanation of how state law affects the regulatory scheme. While agencies have no special authority to pronounce on pre-emption absent delegation by Congress, they do have a unique understanding of the statutes they administer and an attendant ability to make informed determinations about how state requirements may pose an “obstacle to the accomplishment and execution of the full purposes and objectives of Congress.” Hines, 312 U.S, at 67; see Geier, 529 U. S., at 883; Lohr, 518 U. S., at 495–496. The weight we accord the agency’s explanation of state law’s impact on the federal scheme depends on its thoroughness, consistency, and persuasiveness. Cf. United States v. Mead Corp., 533 U. S. 218, 234–235 (2001) ; Skidmore v. Swift & Co., 323 U. S. 134, 140 (1944) .

Under this standard, the FDA’s 2006 preamble does not merit deference. When the FDA issued its notice of proposed rulemaking in December 2000, it explained that the rule would “not contain policies that have federalism implications or that preempt State law.” 65 Fed. Reg. 81103; see also 71 id., at 3969 (noting that the “proposed rule did not propose to preempt state law”). In 2006, the agency finalized the rule and, without offering States or other interested parties notice or opportunity for comment, articulated a sweeping position on the FDCA’s pre-emptive effect in the regulatory preamble. The agency’s views on state law are inherently suspect in light of this procedural failure.

Further, the preamble is at odds with what evidence we have of Congress’ purposes, and it reverses the FDA’s own longstanding position without providing a reasoned explanation, including any discussion of how state law has interfered with the FDA’s regulation of drug labeling during decades of coexistence. The FDA’s 2006 position plainly does not reflect the agency’s own view at all times relevant to this litigation. Not once prior to Levine’s injury did the FDA suggest that state tort law stood as an obstacle to its statutory mission. To the contrary, it cast federal labeling standards as a floor upon which States could build and repeatedly disclaimed any attempt to pre-empt failure-to-warn claims. For instance, in 1998, the FDA stated that it did “not believe that the evolution of state tort law [would] cause the development of standards that would be at odds with the agency’s regulations.” 63 id., at 66384. It further noted that, in establishing “minimal standards” for drug labels, it did not intend “to preclude the states from imposing additional labeling requirements.” Ibid. 10

In keeping with Congress’ decision not to pre-empt common-law tort suits, it appears that the FDA traditionally regarded state law as a complementary form of drug regulation. The FDA has limited resources to monitor the 11,000 drugs on the market, 11 and manufacturers have superior access to information about their drugs, especially in the postmarketing phase as new risks emerge. State tort suits uncover unknown drug hazards and provide incentives for drug manufacturers to disclose safety risks promptly. They also serve a distinct compensatory function that may motivate injured persons to come forward with information. Failure-to-warn actions, in particular, lend force to the FDCA’s premise that manufacturers, not the FDA, bear primary responsibility for their drug labeling at all times. Thus, the FDA long maintained that state law offers an additional, and important, layer of consumer protection that complements FDA regulation. 12 The agency’s 2006 preamble represents a dramatic change in position.

Largely based on the FDA’s new position, Wyeth argues that this case presents a conflict between state and federal law analogous to the one at issue in Geier. There, we held that state tort claims premised on Honda’s failure to install airbags conflicted with a federal regulation that did not require airbags for all cars. The Department of Transportation (DOT) had promulgated a rule that provided car manufacturers with a range of choices among passive restraint devices. Geier, 529 U. S., at 875. Rejecting an “ ‘all airbag’ ” standard, the agency had called for a gradual phase-in of a mix of passive restraints in order to spur technological development and win consumer acceptance. Id., at 879. Because the plaintiff’s claim was that car manufacturers had a duty to install airbags, it presented an obstacle to achieving “the variety and mix of devices that the federal regulation sought.” Id., at 881.

Wyeth and the dissent contend that the regulatory scheme in this case is nearly identical, but, as we have described, it is quite different. In Geier, the DOT conducted a formal rulemaking and then adopted a plan to phase in a mix of passive restraint devices. Examining the rule itself and the DOT’s contemporaneous record, which revealed the factors the agency had weighed and the balance it had struck, we determined that state tort suits presented an obstacle to the federal scheme. After conducting our own pre-emption analysis, we considered the agency’s explanation of how state law interfered with its regulation, regarding it as further support for our independent conclusion that the plaintiff’s tort claim obstructed the federal regime.

By contrast, we have no occasion in this case to consider the pre-emptive effect of a specific agency regulation bearing the force of law. And the FDA’s newfound opinion, expressed in its 2006 preamble, that state law “frustrate[s] the agency’s implementation of its statutory mandate,” 71 Fed. Reg. 3934, does not merit deference for the reasons we have explained. 13 Indeed, the “complex and extensive” regulatory history and background relevant to this case, Geier, 529 U. S., at 883, undercut the FDA’s recent pronouncements of pre-emption, as they reveal the longstanding coexistence of state and federal law and the FDA’s traditional recognition of state-law remedies—a recognition in place each time the agency reviewed Wyeth’s Phenergan label. 14

In short, Wyeth has not persuaded us that failure-to-warn claims like Levine’s obstruct the federal regulation of drug labeling. Congress has repeatedly declined to pre-empt state law, and the FDA’s recently adopted position that state tort suits interfere with its statutory mandate is entitled to no weight. Although we recognize that some state-law claims might well frustrate the achievement of congressional objectives, this is not such a case.

V

We conclude that it is not impossible for Wyeth to comply with its state and federal law obligations and that Levine’s common-law claims do not stand as an obstacle to the accomplishment of Congress’ purposes in the FDCA. Accordingly, the judgment of the Vermont Supreme Court is affirmed.

It is so ordered.


Notes

1 The warning for “Inadvertent Intra-arterial Injection” stated: “Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or inadvertent intra-arterial injection. Reports compatible with inadvertent intra-arterial injection of Phenergan Injection, usually in conjunction with other drugs intended for intravenous use, suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances. Intravenous injection was intended in all the cases reported but perivascular extravasation or arterial placement of the needle is now suspect. There is no proven successful management of this condition after it occurs. . . . Aspiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with Phenergan Injection. Use of syringes with rigid plungers or of small bore needles might obscure typical arterial backflow if this is relied upon alone. When used intravenously, Phenergan Injection should be given in a concentration no greater than 25 mg per mL and at a rate not to exceed 25 mg per minute. When administering any irritant drug intravenously, it is usually preferable to inject it through the tubing of an intravenous infusion set that is known to be functioning satisfactorily. In the event that a patient complains of pain during intended intravenous injection of Phenergan Injection, the injection should be stopped immediately to provide for evaluation of possible arterial placement or perivascular extravasation.” App. 390.

2 The dissent nonetheless suggests that physician malpractice was the exclusive cause of Levine’s injury. See, e.g., post, at 1 (opinion of Alito, J.) (“[I]t is unclear how a ‘stronger’ warning could have helped respondent”); post, at 16–18 (suggesting that the physician assistant’s conduct was the sole cause of the injury). The dissent’s frustration with the jury’s verdict does not put the merits of Levine’s tort claim before us, nor does it change the question we must decide—whether federal law pre-empts Levine’s state-law claims.

3 Wyeth argues that the presumption against pre-emption should not apply to this case because the Federal Government has regulated drug labeling for more than a century. That argument misunderstands the principle: We rely on the presumption because respect for the States as “independent sovereigns in our federal system” leads us to assume that “Congress does not cavalierly pre-empt state-law causes of action.” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) . The presumption thus accounts for the historic presence of state law but does not rely on the absence of federal regulation. For its part, the dissent argues that the presumption against pre-emption should not apply to claims of implied conflict pre-emption at all, post, at 21, but this Court has long held to the contrary. See, e.g., California v. ARC America Corp., 490 U. S. 93, 101–102 (1989) ; Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707, 716 (1985) ; see also Rush Prudential HMO, Inc. v. Moran, 536 U. S. 355, 387 (2002) . The dissent’s reliance on Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341 (2001) , see post, at 21, and n. 14, is especially curious, as that case involved state-law fraud-on-the-agency claims, and the Court distinguished state regulation of health and safety as matters to which the presumption does apply. See 531 U. S., at 347–348.

4 Levine also introduced evidence that Pfizer had withdrawn Vistaril, another antinausea drug, from intravenous use several decades earlier because its intravenous injection had resulted in gangrene and amputations. See App. 79.

5 The record would not, in any event, support such an argument. In 1988, Wyeth did propose different language for Phenergan’s warning about intra-arterial injection, adapted from revisions the FDA proposed in 1987. See App. 339–341, 311–312. When the FDA approved Wyeth’s application, it instructed Wyeth to retain the wording in its current label. During the trial court proceedings, Levine indicated that the language proposed in 1988 would have more strongly warned against IV-push administration. But the trial court and the Vermont Supreme Court found that the 1988 warning did not differ in any material respect from the FDA-approved warning. See ___ Vt. ___, ___, 944 A. 2d 179, 189 (2006) (“Simply stated, the proposed warning was different, but not stronger. It was also no longer or more prominent than the original warning …”); App. 248–250. Indeed, the United States concedes that the FDA did not regard the proposed warning as substantively different: “[I]t appears the FDA viewed the change as non-substantive and rejected it for formatting reasons.” Brief for United States as Amicus Curiae 25; see also ___ Vt., at ___, 944 A. 2d, at 189.

6 The dissent’s suggestion that the FDA intended to prohibit Wyeth from strengthening its warning does not fairly reflect the record. The dissent creatively paraphrases a few FDA orders—for instance by conflating warnings about IV-push administration and intra-arterial injection, see, e.g., post, at 9, 11–12, 15–16—to suggest greater agency attention to the question, and it undertakes a study of Phenergan’s labeling that is more elaborate than any FDA order. But even the dissent’s account does not support the conclusion that the FDA would have prohibited Wyeth from adding a stronger warning pursuant to the CBE regulation.

7 Although the first version of the bill that became the FDCA would have provided a federal cause of action for damages for injured consumers, see H. R. 6110, 73d Cong., 1st Sess., §25 (1933) (as introduced), witnesses testified that such a right of action was unnecessary because common-law claims were already available under state law. See Hearings on S. 1944 before a Subcommittee of the Senate Committee on Commerce, 73d Cong., 2d Sess., 400 (1933) (statement of W. A. Hines); see id., at 403 (statement of J. A. Ladds) (“This act should not attempt to modify or restate the common law with respect to personal injuries”).

8 In 1997, Congress pre-empted certain state requirements concerning over-the-counter medications and cosmetics but expressly preserved product liability actions. See 21 U. S. C. §§379r(e) (“Nothing in this section shall be construed to modify or otherwise affect any action or the liability of any person under the product liability law of any State”).

9 For similar examples, see 47 U. S. C. §§253(a), (d) (2000 ed.) (authorizing the Federal Communications Commission to pre-empt “any [state] statute, regulation, or legal requirement” that “may prohibit or have the effect of prohibiting the ability of any entity to provide any interstate or intrastate telecommunications service”); 30 U. S. C. §1254(g) (2006 ed.) (pre-empting any statute that conflicts with “the purposes and the requirements of this chapter” and permitting the Secretary of the Interior to “set forth any State law or regulation which is preempted and superseded”); and 49 U. S. C. §5125(d) (2000 ed. and Supp. V) (authorizing the Secretary of Transportation to decide whether a state or local statute that conflicts with the regulation of hazardous waste transportation is pre-empted).

10 See also 44Fed. Reg. 37437 (1979) (“It is not the intent of the FDA to influence the civil tort liability of the manufacturer”); 59Fed. Reg. 3948 (1994) (“[P]roduct liability plays an important role in consumer protection”); Porter, The Lohr Decision: FDA Perspective and Position, 52 Food & Drug L. J. 7, 10 (1997) (former chief counsel to the FDA stating that the FDA regarded state law as complementing the agency’s mission of consumer protection).

11 In 1955, the same year that the agency approved Wyeth’s Phenergan application, an FDA advisory committee issued a report finding “conclusively” that “the budget and staff of the Food and Drug Administration are inadequate to permit the discharge of its existing responsibilities for the protection of the American public.” Citizens Advisory Committee on the FDA, Report to the Secretary of Health, Education, and Welfare, H. R. Doc. No. 227, 84th Cong., 1st Sess., 53. Three recent studies have reached similar conclusions. See FDA Science Board, Report of the Subcommittee on Science and Technology: FDA Science and Mission at Risk 2, 6 (2007), online at http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4329b_02_01_FDA Report on Science and Technology.pdf (all Internet materials as visited Feb. 23, 2009, and available in Clerk of Court’s case file) (“[T]he Agency suffers from serious scientific deficiencies and is not positioned to meet current or emerging regulatory responsibilities”); National Academies, Institute of Medicine, The Future of Drug Safety: Promoting and Protecting the Health of the Public 193–194 (2007) (“The [FDA] lacks the resources needed to accomplish its large and complex mission … . There is widespread agreement that resources for postmarketing drug safety work are especially inadequate and that resource limitations have hobbled the agency’s ability to improve and expand this essential component of its mission”); GAO, Drug Safety: Improvement Needed in FDA’s Postmarket Decision-making and Oversight Process 5 (GAO–06–402, 2006), http://www.gao.gov/new.items/d06402.pdf (“FDA lacks a clear and effective process for making decisions about, and providing management oversight of, postmarket safety issues”); see also House Committee on Oversight and Government Reform, Majority Staff Report, FDA Career Staff Objected to Agency Preemption Policies 4 (2008) (“[T]he Office of Chief Counsel ignored the warnings from FDA scientists and career officials that the preemption language [of the 2006 preamble] was based on erroneous assertions about the ability of the drug approval process to ensure accurate and up-to-date drug labels”).

12 See generally Brief for Former FDA Commissioners Drs. Donald Kennedy and David Kessler as Amici Curiae; see also Kessler & Vladeck, A Critical Examination of the FDA’s Efforts To Preempt Failure-To-Warn Claims, 96 Geo. L. J. 461, 463 (2008); Bates v. Dow Agrosciences LLC, 544 U. S. 431, 451 (2005) (noting that state tort suits “can serve as a catalyst” by aiding in the exposure of new dangers and prompting a manufacturer or the federal agency to decide that a revised label is required).

13 The United States’ amicus brief is similarly undeserving of deference. Unlike the Government’s brief in Geier v. American Honda Motor Co., 529 U. S. 861 (2000) , which explained the effects of state law on the DOT’s regulation in a manner consistent with the agency’s prior accounts, see id., at 861, the Government’s explanation of federal drug regulation departs markedly from the FDA’s understanding at all times relevant to this case.

14 Wyeth’s more specific contention—that this case resembles Geier because the FDA determined that no additional warning on IV-push administration was needed, thereby setting a ceiling on Phenergan’s label—is belied by the record. As we have discussed, the FDA did not consider and reject a stronger warning against IV-push injection of Phenergan. See also App. 249–250 (“[A] tort case is unlikely to obstruct the regulatory process when the record shows that the FDA has paid very little attention to the issues raised by the parties at trial”).


TOP

Opinion

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Stevens delivered the opinion of the Court.

Directly injecting the drug Phenergan into a patient’s vein creates a significant risk of catastrophic consequences. A Vermont jury found that petitioner Wyeth, the manufacturer of the drug, had failed to provide an adequate warning of that risk and awarded damages to respondent Diana Levine to compensate her for the amputation of her arm. The warnings on Phenergan’s label had been deemed sufficient by the federal Food and Drug Administration (FDA) when it approved Wyeth’s new drug application in 1955 and when it later approved changes in the drug’s labeling. The question we must decide is whether the FDA’s approvals provide Wyeth with a complete defense to Levine’s tort claims. We conclude that they do not.

I

Phenergan is Wyeth’s brand name for promethazine hydrochloride, an antihistamine used to treat nausea. The injectable form of Phenergan can be administered intramuscularly or intravenously, and it can be administered intravenously through either the “IV-push” method, whereby the drug is injected directly into a patient’s vein, or the “IV-drip” method, whereby the drug is introduced into a saline solution in a hanging intravenous bag and slowly descends through a catheter inserted in a patient’s vein. The drug is corrosive and causes irreversible gangrene if it enters a patient’s artery.

Levine’s injury resulted from an IV-push injection of Phenergan. On April 7, 2000, as on previous visits to her local clinic for treatment of a migraine headache, she received an intramuscular injection of Demerol for her headache and Phenergan for her nausea. Because the combination did not provide relief, she returned later that day and received a second injection of both drugs. This time, the physician assistant administered the drugs by the IV-push method, and Phenergan entered Levine’s artery, either because the needle penetrated an artery directly or because the drug escaped from the vein into surrounding tissue (a phenomenon called “perivascular extravasation”) where it came in contact with arterial blood. As a result, Levine developed gangrene, and doctors amputated first her right hand and then her entire forearm. In addition to her pain and suffering, Levine incurred substantial medical expenses and the loss of her livelihood as a professional musician.

After settling claims against the health center and clinician, Levine brought an action for damages against Wyeth, relying on common-law negligence and strict-liability theories. Although Phenergan’s labeling warned of the danger of gangrene and amputation following inadvertent intra-arterial injection, 1 Levine alleged that the labeling was defective because it failed to instruct clinicians to use the IV-drip method of intravenous administration instead of the higher risk IV-push method. More broadly, she alleged that Phenergan is not reasonably safe for intravenous administration because the foreseeable risks of gangrene and loss of limb are great in relation to the drug’s therapeutic benefits. App. 14–15.

Wyeth filed a motion for summary judgment, arguing that Levine’s failure-to-warn claims were pre-empted by federal law. The court found no merit in either Wyeth’s field pre-emption argument, which it has since abandoned, or its conflict pre-emption argument. With respect to the contention that there was an “actual conflict between a specific FDA order,” id., at 21, and Levine’s failure-to-warn action, the court reviewed the sparse correspondence between Wyeth and the FDA about Phenergan’s labeling and found no evidence that Wyeth had “earnestly attempted” to strengthen the intra-arterial injection warning or that the FDA had “specifically disallowed” stronger language, id., at 23. The record, as then developed, “lack[ed] any evidence that the FDA set a ceiling on this matter.” Ibid.

The evidence presented during the 5-day jury trial showed that the risk of intra-arterial injection or perivascular extravasation can be almost entirely eliminated through the use of IV-drip, rather than IV-push, administration. An IV drip is started with saline, which will not flow properly if the catheter is not in the vein and fluid is entering an artery or surrounding tissue. See id., at 50–51, 60, 66–68, 75. By contrast, even a careful and experienced clinician using the IV-push method will occasionally expose an artery to Phenergan. See id., at 73, 75–76. While Phenergan’s labeling warned against intra-arterial injection and perivascular extravasation and advised that “[w]hen administering any irritant drug intravenously it is usually preferable to inject it through the tubing of an intravenous infusion set that is known to be function-ing satisfactorily,” id., at 390, the labeling did not con-tain a specific warning about the risks of IV-pushadministration.

The trial record also contains correspondence between Wyeth and the FDA discussing Phenergan’s label. The FDA first approved injectable Phenergan in 1955. In 1973 and 1976, Wyeth submitted supplemental new drug applications, which the agency approved after proposing labeling changes. Wyeth submitted a third supplemental application in 1981 in response to a new FDA rule governing drug labels. Over the next 17 years, Wyeth and the FDA intermittently corresponded about Phenergan’s label. The most notable activity occurred in 1987, when the FDA suggested different warnings about the risk of arterial exposure, and in 1988, when Wyeth submitted revised labeling incorporating the proposed changes. The FDA did not respond. Instead, in 1996, it requested from Wyeth the labeling then in use and, without addressing Wyeth’s 1988 submission, instructed it to “[r]etain verbiage in current label” regarding intra-arterial injection. Id., at 359. After a few further changes to the labeling not related to intra-arterial injection, the FDA approved Wyeth’s 1981 application in 1998, instructing that Phenergan’s final printed label “must be identical” to the approved package insert. Id., at 382.

Based on this regulatory history, the trial judge instructed the jury that it could consider evidence of Wyeth’s compliance with FDA requirements but that such compliance did not establish that the warnings were adequate. He also instructed, without objection from Wyeth, that FDA regulations “permit a drug manufacturer to change a product label to add or strengthen a warning about its product without prior FDA approval so long as it later submits the revised warning for review and approval.” Id., at 228.

Answering questions on a special verdict form, the jury found that Wyeth was negligent, that Phenergan was a defective product as a result of inadequate warnings and instructions, and that no intervening cause had broken the causal connection between the product defects and the plaintiff’s injury. Id., at 233–235. It awarded total damages of $7,400,000, which the court reduced to account for Levine’s earlier settlement with the health center and clinician. Id., at 235–236.

On August 3, 2004, the trial court filed a comprehensive opinion denying Wyeth’s motion for judgment as a matter of law. After making findings of fact based on the trial record (supplemented by one letter that Wyeth found after the trial), the court rejected Wyeth’s pre-emption arguments. It determined that there was no direct conflict between FDA regulations and Levine’s state-law claims because those regulations permit strengthened warnings without FDA approval on an interim basis and the record contained evidence of at least 20 reports of amputations similar to Levine’s since the 1960’s. The court also found that state tort liability in this case would not obstruct the FDA’s work because the agency had paid no more than passing attention to the question whether to warn against IV-push administration of Phenergan. In addition, the court noted that state law serves a compensatory function distinct from federal regulation. Id., at 249–252.

The Vermont Supreme Court affirmed. It held that the jury’s verdict “did not conflict with FDA’s labeling requirements for Phenergan because [Wyeth] could have warned against IV-push administration without prior FDA approval, and because federal labeling requirements create a floor, not a ceiling, for state regulation.” ___ Vt. ___, ___ 944 A. 2d 179, 184 (2006). In dissent, Chief Justice Reiber argued that the jury’s verdict conflicted with federal law because it was inconsistent with the FDA’s conclusion that intravenous administration of Phenergan was safe and effective.

The importance of the pre-emption issue, coupled with the fact that the FDA has changed its position on state tort law and now endorses the views expressed in Chief Justice Reiber’s dissent, persuaded us to grant Wyeth’s petition for certiorari. 552 U. S. ___ (2008). The question presented by the petition is whether the FDA’s drug labeling judgments “preempt state law product liability claims premised on the theory that different labeling judgments were necessary to make drugs reasonably safe for use.” Pet. for Cert. i.

II

Wyeth makes two separate pre-emption arguments: first, that it would have been impossible for it to comply with the state-law duty to modify Phenergan’s labeling without violating federal law, see Fidelity Fed. Sav. & Loan Assn. v. De la Cuesta, 458 U. S. 141, 153 (1982) , and second, that recognition of Levine’s state tort action creates an unacceptable “obstacle to the accomplishment and execution of the full purposes and objectives of Congress,” Hines v. Davidowitz, 312 U. S. 52, 67 (1941) , because it substitutes a lay jury’s decision about drug labeling for the expert judgment of the FDA. As a preface to our evaluation of these arguments, we identify two factual propositions decided during the trial court proceedings, emphasize two legal principles that guide our analysis, and review the history of the controlling federal statute.

The trial court proceedings established that Levine’s injury would not have occurred if Phenergan’s label had included an adequate warning about the risks of the IV-push method of administering the drug. The record contains evidence that the physician assistant administered a greater dose than the label prescribed, that she may have inadvertently injected the drug into an artery rather than a vein, and that she continued to inject the drug after Levine complained of pain. Nevertheless, the jury rejected Wyeth’s argument that the clinician’s conduct was an intervening cause that absolved it of liability. See App. 234 (jury verdict), 252–254. In finding Wyeth negligent as well as strictly liable, the jury also determined that Levine’s injury was foreseeable. That the inadequate label was both a but-for and proximate cause of Levine’s injury is supported by the record and no longer challenged by Wyeth. 2

The trial court proceedings further established that the critical defect in Phenergan’s label was the lack of an adequate warning about the risks of IV-push administration. Levine also offered evidence that the IV-push method should be contraindicated and that Phenergan should never be administered intravenously, even by the IV-drip method. Perhaps for this reason, the dissent incorrectly assumes that the state-law duty at issue is the duty to contraindicate the IV-push method. See, e.g., post, at 8, 25. But, as the Vermont Supreme Court explained, the jury verdict established only that Phenergan’s warning was insufficient. It did not mandate a particular replacement warning, nor did it require contraindicating IV-push administration: “There may have been any number of ways for [Wyeth] to strengthen the Phenergan warning without completely eliminating IV-push administration.” ___ Vt., at ___, n. 2, 944 A. 2d, at 189, n. 2. We therefore need not decide whether a state rule proscribing intravenous administration would be pre-empted. The narrower question presented is whether federal law pre-empts Levine’s claim that Phenergan’s label did not contain an adequate warning about using the IV-push method of administration.

Our answer to that question must be guided by two cornerstones of our pre-emption jurisprudence. First, “the purpose of Congress is the ultimate touchstone in every pre-emption case.” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) (internal quotation marks omitted); see Retail Clerks v. Schermerhorn, 375 U. S. 96, 103 (1963) . Second, “[i]n all pre-emption cases, and particularly in those in which Congress has ‘legislated … in a field which the States have traditionally occupied,’ … we ‘start with the assumption that the historic police powers of the States were not to be superseded by the Federal Act unless that was the clear and manifest purpose of Congress.’ ” Lohr, 518 U. S., at 485 (quoting Rice v. Santa Fe Elevator Corp., 331 U. S. 218, 230 (1947) ). 3

In order to identify the “purpose of Congress,” it is appropriate to briefly review the history of federal regulation of drugs and drug labeling. In 1906, Congress enacted its first significant public health law, the Federal Food and Drugs Act, ch. 3915, 34Stat. 768. The Act, which prohibited the manufacture or interstate shipment of adulterated or misbranded drugs, supplemented the protection for consumers already provided by state regulation and common-law liability. In the 1930’s, Congress became increasingly concerned about unsafe drugs and fraudulent marketing, and it enacted the Federal Food, Drug, and Cosmetic Act (FDCA), ch. 675, 52Stat. 1040, as amended, 21 U. S. C. §301 et seq. The Act’s most substantial innovation was its provision for premarket approval of new drugs. It required every manufacturer to submit a new drug application, including reports of investigations and specimens of proposed labeling, to the FDA for review. Until its application became effective, a manufacturer was prohibited from distributing a drug. The FDA could reject an application if it determined that the drug was not safe for use as labeled, though if the agency failed to act, an application became effective 60 days after the filing. FDCA, §505(c), 52Stat. 1052.

In 1962, Congress amended the FDCA and shifted the burden of proof from the FDA to the manufacturer. Before 1962, the agency had to prove harm to keep a drug out of the market, but the amendments required the manufacturer to demonstrate that its drug was “safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling” before it could distribute the drug. §§102(d), 104(b), 76Stat. 781, 784. In addition, the amendments required the manufacturer to prove the drug’s effectiveness by introducing “substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling.” §102(d), id., at 781.

As it enlarged the FDA’s powers to “protect the public health” and “assure the safety, effectiveness, and reliability of drugs,” id., at 780, Congress took care to preserve state law. The 1962 amendments added a saving clause, indicating that a provision of state law would only be invalidated upon a “direct and positive conflict” with the FDCA. §202, id., at 793. Consistent with that provision, state common-law suits “continued unabated despite … FDA regulation.” Riegel v. Medtronic, Inc., 552 U. S. ___, ___ (2008) (slip op., at 8) (Ginsburg, J., dissenting); see ibid., n. 11 (collecting state cases). And when Congress enacted an express pre-emption provision for medical devices in 1976, see §521, 90Stat. 574 (codified at 21 U. S. C. §360k(a)), it declined to enact such a provision for prescription drugs.

In 2007, after Levine’s injury and lawsuit, Congress again amended the FDCA. 121Stat. 823. For the first time, it granted the FDA statutory authority to require a manufacturer to change its drug label based on safety information that becomes available after a drug’s initial approval. §901(a), id., at 924–926. In doing so, however, Congress did not enact a provision in the Senate bill that would have required the FDA to preapprove all changes to drug labels. See S. 1082, 110th Cong., 1st Sess., §208, pp. 107–114 (2007) (as passed) (proposing new §506D). Instead, it adopted a rule of construction to make it clear that manufacturers remain responsible for updating their labels. See 121Stat. 925–926.

III

Wyeth first argues that Levine’s state-law claims are pre-empted because it is impossible for it to comply with both the state-law duties underlying those claims and its federal labeling duties. See De la Cuesta, 458 U. S., at 153. The FDA’s premarket approval of a new drug application includes the approval of the exact text in the proposed label. See 21 U. S. C. §355; 21 CFR §314.105(b) (2008). Generally speaking, a manufacturer may only change a drug label after the FDA approves a supplemental application. There is, however, an FDA regulation that permits a manufacturer to make certain changes to its label before receiving the agency’s approval. Among other things, this “changes being effected” (CBE) regulation provides that if a manufacturer is changing a label to “add or strengthen a contraindication, warning, precaution, or adverse reaction” or to “add or strengthen an instruction about dosage and administration that is intended to increase the safe use of the drug product,” it may make the labeling change upon filing its supplemental application with the FDA; it need not wait for FDA approval. §§314.70(c)(6)(iii)(A), (C).

Wyeth argues that the CBE regulation is not implicated in this case because a 2008 amendment provides that a manufacturer may only change its label “to reflect newly acquired information.” 73 Fed. Reg. 49609. Resting on this language (which Wyeth argues simply reaffirmed the interpretation of the regulation in effect when this case was tried), Wyeth contends that it could have changed Phenergan’s label only in response to new information that the FDA had not considered. And it maintains that Levine has not pointed to any such information concerning the risks of IV-push administration. Thus, Wyeth insists, it was impossible for it to discharge its state-law obligation to provide a stronger warning about IV-push administration without violating federal law. Wyeth’s argument misapprehends both the federal drug regulatory scheme and its burden in establishing a pre-emption defense.

We need not decide whether the 2008 CBE regulation is consistent with the FDCA and the previous version of the regulation, as Wyeth and the United States urge, because Wyeth could have revised Phenergan’s label even in accordance with the amended regulation. As the FDA explained in its notice of the final rule, “ ‘newly acquired information’ ” is not limited to new data, but also encompasses “new analyses of previously submitted data.” Id., at 49604. The rule accounts for the fact that risk information accumulates over time and that the same data may take on a different meaning in light of subsequent developments: “[I]f the sponsor submits adverse event information to FDA, and then later conducts a new analysis of data showing risks of a different type or of greater severity or frequency than did reports previously submitted to FDA, the sponsor meets the requirement for ‘newly acquired information.’ ” Id., at 49607; see also id., at 49606.

The record is limited concerning what newly acquired information Wyeth had or should have had about the risks of IV-push administration of Phenergan because Wyeth did not argue before the trial court that such information was required for a CBE labeling change. Levine did, however, present evidence of at least 20 incidents prior to her injury in which a Phenergan injection resulted in gangrene and an amputation. See App. 74, 252. 4 After the first such incident came to Wyeth’s attention in 1967, it notified the FDA and worked with the agency to change Phenergan’s label. In later years, as amputations continued to occur, Wyeth could have analyzed the accumulating data and added a stronger warning about IV-push administration of the drug.

Wyeth argues that if it had unilaterally added such a warning, it would have violated federal law governing unauthorized distribution and misbranding. Its argument that a change in Phenergan’s labeling would have subjected it to liability for unauthorized distribution rests on the assumption that this labeling change would have rendered Phenergan a new drug lacking an effective application. But strengthening the warning about IV-push administration would not have made Phenergan a new drug. See 21 U. S. C. §321(p)(1) (defining “new drug”); 21 CFR §310.3(h). Nor would this warning have rendered Phenergan misbranded. The FDCA does not provide that a drug is misbranded simply because the manufacturer has altered an FDA-approved label; instead, the misbranding provision focuses on the substance of the label and, among other things, proscribes labels that fail to include “adequate warnings.” 21 U. S. C. §352(f). Moreover, because the statute contemplates that federal juries will resolve most misbranding claims, the FDA’s belief that a drug is misbranded is not conclusive. See §§331, 332, 334(a)–(b). And the very idea that the FDA would bring an enforcement action against a manufacturer for strengthening a warning pursuant to the CBE regulation is difficult to accept—neither Wyeth nor the United States has identified a case in which the FDA has done so.

Wyeth’s cramped reading of the CBE regulation and its broad reading of the FDCA’s misbranding and unauthorized distribution provisions are premised on a more fundamental misunderstanding. Wyeth suggests that the FDA, rather than the manufacturer, bears primary responsibility for drug labeling. Yet through many amendments to the FDCA and to FDA regulations, it has remained a central premise of federal drug regulation that the manufacturer bears responsibility for the content of its label at all times. It is charged both with crafting an adequate label and with ensuring that its warnings remain adequate as long as the drug is on the market. See, e.g., 21 CFR §201.80(e) (requiring a manufacturer to revise its label “to include a warning as soon as there is reasonable evidence of an association of a serious hazard with a drug”);§314.80(b) (placing responsibility for postmarketing surveillance on the manufacturer); 73 Fed. Reg. 49605 (“Manufacturers continue to have a responsibility under Federal law … to maintain their labeling and update the labeling with new safety information”).

Indeed, prior to 2007, the FDA lacked the authority to order manufacturers to revise their labels. See 121Stat. 924–926. When Congress granted the FDA this authority, it reaffirmed the manufacturer’s obligations and referred specifically to the CBE regulation, which both reflects the manufacturer’s ultimate responsibility for its label and provides a mechanism for adding safety information to the label prior to FDA approval. See id., at 925–926(stating that a manufacturer retains the responsibility “to maintain its label in accordance with existing requirements, including subpart B of part 201 and sections 314.70 and 601.12 of title 21, Code of Federal Regulations (or any successor regulations)” (emphasis added)). Thus, when the risk of gangrene from IV-push injection of Phenergan became apparent, Wyeth had a duty to provide a warning that adequately described that risk, and the CBE regulation permitted it to provide such a warning before receiving the FDA’s approval.

Of course, the FDA retains authority to reject labeling changes made pursuant to the CBE regulation in its review of the manufacturer’s supplemental application, just as it retains such authority in reviewing all supplemental applications. But absent clear evidence that the FDA would not have approved a change to Phenergan’s label, we will not conclude that it was impossible for Wyeth to comply with both federal and state requirements.

Wyeth has offered no such evidence. It does not argue that it attempted to give the kind of warning required by the Vermont jury but was prohibited from doing so by the FDA. See Tr. of Oral Arg. 12–13; see also Brief for United States as Amicus Curiae 25. And while it does suggest that the FDA intended to prohibit it from strengthening the warning about IV-push administration because the agency deemed such a warning inappropriate in reviewing Phenergan’s drug applications, both the trial court and the Vermont Supreme Court rejected this account as a matter of fact. In its decision on Wyeth’s motion for judgment as a matter of law, the trial court found “no evidence in this record that either the FDA or the manufacturer gave more than passing attention to the issue of” IV-push versus IV-drip administration. App. 249. The Vermont Supreme Court likewise concluded that the FDA had not made an affirmative decision to preserve the IV-push method or intended to prohibit Wyeth from strengthening its warning about IV-push administration. ___ Vt., at ___, 944 A. 2d, at 188–189. Moreover, Wyeth does not argue that it supplied the FDA with an evaluation or analysis concerning the specific dangers posed by the IV-push method.We accordingly cannot credit Wyeth’s contention that the FDA would have prevented it from adding a stronger warning about the IV-push method of intravenous administration. 6

Impossibility pre-emption is a demanding defense. On the record before us, Wyeth has failed to demonstrate that it was impossible for it to comply with both federal and state requirements. The CBE regulation permitted Wyeth to unilaterally strengthen its warning, and the mere fact that the FDA approved Phenergan’s label does not establish that it would have prohibited such a change.

IV

Wyeth also argues that requiring it to comply with a state-law duty to provide a stronger warning about IV-push administration would obstruct the purposes and objectives of federal drug labeling regulation. Levine’s tort claims, it maintains, are pre-empted because they interfere with “Congress’s purpose to entrust an expert agency to make drug labeling decisions that strike a balance between competing objectives.” Brief for Petitioner 46. We find no merit in this argument, which relies on an untenable interpretation of congressional intent and an overbroad view of an agency’s power to pre-empt state law.

Wyeth contends that the FDCA establishes both a floor and a ceiling for drug regulation: Once the FDA has approved a drug’s label, a state-law verdict may not deem the label inadequate, regardless of whether there is any evidence that the FDA has considered the stronger warning at issue. The most glaring problem with this argument is that all evidence of Congress’ purposes is to the contrary. Building on its 1906 Act, Congress enacted the FDCA to bolster consumer protection against harmful products. See Kordel v. United States, 335 U. S. 345, 349 (1948) ; United States v. Sullivan, 332 U. S. 689, 696 (1948) . Congress did not provide a federal remedy for consumers harmed by unsafe or ineffective drugs in the 1938 statute or in any subsequent amendment. Evidently, it determined that widely available state rights of action provided appropriate relief for injured consumers. 7 It may also have recognized that state-law remedies further consumer protection by motivating manufacturers to produce safe and effective drugs and to give adequate warnings.

If Congress thought state-law suits posed an obstacle to its objectives, it surely would have enacted an express pre-emption provision at some point during the FDCA’s 70-year history. But despite its 1976 enactment of an express pre-emption provision for medical devices, see §521, 90Stat. 574 (codified at 21 U. S. C. §360k(a)), Congress has not enacted such a provision for prescription drugs.See Riegel, 552 U. S., at ___ (slip op., at 14)(“Congress could have applied the pre-emption clause to the entire FDCA. It did not do so, but instead wrote a pre-emption clause that applies only to medical devices”). 8 Its silence on the issue, coupled with its certain awareness of the prevalence of state tort litigation, is powerful evidence that Congress did not intend FDA oversight to be the exclusive means of ensuring drug safety and effectiveness. As Justice O’Connor explained in her opinion for a unanimous Court: “The case for federal pre-emption is particularly weak where Congress has indicated its awareness of the operation of state law in a field of federal interest, and has nonetheless decided to stand by both concepts and to tolerate whatever tension there [is] between them.” Bonito Boats, Inc. v. Thunder Craft Boats, Inc., 489 U. S. 141, 166–167 (1989) (internal quotation marks omitted); see also supra,at 8 (discussing the presumption against pre-emption).

Despite this evidence that Congress did not regard state tort litigation as an obstacle to achieving its purposes, Wyeth nonetheless maintains that, because the FDCA requires the FDA to determine that a drug is safe and effective under the conditions set forth in its labeling, the agency must be presumed to have performed a precise balancing of risks and benefits and to have established a specific labeling standard that leaves no room for different state-law judgments. In advancing this argument, Wyeth relies not on any statement by Congress, but instead on the preamble to a 2006 FDA regulation governing the content and format of prescription drug labels. See Brief for Petitioner 8, 11, 42, 45, and 50 (citing 71Fed. Reg. 3922 (2006)). In that preamble, the FDA declared that the FDCA establishes “both a ‘floor’ and a ‘ceiling,’ ” so that “FDA approval of labeling … preempts conflicting or contrary State law.” Id., at 3934–3935. It further stated that certain state-law actions, such as those involving failure-to-warn claims, “threaten FDA’s statutorily prescribed role as the expert Federal agency responsible for evaluating and regulating drugs.” Id., at 3935.

This Court has recognized that an agency regulation with the force of law can pre-empt conflicting state requirements. See, e.g., Geier v. American Honda Motor Co., 529 U. S. 861 (2000) ; Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707, 713 (1985) . In such cases, the Court has performed its own conflict determination, relying on the substance of state and federal law and not on agency proclamations of pre-emption. We are faced with no such regulation in this case, but rather with an agency’s mere assertion that state law is an obstacle to achieving its statutory objectives. Because Congress has not authorized the FDA to pre-empt state law directly, cf. 21 U. S. C. §360k (authorizing the FDA to determine the scope of the Medical Devices Amendments’ pre-emption clause), 9 the question is what weight we should accord the FDA’s opinion.

In prior cases, we have given “some weight” to an agency’s views about the impact of tort law on federal objectives when “the subject matter is technica[l] and the relevant history and background are complex and extensive.” Geier, 529 U. S., at 883. Even in such cases, however, we have not deferred to an agency’s conclusion that state law is pre-empted. Rather, we have attended to an agency’s explanation of how state law affects the regulatory scheme. While agencies have no special authority to pronounce on pre-emption absent delegation by Congress, they do have a unique understanding of the statutes they administer and an attendant ability to make informed determinations about how state requirements may pose an “obstacle to the accomplishment and execution of the full purposes and objectives of Congress.” Hines, 312 U.S, at 67; see Geier, 529 U. S., at 883; Lohr, 518 U. S., at 495–496. The weight we accord the agency’s explanation of state law’s impact on the federal scheme depends on its thoroughness, consistency, and persuasiveness. Cf. United States v. Mead Corp., 533 U. S. 218, 234–235 (2001) ; Skidmore v. Swift & Co., 323 U. S. 134, 140 (1944) .

Under this standard, the FDA’s 2006 preamble does not merit deference. When the FDA issued its notice of proposed rulemaking in December 2000, it explained that the rule would “not contain policies that have federalism implications or that preempt State law.” 65 Fed. Reg. 81103; see also 71 id., at 3969 (noting that the “proposed rule did not propose to preempt state law”). In 2006, the agency finalized the rule and, without offering States or other interested parties notice or opportunity for comment, articulated a sweeping position on the FDCA’s pre-emptive effect in the regulatory preamble. The agency’s views on state law are inherently suspect in light of this procedural failure.

Further, the preamble is at odds with what evidence we have of Congress’ purposes, and it reverses the FDA’s own longstanding position without providing a reasoned explanation, including any discussion of how state law has interfered with the FDA’s regulation of drug labeling during decades of coexistence. The FDA’s 2006 position plainly does not reflect the agency’s own view at all times relevant to this litigation. Not once prior to Levine’s injury did the FDA suggest that state tort law stood as an obstacle to its statutory mission. To the contrary, it cast federal labeling standards as a floor upon which States could build and repeatedly disclaimed any attempt to pre-empt failure-to-warn claims. For instance, in 1998, the FDA stated that it did “not believe that the evolution of state tort law [would] cause the development of standards that would be at odds with the agency’s regulations.” 63 id., at 66384. It further noted that, in establishing “minimal standards” for drug labels, it did not intend “to preclude the states from imposing additional labeling requirements.” Ibid. 10

In keeping with Congress’ decision not to pre-empt common-law tort suits, it appears that the FDA traditionally regarded state law as a complementary form of drug regulation. The FDA has limited resources to monitor the 11,000 drugs on the market, 11 and manufacturers have superior access to information about their drugs, especially in the postmarketing phase as new risks emerge. State tort suits uncover unknown drug hazards and provide incentives for drug manufacturers to disclose safety risks promptly. They also serve a distinct compensatory function that may motivate injured persons to come forward with information. Failure-to-warn actions, in particular, lend force to the FDCA’s premise that manufacturers, not the FDA, bear primary responsibility for their drug labeling at all times. Thus, the FDA long maintained that state law offers an additional, and important, layer of consumer protection that complements FDA regulation. 12 The agency’s 2006 preamble represents a dramatic change in position.

Largely based on the FDA’s new position, Wyeth argues that this case presents a conflict between state and federal law analogous to the one at issue in Geier. There, we held that state tort claims premised on Honda’s failure to install airbags conflicted with a federal regulation that did not require airbags for all cars. The Department of Transportation (DOT) had promulgated a rule that provided car manufacturers with a range of choices among passive restraint devices. Geier, 529 U. S., at 875. Rejecting an “ ‘all airbag’ ” standard, the agency had called for a gradual phase-in of a mix of passive restraints in order to spur technological development and win consumer acceptance. Id., at 879. Because the plaintiff’s claim was that car manufacturers had a duty to install airbags, it presented an obstacle to achieving “the variety and mix of devices that the federal regulation sought.” Id., at 881.

Wyeth and the dissent contend that the regulatory scheme in this case is nearly identical, but, as we have described, it is quite different. In Geier, the DOT conducted a formal rulemaking and then adopted a plan to phase in a mix of passive restraint devices. Examining the rule itself and the DOT’s contemporaneous record, which revealed the factors the agency had weighed and the balance it had struck, we determined that state tort suits presented an obstacle to the federal scheme. After conducting our own pre-emption analysis, we considered the agency’s explanation of how state law interfered with its regulation, regarding it as further support for our independent conclusion that the plaintiff’s tort claim obstructed the federal regime.

By contrast, we have no occasion in this case to consider the pre-emptive effect of a specific agency regulation bearing the force of law. And the FDA’s newfound opinion, expressed in its 2006 preamble, that state law “frustrate[s] the agency’s implementation of its statutory mandate,” 71 Fed. Reg. 3934, does not merit deference for the reasons we have explained. 13 Indeed, the “complex and extensive” regulatory history and background relevant to this case, Geier, 529 U. S., at 883, undercut the FDA’s recent pronouncements of pre-emption, as they reveal the longstanding coexistence of state and federal law and the FDA’s traditional recognition of state-law remedies—a recognition in place each time the agency reviewed Wyeth’s Phenergan label. 14

In short, Wyeth has not persuaded us that failure-to-warn claims like Levine’s obstruct the federal regulation of drug labeling. Congress has repeatedly declined to pre-empt state law, and the FDA’s recently adopted position that state tort suits interfere with its statutory mandate is entitled to no weight. Although we recognize that some state-law claims might well frustrate the achievement of congressional objectives, this is not such a case.

V

We conclude that it is not impossible for Wyeth to comply with its state and federal law obligations and that Levine’s common-law claims do not stand as an obstacle to the accomplishment of Congress’ purposes in the FDCA. Accordingly, the judgment of the Vermont Supreme Court is affirmed.

It is so ordered.


Notes

1 The warning for “Inadvertent Intra-arterial Injection” stated: “Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or inadvertent intra-arterial injection. Reports compatible with inadvertent intra-arterial injection of Phenergan Injection, usually in conjunction with other drugs intended for intravenous use, suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances. Intravenous injection was intended in all the cases reported but perivascular extravasation or arterial placement of the needle is now suspect. There is no proven successful management of this condition after it occurs. . . . Aspiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with Phenergan Injection. Use of syringes with rigid plungers or of small bore needles might obscure typical arterial backflow if this is relied upon alone. When used intravenously, Phenergan Injection should be given in a concentration no greater than 25 mg per mL and at a rate not to exceed 25 mg per minute. When administering any irritant drug intravenously, it is usually preferable to inject it through the tubing of an intravenous infusion set that is known to be functioning satisfactorily. In the event that a patient complains of pain during intended intravenous injection of Phenergan Injection, the injection should be stopped immediately to provide for evaluation of possible arterial placement or perivascular extravasation.” App. 390.

2 The dissent nonetheless suggests that physician malpractice was the exclusive cause of Levine’s injury. See, e.g., post, at 1 (opinion of Alito, J.) (“[I]t is unclear how a ‘stronger’ warning could have helped respondent”); post, at 16–18 (suggesting that the physician assistant’s conduct was the sole cause of the injury). The dissent’s frustration with the jury’s verdict does not put the merits of Levine’s tort claim before us, nor does it change the question we must decide—whether federal law pre-empts Levine’s state-law claims.

3 Wyeth argues that the presumption against pre-emption should not apply to this case because the Federal Government has regulated drug labeling for more than a century. That argument misunderstands the principle: We rely on the presumption because respect for the States as “independent sovereigns in our federal system” leads us to assume that “Congress does not cavalierly pre-empt state-law causes of action.” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) . The presumption thus accounts for the historic presence of state law but does not rely on the absence of federal regulation. For its part, the dissent argues that the presumption against pre-emption should not apply to claims of implied conflict pre-emption at all, post, at 21, but this Court has long held to the contrary. See, e.g., California v. ARC America Corp., 490 U. S. 93, 101–102 (1989) ; Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707, 716 (1985) ; see also Rush Prudential HMO, Inc. v. Moran, 536 U. S. 355, 387 (2002) . The dissent’s reliance on Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341 (2001) , see post, at 21, and n. 14, is especially curious, as that case involved state-law fraud-on-the-agency claims, and the Court distinguished state regulation of health and safety as matters to which the presumption does apply. See 531 U. S., at 347–348.

4 Levine also introduced evidence that Pfizer had withdrawn Vistaril, another antinausea drug, from intravenous use several decades earlier because its intravenous injection had resulted in gangrene and amputations. See App. 79.

5 The record would not, in any event, support such an argument. In 1988, Wyeth did propose different language for Phenergan’s warning about intra-arterial injection, adapted from revisions the FDA proposed in 1987. See App. 339–341, 311–312. When the FDA approved Wyeth’s application, it instructed Wyeth to retain the wording in its current label. During the trial court proceedings, Levine indicated that the language proposed in 1988 would have more strongly warned against IV-push administration. But the trial court and the Vermont Supreme Court found that the 1988 warning did not differ in any material respect from the FDA-approved warning. See ___ Vt. ___, ___, 944 A. 2d 179, 189 (2006) (“Simply stated, the proposed warning was different, but not stronger. It was also no longer or more prominent than the original warning …”); App. 248–250. Indeed, the United States concedes that the FDA did not regard the proposed warning as substantively different: “[I]t appears the FDA viewed the change as non-substantive and rejected it for formatting reasons.” Brief for United States as Amicus Curiae 25; see also ___ Vt., at ___, 944 A. 2d, at 189.

6 The dissent’s suggestion that the FDA intended to prohibit Wyeth from strengthening its warning does not fairly reflect the record. The dissent creatively paraphrases a few FDA orders—for instance by conflating warnings about IV-push administration and intra-arterial injection, see, e.g., post, at 9, 11–12, 15–16—to suggest greater agency attention to the question, and it undertakes a study of Phenergan’s labeling that is more elaborate than any FDA order. But even the dissent’s account does not support the conclusion that the FDA would have prohibited Wyeth from adding a stronger warning pursuant to the CBE regulation.

7 Although the first version of the bill that became the FDCA would have provided a federal cause of action for damages for injured consumers, see H. R. 6110, 73d Cong., 1st Sess., §25 (1933) (as introduced), witnesses testified that such a right of action was unnecessary because common-law claims were already available under state law. See Hearings on S. 1944 before a Subcommittee of the Senate Committee on Commerce, 73d Cong., 2d Sess., 400 (1933) (statement of W. A. Hines); see id., at 403 (statement of J. A. Ladds) (“This act should not attempt to modify or restate the common law with respect to personal injuries”).

8 In 1997, Congress pre-empted certain state requirements concerning over-the-counter medications and cosmetics but expressly preserved product liability actions. See 21 U. S. C. §§379r(e) (“Nothing in this section shall be construed to modify or otherwise affect any action or the liability of any person under the product liability law of any State”).

9 For similar examples, see 47 U. S. C. §§253(a), (d) (2000 ed.) (authorizing the Federal Communications Commission to pre-empt “any [state] statute, regulation, or legal requirement” that “may prohibit or have the effect of prohibiting the ability of any entity to provide any interstate or intrastate telecommunications service”); 30 U. S. C. §1254(g) (2006 ed.) (pre-empting any statute that conflicts with “the purposes and the requirements of this chapter” and permitting the Secretary of the Interior to “set forth any State law or regulation which is preempted and superseded”); and 49 U. S. C. §5125(d) (2000 ed. and Supp. V) (authorizing the Secretary of Transportation to decide whether a state or local statute that conflicts with the regulation of hazardous waste transportation is pre-empted).

10 See also 44Fed. Reg. 37437 (1979) (“It is not the intent of the FDA to influence the civil tort liability of the manufacturer”); 59Fed. Reg. 3948 (1994) (“[P]roduct liability plays an important role in consumer protection”); Porter, The Lohr Decision: FDA Perspective and Position, 52 Food & Drug L. J. 7, 10 (1997) (former chief counsel to the FDA stating that the FDA regarded state law as complementing the agency’s mission of consumer protection).

11 In 1955, the same year that the agency approved Wyeth’s Phenergan application, an FDA advisory committee issued a report finding “conclusively” that “the budget and staff of the Food and Drug Administration are inadequate to permit the discharge of its existing responsibilities for the protection of the American public.” Citizens Advisory Committee on the FDA, Report to the Secretary of Health, Education, and Welfare, H. R. Doc. No. 227, 84th Cong., 1st Sess., 53. Three recent studies have reached similar conclusions. See FDA Science Board, Report of the Subcommittee on Science and Technology: FDA Science and Mission at Risk 2, 6 (2007), online at http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4329b_02_01_FDA Report on Science and Technology.pdf (all Internet materials as visited Feb. 23, 2009, and available in Clerk of Court’s case file) (“[T]he Agency suffers from serious scientific deficiencies and is not positioned to meet current or emerging regulatory responsibilities”); National Academies, Institute of Medicine, The Future of Drug Safety: Promoting and Protecting the Health of the Public 193–194 (2007) (“The [FDA] lacks the resources needed to accomplish its large and complex mission … . There is widespread agreement that resources for postmarketing drug safety work are especially inadequate and that resource limitations have hobbled the agency’s ability to improve and expand this essential component of its mission”); GAO, Drug Safety: Improvement Needed in FDA’s Postmarket Decision-making and Oversight Process 5 (GAO–06–402, 2006), http://www.gao.gov/new.items/d06402.pdf (“FDA lacks a clear and effective process for making decisions about, and providing management oversight of, postmarket safety issues”); see also House Committee on Oversight and Government Reform, Majority Staff Report, FDA Career Staff Objected to Agency Preemption Policies 4 (2008) (“[T]he Office of Chief Counsel ignored the warnings from FDA scientists and career officials that the preemption language [of the 2006 preamble] was based on erroneous assertions about the ability of the drug approval process to ensure accurate and up-to-date drug labels”).

12 See generally Brief for Former FDA Commissioners Drs. Donald Kennedy and David Kessler as Amici Curiae; see also Kessler & Vladeck, A Critical Examination of the FDA’s Efforts To Preempt Failure-To-Warn Claims, 96 Geo. L. J. 461, 463 (2008); Bates v. Dow Agrosciences LLC, 544 U. S. 431, 451 (2005) (noting that state tort suits “can serve as a catalyst” by aiding in the exposure of new dangers and prompting a manufacturer or the federal agency to decide that a revised label is required).

13 The United States’ amicus brief is similarly undeserving of deference. Unlike the Government’s brief in Geier v. American Honda Motor Co., 529 U. S. 861 (2000) , which explained the effects of state law on the DOT’s regulation in a manner consistent with the agency’s prior accounts, see id., at 861, the Government’s explanation of federal drug regulation departs markedly from the FDA’s understanding at all times relevant to this case.

14 Wyeth’s more specific contention—that this case resembles Geier because the FDA determined that no additional warning on IV-push administration was needed, thereby setting a ceiling on Phenergan’s label—is belied by the record. As we have discussed, the FDA did not consider and reject a stronger warning against IV-push injection of Phenergan. See also App. 249–250 (“[A] tort case is unlikely to obstruct the regulatory process when the record shows that the FDA has paid very little attention to the issues raised by the parties at trial”).


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Concurrence

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Breyer, concurring.

I write separately to emphasize the Court’s statement that “we have no occasion in this case to consider the pre-emptive effect of a specific agency regulation bearing the force of law.” Ante, at 24. State tort law will sometimes help the Food and Drug Administration (FDA) “uncover unknown drug hazards and [encourage] drug manufacturers to disclose safety risks.” Ante, at 23. But it is also possible that state tort law will sometimes interfere with the FDA’s desire to create a drug label containing a specific set of cautions and instructions. I also note that some have argued that state tort law can sometimes raise prices to the point where those who are sick are unable to obtain the drugs they need. See Lasagna, The Chilling Effect of Product Liability on New Drug Development, in The Liability Maze 334, 335–336 (P. Huber & R. Litan eds. 1991). The FDA may seek to determine whether and when state tort law acts as a help or a hindrance to achieving the safe drug-related medical care that Congress sought. Medtronic, Inc. v. Lohr, 518 U. S. 470, 506 (1996) (Breyer, J., concurring in part and concurring in judgment); cf. Bates v. Dow Agrosciences LLC, 544 U. S. 431, 454–455 (2005) (Breyer, J., concurring). It may seek to embody those determinations in lawful specific regulations describing, for example, when labeling requirements serve as a ceiling as well as a floor. And it is possible that such determinations would have pre-emptive effect. See Lohr, supra, at 505 (opinion of Breyer, J.) (citing Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707 (1985) ). I agree with the Court, however, that such a regulation is not at issue in this case.


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Concurrence

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Breyer, concurring.

I write separately to emphasize the Court’s statement that “we have no occasion in this case to consider the pre-emptive effect of a specific agency regulation bearing the force of law.” Ante, at 24. State tort law will sometimes help the Food and Drug Administration (FDA) “uncover unknown drug hazards and [encourage] drug manufacturers to disclose safety risks.” Ante, at 23. But it is also possible that state tort law will sometimes interfere with the FDA’s desire to create a drug label containing a specific set of cautions and instructions. I also note that some have argued that state tort law can sometimes raise prices to the point where those who are sick are unable to obtain the drugs they need. See Lasagna, The Chilling Effect of Product Liability on New Drug Development, in The Liability Maze 334, 335–336 (P. Huber & R. Litan eds. 1991). The FDA may seek to determine whether and when state tort law acts as a help or a hindrance to achieving the safe drug-related medical care that Congress sought. Medtronic, Inc. v. Lohr, 518 U. S. 470, 506 (1996) (Breyer, J., concurring in part and concurring in judgment); cf. Bates v. Dow Agrosciences LLC, 544 U. S. 431, 454–455 (2005) (Breyer, J., concurring). It may seek to embody those determinations in lawful specific regulations describing, for example, when labeling requirements serve as a ceiling as well as a floor. And it is possible that such determinations would have pre-emptive effect. See Lohr, supra, at 505 (opinion of Breyer, J.) (citing Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707 (1985) ). I agree with the Court, however, that such a regulation is not at issue in this case.


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Concurrence

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Breyer, concurring.

I write separately to emphasize the Court’s statement that “we have no occasion in this case to consider the pre-emptive effect of a specific agency regulation bearing the force of law.” Ante, at 24. State tort law will sometimes help the Food and Drug Administration (FDA) “uncover unknown drug hazards and [encourage] drug manufacturers to disclose safety risks.” Ante, at 23. But it is also possible that state tort law will sometimes interfere with the FDA’s desire to create a drug label containing a specific set of cautions and instructions. I also note that some have argued that state tort law can sometimes raise prices to the point where those who are sick are unable to obtain the drugs they need. See Lasagna, The Chilling Effect of Product Liability on New Drug Development, in The Liability Maze 334, 335–336 (P. Huber & R. Litan eds. 1991). The FDA may seek to determine whether and when state tort law acts as a help or a hindrance to achieving the safe drug-related medical care that Congress sought. Medtronic, Inc. v. Lohr, 518 U. S. 470, 506 (1996) (Breyer, J., concurring in part and concurring in judgment); cf. Bates v. Dow Agrosciences LLC, 544 U. S. 431, 454–455 (2005) (Breyer, J., concurring). It may seek to embody those determinations in lawful specific regulations describing, for example, when labeling requirements serve as a ceiling as well as a floor. And it is possible that such determinations would have pre-emptive effect. See Lohr, supra, at 505 (opinion of Breyer, J.) (citing Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707 (1985) ). I agree with the Court, however, that such a regulation is not at issue in this case.


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Concurrence

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Breyer, concurring.

I write separately to emphasize the Court’s statement that “we have no occasion in this case to consider the pre-emptive effect of a specific agency regulation bearing the force of law.” Ante, at 24. State tort law will sometimes help the Food and Drug Administration (FDA) “uncover unknown drug hazards and [encourage] drug manufacturers to disclose safety risks.” Ante, at 23. But it is also possible that state tort law will sometimes interfere with the FDA’s desire to create a drug label containing a specific set of cautions and instructions. I also note that some have argued that state tort law can sometimes raise prices to the point where those who are sick are unable to obtain the drugs they need. See Lasagna, The Chilling Effect of Product Liability on New Drug Development, in The Liability Maze 334, 335–336 (P. Huber & R. Litan eds. 1991). The FDA may seek to determine whether and when state tort law acts as a help or a hindrance to achieving the safe drug-related medical care that Congress sought. Medtronic, Inc. v. Lohr, 518 U. S. 470, 506 (1996) (Breyer, J., concurring in part and concurring in judgment); cf. Bates v. Dow Agrosciences LLC, 544 U. S. 431, 454–455 (2005) (Breyer, J., concurring). It may seek to embody those determinations in lawful specific regulations describing, for example, when labeling requirements serve as a ceiling as well as a floor. And it is possible that such determinations would have pre-emptive effect. See Lohr, supra, at 505 (opinion of Breyer, J.) (citing Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707 (1985) ). I agree with the Court, however, that such a regulation is not at issue in this case.


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Concurrence

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Breyer, concurring.

I write separately to emphasize the Court’s statement that “we have no occasion in this case to consider the pre-emptive effect of a specific agency regulation bearing the force of law.” Ante, at 24. State tort law will sometimes help the Food and Drug Administration (FDA) “uncover unknown drug hazards and [encourage] drug manufacturers to disclose safety risks.” Ante, at 23. But it is also possible that state tort law will sometimes interfere with the FDA’s desire to create a drug label containing a specific set of cautions and instructions. I also note that some have argued that state tort law can sometimes raise prices to the point where those who are sick are unable to obtain the drugs they need. See Lasagna, The Chilling Effect of Product Liability on New Drug Development, in The Liability Maze 334, 335–336 (P. Huber & R. Litan eds. 1991). The FDA may seek to determine whether and when state tort law acts as a help or a hindrance to achieving the safe drug-related medical care that Congress sought. Medtronic, Inc. v. Lohr, 518 U. S. 470, 506 (1996) (Breyer, J., concurring in part and concurring in judgment); cf. Bates v. Dow Agrosciences LLC, 544 U. S. 431, 454–455 (2005) (Breyer, J., concurring). It may seek to embody those determinations in lawful specific regulations describing, for example, when labeling requirements serve as a ceiling as well as a floor. And it is possible that such determinations would have pre-emptive effect. See Lohr, supra, at 505 (opinion of Breyer, J.) (citing Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707 (1985) ). I agree with the Court, however, that such a regulation is not at issue in this case.


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Concurrence

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Breyer, concurring.

I write separately to emphasize the Court’s statement that “we have no occasion in this case to consider the pre-emptive effect of a specific agency regulation bearing the force of law.” Ante, at 24. State tort law will sometimes help the Food and Drug Administration (FDA) “uncover unknown drug hazards and [encourage] drug manufacturers to disclose safety risks.” Ante, at 23. But it is also possible that state tort law will sometimes interfere with the FDA’s desire to create a drug label containing a specific set of cautions and instructions. I also note that some have argued that state tort law can sometimes raise prices to the point where those who are sick are unable to obtain the drugs they need. See Lasagna, The Chilling Effect of Product Liability on New Drug Development, in The Liability Maze 334, 335–336 (P. Huber & R. Litan eds. 1991). The FDA may seek to determine whether and when state tort law acts as a help or a hindrance to achieving the safe drug-related medical care that Congress sought. Medtronic, Inc. v. Lohr, 518 U. S. 470, 506 (1996) (Breyer, J., concurring in part and concurring in judgment); cf. Bates v. Dow Agrosciences LLC, 544 U. S. 431, 454–455 (2005) (Breyer, J., concurring). It may seek to embody those determinations in lawful specific regulations describing, for example, when labeling requirements serve as a ceiling as well as a floor. And it is possible that such determinations would have pre-emptive effect. See Lohr, supra, at 505 (opinion of Breyer, J.) (citing Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707 (1985) ). I agree with the Court, however, that such a regulation is not at issue in this case.


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Concurrence

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Breyer, concurring.

I write separately to emphasize the Court’s statement that “we have no occasion in this case to consider the pre-emptive effect of a specific agency regulation bearing the force of law.” Ante, at 24. State tort law will sometimes help the Food and Drug Administration (FDA) “uncover unknown drug hazards and [encourage] drug manufacturers to disclose safety risks.” Ante, at 23. But it is also possible that state tort law will sometimes interfere with the FDA’s desire to create a drug label containing a specific set of cautions and instructions. I also note that some have argued that state tort law can sometimes raise prices to the point where those who are sick are unable to obtain the drugs they need. See Lasagna, The Chilling Effect of Product Liability on New Drug Development, in The Liability Maze 334, 335–336 (P. Huber & R. Litan eds. 1991). The FDA may seek to determine whether and when state tort law acts as a help or a hindrance to achieving the safe drug-related medical care that Congress sought. Medtronic, Inc. v. Lohr, 518 U. S. 470, 506 (1996) (Breyer, J., concurring in part and concurring in judgment); cf. Bates v. Dow Agrosciences LLC, 544 U. S. 431, 454–455 (2005) (Breyer, J., concurring). It may seek to embody those determinations in lawful specific regulations describing, for example, when labeling requirements serve as a ceiling as well as a floor. And it is possible that such determinations would have pre-emptive effect. See Lohr, supra, at 505 (opinion of Breyer, J.) (citing Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707 (1985) ). I agree with the Court, however, that such a regulation is not at issue in this case.


TOP

Concurrence

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Breyer, concurring.

I write separately to emphasize the Court’s statement that “we have no occasion in this case to consider the pre-emptive effect of a specific agency regulation bearing the force of law.” Ante, at 24. State tort law will sometimes help the Food and Drug Administration (FDA) “uncover unknown drug hazards and [encourage] drug manufacturers to disclose safety risks.” Ante, at 23. But it is also possible that state tort law will sometimes interfere with the FDA’s desire to create a drug label containing a specific set of cautions and instructions. I also note that some have argued that state tort law can sometimes raise prices to the point where those who are sick are unable to obtain the drugs they need. See Lasagna, The Chilling Effect of Product Liability on New Drug Development, in The Liability Maze 334, 335–336 (P. Huber & R. Litan eds. 1991). The FDA may seek to determine whether and when state tort law acts as a help or a hindrance to achieving the safe drug-related medical care that Congress sought. Medtronic, Inc. v. Lohr, 518 U. S. 470, 506 (1996) (Breyer, J., concurring in part and concurring in judgment); cf. Bates v. Dow Agrosciences LLC, 544 U. S. 431, 454–455 (2005) (Breyer, J., concurring). It may seek to embody those determinations in lawful specific regulations describing, for example, when labeling requirements serve as a ceiling as well as a floor. And it is possible that such determinations would have pre-emptive effect. See Lohr, supra, at 505 (opinion of Breyer, J.) (citing Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707 (1985) ). I agree with the Court, however, that such a regulation is not at issue in this case.


TOP

Concurrence

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Breyer, concurring.

I write separately to emphasize the Court’s statement that “we have no occasion in this case to consider the pre-emptive effect of a specific agency regulation bearing the force of law.” Ante, at 24. State tort law will sometimes help the Food and Drug Administration (FDA) “uncover unknown drug hazards and [encourage] drug manufacturers to disclose safety risks.” Ante, at 23. But it is also possible that state tort law will sometimes interfere with the FDA’s desire to create a drug label containing a specific set of cautions and instructions. I also note that some have argued that state tort law can sometimes raise prices to the point where those who are sick are unable to obtain the drugs they need. See Lasagna, The Chilling Effect of Product Liability on New Drug Development, in The Liability Maze 334, 335–336 (P. Huber & R. Litan eds. 1991). The FDA may seek to determine whether and when state tort law acts as a help or a hindrance to achieving the safe drug-related medical care that Congress sought. Medtronic, Inc. v. Lohr, 518 U. S. 470, 506 (1996) (Breyer, J., concurring in part and concurring in judgment); cf. Bates v. Dow Agrosciences LLC, 544 U. S. 431, 454–455 (2005) (Breyer, J., concurring). It may seek to embody those determinations in lawful specific regulations describing, for example, when labeling requirements serve as a ceiling as well as a floor. And it is possible that such determinations would have pre-emptive effect. See Lohr, supra, at 505 (opinion of Breyer, J.) (citing Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707 (1985) ). I agree with the Court, however, that such a regulation is not at issue in this case.


TOP

Concurrence

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Breyer, concurring.

I write separately to emphasize the Court’s statement that “we have no occasion in this case to consider the pre-emptive effect of a specific agency regulation bearing the force of law.” Ante, at 24. State tort law will sometimes help the Food and Drug Administration (FDA) “uncover unknown drug hazards and [encourage] drug manufacturers to disclose safety risks.” Ante, at 23. But it is also possible that state tort law will sometimes interfere with the FDA’s desire to create a drug label containing a specific set of cautions and instructions. I also note that some have argued that state tort law can sometimes raise prices to the point where those who are sick are unable to obtain the drugs they need. See Lasagna, The Chilling Effect of Product Liability on New Drug Development, in The Liability Maze 334, 335–336 (P. Huber & R. Litan eds. 1991). The FDA may seek to determine whether and when state tort law acts as a help or a hindrance to achieving the safe drug-related medical care that Congress sought. Medtronic, Inc. v. Lohr, 518 U. S. 470, 506 (1996) (Breyer, J., concurring in part and concurring in judgment); cf. Bates v. Dow Agrosciences LLC, 544 U. S. 431, 454–455 (2005) (Breyer, J., concurring). It may seek to embody those determinations in lawful specific regulations describing, for example, when labeling requirements serve as a ceiling as well as a floor. And it is possible that such determinations would have pre-emptive effect. See Lohr, supra, at 505 (opinion of Breyer, J.) (citing Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707 (1985) ). I agree with the Court, however, that such a regulation is not at issue in this case.


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Concurrence

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Breyer, concurring.

I write separately to emphasize the Court’s statement that “we have no occasion in this case to consider the pre-emptive effect of a specific agency regulation bearing the force of law.” Ante, at 24. State tort law will sometimes help the Food and Drug Administration (FDA) “uncover unknown drug hazards and [encourage] drug manufacturers to disclose safety risks.” Ante, at 23. But it is also possible that state tort law will sometimes interfere with the FDA’s desire to create a drug label containing a specific set of cautions and instructions. I also note that some have argued that state tort law can sometimes raise prices to the point where those who are sick are unable to obtain the drugs they need. See Lasagna, The Chilling Effect of Product Liability on New Drug Development, in The Liability Maze 334, 335–336 (P. Huber & R. Litan eds. 1991). The FDA may seek to determine whether and when state tort law acts as a help or a hindrance to achieving the safe drug-related medical care that Congress sought. Medtronic, Inc. v. Lohr, 518 U. S. 470, 506 (1996) (Breyer, J., concurring in part and concurring in judgment); cf. Bates v. Dow Agrosciences LLC, 544 U. S. 431, 454–455 (2005) (Breyer, J., concurring). It may seek to embody those determinations in lawful specific regulations describing, for example, when labeling requirements serve as a ceiling as well as a floor. And it is possible that such determinations would have pre-emptive effect. See Lohr, supra, at 505 (opinion of Breyer, J.) (citing Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707 (1985) ). I agree with the Court, however, that such a regulation is not at issue in this case.


TOP

Concurrence

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Breyer, concurring.

I write separately to emphasize the Court’s statement that “we have no occasion in this case to consider the pre-emptive effect of a specific agency regulation bearing the force of law.” Ante, at 24. State tort law will sometimes help the Food and Drug Administration (FDA) “uncover unknown drug hazards and [encourage] drug manufacturers to disclose safety risks.” Ante, at 23. But it is also possible that state tort law will sometimes interfere with the FDA’s desire to create a drug label containing a specific set of cautions and instructions. I also note that some have argued that state tort law can sometimes raise prices to the point where those who are sick are unable to obtain the drugs they need. See Lasagna, The Chilling Effect of Product Liability on New Drug Development, in The Liability Maze 334, 335–336 (P. Huber & R. Litan eds. 1991). The FDA may seek to determine whether and when state tort law acts as a help or a hindrance to achieving the safe drug-related medical care that Congress sought. Medtronic, Inc. v. Lohr, 518 U. S. 470, 506 (1996) (Breyer, J., concurring in part and concurring in judgment); cf. Bates v. Dow Agrosciences LLC, 544 U. S. 431, 454–455 (2005) (Breyer, J., concurring). It may seek to embody those determinations in lawful specific regulations describing, for example, when labeling requirements serve as a ceiling as well as a floor. And it is possible that such determinations would have pre-emptive effect. See Lohr, supra, at 505 (opinion of Breyer, J.) (citing Hillsborough County v. Automated Medical Laboratories, Inc., 471 U. S. 707 (1985) ). I agree with the Court, however, that such a regulation is not at issue in this case.


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Dissent

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Alito, with whom The Chief Justice and Justice Scalia join, dissenting.

This case illustrates that tragic facts make bad law. The Court holds that a state tort jury, rather than the Food and Drug Administration (FDA), is ultimately responsible for regulating warning labels for prescription drugs. That result cannot be reconciled with Geier v. American Honda Motor Co., 529 U. S. 861 (2000) , or general principles of conflict pre-emption. I respectfully dissent.

I

The Court frames the question presented as a “narro[w]” one—namely, whether Wyeth has a duty to provide “an adequate warning about using the IV-push method” to administer Phenergan. Ante, at 8. But that ignores the antecedent question of who—the FDA or a jury in Vermont—has the authority and responsibility for determining the “adequacy” of Phenergan’s warnings. Moreover, it is unclear how a “stronger” warning could have helped respondent, see ante, at 16; after all, the physician’s assistant who treated her disregarded at least six separate warnings that are already on Phenergan’s labeling, so respondent would be hard pressed to prove that a seventh would have made a difference. 1

More to the point, the question presented by this case is not a “narrow” one, and it does not concern whether Phenergan’s label should bear a “stronger” warning. Rather, the real issue is whether a state tort jury can countermand the FDA’s considered judgment that Phenergan’s FDA-mandated warning label renders its intravenous (IV) use “safe.” Indeed, respondent’s amended complaint alleged that Phenergan is “not reasonably safe for intravenous administration,” App. 15, ¶6; respondent’s attorney told the jury that Phenergan’s label should say, “ ‘Do not use this drug intravenously,’ ” id., at 32; respondent’s expert told the jury, “I think the drug should be labeled ‘Not for IV use,’ ” id., at 59; and during his closing argument, respondent’s attorney told the jury, “Thank God we don’t rely on the FDA to … make the safe[ty] decision. You will make the decision. … The FDA doesn’t make the decision, you do,” id., at 211–212. 2

Federal law, however, does rely on the FDA to make safety determinations like the one it made here. The FDA has long known about the risks associated with IV push in general and its use to administer Phenergan in particular. Whether wisely or not, the FDA has concluded—over the course of extensive, 54-year-long regulatory proceedings—that the drug is “safe” and “effective” when used in accordance with its FDA-mandated labeling. The unfortunate fact that respondent’s healthcare providers ignored Phenergan’s labeling may make this an ideal medical-malpractice case. 3 But turning a common-law tort suit into a “frontal assault” on the FDA’s regulatory regime for drug labeling upsets the well-settled meaning of the Supremacy Clause and our conflict pre-emption jurisprudence. Brief for United States as Amicus Curiae 21.

II

A

To the extent that “[t]he purpose of Congress is the ultimate touchstone in every pre-emption case,” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) (internal quotation marks omitted), Congress made its “purpose” plain in authorizing the FDA—not state tort juries—to determine when and under what circumstances a drug is “safe.” “[T]he process for approving new drugs is at least as rigorous as the premarket approval process for medical devices,” Riegel v. Medtronic, Inc., 552 U. S. ___, ___ (2008) (slip op., at 11) (Ginsburg, J., dissenting), and we held that the latter pre-empted a state-law tort suit that conflicted with the FDA’s determination that a medical device was “safe,” id., at ___ (slip op., at 11) (opinion of the Court).

Under the Federal Food, Drug, and Cosmetic Act (FDCA), a drug manufacturer may not market a new drug before first submitting a new drug application (NDA) to the FDA and receiving the agency’s approval. See 21 U. S. C. §355(a). An NDA must contain, among other things, “the labeling proposed to be used for such drug,” §355(b)(1)(F), “full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use,” §355(b)(1)(A), and “a discussion of why the benefits exceed the risks [of the drug] under the conditions stated in the labeling,” 21 CFR §314.50(d)(5)(viii) (2008). The FDA will approve an NDA only if the agency finds, among other things, that the drug is “safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof,” there is “substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof,” and the proposed labeling is not “false or misleading in any particular.” 21 U. S. C. §355(d).

After the FDA approves a drug, the manufacturer remains under an obligation to investigate and report any adverse events associated with the drug, see 21 CFR §314.80, and must periodically submit any new information that may affect the FDA’s previous conclusions about the safety, effectiveness, or labeling of the drug, 21 U. S. C. §355(k). If the FDA finds that the drug is not “safe” when used in accordance with its labeling, the agency “shall” withdraw its approval of the drug. §355(e). The FDA also “shall” deem a drug “misbranded” if “it is dangerous to health when used in the dosage or manner, or with the frequency or duration prescribed, recommended, or suggested in the labeling thereof.” §352(j).

Thus, a drug’s warning label “serves as the standard under which the FDA determines whether a product is safe and effective.” 50Fed. Reg. 7470 (1985). Labeling is “[t]he centerpiece of risk management,” as it “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively.” 71Fed. Reg. 3934 (2006). The FDA has underscored the importance it places on drug labels by promulgating comprehensive regulations—spanning an entire part of the Code of Federal Regulations, see 21 CFR pt. 201, with seven subparts and 70 separate sections—that set forth drug manufacturers’ labeling obligations. Under those regulations, the FDA must be satisfied that a drug’s warning label contains, among other things, “a summary of the essential scientific information needed for the safe and effective use of the drug,” §201.56(1), including a description of “clinically significant adverse reactions,” “other potential safety hazards,” “limitations in use imposed by them, … and steps that should be taken if they occur,” §201.57(c)(6)(i). Neither the FDCA nor its implementing regulations suggest that juries may second-guess the FDA’s labeling decisions.

B

1

Where the FDA determines, in accordance with its statutory mandate, that a drug is on balance “safe,” our conflict pre-emption cases prohibit any State from countermanding that determination. See, e.g., Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 348 (2001) (after the FDA has struck “a somewhat delicate balance of statutory objectives” and determined that petitioner submitted a valid application to manufacture a medical device, a State may not use common law to negate it); International Paper Co. v. Ouellette, 479 U. S. 481, 494 (1987) (after the EPA has struck “the balance of public and private interests so carefully addressed by” the federal permitting regime for water pollution, a State may not use nuisance law to “upse[t]” it); Chicago & North Western Transp. Co. v. Kalo Brick & Tile Co., 450 U. S. 311, 321 (1981) (after the Interstate Commerce Commission has struck a “balance” between competing interests in permitting the abandonment of a railroad line, a State may not use statutory or common law to negate it).

Thus, as the Court itself recognizes, it is irrelevant in conflict pre-emption cases whether Congress “enacted an express pre-emption provision at some point during the FDCA’s 70-year history.” Ante, at 18; see also Geier, 529 U. S., at 869 (holding the absence of an express pre-emption clause “does not bar the ordinary working of conflict pre-emption principles”). Rather, the ordinary principles of conflict pre-emption turn solely on whether a State has upset the regulatory balance struck by the federal agency. Id., at 884–885; see also Chicago & North Western Transp. Co., supra, at 317 (describing conflict pre-emption as “a two-step process of first ascertaining the construction of the [federal and state laws] and then determining the constitutional question whether they are actually in conflict” (internal quotation marks omitted)).

2

A faithful application of this Court’s conflict pre-emption cases compels the conclusion that the FDA’s 40-year-long effort to regulate the safety and efficacy of Phenergan pre-empts respondent’s tort suit. Indeed, that result follows directly from our conclusion in Geier.

Geier arose under the National Traffic and Motor Safety Vehicle Act of 1966, which directs the Secretary of the Department of Transportation (DOT) to “establish by order … motor vehicle safety standards,” 15 U. S. C. §1392(a) (1988 ed.), which are defined as “minimum standard[s] for motor vehicle performance, or motor vehicle equipment performance,” §1391(2). Acting pursuant to that statutory mandate, the Secretary of Transportation promulgated Federal Motor Vehicle Safety Standard 208, which required car manufacturers to include passive restraint systems (i.e., devices that work automatically to protect occupants from injury during a collision) in a certain percentage of their cars built in or after 1987. See 49 CFR §571.208 (1999). Standard 208 did not require installation of any particular type of passive restraint; instead, it gave manufacturers the option to install automatic seatbelts, airbags, or any other suitable technology that they might develop, provided the restraint(s) met the performance requirements specified in the rule. Ibid.

Alexis Geier drove her 1987 Honda Accord into a tree, and although she was wearing her seatbelt, she nonetheless suffered serious injuries. She then sued Honda under state tort law, alleging that her car was negligently and defectively designed because it lacked a driver’s-side airbag. She argued that Congress had empowered the Secretary to set only “minimum standard[s]” for vehicle safety. 15 U. S. C. §1391(2). She also emphasized that the National Traffic and Motor Safety Vehicle Act contains a saving clause, which provides that “[c]ompliance with any Federal motor vehicle safety standard issued under this subchapter does not exempt any person from any liability under common law.” §1397(k).

Notwithstanding the statute’s saving clause, and notwithstanding the fact that Congress gave the Secretary authority to set only “minimum” safety standards, we held Geier’s state tort suit pre-empted. In reaching that result, we relied heavily on the view of the Secretary of Transportation—expressed in an amicus brief—that Standard 208 “ ‘embodies the Secretary’s policy judgment that safety would best be promoted if manufacturers installed alternative protection systems in their fleets rather than one particular system in every car.’ ” 529 U. S., at 881 (quoting Brief for United States as Amicus Curiae,O. T. 1999, No. 98–1811, p. 25). Because the Secretary determined that a menu of alternative technologies was “safe,” the doctrine of conflict pre-emption barred Geier’s efforts to deem some of those federally approved alternatives “unsafe” under state tort law.

The same rationale applies here. Through Phenergan’s label, the FDA offered medical professionals a menu of federally approved, “safe” and “effective” alternatives—including IV push—for administering the drug. Through a state tort suit, respondent attempted to deem IV push “unsafe” and “ineffective.” To be sure, federal law does not prohibit Wyeth from contraindicating IV push, just as federal law did not prohibit Honda from installing airbags in all its cars. But just as we held that States may not compel the latter, so, too, are States precluded from compelling the former. See also Fidelity Fed. Sav. & Loan Assn. v. De la Cuesta, 458 U. S. 141, 155 (1982) (“The conflict does not evaporate because the [agency’s] regulation simply permits, but does not compel,” the action forbidden by state law). If anything, a finding of pre-emption is even more appropriate here because the FDCA—unlike the National Traffic and Motor Safety Vehicle Act—contains no evidence that Congress intended the FDA to set only “minimum standards,” and the FDCA does not contain a saving clause. 4 See also ante, at 18 (conceding Congress’ “silence” on the issue).

III

In its attempt to evade Geier’s applicability to this case, the Court commits both factual and legal errors. First, as a factual matter, it is demonstrably untrue that the FDA failed to consider (and strike a “balance” between) the specific costs and benefits associated with IV push. Second, as a legal matter, Geier does not stand for the legal propositions espoused by the dissenters (and specifically rejected by the majority) in that case. Third, drug labeling by jury verdict undermines both our broader pre-emption jurisprudence and the broader workability of the federal drug-labeling regime.

A

Phenergan’s warning label has been subject to the FDA’s strict regulatory oversight since the 1950’s. For at least the last 34 years, the FDA has focused specifically on whether IV-push administration of Phenergan is “safe” and “effective” when performed in accordance with Phenergan’s label. The agency’s ultimate decision—to retain IV push as one means for administering Phenergan, albeit subject to stringent warnings—is reflected in the plain text of Phenergan’s label (sometimes in boldfaced font and all-capital letters). And the record contains ample evidence that the FDA specifically considered and reconsidered the strength of Phenergan’s IV-push-related warnings in light of new scientific and medical data. The majority’s factual assertions to the contrary are mistaken.

1

The FDA’s focus on IV push as a means of administering Phenergan dates back at least to 1975. In August of that year, several representatives from both the FDA and Wyeth met to discuss Phenergan’s warning label. At that meeting, the FDA specifically proposed “that Phenergan Injection should not be used in Tubex.” 2 Record 583, 586 (Plaintiff’s Trial Exh. 17, Internal Correspondence from W. E. Langeland to File (Sept. 5, 1975) (hereinafter 1975 Memo)). “Tubex” is a syringe system used exclusively for IV push. See App. 43. An FDA official explained that the agency’s concerns arose from medical-malpractice lawsuits involving IV push of the drug, see 1975 Memo 586, and that the FDA was aware of “5 cases involving amputation where the drug had been administered by Tubex together with several additional cases involving necrosis,” id., at 586–587. Rather than contraindicating Phenergan for IV push, however, the agency and Wyeth agreed “that there was a need for better instruction regarding the problems of intraarterial injection.” Id., at 587.

The next year, the FDA convened an advisory committee to study, among other things, the risks associated with the Tubex system and IV push. App. 294. At the conclusion of its study, the committee recommended an additional IV-push-specific warning for Phenergan’s label, see ibid., but did not recommend eliminating IV push from the drug label altogether. In response to the committee’s recommendations, the FDA instructed Wyeth to make several changes to strengthen Phenergan’s label, including the addition of upper case warnings related to IV push. See id., at 279–280, 282–283.

In 1987, the FDA directed Wyeth to amend its label to include the following text:

“ ‘[1] When used intravenously, [Phenergan] should be given in a concentration no greater than 25 mg/ml and at a rate not to exceed 25 mg/minute. [2] Injection through a properly running intravenous infusion may enhance the possibility of detecting arterial placement.’ ” Id., at 311–312.

The first of the two quoted sentences refers specifically to IV push; as respondent’s medical expert testified at trial, the label’s recommended rate of administration (not to exceed 25 mg per minute) refers to “IV push, as opposed to say being in a bag and dripped over a couple of hours.” Id., at 52. The second of the two quoted sentences refers to IV drip. See id., at 15–16 (emphasizing that a “running IV” is the same thing as “IV drip”).

In its 1987 labeling order, the FDA cited voluminous materials to “suppor[t]” its new and stronger warnings related to IV push and the preferability of IV drip. 5 Id., at 313. One of those articles specifically discussed the relative advantages and disadvantages of IV drip compared to IV push, as well as the costs and benefits of administering Phenergan via IV push. 6 The FDA also cited published case reports from the 1960’s of gangrene caused by the intra-arterial injection of Phenergan, 7 and the FDA instructed Wyeth to amend Phenergan’s label in accordance with the latest medical research. 8 The FDA also studied drugs similar to Phenergan and cited numerous cautionary articles—one of which urged the agency to consider contraindicating such drugs for IV use altogether. 9

In “support” of its labeling order, the FDA also cited numerous articles that singled out the inner crook of the elbow—known as the “antecubital fossa” in the medical community—whichis both a commonly used injection site, see id., at 70 (noting that respondent’s injection was pushed into “the antecubital space”), and a universally recognized high-risk area for inadvertent intra-arterial injections. One of the articles explained:

“Because of the numerous superficial positions the ulnar artery might occupy, it has often been entered during attempted venipuncture [of the antecubital fossa]. … However, the brachial and the radial arteries might also be quite superficial in the elbow region… . The arterial variations of the arm, especially in and about the cubital fossa, are common and numerous. If venipuncture must be performed in this area, a higher index of suspicion must be maintained to forestall misdirected injections.” Stone & Donnelly, The Accidental Intra-arterial Injection of Thiopental, 22 Anesthesiology 995, 996 (1961) (footnote omitted; cited in App. 315, no. 20). 10

Based on this and other research, the FDA ordered Wyeth to include a specific warning related to the use of the antecubital space for IV push. 11

2

When respondent was injured in 2000, Phenergan’s label specifically addressed IV push in several passages (sometimes in lieu of and sometimes in addition to those discussed above). For example, the label warned of the risks of intra-arterial injection associated with “aspiration,” which is a technique used only in conjunction with IV push. 12 The label also cautioned against the use of “syringes with rigid plungers,” App. 390, which are used onlyto administer the drug via IV push. As respondent’s medical expert testified at trial, “by talking plungers and rigid needles, that’s the way you do it, to push it with the plunger.” Id., at 53 (testimony of Dr. John Matthew). Moreover, Phenergan’s 2000 label devoted almost a full page to discussing the “Tubex system,” see id., at 391, which, as noted above, is used only to administer the drug via IV push.

While Phenergan’s label very clearly authorized the use of IV push, it also made clear that IV push is the delivery method of last resort. The label specified that “[t]he preferred parenteral route of administration is by deep intramuscular injection.” Id., at 390. If an intramuscular injection is ineffective, then “it is usually preferable to inject [Phenergan] through the tubing of an intravenous infusion set that is known to be functioning satisfactorily.” Ibid. See also id., at 50–51 (testimony of respondent’s medical expert, Dr. John Matthew) (conceding that the best way to determine that an IV set is functioning satisfactorily is to use IV drip). Finally, if for whatever reason a medical professional chooses to use IV push, he or she is on notice that “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY.” Id., at 391; see also id., at 390 (“Under no circumstances should Phenergan Injection be given by intra-arterial injection due to the likelihood of severe arteriospasm and the possibility of resultant gangrene”).

Phenergan’s label also directs medical practitioners to choose veins wisely when using IV push:

“Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or inadvertent intra-arterial injection. Reports compatible with inadvertent intra-arterial injection of Phenergan Injection, usually in conjunction with other drugs intended for intravenous use, suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances.” Ibid.

Thus, it is demonstrably untrue that, as of 2000, Phenergan’s “labeling did not contain a specific warning about the risks of IV-push administration.” Ante, at 4. And whatever else might be said about the extensive medical authorities and case reports that the FDA cited in “support” of its approval of IV-push administration of Phenergan, it cannot be said that the FDA “paid no more than passing attention to” IV push, ante, at 6; nor can it be said that the FDA failed to weigh its costs and benefits, Brief for Respondent 50.

3

For her part, respondent does not dispute the FDA’s conclusion that IV push has certain benefits. At trial, her medical practitioners testified that they used IV push in order to help her “in a swift and timely way” when she showed up at the hospital for the second time in one day complaining of “intractable” migraines, “terrible pain,” inability to “bear light or sound,” sleeplessness, hours-long spasms of “retching” and “vomiting,” and when “every possible” alternative treatment had “failed.” App. 40 (testimony of Dr. John Matthew); id., at 103, 106, 109 (testimony of physician’s assistant Jessica Fisch).

Rather than disputing the benefits of IV push, respondent complains that the FDA and Wyeth underestimated its costs (and hence did not provide sufficient warnings regarding its risks). But when the FDA mandated that Phenergan’s label read, “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY,” id., at 391, and when the FDA required Wyeth to warn that “[u]nder no circumstances should Phenergan Injection be given by intra-arterial injection,” id., at 390, the agency could reasonably assume that medical professionals would take care not to inject Phenergan intra-arterially. See also 71 Fed. Reg. 3934 (noting that a drug’s warning label “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively”). Unfortunately, the physician’s assistant who treated respondent in this case disregarded Phenergan’s label and pushed the drug into the single spot on her arm that is most likely to cause an inadvertent intra-arterial injection.

As noted above, when the FDA approved Phenergan’s label, it was textbook medical knowledge that the “antecubital fossa” creates a high risk of inadvertent intra-arterial injection, given the close proximity of veins and arteries. See supra, at 13–14; see also The Lippincott Manual of Nursing Practice 99 (7th ed. 2001) (noting, in a red-text “NURSING ALERT,” that the antecubital fossa is “not recommended” for administering dangerous drugs, “due to the potential for extravasation”). 13 According to the physician’s assistant who injured respondent, however, “[i]t never crossed my mind” that an antecubital injection of Phenergan could hit an artery. App. 110; see also ibid. (“[It] just wasn’t something that I was aware of at the time”). Oblivious to the risks emphasized in Phenergan’s warnings, the physician’s assistant pushed a double dose of the drug into an antecubital artery over the course of “[p]robably about three to four minutes,” id., at 111; id., at 105, notwithstanding respondent’s complaints of a “ ‘burn[ing]’ ” sensation that she subsequently described as “ ‘one of the most extreme pains that I’ve ever felt,’ ” id., at 110, 180–181. And when asked why she ignored Phenergan’s label and failed to stop pushing the drug after respondent complained of burning pains, the physician’s assistant explained that it would have been “just crazy” to “worr[y] about an [intra-arterial] injection” under the circumstances, id., at 111.

The FDA, however, did not think that the risks associated with IV push—especially in the antecubital space—were “just crazy.” That is why Phenergan’s label so clearly warns against them.

B

Given the “balance” that the FDA struck between the costs and benefits of administering Phenergan via IV push, Geier compels the pre-emption of tort suits (like this one) that would upset that balance. The contrary conclusion requires turning yesterday’s dissent into today’s majority opinion.

First, the Court denies the existence of a federal-state conflict in this case because Vermont merely countermanded the FDA’s determination that IV push is “safe” when performed in accordance with Phenergan’s warning label; the Court concludes that there is no conflict because Vermont did not “mandate a particular” label as a “replacement” for the one that the jury nullified, and because the State stopped short of altogether “contraindicating IV-push administration.” Ante, at 8. But as we emphasized in Geier (over the dissent’s assertions to the contrary), the degree of a State’s intrusion upon federal law is irrelevant—the Supremacy Clause applies with equal force to a state tort law that merely countermands a federal safety determination and to a state law that altogether prohibits car manufacturers from selling cars without airbags. Compare 529 U. S., at 881–882, with id., at 902 (Stevens, J., dissenting). Indeed, as recently as last Term, we held that the Supremacy Clause pre-empts a “[s]tate tort law that requires a manufacturer’s catheters to be safer, but hence less effective, than the model the FDA has approved … .” Riegel, 552 U. S., at ___ (slip op., at 11). It did not matter there that the State stopped short of altogether prohibiting the use of FDA-approved catheters—just as it does not matter here that Vermont stopped short of altogether prohibiting an FDA-approved method for administering Phenergan. See also Lohr, 518 U. S., at 504 (Breyer, J., concurring in part and concurring in judgment) (noting it would be an “anomalous result” if pre-emption applied differently to a state tort suit premised on the inadequacy of the FDA’s safety regulations and a state law that specifically prohibited an FDA-approved design).

Second, the Court today distinguishes Geier because the FDA articulated its pre-emptive intent “without offering States or other interested parties notice or opportunity for comment. Ante, at 21; see also ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that conflict pre-emption is appropriate only where the agency expresses its pre-emptive intent through notice-and-comment rulemaking. Compare 529 U. S., at 885 (“To insist on a specific expression of agency intent to pre-empt, made after notice-and-comment rulemaking, would be in certain cases to tolerate conflicts that an agency, and therefore Congress, is most unlikely to have intended. The dissent, as we have said, apparently welcomes that result … . We do not”), with id., at 908–910 (Stevens, J., dissenting) (emphasizing that “we generally expect an administrative regulation to declare any intention to pre-empt state law with some specificity,” and that “[t]his expectation … serves to ensurethat States will be able to have a dialog with agencies regarding pre-emption decisions ex ante through the normal notice-and-comment procedures of the Administrative Procedure Act” (internal quotation marks omitted)). Indeed, pre-emption is arguably more appropriate here than in Geier because the FDA (unlike the DOT) declared its pre-emptive intent in the Federal Register. See 71 Fed. Reg. 3933–3936. Yet the majority dismisses the FDA’s published preamble as “inherently suspect,” ante, at 21, and an afterthought that is entitled to “no weight,” ante, at 25. Compare Lohr, supra, at 506 (opinion of Breyer, J.) (emphasizing that the FDA has a “special understanding of the likely impact of both state and federal requirements, as well as an understanding of whether (or the extent to which) state requirements may interfere with federal objectives,” and that “[t]he FDA can translate these understandings into particularized pre-emptive intentions … through statements in ‘regulations, pre-ambles, interpretive statements, and responses tocomments’ ”).

Third, the Court distinguishes Geier because the DOT’s regulation “bear[s] the force of law,” whereas the FDA’s preamble does not. Ante, at 24; see also ante, at 19. But it is irrelevant that the FDA’s preamble does not “bear the force of law” because the FDA’s labeling decisions surely do. See 21 U. S. C. §355. It is well within the FDA’s discretion to make its labeling decisions through administrative adjudications rather than through less-formal and less-flexible rulemaking proceedings, see SEC v. Chenery Corp., 332 U. S. 194 (1947) , and we have never previously held that our pre-emption analysis turns on the agency’s choice of the latter over the former. Moreover, it cannot be said that Geier’s outcome hinged on the agency’s choice to promulgate a rule. See ante, at 19, 24. The Geier Court relied—again over the dissenters’ protestations—on materials other than the Secretary’s regulation to explain the conflict between state and federal law. Compare 529 U. S., at 881, with id., at 899–900 (Stevens, J., dissenting), and ante, at 1–2 (Breyer, J., concurring).

Fourth, the Court sandwiches its discussion of Geier between the “presumption against pre-emption,” ante, at 18, and heavy emphasis on “the longstanding coexistence of state and federal law and the FDA’s traditional recognition of state-law remedies,” ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that the “presumption against pre-emption” is relevant to the conflict pre-emption analysis. See 529 U. S., at 906–907 (Stevens, J., dissenting) (“[T]he Court simply ignores the presumption [against pre-emption]”). Rather than invoking such a “presumption,” the Court emphasized that it was applying “ordinary,” “longstanding,” and “experience-proved principles of conflict pre-emption.” Id., at 874. Under these principles, the sole question is whether there is an “actual conflict” between state and federal law; if so, then pre-emption follows automatically by operation of the Supremacy Clause. Id., at 871–872. See also Buckman, 531 U. S., at 347–348 (“[P]etitioner’s dealings with the FDA were prompted by [federal law], and the very subject matter of petitioner’s statements [to the FDA] were dictated by [federal law]. Accordingly—and in contrast to situations implicating ‘federalism concerns and the historic primacy of state regulation of matters of health and safety’—no presumption against pre-emption obtains in this case” (citation omitted)). 14

Finally, the Geier Court went out of its way to emphasize (yet again over the dissenters’ objections) that it placed “some weight” on the DOT’s amicus brief, which explained the agency’s regulatory objectives and the effects of state tort suits on the federal regulatory regime. 529 U. S., at 883; compare id., at 910–911 (Stevens, J., dissenting) (criticizing the majority for “uph[olding] a regulatory claim of frustration-of-purposes implied conflict pre-emption based on nothing more than an ex post administrative litigating position and inferences from regulatory history and final commentary”). See also Lohr, 518 U. S., at 496 (recognizing that the FDA is “uniquely qualified” to explain whether state law conflicts with the FDA’s objectives). Yet today, the FDA’s explanation of the conflict between state tort suits and the federal labeling regime, set forth in the agency’s amicus brief, is not even mentioned in the Court’s opinion. Instead of relying on the FDA’s explanation of its own regulatory purposes, the Court relies on a decade-old and now-repudiated statement, which the majority finds preferable. See ante, at 21–22, 24, n. 13. Cf. Riegel, 552 U. S., at ___ (slip op., at 13) (noting that “the agency’s earlier position (which the dissent describes at some length and finds preferable) is … compromised, indeed deprived of all claim to deference, by the fact that it is no longer the agency’s position” (citation omitted)); Altria Group, Inc. v. Good, 555 U. S. ___, ___ (2008) (slip op., at 16–17) (rejecting petitioners’ reliance on the pre-emptive effect of the agency’s “longstanding policy” because it is inconsistent with the agency’s current one). And Justice Breyer suggests that state tort suits may “help the [FDA],” ante, at 1 (concurring opinion), notwithstanding the FDA’s insistence that state tort suits will “disrupt the agency’s balancing of health risks and benefits,” Brief for United States as Amicus Curiae 9.

Geier does not countenance the use of state tort suits to second-guess the FDA’s labeling decisions. And the Court’s contrary conclusion has potentially far-reaching consequences.

C

By their very nature, juries are ill-equipped to perform the FDA’s cost-benefit-balancing function. As we explained in Riegel, juries tend to focus on the risk of a particular product’s design or warning label that arguably contributed to a particular plaintiff’s injury, not on the overall benefits of that design or label; “the patients who reaped those benefits are not represented in court.” 552 U. S., at ___ (slip op., at 12). Indeed, patients like respondent are the only ones whom tort juries ever see, and for a patient like respondent—who has already suffered a tragic accident—Phenergan’s risks are no longer a matter of probabilities and potentialities.

In contrast, the FDA has the benefit of the long view. Its drug-approval determinations consider the interests of all potential users of a drug, including “those who would suffer without new medical [products]” if juries in all 50 States were free to contradict the FDA’s expert determinations. Id., at ___ (slip op., at 13). And the FDA conveys its warnings with one voice, rather than whipsawing the medical community with 50 (or more) potentially conflicting ones. After today’s ruling, however, parochialism may prevail.

The problem is well illustrated by the labels borne by “vesicant” drugs, many of which are used for chemotherapy. As a class, vesicants are much more dangerous than drugs like Phenergan, 15 but the vast majority of vesicant labels—like Phenergan’s—either allow or do not disallow IV push. See Appendix, infra. Because vesicant extravasation can have devastating consequences, and because the potentially lifesaving benefits of these drugs offer hollow solace to the victim of such a tragedy, a jury’s cost-benefit analysis in a particular case may well differ from the FDA’s.

For example, consider Mustargen (mechlorethamine HCl)—the injectable form of mustard gas—which can be used as an anticancer drug. Mustargen’s FDA-approved label warns in several places that “This drug is HIGHLY TOXIC.” 16 Indeed, the drug is so highly toxic:

“Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water, for at least 15 minutes while removing contaminated clothing and shoes, followed by 2% sodium thiosulfate solution. Medical attention should be sought immediately. Contaminated clothing should be destroyed.” 17

Yet when it comes to administering this highly toxic drug, the label provides that “the drug may be injected directly into any suitable vein, [but] it is injected preferably into the rubber or plastic tubing of a flowing intravenous infusion set. This reduces the possibility of severe local reactions due to extravasation or high concentration of the drug.” (Emphasis added.) Similarly, the FDA-approved labels for other powerful chemotherapeutic vesicants—including Dactinomycin, Oxaliplatin, Vinblastine, and Vincristine—specifically allow IV push, notwithstanding their devastating effects when extravasated.

The fact that the labels for such drugs allow IV push is striking—both because vesicants are much more dangerous than Phenergan, and also because they are so frequently extravasated, see Boyle & Engelking, Vesicant Extravasation: Myths and Realities, 22 Oncology Nursing Forum 57, 58 (1995) (arguing that the rate of extravasation is “considerably higher” than 6.4% of all vesicant administrations). Regardless of the FDA’s reasons for not contraindicating IV push for these drugs, it is odd (to say the least) that a jury in Vermont can now order for Phenergan what the FDA has chosen not to order for mustard gas. 18

***

To be sure, state tort suits can peacefully coexist with the FDA’s labeling regime, and they have done so for decades. Ante, at 17–18. But this case is far from peaceful coexistence. The FDA told Wyeth that Phenergan’s label renders its use “safe.” But the State of Vermont, through its tort law, said: “Not so.”

The state-law rule at issue here is squarely pre-empted. Therefore, I would reverse the judgment of the Supreme Court of Vermont.

Appendix TO OPINION OF ALITO, J.

Vesicant1

IV Push2

Dactinomycin

Specifically allowed

Mechlorethamine (Mustargen)

Specifically allowed

Oxaliplatin

Specifically allowed

Vinblastine

Specifically allowed

Vincristine

Specifically allowed

Bleomycin

Neither mentioned nor prohibited

Carboplatin

Neither mentioned nor prohibited

Dacarbazine

Neither mentioned nor prohibited

Mitomycin

Neither mentioned nor prohibited

Carmustine

Not prohibited; IV drip recommended

Cisplatin

Not prohibited; IV drip recommended

Epirubicin

Not prohibited; IV drip recommended

Etoposide

Not prohibited; IV drip recommended

Ifosfamide

Not prohibited; IV drip recommended

Mitoxantrone

Not prohibited; IV drip recommended

Paclitaxel

Not prohibited; IV drip recommended

Teniposide

Not prohibited; IV drip recommended

Vinorelbine

Not prohibited; IV drip recommended

Daunorubicin

Prohibited

Doxorubicin

Prohibited

1 Wilkes & Barton-Burke, 2008 Oncology Nursing Drug Handbook 27–33 (2008) (Table 1.6).

2 IV-push information is derived from the “dosage and administration” sections of individual drug labels (available in Clerk of Court’s case file).


Notes

1 Indeed, respondent conceded below that Wyeth did propose an adequate warning of Phenergan’s risks. See Plaintiff Diana Levine’s Memorandum in Opposition to Wyeth’s Motion for Summary Judgment in Levine v. American Home Products Corp. (now Wyeth), No. 670–12–01 Wncv (Super. Ct. Washington Cty., Vt.), ¶7, p. 26. Specifically, respondent noted: “In 1988, Wyeth proposed language that would have prevented this accident by requiring a running IV and explaining why a running IV will address and reduce the risk [of intra-arterial injection].” Ibid. See also id., at 24 (“Although not strong enough, this improved the labeling instruction, if followed, would have prevented the inadvertent administration of Phenergan into an artery …”). The FDA rejected Wyeth’s proposal. See App. 359.

2 Moreover, in the trial judge’s final charge, he told the jury that “the critical factual issue which you must decide” is whether Phenergan’s FDA-mandated label reflects a proper balance between “the risks and benefits of intravenous administration and the potential for injury to patients.” Id., at 220. See also ___ Vt. ___, ___, 944 A. 2d 179, 182 (2006) (recognizing that respondent’s argument is that Phenergan’s “label should not have allowed IV push as a means of administration”).

3 Respondent sued her physician, physician’s assistant, and hospital for malpractice. After the parties settled that suit for an undisclosed sum, respondent’s physician sent her a letter in which he admitted “responsibility” for her injury and expressed his “profoun[d] regre[t]” and “remors[e]” for his actions. 1 Tr. 178–179 (Mar. 8, 2004) (testimony of Dr. John Matthew); see also App. 102–103 (testimony of physician’s assistant Jessica Fisch) (noting that her “sense of grief” was so “great” that she “would have gladly cut off [her own] arm” and given it to respondent). Thereafter, both the physician and the physician’s assistant agreed to testify on respondent’s behalf in her suit against Wyeth.

4 To be sure, Congress recognized the principles of conflict pre-emption in the FDCA. See Drug Amendments of 1962, §202, 76Stat. 793 (“Nothing in the amendments made by this Act to the Federal Food, Drug, and Cosmetic Act shall be construed as invalidating any provision of State law … unless there is a direct and positive conflict between such amendments and such provision of State law”). But a provision that simply recognizes the background principles of conflict pre-emption is not a traditional “saving clause,” and even if it were, it would not displace our conflict-pre-emption analysis. See Geier v. American Honda Motor Co., 529 U. S. 861, 869 (2000) (“[T]he saving clause … does not bar the ordinary working of conflict pre-emption principles”); id., at 873–874 (“The Court has … refused to read general ‘saving’ provisions to tolerate actual conflict both in cases involving impossibility and in ‘frustration-of-purpose’ cases” (emphasis deleted and citation omitted)).

5 The FDA cited numerous articles that generally discuss the costs and benefits associated with IV push. See, e.g., Nahrwold & Phelps, Inadvertent Intra-Arterial Injection of Mephenteramine, 70 Rocky Mountain Medical J. 38 (Sept. 1973) (cited in App. 314, no. 14); Albo, Cheung, Ruth, Snyder, & Beemtsma, Effect of Intra-Arterial Injections of Barbituates, 120 Am. J. of Surgery 676 (1970) (cited in App. 314, no. 12); Corser, Masey, Jacob, Kernoff, & Browne, Ischaemia Following Self-administered Intra-arterial Injection of Methylphenidate and Diamorphine, 40 Anesthesiology 51 (1985) (cited in App. 314, no. 9); Correspondence Regarding Thiopental and Thiamylal (3 letters), 59 Anesthesiology 153 (1983) (cited in App. 314, no. 11); Miller, Arthur, & Stratigos, Intra-arterial Injection of a Barbituate, 23 Anesthesia Progress 25 (1976) (cited in App. 315, no. 19).

6 See Webb & Lampert, Accidental Arterial Injections, 101 Am. J. Obstetrics & Gynecology 365 (1968) (cited in App. 313, no. 5).

7 See Hager & Wilson, Gangrene of the Hand Following Intra-arterial Injection, 94 Archives of Surgery 86 (1967) (cited in App. 313, no. 7); Enloe, Sylvester, & Morris, Hazards of Intra-Arterial Injection of Hydroxyzine, 16 Canadian Anaesthetists’ Society J. 425 (1969) (hereinafter Enloe) (noting “recent reports” of “the occurrence of severe necrosis and gangrene following [administration of] promethazine (Phenergan)” (cited in App. 314, no. 15)). See also Mostafavi & Samimi, Accidental Intra-arterial Injection of Promethazine HCl During General Anesthesia, 35 Anesthesiology 645 (1971) (reporting a case of gangrene, which required partial amputation of three fingers, after Phenergan was inadvertently pushed into an artery in the “antecubital” area); Promethazine, p. 7, in Clinical Pharmacology (Gold Standard Multimedia Inc. CD–ROM, version 1.16 (1998) (noting that “[i]nadvertent intra-arterial injection [of Phenergan] can result in arteriospasm … and development of gangrene”)).

8 Hager and Wilson noted that the most common reactions to intra-arterial injections of drugs like Phenergan include “[i]mmediate, severe, burning pain,” as well as “blanching.” 94 Archives of Surgery, at 87–88. The FDA required Wyeth to include Hager and Wilson’s observations on Phenergan’s label. See App. 311 (requiring the label to warn that “ ‘[t]he first sign [of an intra-arterial injection] may be the patient’s reaction to a sensation of fiery burning’ ” pain and “ ‘[b]lanching’ ”).

9 See Enloe 427 (discussing hydroxyzine—an antihistamine with chemical properties similar to those of Phenergan—and suggesting its “temporary” benefits can never outweigh the risks of intra-arterial injection); see also Goldsmith & Trieger, Accidental Intra-Arterial Injection: A Medical Emergency, 22 Anesthesia Progress 180 (1975) (noting the risks of intra-arterial administration of hydroxyzine) (cited in App. 315, no. 18); Klatte, Brooks, & Rhamy, Toxicity of Intra-Arterial Barbituates and Tranquilizing Drugs, 92 Radiology 700 (1969) (same) (cited in App. 314, no. 13). With full knowledge of those risks, FDA retained IV push for Phenergan, although the agency required Wyeth to incorporate observations from the Enloe article into Phenergan’s label. Compare Enloe 427 (arguing that “every precaution should be taken to avoid inadvertent intra-arterial injection,” including the use of “an obviously well-functioning venoclysis”), with App. 312 (FDA’s 1987 changes to Phenergan’s label). In contrast, at some time around 1970, the FDA prohibited all intravenous use of hydroxyzine. See id., at 79 (testimony of Dr. Harold Green). The FDA’s decision to regulate the two drugs differently—notwithstanding (1) the agency’s knowledge of the risks associated with both drugs and (2) the agency’s recognition of the relevance of hydroxyzine-related articles and case reports in its regulation of Phenergan—further demonstrates that the FDA intentionally preserved IV-push administration for Phenergan. See also Haas, Correspondence, 33 Anesthesia Progress 281 (1986) (“[Hydroxyzine’s] restriction does not lie with the medicine itself, but in the practice and malpractice of intravenous techniques. Unfortunately, the practitioner who knows how to treat injection technique problems is usually not the practitioner with the intravenous technique problems”).

10 See also Engler, Freeman, Kanavage, Ogden, & Moretz, Production of Gangrenous Extremities by Intra-Arterial Injections, 30 Am. Surgeon 602 (1964) (“Accidental arterial injection most often occurs in the antecubital region because this is a favorite site for venopuncture and in this area the ulnar and brachial arteries are superficial and easily entered” (cited in App. 313, no. 6)); Engler, Gangrenous Extremities Resulting from Intra-arterial Injections, 94 Archives of Surgery 644 (1966) (similar) (cited in App. 314, no. 16); Lynas & Bisset, Intra-arterial Thiopentone, 24 Anaesthesia 257 (1969) (“Most [anesthesiologists] agree that injections on the medial aspect of the antecubital fossa are best avoided” (cited in App. 314, no. 8)); Waters, Intra-arterial Thiopentone, 21 Anesthesia 346 (1966) (“The risk of producing gangrene of the forearm by accidental injection of sodium thiopentone into an artery at the elbow has been recognised for many years” (cited in App. 314, no. 10)); see also Hager & Wilson, 94 Archives of Surgery, at 88 (emphasizing that one of the best ways to prevent inadvertent intra-arterial injections is to be aware of “aberrant or superficial arteries at the antecubital, forearm, wrist, and hand level”); Mostafavi & Samimi, supra (warning against antecubital injections).

11 See App. 311 (requiring Phenergan’s label to warn that practitioners should “ ‘[b]eware of the close proximity of arteries and veins at commonly used injection sites and consider the possibility of aberrant arteries’ ”).

12 “Aspiration” refers to drawing a small amount of blood back into the needle to determine whether the needle is in an artery or a vein. Ordinarily, arterial blood is brighter than venous blood—but contact with Phenergan causes discoloration, which makes aspiration an unreliable method of protecting against intra-arterial injection. See id., at 282. Therefore, the label warned that when using IV push, a medical professional should beware that “[a]spiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with Phenergan Injection.” Id., at 390.

13 In addition, respondent’s own medical expert testified at trial that it is a principle of “basic anatomy” that the antecubital fossa contains aberrant arteries. See 2 Tr. 34–35 (Mar. 9, 2004) (testimony of Dr. Daniel O’Brien); see also ibid. (noting that Gray’s Anatomy, which is “the Bible of anatomy,” also warns of arteries in the antecubital space).

14 Thus, it is not true that “this Court has long” applied a presumption against pre-emption in conflict pre-emption cases. Ante, at 9, n. 3 (majority opinion). As long ago as Gibbons v. Ogden, 9 Wheat. 1, 210 (1824), the Court inquired whether a state law “interfer[ed] with,” was “contrary to,” or “c[a]me into collision with” federal law—and it did so without ever invoking a “presumption.” See also Davis, Unmasking the Presumption in Favor of Preemption, 53 S. C. L. Rev. 967, 974 (2002) (noting that many of the Court’s early pre-emption cases “resulted in almost automatic preemption of concurrent state regulation”). In subsequent years the Court has sometimes acknowledged a limited “presumption against pre-emption,” but it nonetheless remained an open question—before today—whether that presumption applied in conflict pre-emption cases. See Crosby v. National Foreign Trade Council, 530 U. S. 363, n. 8 (2000) (“We leave for another day a consideration in this context of a presumption against preemption”). Moreover, this Court has never held that the “presumption” applies in an area—such as drug labeling—that has long been “reserved for federal regulation.” United States v. Locke, 529 U. S. 89, 111 (2000) . See also Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 347–348 (2001) .

15 Vesicants may cause “blistering, severe tissue injury, or tissue necrosis” upon extravasation—even if the drug is not injected into an artery. See, e.g., Schulmeister, Administering Vesicants, 9 Clinical J. of Oncology Nursing 469, 469–470 (2005). See also ante, at 4 (majority opinion) (noting that Phenergan is labeled as an “irritant”); cf. Brief for Anju Budhwani et al. as Amici Curiae 15 (suggesting Phenergan should be considered a “vesicant”).

16 FDA, Oncology Tools Product Label Details, online at http://www.accessdata.fda.gov/scripts/cder/onctools/labels.cfm?GN=meclorethamine, nitrogen mustard (as visited Mar. 2, 2009, and available in Clerk of Court’s case file).

17 Ibid.

18 The same is true of FDA’s regulation of hydroxyzine. See n. 9,supra.


TOP

Dissent

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Alito, with whom The Chief Justice and Justice Scalia join, dissenting.

This case illustrates that tragic facts make bad law. The Court holds that a state tort jury, rather than the Food and Drug Administration (FDA), is ultimately responsible for regulating warning labels for prescription drugs. That result cannot be reconciled with Geier v. American Honda Motor Co., 529 U. S. 861 (2000) , or general principles of conflict pre-emption. I respectfully dissent.

I

The Court frames the question presented as a “narro[w]” one—namely, whether Wyeth has a duty to provide “an adequate warning about using the IV-push method” to administer Phenergan. Ante, at 8. But that ignores the antecedent question of who—the FDA or a jury in Vermont—has the authority and responsibility for determining the “adequacy” of Phenergan’s warnings. Moreover, it is unclear how a “stronger” warning could have helped respondent, see ante, at 16; after all, the physician’s assistant who treated her disregarded at least six separate warnings that are already on Phenergan’s labeling, so respondent would be hard pressed to prove that a seventh would have made a difference. 1

More to the point, the question presented by this case is not a “narrow” one, and it does not concern whether Phenergan’s label should bear a “stronger” warning. Rather, the real issue is whether a state tort jury can countermand the FDA’s considered judgment that Phenergan’s FDA-mandated warning label renders its intravenous (IV) use “safe.” Indeed, respondent’s amended complaint alleged that Phenergan is “not reasonably safe for intravenous administration,” App. 15, ¶6; respondent’s attorney told the jury that Phenergan’s label should say, “ ‘Do not use this drug intravenously,’ ” id., at 32; respondent’s expert told the jury, “I think the drug should be labeled ‘Not for IV use,’ ” id., at 59; and during his closing argument, respondent’s attorney told the jury, “Thank God we don’t rely on the FDA to … make the safe[ty] decision. You will make the decision. … The FDA doesn’t make the decision, you do,” id., at 211–212. 2

Federal law, however, does rely on the FDA to make safety determinations like the one it made here. The FDA has long known about the risks associated with IV push in general and its use to administer Phenergan in particular. Whether wisely or not, the FDA has concluded—over the course of extensive, 54-year-long regulatory proceedings—that the drug is “safe” and “effective” when used in accordance with its FDA-mandated labeling. The unfortunate fact that respondent’s healthcare providers ignored Phenergan’s labeling may make this an ideal medical-malpractice case. 3 But turning a common-law tort suit into a “frontal assault” on the FDA’s regulatory regime for drug labeling upsets the well-settled meaning of the Supremacy Clause and our conflict pre-emption jurisprudence. Brief for United States as Amicus Curiae 21.

II

A

To the extent that “[t]he purpose of Congress is the ultimate touchstone in every pre-emption case,” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) (internal quotation marks omitted), Congress made its “purpose” plain in authorizing the FDA—not state tort juries—to determine when and under what circumstances a drug is “safe.” “[T]he process for approving new drugs is at least as rigorous as the premarket approval process for medical devices,” Riegel v. Medtronic, Inc., 552 U. S. ___, ___ (2008) (slip op., at 11) (Ginsburg, J., dissenting), and we held that the latter pre-empted a state-law tort suit that conflicted with the FDA’s determination that a medical device was “safe,” id., at ___ (slip op., at 11) (opinion of the Court).

Under the Federal Food, Drug, and Cosmetic Act (FDCA), a drug manufacturer may not market a new drug before first submitting a new drug application (NDA) to the FDA and receiving the agency’s approval. See 21 U. S. C. §355(a). An NDA must contain, among other things, “the labeling proposed to be used for such drug,” §355(b)(1)(F), “full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use,” §355(b)(1)(A), and “a discussion of why the benefits exceed the risks [of the drug] under the conditions stated in the labeling,” 21 CFR §314.50(d)(5)(viii) (2008). The FDA will approve an NDA only if the agency finds, among other things, that the drug is “safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof,” there is “substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof,” and the proposed labeling is not “false or misleading in any particular.” 21 U. S. C. §355(d).

After the FDA approves a drug, the manufacturer remains under an obligation to investigate and report any adverse events associated with the drug, see 21 CFR §314.80, and must periodically submit any new information that may affect the FDA’s previous conclusions about the safety, effectiveness, or labeling of the drug, 21 U. S. C. §355(k). If the FDA finds that the drug is not “safe” when used in accordance with its labeling, the agency “shall” withdraw its approval of the drug. §355(e). The FDA also “shall” deem a drug “misbranded” if “it is dangerous to health when used in the dosage or manner, or with the frequency or duration prescribed, recommended, or suggested in the labeling thereof.” §352(j).

Thus, a drug’s warning label “serves as the standard under which the FDA determines whether a product is safe and effective.” 50Fed. Reg. 7470 (1985). Labeling is “[t]he centerpiece of risk management,” as it “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively.” 71Fed. Reg. 3934 (2006). The FDA has underscored the importance it places on drug labels by promulgating comprehensive regulations—spanning an entire part of the Code of Federal Regulations, see 21 CFR pt. 201, with seven subparts and 70 separate sections—that set forth drug manufacturers’ labeling obligations. Under those regulations, the FDA must be satisfied that a drug’s warning label contains, among other things, “a summary of the essential scientific information needed for the safe and effective use of the drug,” §201.56(1), including a description of “clinically significant adverse reactions,” “other potential safety hazards,” “limitations in use imposed by them, … and steps that should be taken if they occur,” §201.57(c)(6)(i). Neither the FDCA nor its implementing regulations suggest that juries may second-guess the FDA’s labeling decisions.

B

1

Where the FDA determines, in accordance with its statutory mandate, that a drug is on balance “safe,” our conflict pre-emption cases prohibit any State from countermanding that determination. See, e.g., Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 348 (2001) (after the FDA has struck “a somewhat delicate balance of statutory objectives” and determined that petitioner submitted a valid application to manufacture a medical device, a State may not use common law to negate it); International Paper Co. v. Ouellette, 479 U. S. 481, 494 (1987) (after the EPA has struck “the balance of public and private interests so carefully addressed by” the federal permitting regime for water pollution, a State may not use nuisance law to “upse[t]” it); Chicago & North Western Transp. Co. v. Kalo Brick & Tile Co., 450 U. S. 311, 321 (1981) (after the Interstate Commerce Commission has struck a “balance” between competing interests in permitting the abandonment of a railroad line, a State may not use statutory or common law to negate it).

Thus, as the Court itself recognizes, it is irrelevant in conflict pre-emption cases whether Congress “enacted an express pre-emption provision at some point during the FDCA’s 70-year history.” Ante, at 18; see also Geier, 529 U. S., at 869 (holding the absence of an express pre-emption clause “does not bar the ordinary working of conflict pre-emption principles”). Rather, the ordinary principles of conflict pre-emption turn solely on whether a State has upset the regulatory balance struck by the federal agency. Id., at 884–885; see also Chicago & North Western Transp. Co., supra, at 317 (describing conflict pre-emption as “a two-step process of first ascertaining the construction of the [federal and state laws] and then determining the constitutional question whether they are actually in conflict” (internal quotation marks omitted)).

2

A faithful application of this Court’s conflict pre-emption cases compels the conclusion that the FDA’s 40-year-long effort to regulate the safety and efficacy of Phenergan pre-empts respondent’s tort suit. Indeed, that result follows directly from our conclusion in Geier.

Geier arose under the National Traffic and Motor Safety Vehicle Act of 1966, which directs the Secretary of the Department of Transportation (DOT) to “establish by order … motor vehicle safety standards,” 15 U. S. C. §1392(a) (1988 ed.), which are defined as “minimum standard[s] for motor vehicle performance, or motor vehicle equipment performance,” §1391(2). Acting pursuant to that statutory mandate, the Secretary of Transportation promulgated Federal Motor Vehicle Safety Standard 208, which required car manufacturers to include passive restraint systems (i.e., devices that work automatically to protect occupants from injury during a collision) in a certain percentage of their cars built in or after 1987. See 49 CFR §571.208 (1999). Standard 208 did not require installation of any particular type of passive restraint; instead, it gave manufacturers the option to install automatic seatbelts, airbags, or any other suitable technology that they might develop, provided the restraint(s) met the performance requirements specified in the rule. Ibid.

Alexis Geier drove her 1987 Honda Accord into a tree, and although she was wearing her seatbelt, she nonetheless suffered serious injuries. She then sued Honda under state tort law, alleging that her car was negligently and defectively designed because it lacked a driver’s-side airbag. She argued that Congress had empowered the Secretary to set only “minimum standard[s]” for vehicle safety. 15 U. S. C. §1391(2). She also emphasized that the National Traffic and Motor Safety Vehicle Act contains a saving clause, which provides that “[c]ompliance with any Federal motor vehicle safety standard issued under this subchapter does not exempt any person from any liability under common law.” §1397(k).

Notwithstanding the statute’s saving clause, and notwithstanding the fact that Congress gave the Secretary authority to set only “minimum” safety standards, we held Geier’s state tort suit pre-empted. In reaching that result, we relied heavily on the view of the Secretary of Transportation—expressed in an amicus brief—that Standard 208 “ ‘embodies the Secretary’s policy judgment that safety would best be promoted if manufacturers installed alternative protection systems in their fleets rather than one particular system in every car.’ ” 529 U. S., at 881 (quoting Brief for United States as Amicus Curiae,O. T. 1999, No. 98–1811, p. 25). Because the Secretary determined that a menu of alternative technologies was “safe,” the doctrine of conflict pre-emption barred Geier’s efforts to deem some of those federally approved alternatives “unsafe” under state tort law.

The same rationale applies here. Through Phenergan’s label, the FDA offered medical professionals a menu of federally approved, “safe” and “effective” alternatives—including IV push—for administering the drug. Through a state tort suit, respondent attempted to deem IV push “unsafe” and “ineffective.” To be sure, federal law does not prohibit Wyeth from contraindicating IV push, just as federal law did not prohibit Honda from installing airbags in all its cars. But just as we held that States may not compel the latter, so, too, are States precluded from compelling the former. See also Fidelity Fed. Sav. & Loan Assn. v. De la Cuesta, 458 U. S. 141, 155 (1982) (“The conflict does not evaporate because the [agency’s] regulation simply permits, but does not compel,” the action forbidden by state law). If anything, a finding of pre-emption is even more appropriate here because the FDCA—unlike the National Traffic and Motor Safety Vehicle Act—contains no evidence that Congress intended the FDA to set only “minimum standards,” and the FDCA does not contain a saving clause. 4 See also ante, at 18 (conceding Congress’ “silence” on the issue).

III

In its attempt to evade Geier’s applicability to this case, the Court commits both factual and legal errors. First, as a factual matter, it is demonstrably untrue that the FDA failed to consider (and strike a “balance” between) the specific costs and benefits associated with IV push. Second, as a legal matter, Geier does not stand for the legal propositions espoused by the dissenters (and specifically rejected by the majority) in that case. Third, drug labeling by jury verdict undermines both our broader pre-emption jurisprudence and the broader workability of the federal drug-labeling regime.

A

Phenergan’s warning label has been subject to the FDA’s strict regulatory oversight since the 1950’s. For at least the last 34 years, the FDA has focused specifically on whether IV-push administration of Phenergan is “safe” and “effective” when performed in accordance with Phenergan’s label. The agency’s ultimate decision—to retain IV push as one means for administering Phenergan, albeit subject to stringent warnings—is reflected in the plain text of Phenergan’s label (sometimes in boldfaced font and all-capital letters). And the record contains ample evidence that the FDA specifically considered and reconsidered the strength of Phenergan’s IV-push-related warnings in light of new scientific and medical data. The majority’s factual assertions to the contrary are mistaken.

1

The FDA’s focus on IV push as a means of administering Phenergan dates back at least to 1975. In August of that year, several representatives from both the FDA and Wyeth met to discuss Phenergan’s warning label. At that meeting, the FDA specifically proposed “that Phenergan Injection should not be used in Tubex.” 2 Record 583, 586 (Plaintiff’s Trial Exh. 17, Internal Correspondence from W. E. Langeland to File (Sept. 5, 1975) (hereinafter 1975 Memo)). “Tubex” is a syringe system used exclusively for IV push. See App. 43. An FDA official explained that the agency’s concerns arose from medical-malpractice lawsuits involving IV push of the drug, see 1975 Memo 586, and that the FDA was aware of “5 cases involving amputation where the drug had been administered by Tubex together with several additional cases involving necrosis,” id., at 586–587. Rather than contraindicating Phenergan for IV push, however, the agency and Wyeth agreed “that there was a need for better instruction regarding the problems of intraarterial injection.” Id., at 587.

The next year, the FDA convened an advisory committee to study, among other things, the risks associated with the Tubex system and IV push. App. 294. At the conclusion of its study, the committee recommended an additional IV-push-specific warning for Phenergan’s label, see ibid., but did not recommend eliminating IV push from the drug label altogether. In response to the committee’s recommendations, the FDA instructed Wyeth to make several changes to strengthen Phenergan’s label, including the addition of upper case warnings related to IV push. See id., at 279–280, 282–283.

In 1987, the FDA directed Wyeth to amend its label to include the following text:

“ ‘[1] When used intravenously, [Phenergan] should be given in a concentration no greater than 25 mg/ml and at a rate not to exceed 25 mg/minute. [2] Injection through a properly running intravenous infusion may enhance the possibility of detecting arterial placement.’ ” Id., at 311–312.

The first of the two quoted sentences refers specifically to IV push; as respondent’s medical expert testified at trial, the label’s recommended rate of administration (not to exceed 25 mg per minute) refers to “IV push, as opposed to say being in a bag and dripped over a couple of hours.” Id., at 52. The second of the two quoted sentences refers to IV drip. See id., at 15–16 (emphasizing that a “running IV” is the same thing as “IV drip”).

In its 1987 labeling order, the FDA cited voluminous materials to “suppor[t]” its new and stronger warnings related to IV push and the preferability of IV drip. 5 Id., at 313. One of those articles specifically discussed the relative advantages and disadvantages of IV drip compared to IV push, as well as the costs and benefits of administering Phenergan via IV push. 6 The FDA also cited published case reports from the 1960’s of gangrene caused by the intra-arterial injection of Phenergan, 7 and the FDA instructed Wyeth to amend Phenergan’s label in accordance with the latest medical research. 8 The FDA also studied drugs similar to Phenergan and cited numerous cautionary articles—one of which urged the agency to consider contraindicating such drugs for IV use altogether. 9

In “support” of its labeling order, the FDA also cited numerous articles that singled out the inner crook of the elbow—known as the “antecubital fossa” in the medical community—whichis both a commonly used injection site, see id., at 70 (noting that respondent’s injection was pushed into “the antecubital space”), and a universally recognized high-risk area for inadvertent intra-arterial injections. One of the articles explained:

“Because of the numerous superficial positions the ulnar artery might occupy, it has often been entered during attempted venipuncture [of the antecubital fossa]. … However, the brachial and the radial arteries might also be quite superficial in the elbow region… . The arterial variations of the arm, especially in and about the cubital fossa, are common and numerous. If venipuncture must be performed in this area, a higher index of suspicion must be maintained to forestall misdirected injections.” Stone & Donnelly, The Accidental Intra-arterial Injection of Thiopental, 22 Anesthesiology 995, 996 (1961) (footnote omitted; cited in App. 315, no. 20). 10

Based on this and other research, the FDA ordered Wyeth to include a specific warning related to the use of the antecubital space for IV push. 11

2

When respondent was injured in 2000, Phenergan’s label specifically addressed IV push in several passages (sometimes in lieu of and sometimes in addition to those discussed above). For example, the label warned of the risks of intra-arterial injection associated with “aspiration,” which is a technique used only in conjunction with IV push. 12 The label also cautioned against the use of “syringes with rigid plungers,” App. 390, which are used onlyto administer the drug via IV push. As respondent’s medical expert testified at trial, “by talking plungers and rigid needles, that’s the way you do it, to push it with the plunger.” Id., at 53 (testimony of Dr. John Matthew). Moreover, Phenergan’s 2000 label devoted almost a full page to discussing the “Tubex system,” see id., at 391, which, as noted above, is used only to administer the drug via IV push.

While Phenergan’s label very clearly authorized the use of IV push, it also made clear that IV push is the delivery method of last resort. The label specified that “[t]he preferred parenteral route of administration is by deep intramuscular injection.” Id., at 390. If an intramuscular injection is ineffective, then “it is usually preferable to inject [Phenergan] through the tubing of an intravenous infusion set that is known to be functioning satisfactorily.” Ibid. See also id., at 50–51 (testimony of respondent’s medical expert, Dr. John Matthew) (conceding that the best way to determine that an IV set is functioning satisfactorily is to use IV drip). Finally, if for whatever reason a medical professional chooses to use IV push, he or she is on notice that “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY.” Id., at 391; see also id., at 390 (“Under no circumstances should Phenergan Injection be given by intra-arterial injection due to the likelihood of severe arteriospasm and the possibility of resultant gangrene”).

Phenergan’s label also directs medical practitioners to choose veins wisely when using IV push:

“Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or inadvertent intra-arterial injection. Reports compatible with inadvertent intra-arterial injection of Phenergan Injection, usually in conjunction with other drugs intended for intravenous use, suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances.” Ibid.

Thus, it is demonstrably untrue that, as of 2000, Phenergan’s “labeling did not contain a specific warning about the risks of IV-push administration.” Ante, at 4. And whatever else might be said about the extensive medical authorities and case reports that the FDA cited in “support” of its approval of IV-push administration of Phenergan, it cannot be said that the FDA “paid no more than passing attention to” IV push, ante, at 6; nor can it be said that the FDA failed to weigh its costs and benefits, Brief for Respondent 50.

3

For her part, respondent does not dispute the FDA’s conclusion that IV push has certain benefits. At trial, her medical practitioners testified that they used IV push in order to help her “in a swift and timely way” when she showed up at the hospital for the second time in one day complaining of “intractable” migraines, “terrible pain,” inability to “bear light or sound,” sleeplessness, hours-long spasms of “retching” and “vomiting,” and when “every possible” alternative treatment had “failed.” App. 40 (testimony of Dr. John Matthew); id., at 103, 106, 109 (testimony of physician’s assistant Jessica Fisch).

Rather than disputing the benefits of IV push, respondent complains that the FDA and Wyeth underestimated its costs (and hence did not provide sufficient warnings regarding its risks). But when the FDA mandated that Phenergan’s label read, “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY,” id., at 391, and when the FDA required Wyeth to warn that “[u]nder no circumstances should Phenergan Injection be given by intra-arterial injection,” id., at 390, the agency could reasonably assume that medical professionals would take care not to inject Phenergan intra-arterially. See also 71 Fed. Reg. 3934 (noting that a drug’s warning label “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively”). Unfortunately, the physician’s assistant who treated respondent in this case disregarded Phenergan’s label and pushed the drug into the single spot on her arm that is most likely to cause an inadvertent intra-arterial injection.

As noted above, when the FDA approved Phenergan’s label, it was textbook medical knowledge that the “antecubital fossa” creates a high risk of inadvertent intra-arterial injection, given the close proximity of veins and arteries. See supra, at 13–14; see also The Lippincott Manual of Nursing Practice 99 (7th ed. 2001) (noting, in a red-text “NURSING ALERT,” that the antecubital fossa is “not recommended” for administering dangerous drugs, “due to the potential for extravasation”). 13 According to the physician’s assistant who injured respondent, however, “[i]t never crossed my mind” that an antecubital injection of Phenergan could hit an artery. App. 110; see also ibid. (“[It] just wasn’t something that I was aware of at the time”). Oblivious to the risks emphasized in Phenergan’s warnings, the physician’s assistant pushed a double dose of the drug into an antecubital artery over the course of “[p]robably about three to four minutes,” id., at 111; id., at 105, notwithstanding respondent’s complaints of a “ ‘burn[ing]’ ” sensation that she subsequently described as “ ‘one of the most extreme pains that I’ve ever felt,’ ” id., at 110, 180–181. And when asked why she ignored Phenergan’s label and failed to stop pushing the drug after respondent complained of burning pains, the physician’s assistant explained that it would have been “just crazy” to “worr[y] about an [intra-arterial] injection” under the circumstances, id., at 111.

The FDA, however, did not think that the risks associated with IV push—especially in the antecubital space—were “just crazy.” That is why Phenergan’s label so clearly warns against them.

B

Given the “balance” that the FDA struck between the costs and benefits of administering Phenergan via IV push, Geier compels the pre-emption of tort suits (like this one) that would upset that balance. The contrary conclusion requires turning yesterday’s dissent into today’s majority opinion.

First, the Court denies the existence of a federal-state conflict in this case because Vermont merely countermanded the FDA’s determination that IV push is “safe” when performed in accordance with Phenergan’s warning label; the Court concludes that there is no conflict because Vermont did not “mandate a particular” label as a “replacement” for the one that the jury nullified, and because the State stopped short of altogether “contraindicating IV-push administration.” Ante, at 8. But as we emphasized in Geier (over the dissent’s assertions to the contrary), the degree of a State’s intrusion upon federal law is irrelevant—the Supremacy Clause applies with equal force to a state tort law that merely countermands a federal safety determination and to a state law that altogether prohibits car manufacturers from selling cars without airbags. Compare 529 U. S., at 881–882, with id., at 902 (Stevens, J., dissenting). Indeed, as recently as last Term, we held that the Supremacy Clause pre-empts a “[s]tate tort law that requires a manufacturer’s catheters to be safer, but hence less effective, than the model the FDA has approved … .” Riegel, 552 U. S., at ___ (slip op., at 11). It did not matter there that the State stopped short of altogether prohibiting the use of FDA-approved catheters—just as it does not matter here that Vermont stopped short of altogether prohibiting an FDA-approved method for administering Phenergan. See also Lohr, 518 U. S., at 504 (Breyer, J., concurring in part and concurring in judgment) (noting it would be an “anomalous result” if pre-emption applied differently to a state tort suit premised on the inadequacy of the FDA’s safety regulations and a state law that specifically prohibited an FDA-approved design).

Second, the Court today distinguishes Geier because the FDA articulated its pre-emptive intent “without offering States or other interested parties notice or opportunity for comment. Ante, at 21; see also ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that conflict pre-emption is appropriate only where the agency expresses its pre-emptive intent through notice-and-comment rulemaking. Compare 529 U. S., at 885 (“To insist on a specific expression of agency intent to pre-empt, made after notice-and-comment rulemaking, would be in certain cases to tolerate conflicts that an agency, and therefore Congress, is most unlikely to have intended. The dissent, as we have said, apparently welcomes that result … . We do not”), with id., at 908–910 (Stevens, J., dissenting) (emphasizing that “we generally expect an administrative regulation to declare any intention to pre-empt state law with some specificity,” and that “[t]his expectation … serves to ensurethat States will be able to have a dialog with agencies regarding pre-emption decisions ex ante through the normal notice-and-comment procedures of the Administrative Procedure Act” (internal quotation marks omitted)). Indeed, pre-emption is arguably more appropriate here than in Geier because the FDA (unlike the DOT) declared its pre-emptive intent in the Federal Register. See 71 Fed. Reg. 3933–3936. Yet the majority dismisses the FDA’s published preamble as “inherently suspect,” ante, at 21, and an afterthought that is entitled to “no weight,” ante, at 25. Compare Lohr, supra, at 506 (opinion of Breyer, J.) (emphasizing that the FDA has a “special understanding of the likely impact of both state and federal requirements, as well as an understanding of whether (or the extent to which) state requirements may interfere with federal objectives,” and that “[t]he FDA can translate these understandings into particularized pre-emptive intentions … through statements in ‘regulations, pre-ambles, interpretive statements, and responses tocomments’ ”).

Third, the Court distinguishes Geier because the DOT’s regulation “bear[s] the force of law,” whereas the FDA’s preamble does not. Ante, at 24; see also ante, at 19. But it is irrelevant that the FDA’s preamble does not “bear the force of law” because the FDA’s labeling decisions surely do. See 21 U. S. C. §355. It is well within the FDA’s discretion to make its labeling decisions through administrative adjudications rather than through less-formal and less-flexible rulemaking proceedings, see SEC v. Chenery Corp., 332 U. S. 194 (1947) , and we have never previously held that our pre-emption analysis turns on the agency’s choice of the latter over the former. Moreover, it cannot be said that Geier’s outcome hinged on the agency’s choice to promulgate a rule. See ante, at 19, 24. The Geier Court relied—again over the dissenters’ protestations—on materials other than the Secretary’s regulation to explain the conflict between state and federal law. Compare 529 U. S., at 881, with id., at 899–900 (Stevens, J., dissenting), and ante, at 1–2 (Breyer, J., concurring).

Fourth, the Court sandwiches its discussion of Geier between the “presumption against pre-emption,” ante, at 18, and heavy emphasis on “the longstanding coexistence of state and federal law and the FDA’s traditional recognition of state-law remedies,” ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that the “presumption against pre-emption” is relevant to the conflict pre-emption analysis. See 529 U. S., at 906–907 (Stevens, J., dissenting) (“[T]he Court simply ignores the presumption [against pre-emption]”). Rather than invoking such a “presumption,” the Court emphasized that it was applying “ordinary,” “longstanding,” and “experience-proved principles of conflict pre-emption.” Id., at 874. Under these principles, the sole question is whether there is an “actual conflict” between state and federal law; if so, then pre-emption follows automatically by operation of the Supremacy Clause. Id., at 871–872. See also Buckman, 531 U. S., at 347–348 (“[P]etitioner’s dealings with the FDA were prompted by [federal law], and the very subject matter of petitioner’s statements [to the FDA] were dictated by [federal law]. Accordingly—and in contrast to situations implicating ‘federalism concerns and the historic primacy of state regulation of matters of health and safety’—no presumption against pre-emption obtains in this case” (citation omitted)). 14

Finally, the Geier Court went out of its way to emphasize (yet again over the dissenters’ objections) that it placed “some weight” on the DOT’s amicus brief, which explained the agency’s regulatory objectives and the effects of state tort suits on the federal regulatory regime. 529 U. S., at 883; compare id., at 910–911 (Stevens, J., dissenting) (criticizing the majority for “uph[olding] a regulatory claim of frustration-of-purposes implied conflict pre-emption based on nothing more than an ex post administrative litigating position and inferences from regulatory history and final commentary”). See also Lohr, 518 U. S., at 496 (recognizing that the FDA is “uniquely qualified” to explain whether state law conflicts with the FDA’s objectives). Yet today, the FDA’s explanation of the conflict between state tort suits and the federal labeling regime, set forth in the agency’s amicus brief, is not even mentioned in the Court’s opinion. Instead of relying on the FDA’s explanation of its own regulatory purposes, the Court relies on a decade-old and now-repudiated statement, which the majority finds preferable. See ante, at 21–22, 24, n. 13. Cf. Riegel, 552 U. S., at ___ (slip op., at 13) (noting that “the agency’s earlier position (which the dissent describes at some length and finds preferable) is … compromised, indeed deprived of all claim to deference, by the fact that it is no longer the agency’s position” (citation omitted)); Altria Group, Inc. v. Good, 555 U. S. ___, ___ (2008) (slip op., at 16–17) (rejecting petitioners’ reliance on the pre-emptive effect of the agency’s “longstanding policy” because it is inconsistent with the agency’s current one). And Justice Breyer suggests that state tort suits may “help the [FDA],” ante, at 1 (concurring opinion), notwithstanding the FDA’s insistence that state tort suits will “disrupt the agency’s balancing of health risks and benefits,” Brief for United States as Amicus Curiae 9.

Geier does not countenance the use of state tort suits to second-guess the FDA’s labeling decisions. And the Court’s contrary conclusion has potentially far-reaching consequences.

C

By their very nature, juries are ill-equipped to perform the FDA’s cost-benefit-balancing function. As we explained in Riegel, juries tend to focus on the risk of a particular product’s design or warning label that arguably contributed to a particular plaintiff’s injury, not on the overall benefits of that design or label; “the patients who reaped those benefits are not represented in court.” 552 U. S., at ___ (slip op., at 12). Indeed, patients like respondent are the only ones whom tort juries ever see, and for a patient like respondent—who has already suffered a tragic accident—Phenergan’s risks are no longer a matter of probabilities and potentialities.

In contrast, the FDA has the benefit of the long view. Its drug-approval determinations consider the interests of all potential users of a drug, including “those who would suffer without new medical [products]” if juries in all 50 States were free to contradict the FDA’s expert determinations. Id., at ___ (slip op., at 13). And the FDA conveys its warnings with one voice, rather than whipsawing the medical community with 50 (or more) potentially conflicting ones. After today’s ruling, however, parochialism may prevail.

The problem is well illustrated by the labels borne by “vesicant” drugs, many of which are used for chemotherapy. As a class, vesicants are much more dangerous than drugs like Phenergan, 15 but the vast majority of vesicant labels—like Phenergan’s—either allow or do not disallow IV push. See Appendix, infra. Because vesicant extravasation can have devastating consequences, and because the potentially lifesaving benefits of these drugs offer hollow solace to the victim of such a tragedy, a jury’s cost-benefit analysis in a particular case may well differ from the FDA’s.

For example, consider Mustargen (mechlorethamine HCl)—the injectable form of mustard gas—which can be used as an anticancer drug. Mustargen’s FDA-approved label warns in several places that “This drug is HIGHLY TOXIC.” 16 Indeed, the drug is so highly toxic:

“Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water, for at least 15 minutes while removing contaminated clothing and shoes, followed by 2% sodium thiosulfate solution. Medical attention should be sought immediately. Contaminated clothing should be destroyed.” 17

Yet when it comes to administering this highly toxic drug, the label provides that “the drug may be injected directly into any suitable vein, [but] it is injected preferably into the rubber or plastic tubing of a flowing intravenous infusion set. This reduces the possibility of severe local reactions due to extravasation or high concentration of the drug.” (Emphasis added.) Similarly, the FDA-approved labels for other powerful chemotherapeutic vesicants—including Dactinomycin, Oxaliplatin, Vinblastine, and Vincristine—specifically allow IV push, notwithstanding their devastating effects when extravasated.

The fact that the labels for such drugs allow IV push is striking—both because vesicants are much more dangerous than Phenergan, and also because they are so frequently extravasated, see Boyle & Engelking, Vesicant Extravasation: Myths and Realities, 22 Oncology Nursing Forum 57, 58 (1995) (arguing that the rate of extravasation is “considerably higher” than 6.4% of all vesicant administrations). Regardless of the FDA’s reasons for not contraindicating IV push for these drugs, it is odd (to say the least) that a jury in Vermont can now order for Phenergan what the FDA has chosen not to order for mustard gas. 18

***

To be sure, state tort suits can peacefully coexist with the FDA’s labeling regime, and they have done so for decades. Ante, at 17–18. But this case is far from peaceful coexistence. The FDA told Wyeth that Phenergan’s label renders its use “safe.” But the State of Vermont, through its tort law, said: “Not so.”

The state-law rule at issue here is squarely pre-empted. Therefore, I would reverse the judgment of the Supreme Court of Vermont.

Appendix TO OPINION OF ALITO, J.

Vesicant1

IV Push2

Dactinomycin

Specifically allowed

Mechlorethamine (Mustargen)

Specifically allowed

Oxaliplatin

Specifically allowed

Vinblastine

Specifically allowed

Vincristine

Specifically allowed

Bleomycin

Neither mentioned nor prohibited

Carboplatin

Neither mentioned nor prohibited

Dacarbazine

Neither mentioned nor prohibited

Mitomycin

Neither mentioned nor prohibited

Carmustine

Not prohibited; IV drip recommended

Cisplatin

Not prohibited; IV drip recommended

Epirubicin

Not prohibited; IV drip recommended

Etoposide

Not prohibited; IV drip recommended

Ifosfamide

Not prohibited; IV drip recommended

Mitoxantrone

Not prohibited; IV drip recommended

Paclitaxel

Not prohibited; IV drip recommended

Teniposide

Not prohibited; IV drip recommended

Vinorelbine

Not prohibited; IV drip recommended

Daunorubicin

Prohibited

Doxorubicin

Prohibited

1 Wilkes & Barton-Burke, 2008 Oncology Nursing Drug Handbook 27–33 (2008) (Table 1.6).

2 IV-push information is derived from the “dosage and administration” sections of individual drug labels (available in Clerk of Court’s case file).


Notes

1 Indeed, respondent conceded below that Wyeth did propose an adequate warning of Phenergan’s risks. See Plaintiff Diana Levine’s Memorandum in Opposition to Wyeth’s Motion for Summary Judgment in Levine v. American Home Products Corp. (now Wyeth), No. 670–12–01 Wncv (Super. Ct. Washington Cty., Vt.), ¶7, p. 26. Specifically, respondent noted: “In 1988, Wyeth proposed language that would have prevented this accident by requiring a running IV and explaining why a running IV will address and reduce the risk [of intra-arterial injection].” Ibid. See also id., at 24 (“Although not strong enough, this improved the labeling instruction, if followed, would have prevented the inadvertent administration of Phenergan into an artery …”). The FDA rejected Wyeth’s proposal. See App. 359.

2 Moreover, in the trial judge’s final charge, he told the jury that “the critical factual issue which you must decide” is whether Phenergan’s FDA-mandated label reflects a proper balance between “the risks and benefits of intravenous administration and the potential for injury to patients.” Id., at 220. See also ___ Vt. ___, ___, 944 A. 2d 179, 182 (2006) (recognizing that respondent’s argument is that Phenergan’s “label should not have allowed IV push as a means of administration”).

3 Respondent sued her physician, physician’s assistant, and hospital for malpractice. After the parties settled that suit for an undisclosed sum, respondent’s physician sent her a letter in which he admitted “responsibility” for her injury and expressed his “profoun[d] regre[t]” and “remors[e]” for his actions. 1 Tr. 178–179 (Mar. 8, 2004) (testimony of Dr. John Matthew); see also App. 102–103 (testimony of physician’s assistant Jessica Fisch) (noting that her “sense of grief” was so “great” that she “would have gladly cut off [her own] arm” and given it to respondent). Thereafter, both the physician and the physician’s assistant agreed to testify on respondent’s behalf in her suit against Wyeth.

4 To be sure, Congress recognized the principles of conflict pre-emption in the FDCA. See Drug Amendments of 1962, §202, 76Stat. 793 (“Nothing in the amendments made by this Act to the Federal Food, Drug, and Cosmetic Act shall be construed as invalidating any provision of State law … unless there is a direct and positive conflict between such amendments and such provision of State law”). But a provision that simply recognizes the background principles of conflict pre-emption is not a traditional “saving clause,” and even if it were, it would not displace our conflict-pre-emption analysis. See Geier v. American Honda Motor Co., 529 U. S. 861, 869 (2000) (“[T]he saving clause … does not bar the ordinary working of conflict pre-emption principles”); id., at 873–874 (“The Court has … refused to read general ‘saving’ provisions to tolerate actual conflict both in cases involving impossibility and in ‘frustration-of-purpose’ cases” (emphasis deleted and citation omitted)).

5 The FDA cited numerous articles that generally discuss the costs and benefits associated with IV push. See, e.g., Nahrwold & Phelps, Inadvertent Intra-Arterial Injection of Mephenteramine, 70 Rocky Mountain Medical J. 38 (Sept. 1973) (cited in App. 314, no. 14); Albo, Cheung, Ruth, Snyder, & Beemtsma, Effect of Intra-Arterial Injections of Barbituates, 120 Am. J. of Surgery 676 (1970) (cited in App. 314, no. 12); Corser, Masey, Jacob, Kernoff, & Browne, Ischaemia Following Self-administered Intra-arterial Injection of Methylphenidate and Diamorphine, 40 Anesthesiology 51 (1985) (cited in App. 314, no. 9); Correspondence Regarding Thiopental and Thiamylal (3 letters), 59 Anesthesiology 153 (1983) (cited in App. 314, no. 11); Miller, Arthur, & Stratigos, Intra-arterial Injection of a Barbituate, 23 Anesthesia Progress 25 (1976) (cited in App. 315, no. 19).

6 See Webb & Lampert, Accidental Arterial Injections, 101 Am. J. Obstetrics & Gynecology 365 (1968) (cited in App. 313, no. 5).

7 See Hager & Wilson, Gangrene of the Hand Following Intra-arterial Injection, 94 Archives of Surgery 86 (1967) (cited in App. 313, no. 7); Enloe, Sylvester, & Morris, Hazards of Intra-Arterial Injection of Hydroxyzine, 16 Canadian Anaesthetists’ Society J. 425 (1969) (hereinafter Enloe) (noting “recent reports” of “the occurrence of severe necrosis and gangrene following [administration of] promethazine (Phenergan)” (cited in App. 314, no. 15)). See also Mostafavi & Samimi, Accidental Intra-arterial Injection of Promethazine HCl During General Anesthesia, 35 Anesthesiology 645 (1971) (reporting a case of gangrene, which required partial amputation of three fingers, after Phenergan was inadvertently pushed into an artery in the “antecubital” area); Promethazine, p. 7, in Clinical Pharmacology (Gold Standard Multimedia Inc. CD–ROM, version 1.16 (1998) (noting that “[i]nadvertent intra-arterial injection [of Phenergan] can result in arteriospasm … and development of gangrene”)).

8 Hager and Wilson noted that the most common reactions to intra-arterial injections of drugs like Phenergan include “[i]mmediate, severe, burning pain,” as well as “blanching.” 94 Archives of Surgery, at 87–88. The FDA required Wyeth to include Hager and Wilson’s observations on Phenergan’s label. See App. 311 (requiring the label to warn that “ ‘[t]he first sign [of an intra-arterial injection] may be the patient’s reaction to a sensation of fiery burning’ ” pain and “ ‘[b]lanching’ ”).

9 See Enloe 427 (discussing hydroxyzine—an antihistamine with chemical properties similar to those of Phenergan—and suggesting its “temporary” benefits can never outweigh the risks of intra-arterial injection); see also Goldsmith & Trieger, Accidental Intra-Arterial Injection: A Medical Emergency, 22 Anesthesia Progress 180 (1975) (noting the risks of intra-arterial administration of hydroxyzine) (cited in App. 315, no. 18); Klatte, Brooks, & Rhamy, Toxicity of Intra-Arterial Barbituates and Tranquilizing Drugs, 92 Radiology 700 (1969) (same) (cited in App. 314, no. 13). With full knowledge of those risks, FDA retained IV push for Phenergan, although the agency required Wyeth to incorporate observations from the Enloe article into Phenergan’s label. Compare Enloe 427 (arguing that “every precaution should be taken to avoid inadvertent intra-arterial injection,” including the use of “an obviously well-functioning venoclysis”), with App. 312 (FDA’s 1987 changes to Phenergan’s label). In contrast, at some time around 1970, the FDA prohibited all intravenous use of hydroxyzine. See id., at 79 (testimony of Dr. Harold Green). The FDA’s decision to regulate the two drugs differently—notwithstanding (1) the agency’s knowledge of the risks associated with both drugs and (2) the agency’s recognition of the relevance of hydroxyzine-related articles and case reports in its regulation of Phenergan—further demonstrates that the FDA intentionally preserved IV-push administration for Phenergan. See also Haas, Correspondence, 33 Anesthesia Progress 281 (1986) (“[Hydroxyzine’s] restriction does not lie with the medicine itself, but in the practice and malpractice of intravenous techniques. Unfortunately, the practitioner who knows how to treat injection technique problems is usually not the practitioner with the intravenous technique problems”).

10 See also Engler, Freeman, Kanavage, Ogden, & Moretz, Production of Gangrenous Extremities by Intra-Arterial Injections, 30 Am. Surgeon 602 (1964) (“Accidental arterial injection most often occurs in the antecubital region because this is a favorite site for venopuncture and in this area the ulnar and brachial arteries are superficial and easily entered” (cited in App. 313, no. 6)); Engler, Gangrenous Extremities Resulting from Intra-arterial Injections, 94 Archives of Surgery 644 (1966) (similar) (cited in App. 314, no. 16); Lynas & Bisset, Intra-arterial Thiopentone, 24 Anaesthesia 257 (1969) (“Most [anesthesiologists] agree that injections on the medial aspect of the antecubital fossa are best avoided” (cited in App. 314, no. 8)); Waters, Intra-arterial Thiopentone, 21 Anesthesia 346 (1966) (“The risk of producing gangrene of the forearm by accidental injection of sodium thiopentone into an artery at the elbow has been recognised for many years” (cited in App. 314, no. 10)); see also Hager & Wilson, 94 Archives of Surgery, at 88 (emphasizing that one of the best ways to prevent inadvertent intra-arterial injections is to be aware of “aberrant or superficial arteries at the antecubital, forearm, wrist, and hand level”); Mostafavi & Samimi, supra (warning against antecubital injections).

11 See App. 311 (requiring Phenergan’s label to warn that practitioners should “ ‘[b]eware of the close proximity of arteries and veins at commonly used injection sites and consider the possibility of aberrant arteries’ ”).

12 “Aspiration” refers to drawing a small amount of blood back into the needle to determine whether the needle is in an artery or a vein. Ordinarily, arterial blood is brighter than venous blood—but contact with Phenergan causes discoloration, which makes aspiration an unreliable method of protecting against intra-arterial injection. See id., at 282. Therefore, the label warned that when using IV push, a medical professional should beware that “[a]spiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with Phenergan Injection.” Id., at 390.

13 In addition, respondent’s own medical expert testified at trial that it is a principle of “basic anatomy” that the antecubital fossa contains aberrant arteries. See 2 Tr. 34–35 (Mar. 9, 2004) (testimony of Dr. Daniel O’Brien); see also ibid. (noting that Gray’s Anatomy, which is “the Bible of anatomy,” also warns of arteries in the antecubital space).

14 Thus, it is not true that “this Court has long” applied a presumption against pre-emption in conflict pre-emption cases. Ante, at 9, n. 3 (majority opinion). As long ago as Gibbons v. Ogden, 9 Wheat. 1, 210 (1824), the Court inquired whether a state law “interfer[ed] with,” was “contrary to,” or “c[a]me into collision with” federal law—and it did so without ever invoking a “presumption.” See also Davis, Unmasking the Presumption in Favor of Preemption, 53 S. C. L. Rev. 967, 974 (2002) (noting that many of the Court’s early pre-emption cases “resulted in almost automatic preemption of concurrent state regulation”). In subsequent years the Court has sometimes acknowledged a limited “presumption against pre-emption,” but it nonetheless remained an open question—before today—whether that presumption applied in conflict pre-emption cases. See Crosby v. National Foreign Trade Council, 530 U. S. 363, n. 8 (2000) (“We leave for another day a consideration in this context of a presumption against preemption”). Moreover, this Court has never held that the “presumption” applies in an area—such as drug labeling—that has long been “reserved for federal regulation.” United States v. Locke, 529 U. S. 89, 111 (2000) . See also Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 347–348 (2001) .

15 Vesicants may cause “blistering, severe tissue injury, or tissue necrosis” upon extravasation—even if the drug is not injected into an artery. See, e.g., Schulmeister, Administering Vesicants, 9 Clinical J. of Oncology Nursing 469, 469–470 (2005). See also ante, at 4 (majority opinion) (noting that Phenergan is labeled as an “irritant”); cf. Brief for Anju Budhwani et al. as Amici Curiae 15 (suggesting Phenergan should be considered a “vesicant”).

16 FDA, Oncology Tools Product Label Details, online at http://www.accessdata.fda.gov/scripts/cder/onctools/labels.cfm?GN=meclorethamine, nitrogen mustard (as visited Mar. 2, 2009, and available in Clerk of Court’s case file).

17 Ibid.

18 The same is true of FDA’s regulation of hydroxyzine. See n. 9,supra.


TOP

Dissent

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Alito, with whom The Chief Justice and Justice Scalia join, dissenting.

This case illustrates that tragic facts make bad law. The Court holds that a state tort jury, rather than the Food and Drug Administration (FDA), is ultimately responsible for regulating warning labels for prescription drugs. That result cannot be reconciled with Geier v. American Honda Motor Co., 529 U. S. 861 (2000) , or general principles of conflict pre-emption. I respectfully dissent.

I

The Court frames the question presented as a “narro[w]” one—namely, whether Wyeth has a duty to provide “an adequate warning about using the IV-push method” to administer Phenergan. Ante, at 8. But that ignores the antecedent question of who—the FDA or a jury in Vermont—has the authority and responsibility for determining the “adequacy” of Phenergan’s warnings. Moreover, it is unclear how a “stronger” warning could have helped respondent, see ante, at 16; after all, the physician’s assistant who treated her disregarded at least six separate warnings that are already on Phenergan’s labeling, so respondent would be hard pressed to prove that a seventh would have made a difference. 1

More to the point, the question presented by this case is not a “narrow” one, and it does not concern whether Phenergan’s label should bear a “stronger” warning. Rather, the real issue is whether a state tort jury can countermand the FDA’s considered judgment that Phenergan’s FDA-mandated warning label renders its intravenous (IV) use “safe.” Indeed, respondent’s amended complaint alleged that Phenergan is “not reasonably safe for intravenous administration,” App. 15, ¶6; respondent’s attorney told the jury that Phenergan’s label should say, “ ‘Do not use this drug intravenously,’ ” id., at 32; respondent’s expert told the jury, “I think the drug should be labeled ‘Not for IV use,’ ” id., at 59; and during his closing argument, respondent’s attorney told the jury, “Thank God we don’t rely on the FDA to … make the safe[ty] decision. You will make the decision. … The FDA doesn’t make the decision, you do,” id., at 211–212. 2

Federal law, however, does rely on the FDA to make safety determinations like the one it made here. The FDA has long known about the risks associated with IV push in general and its use to administer Phenergan in particular. Whether wisely or not, the FDA has concluded—over the course of extensive, 54-year-long regulatory proceedings—that the drug is “safe” and “effective” when used in accordance with its FDA-mandated labeling. The unfortunate fact that respondent’s healthcare providers ignored Phenergan’s labeling may make this an ideal medical-malpractice case. 3 But turning a common-law tort suit into a “frontal assault” on the FDA’s regulatory regime for drug labeling upsets the well-settled meaning of the Supremacy Clause and our conflict pre-emption jurisprudence. Brief for United States as Amicus Curiae 21.

II

A

To the extent that “[t]he purpose of Congress is the ultimate touchstone in every pre-emption case,” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) (internal quotation marks omitted), Congress made its “purpose” plain in authorizing the FDA—not state tort juries—to determine when and under what circumstances a drug is “safe.” “[T]he process for approving new drugs is at least as rigorous as the premarket approval process for medical devices,” Riegel v. Medtronic, Inc., 552 U. S. ___, ___ (2008) (slip op., at 11) (Ginsburg, J., dissenting), and we held that the latter pre-empted a state-law tort suit that conflicted with the FDA’s determination that a medical device was “safe,” id., at ___ (slip op., at 11) (opinion of the Court).

Under the Federal Food, Drug, and Cosmetic Act (FDCA), a drug manufacturer may not market a new drug before first submitting a new drug application (NDA) to the FDA and receiving the agency’s approval. See 21 U. S. C. §355(a). An NDA must contain, among other things, “the labeling proposed to be used for such drug,” §355(b)(1)(F), “full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use,” §355(b)(1)(A), and “a discussion of why the benefits exceed the risks [of the drug] under the conditions stated in the labeling,” 21 CFR §314.50(d)(5)(viii) (2008). The FDA will approve an NDA only if the agency finds, among other things, that the drug is “safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof,” there is “substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof,” and the proposed labeling is not “false or misleading in any particular.” 21 U. S. C. §355(d).

After the FDA approves a drug, the manufacturer remains under an obligation to investigate and report any adverse events associated with the drug, see 21 CFR §314.80, and must periodically submit any new information that may affect the FDA’s previous conclusions about the safety, effectiveness, or labeling of the drug, 21 U. S. C. §355(k). If the FDA finds that the drug is not “safe” when used in accordance with its labeling, the agency “shall” withdraw its approval of the drug. §355(e). The FDA also “shall” deem a drug “misbranded” if “it is dangerous to health when used in the dosage or manner, or with the frequency or duration prescribed, recommended, or suggested in the labeling thereof.” §352(j).

Thus, a drug’s warning label “serves as the standard under which the FDA determines whether a product is safe and effective.” 50Fed. Reg. 7470 (1985). Labeling is “[t]he centerpiece of risk management,” as it “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively.” 71Fed. Reg. 3934 (2006). The FDA has underscored the importance it places on drug labels by promulgating comprehensive regulations—spanning an entire part of the Code of Federal Regulations, see 21 CFR pt. 201, with seven subparts and 70 separate sections—that set forth drug manufacturers’ labeling obligations. Under those regulations, the FDA must be satisfied that a drug’s warning label contains, among other things, “a summary of the essential scientific information needed for the safe and effective use of the drug,” §201.56(1), including a description of “clinically significant adverse reactions,” “other potential safety hazards,” “limitations in use imposed by them, … and steps that should be taken if they occur,” §201.57(c)(6)(i). Neither the FDCA nor its implementing regulations suggest that juries may second-guess the FDA’s labeling decisions.

B

1

Where the FDA determines, in accordance with its statutory mandate, that a drug is on balance “safe,” our conflict pre-emption cases prohibit any State from countermanding that determination. See, e.g., Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 348 (2001) (after the FDA has struck “a somewhat delicate balance of statutory objectives” and determined that petitioner submitted a valid application to manufacture a medical device, a State may not use common law to negate it); International Paper Co. v. Ouellette, 479 U. S. 481, 494 (1987) (after the EPA has struck “the balance of public and private interests so carefully addressed by” the federal permitting regime for water pollution, a State may not use nuisance law to “upse[t]” it); Chicago & North Western Transp. Co. v. Kalo Brick & Tile Co., 450 U. S. 311, 321 (1981) (after the Interstate Commerce Commission has struck a “balance” between competing interests in permitting the abandonment of a railroad line, a State may not use statutory or common law to negate it).

Thus, as the Court itself recognizes, it is irrelevant in conflict pre-emption cases whether Congress “enacted an express pre-emption provision at some point during the FDCA’s 70-year history.” Ante, at 18; see also Geier, 529 U. S., at 869 (holding the absence of an express pre-emption clause “does not bar the ordinary working of conflict pre-emption principles”). Rather, the ordinary principles of conflict pre-emption turn solely on whether a State has upset the regulatory balance struck by the federal agency. Id., at 884–885; see also Chicago & North Western Transp. Co., supra, at 317 (describing conflict pre-emption as “a two-step process of first ascertaining the construction of the [federal and state laws] and then determining the constitutional question whether they are actually in conflict” (internal quotation marks omitted)).

2

A faithful application of this Court’s conflict pre-emption cases compels the conclusion that the FDA’s 40-year-long effort to regulate the safety and efficacy of Phenergan pre-empts respondent’s tort suit. Indeed, that result follows directly from our conclusion in Geier.

Geier arose under the National Traffic and Motor Safety Vehicle Act of 1966, which directs the Secretary of the Department of Transportation (DOT) to “establish by order … motor vehicle safety standards,” 15 U. S. C. §1392(a) (1988 ed.), which are defined as “minimum standard[s] for motor vehicle performance, or motor vehicle equipment performance,” §1391(2). Acting pursuant to that statutory mandate, the Secretary of Transportation promulgated Federal Motor Vehicle Safety Standard 208, which required car manufacturers to include passive restraint systems (i.e., devices that work automatically to protect occupants from injury during a collision) in a certain percentage of their cars built in or after 1987. See 49 CFR §571.208 (1999). Standard 208 did not require installation of any particular type of passive restraint; instead, it gave manufacturers the option to install automatic seatbelts, airbags, or any other suitable technology that they might develop, provided the restraint(s) met the performance requirements specified in the rule. Ibid.

Alexis Geier drove her 1987 Honda Accord into a tree, and although she was wearing her seatbelt, she nonetheless suffered serious injuries. She then sued Honda under state tort law, alleging that her car was negligently and defectively designed because it lacked a driver’s-side airbag. She argued that Congress had empowered the Secretary to set only “minimum standard[s]” for vehicle safety. 15 U. S. C. §1391(2). She also emphasized that the National Traffic and Motor Safety Vehicle Act contains a saving clause, which provides that “[c]ompliance with any Federal motor vehicle safety standard issued under this subchapter does not exempt any person from any liability under common law.” §1397(k).

Notwithstanding the statute’s saving clause, and notwithstanding the fact that Congress gave the Secretary authority to set only “minimum” safety standards, we held Geier’s state tort suit pre-empted. In reaching that result, we relied heavily on the view of the Secretary of Transportation—expressed in an amicus brief—that Standard 208 “ ‘embodies the Secretary’s policy judgment that safety would best be promoted if manufacturers installed alternative protection systems in their fleets rather than one particular system in every car.’ ” 529 U. S., at 881 (quoting Brief for United States as Amicus Curiae,O. T. 1999, No. 98–1811, p. 25). Because the Secretary determined that a menu of alternative technologies was “safe,” the doctrine of conflict pre-emption barred Geier’s efforts to deem some of those federally approved alternatives “unsafe” under state tort law.

The same rationale applies here. Through Phenergan’s label, the FDA offered medical professionals a menu of federally approved, “safe” and “effective” alternatives—including IV push—for administering the drug. Through a state tort suit, respondent attempted to deem IV push “unsafe” and “ineffective.” To be sure, federal law does not prohibit Wyeth from contraindicating IV push, just as federal law did not prohibit Honda from installing airbags in all its cars. But just as we held that States may not compel the latter, so, too, are States precluded from compelling the former. See also Fidelity Fed. Sav. & Loan Assn. v. De la Cuesta, 458 U. S. 141, 155 (1982) (“The conflict does not evaporate because the [agency’s] regulation simply permits, but does not compel,” the action forbidden by state law). If anything, a finding of pre-emption is even more appropriate here because the FDCA—unlike the National Traffic and Motor Safety Vehicle Act—contains no evidence that Congress intended the FDA to set only “minimum standards,” and the FDCA does not contain a saving clause. 4 See also ante, at 18 (conceding Congress’ “silence” on the issue).

III

In its attempt to evade Geier’s applicability to this case, the Court commits both factual and legal errors. First, as a factual matter, it is demonstrably untrue that the FDA failed to consider (and strike a “balance” between) the specific costs and benefits associated with IV push. Second, as a legal matter, Geier does not stand for the legal propositions espoused by the dissenters (and specifically rejected by the majority) in that case. Third, drug labeling by jury verdict undermines both our broader pre-emption jurisprudence and the broader workability of the federal drug-labeling regime.

A

Phenergan’s warning label has been subject to the FDA’s strict regulatory oversight since the 1950’s. For at least the last 34 years, the FDA has focused specifically on whether IV-push administration of Phenergan is “safe” and “effective” when performed in accordance with Phenergan’s label. The agency’s ultimate decision—to retain IV push as one means for administering Phenergan, albeit subject to stringent warnings—is reflected in the plain text of Phenergan’s label (sometimes in boldfaced font and all-capital letters). And the record contains ample evidence that the FDA specifically considered and reconsidered the strength of Phenergan’s IV-push-related warnings in light of new scientific and medical data. The majority’s factual assertions to the contrary are mistaken.

1

The FDA’s focus on IV push as a means of administering Phenergan dates back at least to 1975. In August of that year, several representatives from both the FDA and Wyeth met to discuss Phenergan’s warning label. At that meeting, the FDA specifically proposed “that Phenergan Injection should not be used in Tubex.” 2 Record 583, 586 (Plaintiff’s Trial Exh. 17, Internal Correspondence from W. E. Langeland to File (Sept. 5, 1975) (hereinafter 1975 Memo)). “Tubex” is a syringe system used exclusively for IV push. See App. 43. An FDA official explained that the agency’s concerns arose from medical-malpractice lawsuits involving IV push of the drug, see 1975 Memo 586, and that the FDA was aware of “5 cases involving amputation where the drug had been administered by Tubex together with several additional cases involving necrosis,” id., at 586–587. Rather than contraindicating Phenergan for IV push, however, the agency and Wyeth agreed “that there was a need for better instruction regarding the problems of intraarterial injection.” Id., at 587.

The next year, the FDA convened an advisory committee to study, among other things, the risks associated with the Tubex system and IV push. App. 294. At the conclusion of its study, the committee recommended an additional IV-push-specific warning for Phenergan’s label, see ibid., but did not recommend eliminating IV push from the drug label altogether. In response to the committee’s recommendations, the FDA instructed Wyeth to make several changes to strengthen Phenergan’s label, including the addition of upper case warnings related to IV push. See id., at 279–280, 282–283.

In 1987, the FDA directed Wyeth to amend its label to include the following text:

“ ‘[1] When used intravenously, [Phenergan] should be given in a concentration no greater than 25 mg/ml and at a rate not to exceed 25 mg/minute. [2] Injection through a properly running intravenous infusion may enhance the possibility of detecting arterial placement.’ ” Id., at 311–312.

The first of the two quoted sentences refers specifically to IV push; as respondent’s medical expert testified at trial, the label’s recommended rate of administration (not to exceed 25 mg per minute) refers to “IV push, as opposed to say being in a bag and dripped over a couple of hours.” Id., at 52. The second of the two quoted sentences refers to IV drip. See id., at 15–16 (emphasizing that a “running IV” is the same thing as “IV drip”).

In its 1987 labeling order, the FDA cited voluminous materials to “suppor[t]” its new and stronger warnings related to IV push and the preferability of IV drip. 5 Id., at 313. One of those articles specifically discussed the relative advantages and disadvantages of IV drip compared to IV push, as well as the costs and benefits of administering Phenergan via IV push. 6 The FDA also cited published case reports from the 1960’s of gangrene caused by the intra-arterial injection of Phenergan, 7 and the FDA instructed Wyeth to amend Phenergan’s label in accordance with the latest medical research. 8 The FDA also studied drugs similar to Phenergan and cited numerous cautionary articles—one of which urged the agency to consider contraindicating such drugs for IV use altogether. 9

In “support” of its labeling order, the FDA also cited numerous articles that singled out the inner crook of the elbow—known as the “antecubital fossa” in the medical community—whichis both a commonly used injection site, see id., at 70 (noting that respondent’s injection was pushed into “the antecubital space”), and a universally recognized high-risk area for inadvertent intra-arterial injections. One of the articles explained:

“Because of the numerous superficial positions the ulnar artery might occupy, it has often been entered during attempted venipuncture [of the antecubital fossa]. … However, the brachial and the radial arteries might also be quite superficial in the elbow region… . The arterial variations of the arm, especially in and about the cubital fossa, are common and numerous. If venipuncture must be performed in this area, a higher index of suspicion must be maintained to forestall misdirected injections.” Stone & Donnelly, The Accidental Intra-arterial Injection of Thiopental, 22 Anesthesiology 995, 996 (1961) (footnote omitted; cited in App. 315, no. 20). 10

Based on this and other research, the FDA ordered Wyeth to include a specific warning related to the use of the antecubital space for IV push. 11

2

When respondent was injured in 2000, Phenergan’s label specifically addressed IV push in several passages (sometimes in lieu of and sometimes in addition to those discussed above). For example, the label warned of the risks of intra-arterial injection associated with “aspiration,” which is a technique used only in conjunction with IV push. 12 The label also cautioned against the use of “syringes with rigid plungers,” App. 390, which are used onlyto administer the drug via IV push. As respondent’s medical expert testified at trial, “by talking plungers and rigid needles, that’s the way you do it, to push it with the plunger.” Id., at 53 (testimony of Dr. John Matthew). Moreover, Phenergan’s 2000 label devoted almost a full page to discussing the “Tubex system,” see id., at 391, which, as noted above, is used only to administer the drug via IV push.

While Phenergan’s label very clearly authorized the use of IV push, it also made clear that IV push is the delivery method of last resort. The label specified that “[t]he preferred parenteral route of administration is by deep intramuscular injection.” Id., at 390. If an intramuscular injection is ineffective, then “it is usually preferable to inject [Phenergan] through the tubing of an intravenous infusion set that is known to be functioning satisfactorily.” Ibid. See also id., at 50–51 (testimony of respondent’s medical expert, Dr. John Matthew) (conceding that the best way to determine that an IV set is functioning satisfactorily is to use IV drip). Finally, if for whatever reason a medical professional chooses to use IV push, he or she is on notice that “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY.” Id., at 391; see also id., at 390 (“Under no circumstances should Phenergan Injection be given by intra-arterial injection due to the likelihood of severe arteriospasm and the possibility of resultant gangrene”).

Phenergan’s label also directs medical practitioners to choose veins wisely when using IV push:

“Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or inadvertent intra-arterial injection. Reports compatible with inadvertent intra-arterial injection of Phenergan Injection, usually in conjunction with other drugs intended for intravenous use, suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances.” Ibid.

Thus, it is demonstrably untrue that, as of 2000, Phenergan’s “labeling did not contain a specific warning about the risks of IV-push administration.” Ante, at 4. And whatever else might be said about the extensive medical authorities and case reports that the FDA cited in “support” of its approval of IV-push administration of Phenergan, it cannot be said that the FDA “paid no more than passing attention to” IV push, ante, at 6; nor can it be said that the FDA failed to weigh its costs and benefits, Brief for Respondent 50.

3

For her part, respondent does not dispute the FDA’s conclusion that IV push has certain benefits. At trial, her medical practitioners testified that they used IV push in order to help her “in a swift and timely way” when she showed up at the hospital for the second time in one day complaining of “intractable” migraines, “terrible pain,” inability to “bear light or sound,” sleeplessness, hours-long spasms of “retching” and “vomiting,” and when “every possible” alternative treatment had “failed.” App. 40 (testimony of Dr. John Matthew); id., at 103, 106, 109 (testimony of physician’s assistant Jessica Fisch).

Rather than disputing the benefits of IV push, respondent complains that the FDA and Wyeth underestimated its costs (and hence did not provide sufficient warnings regarding its risks). But when the FDA mandated that Phenergan’s label read, “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY,” id., at 391, and when the FDA required Wyeth to warn that “[u]nder no circumstances should Phenergan Injection be given by intra-arterial injection,” id., at 390, the agency could reasonably assume that medical professionals would take care not to inject Phenergan intra-arterially. See also 71 Fed. Reg. 3934 (noting that a drug’s warning label “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively”). Unfortunately, the physician’s assistant who treated respondent in this case disregarded Phenergan’s label and pushed the drug into the single spot on her arm that is most likely to cause an inadvertent intra-arterial injection.

As noted above, when the FDA approved Phenergan’s label, it was textbook medical knowledge that the “antecubital fossa” creates a high risk of inadvertent intra-arterial injection, given the close proximity of veins and arteries. See supra, at 13–14; see also The Lippincott Manual of Nursing Practice 99 (7th ed. 2001) (noting, in a red-text “NURSING ALERT,” that the antecubital fossa is “not recommended” for administering dangerous drugs, “due to the potential for extravasation”). 13 According to the physician’s assistant who injured respondent, however, “[i]t never crossed my mind” that an antecubital injection of Phenergan could hit an artery. App. 110; see also ibid. (“[It] just wasn’t something that I was aware of at the time”). Oblivious to the risks emphasized in Phenergan’s warnings, the physician’s assistant pushed a double dose of the drug into an antecubital artery over the course of “[p]robably about three to four minutes,” id., at 111; id., at 105, notwithstanding respondent’s complaints of a “ ‘burn[ing]’ ” sensation that she subsequently described as “ ‘one of the most extreme pains that I’ve ever felt,’ ” id., at 110, 180–181. And when asked why she ignored Phenergan’s label and failed to stop pushing the drug after respondent complained of burning pains, the physician’s assistant explained that it would have been “just crazy” to “worr[y] about an [intra-arterial] injection” under the circumstances, id., at 111.

The FDA, however, did not think that the risks associated with IV push—especially in the antecubital space—were “just crazy.” That is why Phenergan’s label so clearly warns against them.

B

Given the “balance” that the FDA struck between the costs and benefits of administering Phenergan via IV push, Geier compels the pre-emption of tort suits (like this one) that would upset that balance. The contrary conclusion requires turning yesterday’s dissent into today’s majority opinion.

First, the Court denies the existence of a federal-state conflict in this case because Vermont merely countermanded the FDA’s determination that IV push is “safe” when performed in accordance with Phenergan’s warning label; the Court concludes that there is no conflict because Vermont did not “mandate a particular” label as a “replacement” for the one that the jury nullified, and because the State stopped short of altogether “contraindicating IV-push administration.” Ante, at 8. But as we emphasized in Geier (over the dissent’s assertions to the contrary), the degree of a State’s intrusion upon federal law is irrelevant—the Supremacy Clause applies with equal force to a state tort law that merely countermands a federal safety determination and to a state law that altogether prohibits car manufacturers from selling cars without airbags. Compare 529 U. S., at 881–882, with id., at 902 (Stevens, J., dissenting). Indeed, as recently as last Term, we held that the Supremacy Clause pre-empts a “[s]tate tort law that requires a manufacturer’s catheters to be safer, but hence less effective, than the model the FDA has approved … .” Riegel, 552 U. S., at ___ (slip op., at 11). It did not matter there that the State stopped short of altogether prohibiting the use of FDA-approved catheters—just as it does not matter here that Vermont stopped short of altogether prohibiting an FDA-approved method for administering Phenergan. See also Lohr, 518 U. S., at 504 (Breyer, J., concurring in part and concurring in judgment) (noting it would be an “anomalous result” if pre-emption applied differently to a state tort suit premised on the inadequacy of the FDA’s safety regulations and a state law that specifically prohibited an FDA-approved design).

Second, the Court today distinguishes Geier because the FDA articulated its pre-emptive intent “without offering States or other interested parties notice or opportunity for comment. Ante, at 21; see also ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that conflict pre-emption is appropriate only where the agency expresses its pre-emptive intent through notice-and-comment rulemaking. Compare 529 U. S., at 885 (“To insist on a specific expression of agency intent to pre-empt, made after notice-and-comment rulemaking, would be in certain cases to tolerate conflicts that an agency, and therefore Congress, is most unlikely to have intended. The dissent, as we have said, apparently welcomes that result … . We do not”), with id., at 908–910 (Stevens, J., dissenting) (emphasizing that “we generally expect an administrative regulation to declare any intention to pre-empt state law with some specificity,” and that “[t]his expectation … serves to ensurethat States will be able to have a dialog with agencies regarding pre-emption decisions ex ante through the normal notice-and-comment procedures of the Administrative Procedure Act” (internal quotation marks omitted)). Indeed, pre-emption is arguably more appropriate here than in Geier because the FDA (unlike the DOT) declared its pre-emptive intent in the Federal Register. See 71 Fed. Reg. 3933–3936. Yet the majority dismisses the FDA’s published preamble as “inherently suspect,” ante, at 21, and an afterthought that is entitled to “no weight,” ante, at 25. Compare Lohr, supra, at 506 (opinion of Breyer, J.) (emphasizing that the FDA has a “special understanding of the likely impact of both state and federal requirements, as well as an understanding of whether (or the extent to which) state requirements may interfere with federal objectives,” and that “[t]he FDA can translate these understandings into particularized pre-emptive intentions … through statements in ‘regulations, pre-ambles, interpretive statements, and responses tocomments’ ”).

Third, the Court distinguishes Geier because the DOT’s regulation “bear[s] the force of law,” whereas the FDA’s preamble does not. Ante, at 24; see also ante, at 19. But it is irrelevant that the FDA’s preamble does not “bear the force of law” because the FDA’s labeling decisions surely do. See 21 U. S. C. §355. It is well within the FDA’s discretion to make its labeling decisions through administrative adjudications rather than through less-formal and less-flexible rulemaking proceedings, see SEC v. Chenery Corp., 332 U. S. 194 (1947) , and we have never previously held that our pre-emption analysis turns on the agency’s choice of the latter over the former. Moreover, it cannot be said that Geier’s outcome hinged on the agency’s choice to promulgate a rule. See ante, at 19, 24. The Geier Court relied—again over the dissenters’ protestations—on materials other than the Secretary’s regulation to explain the conflict between state and federal law. Compare 529 U. S., at 881, with id., at 899–900 (Stevens, J., dissenting), and ante, at 1–2 (Breyer, J., concurring).

Fourth, the Court sandwiches its discussion of Geier between the “presumption against pre-emption,” ante, at 18, and heavy emphasis on “the longstanding coexistence of state and federal law and the FDA’s traditional recognition of state-law remedies,” ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that the “presumption against pre-emption” is relevant to the conflict pre-emption analysis. See 529 U. S., at 906–907 (Stevens, J., dissenting) (“[T]he Court simply ignores the presumption [against pre-emption]”). Rather than invoking such a “presumption,” the Court emphasized that it was applying “ordinary,” “longstanding,” and “experience-proved principles of conflict pre-emption.” Id., at 874. Under these principles, the sole question is whether there is an “actual conflict” between state and federal law; if so, then pre-emption follows automatically by operation of the Supremacy Clause. Id., at 871–872. See also Buckman, 531 U. S., at 347–348 (“[P]etitioner’s dealings with the FDA were prompted by [federal law], and the very subject matter of petitioner’s statements [to the FDA] were dictated by [federal law]. Accordingly—and in contrast to situations implicating ‘federalism concerns and the historic primacy of state regulation of matters of health and safety’—no presumption against pre-emption obtains in this case” (citation omitted)). 14

Finally, the Geier Court went out of its way to emphasize (yet again over the dissenters’ objections) that it placed “some weight” on the DOT’s amicus brief, which explained the agency’s regulatory objectives and the effects of state tort suits on the federal regulatory regime. 529 U. S., at 883; compare id., at 910–911 (Stevens, J., dissenting) (criticizing the majority for “uph[olding] a regulatory claim of frustration-of-purposes implied conflict pre-emption based on nothing more than an ex post administrative litigating position and inferences from regulatory history and final commentary”). See also Lohr, 518 U. S., at 496 (recognizing that the FDA is “uniquely qualified” to explain whether state law conflicts with the FDA’s objectives). Yet today, the FDA’s explanation of the conflict between state tort suits and the federal labeling regime, set forth in the agency’s amicus brief, is not even mentioned in the Court’s opinion. Instead of relying on the FDA’s explanation of its own regulatory purposes, the Court relies on a decade-old and now-repudiated statement, which the majority finds preferable. See ante, at 21–22, 24, n. 13. Cf. Riegel, 552 U. S., at ___ (slip op., at 13) (noting that “the agency’s earlier position (which the dissent describes at some length and finds preferable) is … compromised, indeed deprived of all claim to deference, by the fact that it is no longer the agency’s position” (citation omitted)); Altria Group, Inc. v. Good, 555 U. S. ___, ___ (2008) (slip op., at 16–17) (rejecting petitioners’ reliance on the pre-emptive effect of the agency’s “longstanding policy” because it is inconsistent with the agency’s current one). And Justice Breyer suggests that state tort suits may “help the [FDA],” ante, at 1 (concurring opinion), notwithstanding the FDA’s insistence that state tort suits will “disrupt the agency’s balancing of health risks and benefits,” Brief for United States as Amicus Curiae 9.

Geier does not countenance the use of state tort suits to second-guess the FDA’s labeling decisions. And the Court’s contrary conclusion has potentially far-reaching consequences.

C

By their very nature, juries are ill-equipped to perform the FDA’s cost-benefit-balancing function. As we explained in Riegel, juries tend to focus on the risk of a particular product’s design or warning label that arguably contributed to a particular plaintiff’s injury, not on the overall benefits of that design or label; “the patients who reaped those benefits are not represented in court.” 552 U. S., at ___ (slip op., at 12). Indeed, patients like respondent are the only ones whom tort juries ever see, and for a patient like respondent—who has already suffered a tragic accident—Phenergan’s risks are no longer a matter of probabilities and potentialities.

In contrast, the FDA has the benefit of the long view. Its drug-approval determinations consider the interests of all potential users of a drug, including “those who would suffer without new medical [products]” if juries in all 50 States were free to contradict the FDA’s expert determinations. Id., at ___ (slip op., at 13). And the FDA conveys its warnings with one voice, rather than whipsawing the medical community with 50 (or more) potentially conflicting ones. After today’s ruling, however, parochialism may prevail.

The problem is well illustrated by the labels borne by “vesicant” drugs, many of which are used for chemotherapy. As a class, vesicants are much more dangerous than drugs like Phenergan, 15 but the vast majority of vesicant labels—like Phenergan’s—either allow or do not disallow IV push. See Appendix, infra. Because vesicant extravasation can have devastating consequences, and because the potentially lifesaving benefits of these drugs offer hollow solace to the victim of such a tragedy, a jury’s cost-benefit analysis in a particular case may well differ from the FDA’s.

For example, consider Mustargen (mechlorethamine HCl)—the injectable form of mustard gas—which can be used as an anticancer drug. Mustargen’s FDA-approved label warns in several places that “This drug is HIGHLY TOXIC.” 16 Indeed, the drug is so highly toxic:

“Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water, for at least 15 minutes while removing contaminated clothing and shoes, followed by 2% sodium thiosulfate solution. Medical attention should be sought immediately. Contaminated clothing should be destroyed.” 17

Yet when it comes to administering this highly toxic drug, the label provides that “the drug may be injected directly into any suitable vein, [but] it is injected preferably into the rubber or plastic tubing of a flowing intravenous infusion set. This reduces the possibility of severe local reactions due to extravasation or high concentration of the drug.” (Emphasis added.) Similarly, the FDA-approved labels for other powerful chemotherapeutic vesicants—including Dactinomycin, Oxaliplatin, Vinblastine, and Vincristine—specifically allow IV push, notwithstanding their devastating effects when extravasated.

The fact that the labels for such drugs allow IV push is striking—both because vesicants are much more dangerous than Phenergan, and also because they are so frequently extravasated, see Boyle & Engelking, Vesicant Extravasation: Myths and Realities, 22 Oncology Nursing Forum 57, 58 (1995) (arguing that the rate of extravasation is “considerably higher” than 6.4% of all vesicant administrations). Regardless of the FDA’s reasons for not contraindicating IV push for these drugs, it is odd (to say the least) that a jury in Vermont can now order for Phenergan what the FDA has chosen not to order for mustard gas. 18

***

To be sure, state tort suits can peacefully coexist with the FDA’s labeling regime, and they have done so for decades. Ante, at 17–18. But this case is far from peaceful coexistence. The FDA told Wyeth that Phenergan’s label renders its use “safe.” But the State of Vermont, through its tort law, said: “Not so.”

The state-law rule at issue here is squarely pre-empted. Therefore, I would reverse the judgment of the Supreme Court of Vermont.

Appendix TO OPINION OF ALITO, J.

Vesicant1

IV Push2

Dactinomycin

Specifically allowed

Mechlorethamine (Mustargen)

Specifically allowed

Oxaliplatin

Specifically allowed

Vinblastine

Specifically allowed

Vincristine

Specifically allowed

Bleomycin

Neither mentioned nor prohibited

Carboplatin

Neither mentioned nor prohibited

Dacarbazine

Neither mentioned nor prohibited

Mitomycin

Neither mentioned nor prohibited

Carmustine

Not prohibited; IV drip recommended

Cisplatin

Not prohibited; IV drip recommended

Epirubicin

Not prohibited; IV drip recommended

Etoposide

Not prohibited; IV drip recommended

Ifosfamide

Not prohibited; IV drip recommended

Mitoxantrone

Not prohibited; IV drip recommended

Paclitaxel

Not prohibited; IV drip recommended

Teniposide

Not prohibited; IV drip recommended

Vinorelbine

Not prohibited; IV drip recommended

Daunorubicin

Prohibited

Doxorubicin

Prohibited

1 Wilkes & Barton-Burke, 2008 Oncology Nursing Drug Handbook 27–33 (2008) (Table 1.6).

2 IV-push information is derived from the “dosage and administration” sections of individual drug labels (available in Clerk of Court’s case file).


Notes

1 Indeed, respondent conceded below that Wyeth did propose an adequate warning of Phenergan’s risks. See Plaintiff Diana Levine’s Memorandum in Opposition to Wyeth’s Motion for Summary Judgment in Levine v. American Home Products Corp. (now Wyeth), No. 670–12–01 Wncv (Super. Ct. Washington Cty., Vt.), ¶7, p. 26. Specifically, respondent noted: “In 1988, Wyeth proposed language that would have prevented this accident by requiring a running IV and explaining why a running IV will address and reduce the risk [of intra-arterial injection].” Ibid. See also id., at 24 (“Although not strong enough, this improved the labeling instruction, if followed, would have prevented the inadvertent administration of Phenergan into an artery …”). The FDA rejected Wyeth’s proposal. See App. 359.

2 Moreover, in the trial judge’s final charge, he told the jury that “the critical factual issue which you must decide” is whether Phenergan’s FDA-mandated label reflects a proper balance between “the risks and benefits of intravenous administration and the potential for injury to patients.” Id., at 220. See also ___ Vt. ___, ___, 944 A. 2d 179, 182 (2006) (recognizing that respondent’s argument is that Phenergan’s “label should not have allowed IV push as a means of administration”).

3 Respondent sued her physician, physician’s assistant, and hospital for malpractice. After the parties settled that suit for an undisclosed sum, respondent’s physician sent her a letter in which he admitted “responsibility” for her injury and expressed his “profoun[d] regre[t]” and “remors[e]” for his actions. 1 Tr. 178–179 (Mar. 8, 2004) (testimony of Dr. John Matthew); see also App. 102–103 (testimony of physician’s assistant Jessica Fisch) (noting that her “sense of grief” was so “great” that she “would have gladly cut off [her own] arm” and given it to respondent). Thereafter, both the physician and the physician’s assistant agreed to testify on respondent’s behalf in her suit against Wyeth.

4 To be sure, Congress recognized the principles of conflict pre-emption in the FDCA. See Drug Amendments of 1962, §202, 76Stat. 793 (“Nothing in the amendments made by this Act to the Federal Food, Drug, and Cosmetic Act shall be construed as invalidating any provision of State law … unless there is a direct and positive conflict between such amendments and such provision of State law”). But a provision that simply recognizes the background principles of conflict pre-emption is not a traditional “saving clause,” and even if it were, it would not displace our conflict-pre-emption analysis. See Geier v. American Honda Motor Co., 529 U. S. 861, 869 (2000) (“[T]he saving clause … does not bar the ordinary working of conflict pre-emption principles”); id., at 873–874 (“The Court has … refused to read general ‘saving’ provisions to tolerate actual conflict both in cases involving impossibility and in ‘frustration-of-purpose’ cases” (emphasis deleted and citation omitted)).

5 The FDA cited numerous articles that generally discuss the costs and benefits associated with IV push. See, e.g., Nahrwold & Phelps, Inadvertent Intra-Arterial Injection of Mephenteramine, 70 Rocky Mountain Medical J. 38 (Sept. 1973) (cited in App. 314, no. 14); Albo, Cheung, Ruth, Snyder, & Beemtsma, Effect of Intra-Arterial Injections of Barbituates, 120 Am. J. of Surgery 676 (1970) (cited in App. 314, no. 12); Corser, Masey, Jacob, Kernoff, & Browne, Ischaemia Following Self-administered Intra-arterial Injection of Methylphenidate and Diamorphine, 40 Anesthesiology 51 (1985) (cited in App. 314, no. 9); Correspondence Regarding Thiopental and Thiamylal (3 letters), 59 Anesthesiology 153 (1983) (cited in App. 314, no. 11); Miller, Arthur, & Stratigos, Intra-arterial Injection of a Barbituate, 23 Anesthesia Progress 25 (1976) (cited in App. 315, no. 19).

6 See Webb & Lampert, Accidental Arterial Injections, 101 Am. J. Obstetrics & Gynecology 365 (1968) (cited in App. 313, no. 5).

7 See Hager & Wilson, Gangrene of the Hand Following Intra-arterial Injection, 94 Archives of Surgery 86 (1967) (cited in App. 313, no. 7); Enloe, Sylvester, & Morris, Hazards of Intra-Arterial Injection of Hydroxyzine, 16 Canadian Anaesthetists’ Society J. 425 (1969) (hereinafter Enloe) (noting “recent reports” of “the occurrence of severe necrosis and gangrene following [administration of] promethazine (Phenergan)” (cited in App. 314, no. 15)). See also Mostafavi & Samimi, Accidental Intra-arterial Injection of Promethazine HCl During General Anesthesia, 35 Anesthesiology 645 (1971) (reporting a case of gangrene, which required partial amputation of three fingers, after Phenergan was inadvertently pushed into an artery in the “antecubital” area); Promethazine, p. 7, in Clinical Pharmacology (Gold Standard Multimedia Inc. CD–ROM, version 1.16 (1998) (noting that “[i]nadvertent intra-arterial injection [of Phenergan] can result in arteriospasm … and development of gangrene”)).

8 Hager and Wilson noted that the most common reactions to intra-arterial injections of drugs like Phenergan include “[i]mmediate, severe, burning pain,” as well as “blanching.” 94 Archives of Surgery, at 87–88. The FDA required Wyeth to include Hager and Wilson’s observations on Phenergan’s label. See App. 311 (requiring the label to warn that “ ‘[t]he first sign [of an intra-arterial injection] may be the patient’s reaction to a sensation of fiery burning’ ” pain and “ ‘[b]lanching’ ”).

9 See Enloe 427 (discussing hydroxyzine—an antihistamine with chemical properties similar to those of Phenergan—and suggesting its “temporary” benefits can never outweigh the risks of intra-arterial injection); see also Goldsmith & Trieger, Accidental Intra-Arterial Injection: A Medical Emergency, 22 Anesthesia Progress 180 (1975) (noting the risks of intra-arterial administration of hydroxyzine) (cited in App. 315, no. 18); Klatte, Brooks, & Rhamy, Toxicity of Intra-Arterial Barbituates and Tranquilizing Drugs, 92 Radiology 700 (1969) (same) (cited in App. 314, no. 13). With full knowledge of those risks, FDA retained IV push for Phenergan, although the agency required Wyeth to incorporate observations from the Enloe article into Phenergan’s label. Compare Enloe 427 (arguing that “every precaution should be taken to avoid inadvertent intra-arterial injection,” including the use of “an obviously well-functioning venoclysis”), with App. 312 (FDA’s 1987 changes to Phenergan’s label). In contrast, at some time around 1970, the FDA prohibited all intravenous use of hydroxyzine. See id., at 79 (testimony of Dr. Harold Green). The FDA’s decision to regulate the two drugs differently—notwithstanding (1) the agency’s knowledge of the risks associated with both drugs and (2) the agency’s recognition of the relevance of hydroxyzine-related articles and case reports in its regulation of Phenergan—further demonstrates that the FDA intentionally preserved IV-push administration for Phenergan. See also Haas, Correspondence, 33 Anesthesia Progress 281 (1986) (“[Hydroxyzine’s] restriction does not lie with the medicine itself, but in the practice and malpractice of intravenous techniques. Unfortunately, the practitioner who knows how to treat injection technique problems is usually not the practitioner with the intravenous technique problems”).

10 See also Engler, Freeman, Kanavage, Ogden, & Moretz, Production of Gangrenous Extremities by Intra-Arterial Injections, 30 Am. Surgeon 602 (1964) (“Accidental arterial injection most often occurs in the antecubital region because this is a favorite site for venopuncture and in this area the ulnar and brachial arteries are superficial and easily entered” (cited in App. 313, no. 6)); Engler, Gangrenous Extremities Resulting from Intra-arterial Injections, 94 Archives of Surgery 644 (1966) (similar) (cited in App. 314, no. 16); Lynas & Bisset, Intra-arterial Thiopentone, 24 Anaesthesia 257 (1969) (“Most [anesthesiologists] agree that injections on the medial aspect of the antecubital fossa are best avoided” (cited in App. 314, no. 8)); Waters, Intra-arterial Thiopentone, 21 Anesthesia 346 (1966) (“The risk of producing gangrene of the forearm by accidental injection of sodium thiopentone into an artery at the elbow has been recognised for many years” (cited in App. 314, no. 10)); see also Hager & Wilson, 94 Archives of Surgery, at 88 (emphasizing that one of the best ways to prevent inadvertent intra-arterial injections is to be aware of “aberrant or superficial arteries at the antecubital, forearm, wrist, and hand level”); Mostafavi & Samimi, supra (warning against antecubital injections).

11 See App. 311 (requiring Phenergan’s label to warn that practitioners should “ ‘[b]eware of the close proximity of arteries and veins at commonly used injection sites and consider the possibility of aberrant arteries’ ”).

12 “Aspiration” refers to drawing a small amount of blood back into the needle to determine whether the needle is in an artery or a vein. Ordinarily, arterial blood is brighter than venous blood—but contact with Phenergan causes discoloration, which makes aspiration an unreliable method of protecting against intra-arterial injection. See id., at 282. Therefore, the label warned that when using IV push, a medical professional should beware that “[a]spiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with Phenergan Injection.” Id., at 390.

13 In addition, respondent’s own medical expert testified at trial that it is a principle of “basic anatomy” that the antecubital fossa contains aberrant arteries. See 2 Tr. 34–35 (Mar. 9, 2004) (testimony of Dr. Daniel O’Brien); see also ibid. (noting that Gray’s Anatomy, which is “the Bible of anatomy,” also warns of arteries in the antecubital space).

14 Thus, it is not true that “this Court has long” applied a presumption against pre-emption in conflict pre-emption cases. Ante, at 9, n. 3 (majority opinion). As long ago as Gibbons v. Ogden, 9 Wheat. 1, 210 (1824), the Court inquired whether a state law “interfer[ed] with,” was “contrary to,” or “c[a]me into collision with” federal law—and it did so without ever invoking a “presumption.” See also Davis, Unmasking the Presumption in Favor of Preemption, 53 S. C. L. Rev. 967, 974 (2002) (noting that many of the Court’s early pre-emption cases “resulted in almost automatic preemption of concurrent state regulation”). In subsequent years the Court has sometimes acknowledged a limited “presumption against pre-emption,” but it nonetheless remained an open question—before today—whether that presumption applied in conflict pre-emption cases. See Crosby v. National Foreign Trade Council, 530 U. S. 363, n. 8 (2000) (“We leave for another day a consideration in this context of a presumption against preemption”). Moreover, this Court has never held that the “presumption” applies in an area—such as drug labeling—that has long been “reserved for federal regulation.” United States v. Locke, 529 U. S. 89, 111 (2000) . See also Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 347–348 (2001) .

15 Vesicants may cause “blistering, severe tissue injury, or tissue necrosis” upon extravasation—even if the drug is not injected into an artery. See, e.g., Schulmeister, Administering Vesicants, 9 Clinical J. of Oncology Nursing 469, 469–470 (2005). See also ante, at 4 (majority opinion) (noting that Phenergan is labeled as an “irritant”); cf. Brief for Anju Budhwani et al. as Amici Curiae 15 (suggesting Phenergan should be considered a “vesicant”).

16 FDA, Oncology Tools Product Label Details, online at http://www.accessdata.fda.gov/scripts/cder/onctools/labels.cfm?GN=meclorethamine, nitrogen mustard (as visited Mar. 2, 2009, and available in Clerk of Court’s case file).

17 Ibid.

18 The same is true of FDA’s regulation of hydroxyzine. See n. 9,supra.


TOP

Dissent

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Alito, with whom The Chief Justice and Justice Scalia join, dissenting.

This case illustrates that tragic facts make bad law. The Court holds that a state tort jury, rather than the Food and Drug Administration (FDA), is ultimately responsible for regulating warning labels for prescription drugs. That result cannot be reconciled with Geier v. American Honda Motor Co., 529 U. S. 861 (2000) , or general principles of conflict pre-emption. I respectfully dissent.

I

The Court frames the question presented as a “narro[w]” one—namely, whether Wyeth has a duty to provide “an adequate warning about using the IV-push method” to administer Phenergan. Ante, at 8. But that ignores the antecedent question of who—the FDA or a jury in Vermont—has the authority and responsibility for determining the “adequacy” of Phenergan’s warnings. Moreover, it is unclear how a “stronger” warning could have helped respondent, see ante, at 16; after all, the physician’s assistant who treated her disregarded at least six separate warnings that are already on Phenergan’s labeling, so respondent would be hard pressed to prove that a seventh would have made a difference. 1

More to the point, the question presented by this case is not a “narrow” one, and it does not concern whether Phenergan’s label should bear a “stronger” warning. Rather, the real issue is whether a state tort jury can countermand the FDA’s considered judgment that Phenergan’s FDA-mandated warning label renders its intravenous (IV) use “safe.” Indeed, respondent’s amended complaint alleged that Phenergan is “not reasonably safe for intravenous administration,” App. 15, ¶6; respondent’s attorney told the jury that Phenergan’s label should say, “ ‘Do not use this drug intravenously,’ ” id., at 32; respondent’s expert told the jury, “I think the drug should be labeled ‘Not for IV use,’ ” id., at 59; and during his closing argument, respondent’s attorney told the jury, “Thank God we don’t rely on the FDA to … make the safe[ty] decision. You will make the decision. … The FDA doesn’t make the decision, you do,” id., at 211–212. 2

Federal law, however, does rely on the FDA to make safety determinations like the one it made here. The FDA has long known about the risks associated with IV push in general and its use to administer Phenergan in particular. Whether wisely or not, the FDA has concluded—over the course of extensive, 54-year-long regulatory proceedings—that the drug is “safe” and “effective” when used in accordance with its FDA-mandated labeling. The unfortunate fact that respondent’s healthcare providers ignored Phenergan’s labeling may make this an ideal medical-malpractice case. 3 But turning a common-law tort suit into a “frontal assault” on the FDA’s regulatory regime for drug labeling upsets the well-settled meaning of the Supremacy Clause and our conflict pre-emption jurisprudence. Brief for United States as Amicus Curiae 21.

II

A

To the extent that “[t]he purpose of Congress is the ultimate touchstone in every pre-emption case,” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) (internal quotation marks omitted), Congress made its “purpose” plain in authorizing the FDA—not state tort juries—to determine when and under what circumstances a drug is “safe.” “[T]he process for approving new drugs is at least as rigorous as the premarket approval process for medical devices,” Riegel v. Medtronic, Inc., 552 U. S. ___, ___ (2008) (slip op., at 11) (Ginsburg, J., dissenting), and we held that the latter pre-empted a state-law tort suit that conflicted with the FDA’s determination that a medical device was “safe,” id., at ___ (slip op., at 11) (opinion of the Court).

Under the Federal Food, Drug, and Cosmetic Act (FDCA), a drug manufacturer may not market a new drug before first submitting a new drug application (NDA) to the FDA and receiving the agency’s approval. See 21 U. S. C. §355(a). An NDA must contain, among other things, “the labeling proposed to be used for such drug,” §355(b)(1)(F), “full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use,” §355(b)(1)(A), and “a discussion of why the benefits exceed the risks [of the drug] under the conditions stated in the labeling,” 21 CFR §314.50(d)(5)(viii) (2008). The FDA will approve an NDA only if the agency finds, among other things, that the drug is “safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof,” there is “substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof,” and the proposed labeling is not “false or misleading in any particular.” 21 U. S. C. §355(d).

After the FDA approves a drug, the manufacturer remains under an obligation to investigate and report any adverse events associated with the drug, see 21 CFR §314.80, and must periodically submit any new information that may affect the FDA’s previous conclusions about the safety, effectiveness, or labeling of the drug, 21 U. S. C. §355(k). If the FDA finds that the drug is not “safe” when used in accordance with its labeling, the agency “shall” withdraw its approval of the drug. §355(e). The FDA also “shall” deem a drug “misbranded” if “it is dangerous to health when used in the dosage or manner, or with the frequency or duration prescribed, recommended, or suggested in the labeling thereof.” §352(j).

Thus, a drug’s warning label “serves as the standard under which the FDA determines whether a product is safe and effective.” 50Fed. Reg. 7470 (1985). Labeling is “[t]he centerpiece of risk management,” as it “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively.” 71Fed. Reg. 3934 (2006). The FDA has underscored the importance it places on drug labels by promulgating comprehensive regulations—spanning an entire part of the Code of Federal Regulations, see 21 CFR pt. 201, with seven subparts and 70 separate sections—that set forth drug manufacturers’ labeling obligations. Under those regulations, the FDA must be satisfied that a drug’s warning label contains, among other things, “a summary of the essential scientific information needed for the safe and effective use of the drug,” §201.56(1), including a description of “clinically significant adverse reactions,” “other potential safety hazards,” “limitations in use imposed by them, … and steps that should be taken if they occur,” §201.57(c)(6)(i). Neither the FDCA nor its implementing regulations suggest that juries may second-guess the FDA’s labeling decisions.

B

1

Where the FDA determines, in accordance with its statutory mandate, that a drug is on balance “safe,” our conflict pre-emption cases prohibit any State from countermanding that determination. See, e.g., Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 348 (2001) (after the FDA has struck “a somewhat delicate balance of statutory objectives” and determined that petitioner submitted a valid application to manufacture a medical device, a State may not use common law to negate it); International Paper Co. v. Ouellette, 479 U. S. 481, 494 (1987) (after the EPA has struck “the balance of public and private interests so carefully addressed by” the federal permitting regime for water pollution, a State may not use nuisance law to “upse[t]” it); Chicago & North Western Transp. Co. v. Kalo Brick & Tile Co., 450 U. S. 311, 321 (1981) (after the Interstate Commerce Commission has struck a “balance” between competing interests in permitting the abandonment of a railroad line, a State may not use statutory or common law to negate it).

Thus, as the Court itself recognizes, it is irrelevant in conflict pre-emption cases whether Congress “enacted an express pre-emption provision at some point during the FDCA’s 70-year history.” Ante, at 18; see also Geier, 529 U. S., at 869 (holding the absence of an express pre-emption clause “does not bar the ordinary working of conflict pre-emption principles”). Rather, the ordinary principles of conflict pre-emption turn solely on whether a State has upset the regulatory balance struck by the federal agency. Id., at 884–885; see also Chicago & North Western Transp. Co., supra, at 317 (describing conflict pre-emption as “a two-step process of first ascertaining the construction of the [federal and state laws] and then determining the constitutional question whether they are actually in conflict” (internal quotation marks omitted)).

2

A faithful application of this Court’s conflict pre-emption cases compels the conclusion that the FDA’s 40-year-long effort to regulate the safety and efficacy of Phenergan pre-empts respondent’s tort suit. Indeed, that result follows directly from our conclusion in Geier.

Geier arose under the National Traffic and Motor Safety Vehicle Act of 1966, which directs the Secretary of the Department of Transportation (DOT) to “establish by order … motor vehicle safety standards,” 15 U. S. C. §1392(a) (1988 ed.), which are defined as “minimum standard[s] for motor vehicle performance, or motor vehicle equipment performance,” §1391(2). Acting pursuant to that statutory mandate, the Secretary of Transportation promulgated Federal Motor Vehicle Safety Standard 208, which required car manufacturers to include passive restraint systems (i.e., devices that work automatically to protect occupants from injury during a collision) in a certain percentage of their cars built in or after 1987. See 49 CFR §571.208 (1999). Standard 208 did not require installation of any particular type of passive restraint; instead, it gave manufacturers the option to install automatic seatbelts, airbags, or any other suitable technology that they might develop, provided the restraint(s) met the performance requirements specified in the rule. Ibid.

Alexis Geier drove her 1987 Honda Accord into a tree, and although she was wearing her seatbelt, she nonetheless suffered serious injuries. She then sued Honda under state tort law, alleging that her car was negligently and defectively designed because it lacked a driver’s-side airbag. She argued that Congress had empowered the Secretary to set only “minimum standard[s]” for vehicle safety. 15 U. S. C. §1391(2). She also emphasized that the National Traffic and Motor Safety Vehicle Act contains a saving clause, which provides that “[c]ompliance with any Federal motor vehicle safety standard issued under this subchapter does not exempt any person from any liability under common law.” §1397(k).

Notwithstanding the statute’s saving clause, and notwithstanding the fact that Congress gave the Secretary authority to set only “minimum” safety standards, we held Geier’s state tort suit pre-empted. In reaching that result, we relied heavily on the view of the Secretary of Transportation—expressed in an amicus brief—that Standard 208 “ ‘embodies the Secretary’s policy judgment that safety would best be promoted if manufacturers installed alternative protection systems in their fleets rather than one particular system in every car.’ ” 529 U. S., at 881 (quoting Brief for United States as Amicus Curiae,O. T. 1999, No. 98–1811, p. 25). Because the Secretary determined that a menu of alternative technologies was “safe,” the doctrine of conflict pre-emption barred Geier’s efforts to deem some of those federally approved alternatives “unsafe” under state tort law.

The same rationale applies here. Through Phenergan’s label, the FDA offered medical professionals a menu of federally approved, “safe” and “effective” alternatives—including IV push—for administering the drug. Through a state tort suit, respondent attempted to deem IV push “unsafe” and “ineffective.” To be sure, federal law does not prohibit Wyeth from contraindicating IV push, just as federal law did not prohibit Honda from installing airbags in all its cars. But just as we held that States may not compel the latter, so, too, are States precluded from compelling the former. See also Fidelity Fed. Sav. & Loan Assn. v. De la Cuesta, 458 U. S. 141, 155 (1982) (“The conflict does not evaporate because the [agency’s] regulation simply permits, but does not compel,” the action forbidden by state law). If anything, a finding of pre-emption is even more appropriate here because the FDCA—unlike the National Traffic and Motor Safety Vehicle Act—contains no evidence that Congress intended the FDA to set only “minimum standards,” and the FDCA does not contain a saving clause. 4 See also ante, at 18 (conceding Congress’ “silence” on the issue).

III

In its attempt to evade Geier’s applicability to this case, the Court commits both factual and legal errors. First, as a factual matter, it is demonstrably untrue that the FDA failed to consider (and strike a “balance” between) the specific costs and benefits associated with IV push. Second, as a legal matter, Geier does not stand for the legal propositions espoused by the dissenters (and specifically rejected by the majority) in that case. Third, drug labeling by jury verdict undermines both our broader pre-emption jurisprudence and the broader workability of the federal drug-labeling regime.

A

Phenergan’s warning label has been subject to the FDA’s strict regulatory oversight since the 1950’s. For at least the last 34 years, the FDA has focused specifically on whether IV-push administration of Phenergan is “safe” and “effective” when performed in accordance with Phenergan’s label. The agency’s ultimate decision—to retain IV push as one means for administering Phenergan, albeit subject to stringent warnings—is reflected in the plain text of Phenergan’s label (sometimes in boldfaced font and all-capital letters). And the record contains ample evidence that the FDA specifically considered and reconsidered the strength of Phenergan’s IV-push-related warnings in light of new scientific and medical data. The majority’s factual assertions to the contrary are mistaken.

1

The FDA’s focus on IV push as a means of administering Phenergan dates back at least to 1975. In August of that year, several representatives from both the FDA and Wyeth met to discuss Phenergan’s warning label. At that meeting, the FDA specifically proposed “that Phenergan Injection should not be used in Tubex.” 2 Record 583, 586 (Plaintiff’s Trial Exh. 17, Internal Correspondence from W. E. Langeland to File (Sept. 5, 1975) (hereinafter 1975 Memo)). “Tubex” is a syringe system used exclusively for IV push. See App. 43. An FDA official explained that the agency’s concerns arose from medical-malpractice lawsuits involving IV push of the drug, see 1975 Memo 586, and that the FDA was aware of “5 cases involving amputation where the drug had been administered by Tubex together with several additional cases involving necrosis,” id., at 586–587. Rather than contraindicating Phenergan for IV push, however, the agency and Wyeth agreed “that there was a need for better instruction regarding the problems of intraarterial injection.” Id., at 587.

The next year, the FDA convened an advisory committee to study, among other things, the risks associated with the Tubex system and IV push. App. 294. At the conclusion of its study, the committee recommended an additional IV-push-specific warning for Phenergan’s label, see ibid., but did not recommend eliminating IV push from the drug label altogether. In response to the committee’s recommendations, the FDA instructed Wyeth to make several changes to strengthen Phenergan’s label, including the addition of upper case warnings related to IV push. See id., at 279–280, 282–283.

In 1987, the FDA directed Wyeth to amend its label to include the following text:

“ ‘[1] When used intravenously, [Phenergan] should be given in a concentration no greater than 25 mg/ml and at a rate not to exceed 25 mg/minute. [2] Injection through a properly running intravenous infusion may enhance the possibility of detecting arterial placement.’ ” Id., at 311–312.

The first of the two quoted sentences refers specifically to IV push; as respondent’s medical expert testified at trial, the label’s recommended rate of administration (not to exceed 25 mg per minute) refers to “IV push, as opposed to say being in a bag and dripped over a couple of hours.” Id., at 52. The second of the two quoted sentences refers to IV drip. See id., at 15–16 (emphasizing that a “running IV” is the same thing as “IV drip”).

In its 1987 labeling order, the FDA cited voluminous materials to “suppor[t]” its new and stronger warnings related to IV push and the preferability of IV drip. 5 Id., at 313. One of those articles specifically discussed the relative advantages and disadvantages of IV drip compared to IV push, as well as the costs and benefits of administering Phenergan via IV push. 6 The FDA also cited published case reports from the 1960’s of gangrene caused by the intra-arterial injection of Phenergan, 7 and the FDA instructed Wyeth to amend Phenergan’s label in accordance with the latest medical research. 8 The FDA also studied drugs similar to Phenergan and cited numerous cautionary articles—one of which urged the agency to consider contraindicating such drugs for IV use altogether. 9

In “support” of its labeling order, the FDA also cited numerous articles that singled out the inner crook of the elbow—known as the “antecubital fossa” in the medical community—whichis both a commonly used injection site, see id., at 70 (noting that respondent’s injection was pushed into “the antecubital space”), and a universally recognized high-risk area for inadvertent intra-arterial injections. One of the articles explained:

“Because of the numerous superficial positions the ulnar artery might occupy, it has often been entered during attempted venipuncture [of the antecubital fossa]. … However, the brachial and the radial arteries might also be quite superficial in the elbow region… . The arterial variations of the arm, especially in and about the cubital fossa, are common and numerous. If venipuncture must be performed in this area, a higher index of suspicion must be maintained to forestall misdirected injections.” Stone & Donnelly, The Accidental Intra-arterial Injection of Thiopental, 22 Anesthesiology 995, 996 (1961) (footnote omitted; cited in App. 315, no. 20). 10

Based on this and other research, the FDA ordered Wyeth to include a specific warning related to the use of the antecubital space for IV push. 11

2

When respondent was injured in 2000, Phenergan’s label specifically addressed IV push in several passages (sometimes in lieu of and sometimes in addition to those discussed above). For example, the label warned of the risks of intra-arterial injection associated with “aspiration,” which is a technique used only in conjunction with IV push. 12 The label also cautioned against the use of “syringes with rigid plungers,” App. 390, which are used onlyto administer the drug via IV push. As respondent’s medical expert testified at trial, “by talking plungers and rigid needles, that’s the way you do it, to push it with the plunger.” Id., at 53 (testimony of Dr. John Matthew). Moreover, Phenergan’s 2000 label devoted almost a full page to discussing the “Tubex system,” see id., at 391, which, as noted above, is used only to administer the drug via IV push.

While Phenergan’s label very clearly authorized the use of IV push, it also made clear that IV push is the delivery method of last resort. The label specified that “[t]he preferred parenteral route of administration is by deep intramuscular injection.” Id., at 390. If an intramuscular injection is ineffective, then “it is usually preferable to inject [Phenergan] through the tubing of an intravenous infusion set that is known to be functioning satisfactorily.” Ibid. See also id., at 50–51 (testimony of respondent’s medical expert, Dr. John Matthew) (conceding that the best way to determine that an IV set is functioning satisfactorily is to use IV drip). Finally, if for whatever reason a medical professional chooses to use IV push, he or she is on notice that “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY.” Id., at 391; see also id., at 390 (“Under no circumstances should Phenergan Injection be given by intra-arterial injection due to the likelihood of severe arteriospasm and the possibility of resultant gangrene”).

Phenergan’s label also directs medical practitioners to choose veins wisely when using IV push:

“Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or inadvertent intra-arterial injection. Reports compatible with inadvertent intra-arterial injection of Phenergan Injection, usually in conjunction with other drugs intended for intravenous use, suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances.” Ibid.

Thus, it is demonstrably untrue that, as of 2000, Phenergan’s “labeling did not contain a specific warning about the risks of IV-push administration.” Ante, at 4. And whatever else might be said about the extensive medical authorities and case reports that the FDA cited in “support” of its approval of IV-push administration of Phenergan, it cannot be said that the FDA “paid no more than passing attention to” IV push, ante, at 6; nor can it be said that the FDA failed to weigh its costs and benefits, Brief for Respondent 50.

3

For her part, respondent does not dispute the FDA’s conclusion that IV push has certain benefits. At trial, her medical practitioners testified that they used IV push in order to help her “in a swift and timely way” when she showed up at the hospital for the second time in one day complaining of “intractable” migraines, “terrible pain,” inability to “bear light or sound,” sleeplessness, hours-long spasms of “retching” and “vomiting,” and when “every possible” alternative treatment had “failed.” App. 40 (testimony of Dr. John Matthew); id., at 103, 106, 109 (testimony of physician’s assistant Jessica Fisch).

Rather than disputing the benefits of IV push, respondent complains that the FDA and Wyeth underestimated its costs (and hence did not provide sufficient warnings regarding its risks). But when the FDA mandated that Phenergan’s label read, “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY,” id., at 391, and when the FDA required Wyeth to warn that “[u]nder no circumstances should Phenergan Injection be given by intra-arterial injection,” id., at 390, the agency could reasonably assume that medical professionals would take care not to inject Phenergan intra-arterially. See also 71 Fed. Reg. 3934 (noting that a drug’s warning label “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively”). Unfortunately, the physician’s assistant who treated respondent in this case disregarded Phenergan’s label and pushed the drug into the single spot on her arm that is most likely to cause an inadvertent intra-arterial injection.

As noted above, when the FDA approved Phenergan’s label, it was textbook medical knowledge that the “antecubital fossa” creates a high risk of inadvertent intra-arterial injection, given the close proximity of veins and arteries. See supra, at 13–14; see also The Lippincott Manual of Nursing Practice 99 (7th ed. 2001) (noting, in a red-text “NURSING ALERT,” that the antecubital fossa is “not recommended” for administering dangerous drugs, “due to the potential for extravasation”). 13 According to the physician’s assistant who injured respondent, however, “[i]t never crossed my mind” that an antecubital injection of Phenergan could hit an artery. App. 110; see also ibid. (“[It] just wasn’t something that I was aware of at the time”). Oblivious to the risks emphasized in Phenergan’s warnings, the physician’s assistant pushed a double dose of the drug into an antecubital artery over the course of “[p]robably about three to four minutes,” id., at 111; id., at 105, notwithstanding respondent’s complaints of a “ ‘burn[ing]’ ” sensation that she subsequently described as “ ‘one of the most extreme pains that I’ve ever felt,’ ” id., at 110, 180–181. And when asked why she ignored Phenergan’s label and failed to stop pushing the drug after respondent complained of burning pains, the physician’s assistant explained that it would have been “just crazy” to “worr[y] about an [intra-arterial] injection” under the circumstances, id., at 111.

The FDA, however, did not think that the risks associated with IV push—especially in the antecubital space—were “just crazy.” That is why Phenergan’s label so clearly warns against them.

B

Given the “balance” that the FDA struck between the costs and benefits of administering Phenergan via IV push, Geier compels the pre-emption of tort suits (like this one) that would upset that balance. The contrary conclusion requires turning yesterday’s dissent into today’s majority opinion.

First, the Court denies the existence of a federal-state conflict in this case because Vermont merely countermanded the FDA’s determination that IV push is “safe” when performed in accordance with Phenergan’s warning label; the Court concludes that there is no conflict because Vermont did not “mandate a particular” label as a “replacement” for the one that the jury nullified, and because the State stopped short of altogether “contraindicating IV-push administration.” Ante, at 8. But as we emphasized in Geier (over the dissent’s assertions to the contrary), the degree of a State’s intrusion upon federal law is irrelevant—the Supremacy Clause applies with equal force to a state tort law that merely countermands a federal safety determination and to a state law that altogether prohibits car manufacturers from selling cars without airbags. Compare 529 U. S., at 881–882, with id., at 902 (Stevens, J., dissenting). Indeed, as recently as last Term, we held that the Supremacy Clause pre-empts a “[s]tate tort law that requires a manufacturer’s catheters to be safer, but hence less effective, than the model the FDA has approved … .” Riegel, 552 U. S., at ___ (slip op., at 11). It did not matter there that the State stopped short of altogether prohibiting the use of FDA-approved catheters—just as it does not matter here that Vermont stopped short of altogether prohibiting an FDA-approved method for administering Phenergan. See also Lohr, 518 U. S., at 504 (Breyer, J., concurring in part and concurring in judgment) (noting it would be an “anomalous result” if pre-emption applied differently to a state tort suit premised on the inadequacy of the FDA’s safety regulations and a state law that specifically prohibited an FDA-approved design).

Second, the Court today distinguishes Geier because the FDA articulated its pre-emptive intent “without offering States or other interested parties notice or opportunity for comment. Ante, at 21; see also ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that conflict pre-emption is appropriate only where the agency expresses its pre-emptive intent through notice-and-comment rulemaking. Compare 529 U. S., at 885 (“To insist on a specific expression of agency intent to pre-empt, made after notice-and-comment rulemaking, would be in certain cases to tolerate conflicts that an agency, and therefore Congress, is most unlikely to have intended. The dissent, as we have said, apparently welcomes that result … . We do not”), with id., at 908–910 (Stevens, J., dissenting) (emphasizing that “we generally expect an administrative regulation to declare any intention to pre-empt state law with some specificity,” and that “[t]his expectation … serves to ensurethat States will be able to have a dialog with agencies regarding pre-emption decisions ex ante through the normal notice-and-comment procedures of the Administrative Procedure Act” (internal quotation marks omitted)). Indeed, pre-emption is arguably more appropriate here than in Geier because the FDA (unlike the DOT) declared its pre-emptive intent in the Federal Register. See 71 Fed. Reg. 3933–3936. Yet the majority dismisses the FDA’s published preamble as “inherently suspect,” ante, at 21, and an afterthought that is entitled to “no weight,” ante, at 25. Compare Lohr, supra, at 506 (opinion of Breyer, J.) (emphasizing that the FDA has a “special understanding of the likely impact of both state and federal requirements, as well as an understanding of whether (or the extent to which) state requirements may interfere with federal objectives,” and that “[t]he FDA can translate these understandings into particularized pre-emptive intentions … through statements in ‘regulations, pre-ambles, interpretive statements, and responses tocomments’ ”).

Third, the Court distinguishes Geier because the DOT’s regulation “bear[s] the force of law,” whereas the FDA’s preamble does not. Ante, at 24; see also ante, at 19. But it is irrelevant that the FDA’s preamble does not “bear the force of law” because the FDA’s labeling decisions surely do. See 21 U. S. C. §355. It is well within the FDA’s discretion to make its labeling decisions through administrative adjudications rather than through less-formal and less-flexible rulemaking proceedings, see SEC v. Chenery Corp., 332 U. S. 194 (1947) , and we have never previously held that our pre-emption analysis turns on the agency’s choice of the latter over the former. Moreover, it cannot be said that Geier’s outcome hinged on the agency’s choice to promulgate a rule. See ante, at 19, 24. The Geier Court relied—again over the dissenters’ protestations—on materials other than the Secretary’s regulation to explain the conflict between state and federal law. Compare 529 U. S., at 881, with id., at 899–900 (Stevens, J., dissenting), and ante, at 1–2 (Breyer, J., concurring).

Fourth, the Court sandwiches its discussion of Geier between the “presumption against pre-emption,” ante, at 18, and heavy emphasis on “the longstanding coexistence of state and federal law and the FDA’s traditional recognition of state-law remedies,” ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that the “presumption against pre-emption” is relevant to the conflict pre-emption analysis. See 529 U. S., at 906–907 (Stevens, J., dissenting) (“[T]he Court simply ignores the presumption [against pre-emption]”). Rather than invoking such a “presumption,” the Court emphasized that it was applying “ordinary,” “longstanding,” and “experience-proved principles of conflict pre-emption.” Id., at 874. Under these principles, the sole question is whether there is an “actual conflict” between state and federal law; if so, then pre-emption follows automatically by operation of the Supremacy Clause. Id., at 871–872. See also Buckman, 531 U. S., at 347–348 (“[P]etitioner’s dealings with the FDA were prompted by [federal law], and the very subject matter of petitioner’s statements [to the FDA] were dictated by [federal law]. Accordingly—and in contrast to situations implicating ‘federalism concerns and the historic primacy of state regulation of matters of health and safety’—no presumption against pre-emption obtains in this case” (citation omitted)). 14

Finally, the Geier Court went out of its way to emphasize (yet again over the dissenters’ objections) that it placed “some weight” on the DOT’s amicus brief, which explained the agency’s regulatory objectives and the effects of state tort suits on the federal regulatory regime. 529 U. S., at 883; compare id., at 910–911 (Stevens, J., dissenting) (criticizing the majority for “uph[olding] a regulatory claim of frustration-of-purposes implied conflict pre-emption based on nothing more than an ex post administrative litigating position and inferences from regulatory history and final commentary”). See also Lohr, 518 U. S., at 496 (recognizing that the FDA is “uniquely qualified” to explain whether state law conflicts with the FDA’s objectives). Yet today, the FDA’s explanation of the conflict between state tort suits and the federal labeling regime, set forth in the agency’s amicus brief, is not even mentioned in the Court’s opinion. Instead of relying on the FDA’s explanation of its own regulatory purposes, the Court relies on a decade-old and now-repudiated statement, which the majority finds preferable. See ante, at 21–22, 24, n. 13. Cf. Riegel, 552 U. S., at ___ (slip op., at 13) (noting that “the agency’s earlier position (which the dissent describes at some length and finds preferable) is … compromised, indeed deprived of all claim to deference, by the fact that it is no longer the agency’s position” (citation omitted)); Altria Group, Inc. v. Good, 555 U. S. ___, ___ (2008) (slip op., at 16–17) (rejecting petitioners’ reliance on the pre-emptive effect of the agency’s “longstanding policy” because it is inconsistent with the agency’s current one). And Justice Breyer suggests that state tort suits may “help the [FDA],” ante, at 1 (concurring opinion), notwithstanding the FDA’s insistence that state tort suits will “disrupt the agency’s balancing of health risks and benefits,” Brief for United States as Amicus Curiae 9.

Geier does not countenance the use of state tort suits to second-guess the FDA’s labeling decisions. And the Court’s contrary conclusion has potentially far-reaching consequences.

C

By their very nature, juries are ill-equipped to perform the FDA’s cost-benefit-balancing function. As we explained in Riegel, juries tend to focus on the risk of a particular product’s design or warning label that arguably contributed to a particular plaintiff’s injury, not on the overall benefits of that design or label; “the patients who reaped those benefits are not represented in court.” 552 U. S., at ___ (slip op., at 12). Indeed, patients like respondent are the only ones whom tort juries ever see, and for a patient like respondent—who has already suffered a tragic accident—Phenergan’s risks are no longer a matter of probabilities and potentialities.

In contrast, the FDA has the benefit of the long view. Its drug-approval determinations consider the interests of all potential users of a drug, including “those who would suffer without new medical [products]” if juries in all 50 States were free to contradict the FDA’s expert determinations. Id., at ___ (slip op., at 13). And the FDA conveys its warnings with one voice, rather than whipsawing the medical community with 50 (or more) potentially conflicting ones. After today’s ruling, however, parochialism may prevail.

The problem is well illustrated by the labels borne by “vesicant” drugs, many of which are used for chemotherapy. As a class, vesicants are much more dangerous than drugs like Phenergan, 15 but the vast majority of vesicant labels—like Phenergan’s—either allow or do not disallow IV push. See Appendix, infra. Because vesicant extravasation can have devastating consequences, and because the potentially lifesaving benefits of these drugs offer hollow solace to the victim of such a tragedy, a jury’s cost-benefit analysis in a particular case may well differ from the FDA’s.

For example, consider Mustargen (mechlorethamine HCl)—the injectable form of mustard gas—which can be used as an anticancer drug. Mustargen’s FDA-approved label warns in several places that “This drug is HIGHLY TOXIC.” 16 Indeed, the drug is so highly toxic:

“Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water, for at least 15 minutes while removing contaminated clothing and shoes, followed by 2% sodium thiosulfate solution. Medical attention should be sought immediately. Contaminated clothing should be destroyed.” 17

Yet when it comes to administering this highly toxic drug, the label provides that “the drug may be injected directly into any suitable vein, [but] it is injected preferably into the rubber or plastic tubing of a flowing intravenous infusion set. This reduces the possibility of severe local reactions due to extravasation or high concentration of the drug.” (Emphasis added.) Similarly, the FDA-approved labels for other powerful chemotherapeutic vesicants—including Dactinomycin, Oxaliplatin, Vinblastine, and Vincristine—specifically allow IV push, notwithstanding their devastating effects when extravasated.

The fact that the labels for such drugs allow IV push is striking—both because vesicants are much more dangerous than Phenergan, and also because they are so frequently extravasated, see Boyle & Engelking, Vesicant Extravasation: Myths and Realities, 22 Oncology Nursing Forum 57, 58 (1995) (arguing that the rate of extravasation is “considerably higher” than 6.4% of all vesicant administrations). Regardless of the FDA’s reasons for not contraindicating IV push for these drugs, it is odd (to say the least) that a jury in Vermont can now order for Phenergan what the FDA has chosen not to order for mustard gas. 18

***

To be sure, state tort suits can peacefully coexist with the FDA’s labeling regime, and they have done so for decades. Ante, at 17–18. But this case is far from peaceful coexistence. The FDA told Wyeth that Phenergan’s label renders its use “safe.” But the State of Vermont, through its tort law, said: “Not so.”

The state-law rule at issue here is squarely pre-empted. Therefore, I would reverse the judgment of the Supreme Court of Vermont.

Appendix TO OPINION OF ALITO, J.

Vesicant1

IV Push2

Dactinomycin

Specifically allowed

Mechlorethamine (Mustargen)

Specifically allowed

Oxaliplatin

Specifically allowed

Vinblastine

Specifically allowed

Vincristine

Specifically allowed

Bleomycin

Neither mentioned nor prohibited

Carboplatin

Neither mentioned nor prohibited

Dacarbazine

Neither mentioned nor prohibited

Mitomycin

Neither mentioned nor prohibited

Carmustine

Not prohibited; IV drip recommended

Cisplatin

Not prohibited; IV drip recommended

Epirubicin

Not prohibited; IV drip recommended

Etoposide

Not prohibited; IV drip recommended

Ifosfamide

Not prohibited; IV drip recommended

Mitoxantrone

Not prohibited; IV drip recommended

Paclitaxel

Not prohibited; IV drip recommended

Teniposide

Not prohibited; IV drip recommended

Vinorelbine

Not prohibited; IV drip recommended

Daunorubicin

Prohibited

Doxorubicin

Prohibited

1 Wilkes & Barton-Burke, 2008 Oncology Nursing Drug Handbook 27–33 (2008) (Table 1.6).

2 IV-push information is derived from the “dosage and administration” sections of individual drug labels (available in Clerk of Court’s case file).


Notes

1 Indeed, respondent conceded below that Wyeth did propose an adequate warning of Phenergan’s risks. See Plaintiff Diana Levine’s Memorandum in Opposition to Wyeth’s Motion for Summary Judgment in Levine v. American Home Products Corp. (now Wyeth), No. 670–12–01 Wncv (Super. Ct. Washington Cty., Vt.), ¶7, p. 26. Specifically, respondent noted: “In 1988, Wyeth proposed language that would have prevented this accident by requiring a running IV and explaining why a running IV will address and reduce the risk [of intra-arterial injection].” Ibid. See also id., at 24 (“Although not strong enough, this improved the labeling instruction, if followed, would have prevented the inadvertent administration of Phenergan into an artery …”). The FDA rejected Wyeth’s proposal. See App. 359.

2 Moreover, in the trial judge’s final charge, he told the jury that “the critical factual issue which you must decide” is whether Phenergan’s FDA-mandated label reflects a proper balance between “the risks and benefits of intravenous administration and the potential for injury to patients.” Id., at 220. See also ___ Vt. ___, ___, 944 A. 2d 179, 182 (2006) (recognizing that respondent’s argument is that Phenergan’s “label should not have allowed IV push as a means of administration”).

3 Respondent sued her physician, physician’s assistant, and hospital for malpractice. After the parties settled that suit for an undisclosed sum, respondent’s physician sent her a letter in which he admitted “responsibility” for her injury and expressed his “profoun[d] regre[t]” and “remors[e]” for his actions. 1 Tr. 178–179 (Mar. 8, 2004) (testimony of Dr. John Matthew); see also App. 102–103 (testimony of physician’s assistant Jessica Fisch) (noting that her “sense of grief” was so “great” that she “would have gladly cut off [her own] arm” and given it to respondent). Thereafter, both the physician and the physician’s assistant agreed to testify on respondent’s behalf in her suit against Wyeth.

4 To be sure, Congress recognized the principles of conflict pre-emption in the FDCA. See Drug Amendments of 1962, §202, 76Stat. 793 (“Nothing in the amendments made by this Act to the Federal Food, Drug, and Cosmetic Act shall be construed as invalidating any provision of State law … unless there is a direct and positive conflict between such amendments and such provision of State law”). But a provision that simply recognizes the background principles of conflict pre-emption is not a traditional “saving clause,” and even if it were, it would not displace our conflict-pre-emption analysis. See Geier v. American Honda Motor Co., 529 U. S. 861, 869 (2000) (“[T]he saving clause … does not bar the ordinary working of conflict pre-emption principles”); id., at 873–874 (“The Court has … refused to read general ‘saving’ provisions to tolerate actual conflict both in cases involving impossibility and in ‘frustration-of-purpose’ cases” (emphasis deleted and citation omitted)).

5 The FDA cited numerous articles that generally discuss the costs and benefits associated with IV push. See, e.g., Nahrwold & Phelps, Inadvertent Intra-Arterial Injection of Mephenteramine, 70 Rocky Mountain Medical J. 38 (Sept. 1973) (cited in App. 314, no. 14); Albo, Cheung, Ruth, Snyder, & Beemtsma, Effect of Intra-Arterial Injections of Barbituates, 120 Am. J. of Surgery 676 (1970) (cited in App. 314, no. 12); Corser, Masey, Jacob, Kernoff, & Browne, Ischaemia Following Self-administered Intra-arterial Injection of Methylphenidate and Diamorphine, 40 Anesthesiology 51 (1985) (cited in App. 314, no. 9); Correspondence Regarding Thiopental and Thiamylal (3 letters), 59 Anesthesiology 153 (1983) (cited in App. 314, no. 11); Miller, Arthur, & Stratigos, Intra-arterial Injection of a Barbituate, 23 Anesthesia Progress 25 (1976) (cited in App. 315, no. 19).

6 See Webb & Lampert, Accidental Arterial Injections, 101 Am. J. Obstetrics & Gynecology 365 (1968) (cited in App. 313, no. 5).

7 See Hager & Wilson, Gangrene of the Hand Following Intra-arterial Injection, 94 Archives of Surgery 86 (1967) (cited in App. 313, no. 7); Enloe, Sylvester, & Morris, Hazards of Intra-Arterial Injection of Hydroxyzine, 16 Canadian Anaesthetists’ Society J. 425 (1969) (hereinafter Enloe) (noting “recent reports” of “the occurrence of severe necrosis and gangrene following [administration of] promethazine (Phenergan)” (cited in App. 314, no. 15)). See also Mostafavi & Samimi, Accidental Intra-arterial Injection of Promethazine HCl During General Anesthesia, 35 Anesthesiology 645 (1971) (reporting a case of gangrene, which required partial amputation of three fingers, after Phenergan was inadvertently pushed into an artery in the “antecubital” area); Promethazine, p. 7, in Clinical Pharmacology (Gold Standard Multimedia Inc. CD–ROM, version 1.16 (1998) (noting that “[i]nadvertent intra-arterial injection [of Phenergan] can result in arteriospasm … and development of gangrene”)).

8 Hager and Wilson noted that the most common reactions to intra-arterial injections of drugs like Phenergan include “[i]mmediate, severe, burning pain,” as well as “blanching.” 94 Archives of Surgery, at 87–88. The FDA required Wyeth to include Hager and Wilson’s observations on Phenergan’s label. See App. 311 (requiring the label to warn that “ ‘[t]he first sign [of an intra-arterial injection] may be the patient’s reaction to a sensation of fiery burning’ ” pain and “ ‘[b]lanching’ ”).

9 See Enloe 427 (discussing hydroxyzine—an antihistamine with chemical properties similar to those of Phenergan—and suggesting its “temporary” benefits can never outweigh the risks of intra-arterial injection); see also Goldsmith & Trieger, Accidental Intra-Arterial Injection: A Medical Emergency, 22 Anesthesia Progress 180 (1975) (noting the risks of intra-arterial administration of hydroxyzine) (cited in App. 315, no. 18); Klatte, Brooks, & Rhamy, Toxicity of Intra-Arterial Barbituates and Tranquilizing Drugs, 92 Radiology 700 (1969) (same) (cited in App. 314, no. 13). With full knowledge of those risks, FDA retained IV push for Phenergan, although the agency required Wyeth to incorporate observations from the Enloe article into Phenergan’s label. Compare Enloe 427 (arguing that “every precaution should be taken to avoid inadvertent intra-arterial injection,” including the use of “an obviously well-functioning venoclysis”), with App. 312 (FDA’s 1987 changes to Phenergan’s label). In contrast, at some time around 1970, the FDA prohibited all intravenous use of hydroxyzine. See id., at 79 (testimony of Dr. Harold Green). The FDA’s decision to regulate the two drugs differently—notwithstanding (1) the agency’s knowledge of the risks associated with both drugs and (2) the agency’s recognition of the relevance of hydroxyzine-related articles and case reports in its regulation of Phenergan—further demonstrates that the FDA intentionally preserved IV-push administration for Phenergan. See also Haas, Correspondence, 33 Anesthesia Progress 281 (1986) (“[Hydroxyzine’s] restriction does not lie with the medicine itself, but in the practice and malpractice of intravenous techniques. Unfortunately, the practitioner who knows how to treat injection technique problems is usually not the practitioner with the intravenous technique problems”).

10 See also Engler, Freeman, Kanavage, Ogden, & Moretz, Production of Gangrenous Extremities by Intra-Arterial Injections, 30 Am. Surgeon 602 (1964) (“Accidental arterial injection most often occurs in the antecubital region because this is a favorite site for venopuncture and in this area the ulnar and brachial arteries are superficial and easily entered” (cited in App. 313, no. 6)); Engler, Gangrenous Extremities Resulting from Intra-arterial Injections, 94 Archives of Surgery 644 (1966) (similar) (cited in App. 314, no. 16); Lynas & Bisset, Intra-arterial Thiopentone, 24 Anaesthesia 257 (1969) (“Most [anesthesiologists] agree that injections on the medial aspect of the antecubital fossa are best avoided” (cited in App. 314, no. 8)); Waters, Intra-arterial Thiopentone, 21 Anesthesia 346 (1966) (“The risk of producing gangrene of the forearm by accidental injection of sodium thiopentone into an artery at the elbow has been recognised for many years” (cited in App. 314, no. 10)); see also Hager & Wilson, 94 Archives of Surgery, at 88 (emphasizing that one of the best ways to prevent inadvertent intra-arterial injections is to be aware of “aberrant or superficial arteries at the antecubital, forearm, wrist, and hand level”); Mostafavi & Samimi, supra (warning against antecubital injections).

11 See App. 311 (requiring Phenergan’s label to warn that practitioners should “ ‘[b]eware of the close proximity of arteries and veins at commonly used injection sites and consider the possibility of aberrant arteries’ ”).

12 “Aspiration” refers to drawing a small amount of blood back into the needle to determine whether the needle is in an artery or a vein. Ordinarily, arterial blood is brighter than venous blood—but contact with Phenergan causes discoloration, which makes aspiration an unreliable method of protecting against intra-arterial injection. See id., at 282. Therefore, the label warned that when using IV push, a medical professional should beware that “[a]spiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with Phenergan Injection.” Id., at 390.

13 In addition, respondent’s own medical expert testified at trial that it is a principle of “basic anatomy” that the antecubital fossa contains aberrant arteries. See 2 Tr. 34–35 (Mar. 9, 2004) (testimony of Dr. Daniel O’Brien); see also ibid. (noting that Gray’s Anatomy, which is “the Bible of anatomy,” also warns of arteries in the antecubital space).

14 Thus, it is not true that “this Court has long” applied a presumption against pre-emption in conflict pre-emption cases. Ante, at 9, n. 3 (majority opinion). As long ago as Gibbons v. Ogden, 9 Wheat. 1, 210 (1824), the Court inquired whether a state law “interfer[ed] with,” was “contrary to,” or “c[a]me into collision with” federal law—and it did so without ever invoking a “presumption.” See also Davis, Unmasking the Presumption in Favor of Preemption, 53 S. C. L. Rev. 967, 974 (2002) (noting that many of the Court’s early pre-emption cases “resulted in almost automatic preemption of concurrent state regulation”). In subsequent years the Court has sometimes acknowledged a limited “presumption against pre-emption,” but it nonetheless remained an open question—before today—whether that presumption applied in conflict pre-emption cases. See Crosby v. National Foreign Trade Council, 530 U. S. 363, n. 8 (2000) (“We leave for another day a consideration in this context of a presumption against preemption”). Moreover, this Court has never held that the “presumption” applies in an area—such as drug labeling—that has long been “reserved for federal regulation.” United States v. Locke, 529 U. S. 89, 111 (2000) . See also Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 347–348 (2001) .

15 Vesicants may cause “blistering, severe tissue injury, or tissue necrosis” upon extravasation—even if the drug is not injected into an artery. See, e.g., Schulmeister, Administering Vesicants, 9 Clinical J. of Oncology Nursing 469, 469–470 (2005). See also ante, at 4 (majority opinion) (noting that Phenergan is labeled as an “irritant”); cf. Brief for Anju Budhwani et al. as Amici Curiae 15 (suggesting Phenergan should be considered a “vesicant”).

16 FDA, Oncology Tools Product Label Details, online at http://www.accessdata.fda.gov/scripts/cder/onctools/labels.cfm?GN=meclorethamine, nitrogen mustard (as visited Mar. 2, 2009, and available in Clerk of Court’s case file).

17 Ibid.

18 The same is true of FDA’s regulation of hydroxyzine. See n. 9,supra.


TOP

Dissent

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Alito, with whom The Chief Justice and Justice Scalia join, dissenting.

This case illustrates that tragic facts make bad law. The Court holds that a state tort jury, rather than the Food and Drug Administration (FDA), is ultimately responsible for regulating warning labels for prescription drugs. That result cannot be reconciled with Geier v. American Honda Motor Co., 529 U. S. 861 (2000) , or general principles of conflict pre-emption. I respectfully dissent.

I

The Court frames the question presented as a “narro[w]” one—namely, whether Wyeth has a duty to provide “an adequate warning about using the IV-push method” to administer Phenergan. Ante, at 8. But that ignores the antecedent question of who—the FDA or a jury in Vermont—has the authority and responsibility for determining the “adequacy” of Phenergan’s warnings. Moreover, it is unclear how a “stronger” warning could have helped respondent, see ante, at 16; after all, the physician’s assistant who treated her disregarded at least six separate warnings that are already on Phenergan’s labeling, so respondent would be hard pressed to prove that a seventh would have made a difference. 1

More to the point, the question presented by this case is not a “narrow” one, and it does not concern whether Phenergan’s label should bear a “stronger” warning. Rather, the real issue is whether a state tort jury can countermand the FDA’s considered judgment that Phenergan’s FDA-mandated warning label renders its intravenous (IV) use “safe.” Indeed, respondent’s amended complaint alleged that Phenergan is “not reasonably safe for intravenous administration,” App. 15, ¶6; respondent’s attorney told the jury that Phenergan’s label should say, “ ‘Do not use this drug intravenously,’ ” id., at 32; respondent’s expert told the jury, “I think the drug should be labeled ‘Not for IV use,’ ” id., at 59; and during his closing argument, respondent’s attorney told the jury, “Thank God we don’t rely on the FDA to … make the safe[ty] decision. You will make the decision. … The FDA doesn’t make the decision, you do,” id., at 211–212. 2

Federal law, however, does rely on the FDA to make safety determinations like the one it made here. The FDA has long known about the risks associated with IV push in general and its use to administer Phenergan in particular. Whether wisely or not, the FDA has concluded—over the course of extensive, 54-year-long regulatory proceedings—that the drug is “safe” and “effective” when used in accordance with its FDA-mandated labeling. The unfortunate fact that respondent’s healthcare providers ignored Phenergan’s labeling may make this an ideal medical-malpractice case. 3 But turning a common-law tort suit into a “frontal assault” on the FDA’s regulatory regime for drug labeling upsets the well-settled meaning of the Supremacy Clause and our conflict pre-emption jurisprudence. Brief for United States as Amicus Curiae 21.

II

A

To the extent that “[t]he purpose of Congress is the ultimate touchstone in every pre-emption case,” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) (internal quotation marks omitted), Congress made its “purpose” plain in authorizing the FDA—not state tort juries—to determine when and under what circumstances a drug is “safe.” “[T]he process for approving new drugs is at least as rigorous as the premarket approval process for medical devices,” Riegel v. Medtronic, Inc., 552 U. S. ___, ___ (2008) (slip op., at 11) (Ginsburg, J., dissenting), and we held that the latter pre-empted a state-law tort suit that conflicted with the FDA’s determination that a medical device was “safe,” id., at ___ (slip op., at 11) (opinion of the Court).

Under the Federal Food, Drug, and Cosmetic Act (FDCA), a drug manufacturer may not market a new drug before first submitting a new drug application (NDA) to the FDA and receiving the agency’s approval. See 21 U. S. C. §355(a). An NDA must contain, among other things, “the labeling proposed to be used for such drug,” §355(b)(1)(F), “full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use,” §355(b)(1)(A), and “a discussion of why the benefits exceed the risks [of the drug] under the conditions stated in the labeling,” 21 CFR §314.50(d)(5)(viii) (2008). The FDA will approve an NDA only if the agency finds, among other things, that the drug is “safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof,” there is “substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof,” and the proposed labeling is not “false or misleading in any particular.” 21 U. S. C. §355(d).

After the FDA approves a drug, the manufacturer remains under an obligation to investigate and report any adverse events associated with the drug, see 21 CFR §314.80, and must periodically submit any new information that may affect the FDA’s previous conclusions about the safety, effectiveness, or labeling of the drug, 21 U. S. C. §355(k). If the FDA finds that the drug is not “safe” when used in accordance with its labeling, the agency “shall” withdraw its approval of the drug. §355(e). The FDA also “shall” deem a drug “misbranded” if “it is dangerous to health when used in the dosage or manner, or with the frequency or duration prescribed, recommended, or suggested in the labeling thereof.” §352(j).

Thus, a drug’s warning label “serves as the standard under which the FDA determines whether a product is safe and effective.” 50Fed. Reg. 7470 (1985). Labeling is “[t]he centerpiece of risk management,” as it “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively.” 71Fed. Reg. 3934 (2006). The FDA has underscored the importance it places on drug labels by promulgating comprehensive regulations—spanning an entire part of the Code of Federal Regulations, see 21 CFR pt. 201, with seven subparts and 70 separate sections—that set forth drug manufacturers’ labeling obligations. Under those regulations, the FDA must be satisfied that a drug’s warning label contains, among other things, “a summary of the essential scientific information needed for the safe and effective use of the drug,” §201.56(1), including a description of “clinically significant adverse reactions,” “other potential safety hazards,” “limitations in use imposed by them, … and steps that should be taken if they occur,” §201.57(c)(6)(i). Neither the FDCA nor its implementing regulations suggest that juries may second-guess the FDA’s labeling decisions.

B

1

Where the FDA determines, in accordance with its statutory mandate, that a drug is on balance “safe,” our conflict pre-emption cases prohibit any State from countermanding that determination. See, e.g., Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 348 (2001) (after the FDA has struck “a somewhat delicate balance of statutory objectives” and determined that petitioner submitted a valid application to manufacture a medical device, a State may not use common law to negate it); International Paper Co. v. Ouellette, 479 U. S. 481, 494 (1987) (after the EPA has struck “the balance of public and private interests so carefully addressed by” the federal permitting regime for water pollution, a State may not use nuisance law to “upse[t]” it); Chicago & North Western Transp. Co. v. Kalo Brick & Tile Co., 450 U. S. 311, 321 (1981) (after the Interstate Commerce Commission has struck a “balance” between competing interests in permitting the abandonment of a railroad line, a State may not use statutory or common law to negate it).

Thus, as the Court itself recognizes, it is irrelevant in conflict pre-emption cases whether Congress “enacted an express pre-emption provision at some point during the FDCA’s 70-year history.” Ante, at 18; see also Geier, 529 U. S., at 869 (holding the absence of an express pre-emption clause “does not bar the ordinary working of conflict pre-emption principles”). Rather, the ordinary principles of conflict pre-emption turn solely on whether a State has upset the regulatory balance struck by the federal agency. Id., at 884–885; see also Chicago & North Western Transp. Co., supra, at 317 (describing conflict pre-emption as “a two-step process of first ascertaining the construction of the [federal and state laws] and then determining the constitutional question whether they are actually in conflict” (internal quotation marks omitted)).

2

A faithful application of this Court’s conflict pre-emption cases compels the conclusion that the FDA’s 40-year-long effort to regulate the safety and efficacy of Phenergan pre-empts respondent’s tort suit. Indeed, that result follows directly from our conclusion in Geier.

Geier arose under the National Traffic and Motor Safety Vehicle Act of 1966, which directs the Secretary of the Department of Transportation (DOT) to “establish by order … motor vehicle safety standards,” 15 U. S. C. §1392(a) (1988 ed.), which are defined as “minimum standard[s] for motor vehicle performance, or motor vehicle equipment performance,” §1391(2). Acting pursuant to that statutory mandate, the Secretary of Transportation promulgated Federal Motor Vehicle Safety Standard 208, which required car manufacturers to include passive restraint systems (i.e., devices that work automatically to protect occupants from injury during a collision) in a certain percentage of their cars built in or after 1987. See 49 CFR §571.208 (1999). Standard 208 did not require installation of any particular type of passive restraint; instead, it gave manufacturers the option to install automatic seatbelts, airbags, or any other suitable technology that they might develop, provided the restraint(s) met the performance requirements specified in the rule. Ibid.

Alexis Geier drove her 1987 Honda Accord into a tree, and although she was wearing her seatbelt, she nonetheless suffered serious injuries. She then sued Honda under state tort law, alleging that her car was negligently and defectively designed because it lacked a driver’s-side airbag. She argued that Congress had empowered the Secretary to set only “minimum standard[s]” for vehicle safety. 15 U. S. C. §1391(2). She also emphasized that the National Traffic and Motor Safety Vehicle Act contains a saving clause, which provides that “[c]ompliance with any Federal motor vehicle safety standard issued under this subchapter does not exempt any person from any liability under common law.” §1397(k).

Notwithstanding the statute’s saving clause, and notwithstanding the fact that Congress gave the Secretary authority to set only “minimum” safety standards, we held Geier’s state tort suit pre-empted. In reaching that result, we relied heavily on the view of the Secretary of Transportation—expressed in an amicus brief—that Standard 208 “ ‘embodies the Secretary’s policy judgment that safety would best be promoted if manufacturers installed alternative protection systems in their fleets rather than one particular system in every car.’ ” 529 U. S., at 881 (quoting Brief for United States as Amicus Curiae,O. T. 1999, No. 98–1811, p. 25). Because the Secretary determined that a menu of alternative technologies was “safe,” the doctrine of conflict pre-emption barred Geier’s efforts to deem some of those federally approved alternatives “unsafe” under state tort law.

The same rationale applies here. Through Phenergan’s label, the FDA offered medical professionals a menu of federally approved, “safe” and “effective” alternatives—including IV push—for administering the drug. Through a state tort suit, respondent attempted to deem IV push “unsafe” and “ineffective.” To be sure, federal law does not prohibit Wyeth from contraindicating IV push, just as federal law did not prohibit Honda from installing airbags in all its cars. But just as we held that States may not compel the latter, so, too, are States precluded from compelling the former. See also Fidelity Fed. Sav. & Loan Assn. v. De la Cuesta, 458 U. S. 141, 155 (1982) (“The conflict does not evaporate because the [agency’s] regulation simply permits, but does not compel,” the action forbidden by state law). If anything, a finding of pre-emption is even more appropriate here because the FDCA—unlike the National Traffic and Motor Safety Vehicle Act—contains no evidence that Congress intended the FDA to set only “minimum standards,” and the FDCA does not contain a saving clause. 4 See also ante, at 18 (conceding Congress’ “silence” on the issue).

III

In its attempt to evade Geier’s applicability to this case, the Court commits both factual and legal errors. First, as a factual matter, it is demonstrably untrue that the FDA failed to consider (and strike a “balance” between) the specific costs and benefits associated with IV push. Second, as a legal matter, Geier does not stand for the legal propositions espoused by the dissenters (and specifically rejected by the majority) in that case. Third, drug labeling by jury verdict undermines both our broader pre-emption jurisprudence and the broader workability of the federal drug-labeling regime.

A

Phenergan’s warning label has been subject to the FDA’s strict regulatory oversight since the 1950’s. For at least the last 34 years, the FDA has focused specifically on whether IV-push administration of Phenergan is “safe” and “effective” when performed in accordance with Phenergan’s label. The agency’s ultimate decision—to retain IV push as one means for administering Phenergan, albeit subject to stringent warnings—is reflected in the plain text of Phenergan’s label (sometimes in boldfaced font and all-capital letters). And the record contains ample evidence that the FDA specifically considered and reconsidered the strength of Phenergan’s IV-push-related warnings in light of new scientific and medical data. The majority’s factual assertions to the contrary are mistaken.

1

The FDA’s focus on IV push as a means of administering Phenergan dates back at least to 1975. In August of that year, several representatives from both the FDA and Wyeth met to discuss Phenergan’s warning label. At that meeting, the FDA specifically proposed “that Phenergan Injection should not be used in Tubex.” 2 Record 583, 586 (Plaintiff’s Trial Exh. 17, Internal Correspondence from W. E. Langeland to File (Sept. 5, 1975) (hereinafter 1975 Memo)). “Tubex” is a syringe system used exclusively for IV push. See App. 43. An FDA official explained that the agency’s concerns arose from medical-malpractice lawsuits involving IV push of the drug, see 1975 Memo 586, and that the FDA was aware of “5 cases involving amputation where the drug had been administered by Tubex together with several additional cases involving necrosis,” id., at 586–587. Rather than contraindicating Phenergan for IV push, however, the agency and Wyeth agreed “that there was a need for better instruction regarding the problems of intraarterial injection.” Id., at 587.

The next year, the FDA convened an advisory committee to study, among other things, the risks associated with the Tubex system and IV push. App. 294. At the conclusion of its study, the committee recommended an additional IV-push-specific warning for Phenergan’s label, see ibid., but did not recommend eliminating IV push from the drug label altogether. In response to the committee’s recommendations, the FDA instructed Wyeth to make several changes to strengthen Phenergan’s label, including the addition of upper case warnings related to IV push. See id., at 279–280, 282–283.

In 1987, the FDA directed Wyeth to amend its label to include the following text:

“ ‘[1] When used intravenously, [Phenergan] should be given in a concentration no greater than 25 mg/ml and at a rate not to exceed 25 mg/minute. [2] Injection through a properly running intravenous infusion may enhance the possibility of detecting arterial placement.’ ” Id., at 311–312.

The first of the two quoted sentences refers specifically to IV push; as respondent’s medical expert testified at trial, the label’s recommended rate of administration (not to exceed 25 mg per minute) refers to “IV push, as opposed to say being in a bag and dripped over a couple of hours.” Id., at 52. The second of the two quoted sentences refers to IV drip. See id., at 15–16 (emphasizing that a “running IV” is the same thing as “IV drip”).

In its 1987 labeling order, the FDA cited voluminous materials to “suppor[t]” its new and stronger warnings related to IV push and the preferability of IV drip. 5 Id., at 313. One of those articles specifically discussed the relative advantages and disadvantages of IV drip compared to IV push, as well as the costs and benefits of administering Phenergan via IV push. 6 The FDA also cited published case reports from the 1960’s of gangrene caused by the intra-arterial injection of Phenergan, 7 and the FDA instructed Wyeth to amend Phenergan’s label in accordance with the latest medical research. 8 The FDA also studied drugs similar to Phenergan and cited numerous cautionary articles—one of which urged the agency to consider contraindicating such drugs for IV use altogether. 9

In “support” of its labeling order, the FDA also cited numerous articles that singled out the inner crook of the elbow—known as the “antecubital fossa” in the medical community—whichis both a commonly used injection site, see id., at 70 (noting that respondent’s injection was pushed into “the antecubital space”), and a universally recognized high-risk area for inadvertent intra-arterial injections. One of the articles explained:

“Because of the numerous superficial positions the ulnar artery might occupy, it has often been entered during attempted venipuncture [of the antecubital fossa]. … However, the brachial and the radial arteries might also be quite superficial in the elbow region… . The arterial variations of the arm, especially in and about the cubital fossa, are common and numerous. If venipuncture must be performed in this area, a higher index of suspicion must be maintained to forestall misdirected injections.” Stone & Donnelly, The Accidental Intra-arterial Injection of Thiopental, 22 Anesthesiology 995, 996 (1961) (footnote omitted; cited in App. 315, no. 20). 10

Based on this and other research, the FDA ordered Wyeth to include a specific warning related to the use of the antecubital space for IV push. 11

2

When respondent was injured in 2000, Phenergan’s label specifically addressed IV push in several passages (sometimes in lieu of and sometimes in addition to those discussed above). For example, the label warned of the risks of intra-arterial injection associated with “aspiration,” which is a technique used only in conjunction with IV push. 12 The label also cautioned against the use of “syringes with rigid plungers,” App. 390, which are used onlyto administer the drug via IV push. As respondent’s medical expert testified at trial, “by talking plungers and rigid needles, that’s the way you do it, to push it with the plunger.” Id., at 53 (testimony of Dr. John Matthew). Moreover, Phenergan’s 2000 label devoted almost a full page to discussing the “Tubex system,” see id., at 391, which, as noted above, is used only to administer the drug via IV push.

While Phenergan’s label very clearly authorized the use of IV push, it also made clear that IV push is the delivery method of last resort. The label specified that “[t]he preferred parenteral route of administration is by deep intramuscular injection.” Id., at 390. If an intramuscular injection is ineffective, then “it is usually preferable to inject [Phenergan] through the tubing of an intravenous infusion set that is known to be functioning satisfactorily.” Ibid. See also id., at 50–51 (testimony of respondent’s medical expert, Dr. John Matthew) (conceding that the best way to determine that an IV set is functioning satisfactorily is to use IV drip). Finally, if for whatever reason a medical professional chooses to use IV push, he or she is on notice that “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY.” Id., at 391; see also id., at 390 (“Under no circumstances should Phenergan Injection be given by intra-arterial injection due to the likelihood of severe arteriospasm and the possibility of resultant gangrene”).

Phenergan’s label also directs medical practitioners to choose veins wisely when using IV push:

“Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or inadvertent intra-arterial injection. Reports compatible with inadvertent intra-arterial injection of Phenergan Injection, usually in conjunction with other drugs intended for intravenous use, suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances.” Ibid.

Thus, it is demonstrably untrue that, as of 2000, Phenergan’s “labeling did not contain a specific warning about the risks of IV-push administration.” Ante, at 4. And whatever else might be said about the extensive medical authorities and case reports that the FDA cited in “support” of its approval of IV-push administration of Phenergan, it cannot be said that the FDA “paid no more than passing attention to” IV push, ante, at 6; nor can it be said that the FDA failed to weigh its costs and benefits, Brief for Respondent 50.

3

For her part, respondent does not dispute the FDA’s conclusion that IV push has certain benefits. At trial, her medical practitioners testified that they used IV push in order to help her “in a swift and timely way” when she showed up at the hospital for the second time in one day complaining of “intractable” migraines, “terrible pain,” inability to “bear light or sound,” sleeplessness, hours-long spasms of “retching” and “vomiting,” and when “every possible” alternative treatment had “failed.” App. 40 (testimony of Dr. John Matthew); id., at 103, 106, 109 (testimony of physician’s assistant Jessica Fisch).

Rather than disputing the benefits of IV push, respondent complains that the FDA and Wyeth underestimated its costs (and hence did not provide sufficient warnings regarding its risks). But when the FDA mandated that Phenergan’s label read, “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY,” id., at 391, and when the FDA required Wyeth to warn that “[u]nder no circumstances should Phenergan Injection be given by intra-arterial injection,” id., at 390, the agency could reasonably assume that medical professionals would take care not to inject Phenergan intra-arterially. See also 71 Fed. Reg. 3934 (noting that a drug’s warning label “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively”). Unfortunately, the physician’s assistant who treated respondent in this case disregarded Phenergan’s label and pushed the drug into the single spot on her arm that is most likely to cause an inadvertent intra-arterial injection.

As noted above, when the FDA approved Phenergan’s label, it was textbook medical knowledge that the “antecubital fossa” creates a high risk of inadvertent intra-arterial injection, given the close proximity of veins and arteries. See supra, at 13–14; see also The Lippincott Manual of Nursing Practice 99 (7th ed. 2001) (noting, in a red-text “NURSING ALERT,” that the antecubital fossa is “not recommended” for administering dangerous drugs, “due to the potential for extravasation”). 13 According to the physician’s assistant who injured respondent, however, “[i]t never crossed my mind” that an antecubital injection of Phenergan could hit an artery. App. 110; see also ibid. (“[It] just wasn’t something that I was aware of at the time”). Oblivious to the risks emphasized in Phenergan’s warnings, the physician’s assistant pushed a double dose of the drug into an antecubital artery over the course of “[p]robably about three to four minutes,” id., at 111; id., at 105, notwithstanding respondent’s complaints of a “ ‘burn[ing]’ ” sensation that she subsequently described as “ ‘one of the most extreme pains that I’ve ever felt,’ ” id., at 110, 180–181. And when asked why she ignored Phenergan’s label and failed to stop pushing the drug after respondent complained of burning pains, the physician’s assistant explained that it would have been “just crazy” to “worr[y] about an [intra-arterial] injection” under the circumstances, id., at 111.

The FDA, however, did not think that the risks associated with IV push—especially in the antecubital space—were “just crazy.” That is why Phenergan’s label so clearly warns against them.

B

Given the “balance” that the FDA struck between the costs and benefits of administering Phenergan via IV push, Geier compels the pre-emption of tort suits (like this one) that would upset that balance. The contrary conclusion requires turning yesterday’s dissent into today’s majority opinion.

First, the Court denies the existence of a federal-state conflict in this case because Vermont merely countermanded the FDA’s determination that IV push is “safe” when performed in accordance with Phenergan’s warning label; the Court concludes that there is no conflict because Vermont did not “mandate a particular” label as a “replacement” for the one that the jury nullified, and because the State stopped short of altogether “contraindicating IV-push administration.” Ante, at 8. But as we emphasized in Geier (over the dissent’s assertions to the contrary), the degree of a State’s intrusion upon federal law is irrelevant—the Supremacy Clause applies with equal force to a state tort law that merely countermands a federal safety determination and to a state law that altogether prohibits car manufacturers from selling cars without airbags. Compare 529 U. S., at 881–882, with id., at 902 (Stevens, J., dissenting). Indeed, as recently as last Term, we held that the Supremacy Clause pre-empts a “[s]tate tort law that requires a manufacturer’s catheters to be safer, but hence less effective, than the model the FDA has approved … .” Riegel, 552 U. S., at ___ (slip op., at 11). It did not matter there that the State stopped short of altogether prohibiting the use of FDA-approved catheters—just as it does not matter here that Vermont stopped short of altogether prohibiting an FDA-approved method for administering Phenergan. See also Lohr, 518 U. S., at 504 (Breyer, J., concurring in part and concurring in judgment) (noting it would be an “anomalous result” if pre-emption applied differently to a state tort suit premised on the inadequacy of the FDA’s safety regulations and a state law that specifically prohibited an FDA-approved design).

Second, the Court today distinguishes Geier because the FDA articulated its pre-emptive intent “without offering States or other interested parties notice or opportunity for comment. Ante, at 21; see also ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that conflict pre-emption is appropriate only where the agency expresses its pre-emptive intent through notice-and-comment rulemaking. Compare 529 U. S., at 885 (“To insist on a specific expression of agency intent to pre-empt, made after notice-and-comment rulemaking, would be in certain cases to tolerate conflicts that an agency, and therefore Congress, is most unlikely to have intended. The dissent, as we have said, apparently welcomes that result … . We do not”), with id., at 908–910 (Stevens, J., dissenting) (emphasizing that “we generally expect an administrative regulation to declare any intention to pre-empt state law with some specificity,” and that “[t]his expectation … serves to ensurethat States will be able to have a dialog with agencies regarding pre-emption decisions ex ante through the normal notice-and-comment procedures of the Administrative Procedure Act” (internal quotation marks omitted)). Indeed, pre-emption is arguably more appropriate here than in Geier because the FDA (unlike the DOT) declared its pre-emptive intent in the Federal Register. See 71 Fed. Reg. 3933–3936. Yet the majority dismisses the FDA’s published preamble as “inherently suspect,” ante, at 21, and an afterthought that is entitled to “no weight,” ante, at 25. Compare Lohr, supra, at 506 (opinion of Breyer, J.) (emphasizing that the FDA has a “special understanding of the likely impact of both state and federal requirements, as well as an understanding of whether (or the extent to which) state requirements may interfere with federal objectives,” and that “[t]he FDA can translate these understandings into particularized pre-emptive intentions … through statements in ‘regulations, pre-ambles, interpretive statements, and responses tocomments’ ”).

Third, the Court distinguishes Geier because the DOT’s regulation “bear[s] the force of law,” whereas the FDA’s preamble does not. Ante, at 24; see also ante, at 19. But it is irrelevant that the FDA’s preamble does not “bear the force of law” because the FDA’s labeling decisions surely do. See 21 U. S. C. §355. It is well within the FDA’s discretion to make its labeling decisions through administrative adjudications rather than through less-formal and less-flexible rulemaking proceedings, see SEC v. Chenery Corp., 332 U. S. 194 (1947) , and we have never previously held that our pre-emption analysis turns on the agency’s choice of the latter over the former. Moreover, it cannot be said that Geier’s outcome hinged on the agency’s choice to promulgate a rule. See ante, at 19, 24. The Geier Court relied—again over the dissenters’ protestations—on materials other than the Secretary’s regulation to explain the conflict between state and federal law. Compare 529 U. S., at 881, with id., at 899–900 (Stevens, J., dissenting), and ante, at 1–2 (Breyer, J., concurring).

Fourth, the Court sandwiches its discussion of Geier between the “presumption against pre-emption,” ante, at 18, and heavy emphasis on “the longstanding coexistence of state and federal law and the FDA’s traditional recognition of state-law remedies,” ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that the “presumption against pre-emption” is relevant to the conflict pre-emption analysis. See 529 U. S., at 906–907 (Stevens, J., dissenting) (“[T]he Court simply ignores the presumption [against pre-emption]”). Rather than invoking such a “presumption,” the Court emphasized that it was applying “ordinary,” “longstanding,” and “experience-proved principles of conflict pre-emption.” Id., at 874. Under these principles, the sole question is whether there is an “actual conflict” between state and federal law; if so, then pre-emption follows automatically by operation of the Supremacy Clause. Id., at 871–872. See also Buckman, 531 U. S., at 347–348 (“[P]etitioner’s dealings with the FDA were prompted by [federal law], and the very subject matter of petitioner’s statements [to the FDA] were dictated by [federal law]. Accordingly—and in contrast to situations implicating ‘federalism concerns and the historic primacy of state regulation of matters of health and safety’—no presumption against pre-emption obtains in this case” (citation omitted)). 14

Finally, the Geier Court went out of its way to emphasize (yet again over the dissenters’ objections) that it placed “some weight” on the DOT’s amicus brief, which explained the agency’s regulatory objectives and the effects of state tort suits on the federal regulatory regime. 529 U. S., at 883; compare id., at 910–911 (Stevens, J., dissenting) (criticizing the majority for “uph[olding] a regulatory claim of frustration-of-purposes implied conflict pre-emption based on nothing more than an ex post administrative litigating position and inferences from regulatory history and final commentary”). See also Lohr, 518 U. S., at 496 (recognizing that the FDA is “uniquely qualified” to explain whether state law conflicts with the FDA’s objectives). Yet today, the FDA’s explanation of the conflict between state tort suits and the federal labeling regime, set forth in the agency’s amicus brief, is not even mentioned in the Court’s opinion. Instead of relying on the FDA’s explanation of its own regulatory purposes, the Court relies on a decade-old and now-repudiated statement, which the majority finds preferable. See ante, at 21–22, 24, n. 13. Cf. Riegel, 552 U. S., at ___ (slip op., at 13) (noting that “the agency’s earlier position (which the dissent describes at some length and finds preferable) is … compromised, indeed deprived of all claim to deference, by the fact that it is no longer the agency’s position” (citation omitted)); Altria Group, Inc. v. Good, 555 U. S. ___, ___ (2008) (slip op., at 16–17) (rejecting petitioners’ reliance on the pre-emptive effect of the agency’s “longstanding policy” because it is inconsistent with the agency’s current one). And Justice Breyer suggests that state tort suits may “help the [FDA],” ante, at 1 (concurring opinion), notwithstanding the FDA’s insistence that state tort suits will “disrupt the agency’s balancing of health risks and benefits,” Brief for United States as Amicus Curiae 9.

Geier does not countenance the use of state tort suits to second-guess the FDA’s labeling decisions. And the Court’s contrary conclusion has potentially far-reaching consequences.

C

By their very nature, juries are ill-equipped to perform the FDA’s cost-benefit-balancing function. As we explained in Riegel, juries tend to focus on the risk of a particular product’s design or warning label that arguably contributed to a particular plaintiff’s injury, not on the overall benefits of that design or label; “the patients who reaped those benefits are not represented in court.” 552 U. S., at ___ (slip op., at 12). Indeed, patients like respondent are the only ones whom tort juries ever see, and for a patient like respondent—who has already suffered a tragic accident—Phenergan’s risks are no longer a matter of probabilities and potentialities.

In contrast, the FDA has the benefit of the long view. Its drug-approval determinations consider the interests of all potential users of a drug, including “those who would suffer without new medical [products]” if juries in all 50 States were free to contradict the FDA’s expert determinations. Id., at ___ (slip op., at 13). And the FDA conveys its warnings with one voice, rather than whipsawing the medical community with 50 (or more) potentially conflicting ones. After today’s ruling, however, parochialism may prevail.

The problem is well illustrated by the labels borne by “vesicant” drugs, many of which are used for chemotherapy. As a class, vesicants are much more dangerous than drugs like Phenergan, 15 but the vast majority of vesicant labels—like Phenergan’s—either allow or do not disallow IV push. See Appendix, infra. Because vesicant extravasation can have devastating consequences, and because the potentially lifesaving benefits of these drugs offer hollow solace to the victim of such a tragedy, a jury’s cost-benefit analysis in a particular case may well differ from the FDA’s.

For example, consider Mustargen (mechlorethamine HCl)—the injectable form of mustard gas—which can be used as an anticancer drug. Mustargen’s FDA-approved label warns in several places that “This drug is HIGHLY TOXIC.” 16 Indeed, the drug is so highly toxic:

“Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water, for at least 15 minutes while removing contaminated clothing and shoes, followed by 2% sodium thiosulfate solution. Medical attention should be sought immediately. Contaminated clothing should be destroyed.” 17

Yet when it comes to administering this highly toxic drug, the label provides that “the drug may be injected directly into any suitable vein, [but] it is injected preferably into the rubber or plastic tubing of a flowing intravenous infusion set. This reduces the possibility of severe local reactions due to extravasation or high concentration of the drug.” (Emphasis added.) Similarly, the FDA-approved labels for other powerful chemotherapeutic vesicants—including Dactinomycin, Oxaliplatin, Vinblastine, and Vincristine—specifically allow IV push, notwithstanding their devastating effects when extravasated.

The fact that the labels for such drugs allow IV push is striking—both because vesicants are much more dangerous than Phenergan, and also because they are so frequently extravasated, see Boyle & Engelking, Vesicant Extravasation: Myths and Realities, 22 Oncology Nursing Forum 57, 58 (1995) (arguing that the rate of extravasation is “considerably higher” than 6.4% of all vesicant administrations). Regardless of the FDA’s reasons for not contraindicating IV push for these drugs, it is odd (to say the least) that a jury in Vermont can now order for Phenergan what the FDA has chosen not to order for mustard gas. 18

***

To be sure, state tort suits can peacefully coexist with the FDA’s labeling regime, and they have done so for decades. Ante, at 17–18. But this case is far from peaceful coexistence. The FDA told Wyeth that Phenergan’s label renders its use “safe.” But the State of Vermont, through its tort law, said: “Not so.”

The state-law rule at issue here is squarely pre-empted. Therefore, I would reverse the judgment of the Supreme Court of Vermont.

Appendix TO OPINION OF ALITO, J.

Vesicant1

IV Push2

Dactinomycin

Specifically allowed

Mechlorethamine (Mustargen)

Specifically allowed

Oxaliplatin

Specifically allowed

Vinblastine

Specifically allowed

Vincristine

Specifically allowed

Bleomycin

Neither mentioned nor prohibited

Carboplatin

Neither mentioned nor prohibited

Dacarbazine

Neither mentioned nor prohibited

Mitomycin

Neither mentioned nor prohibited

Carmustine

Not prohibited; IV drip recommended

Cisplatin

Not prohibited; IV drip recommended

Epirubicin

Not prohibited; IV drip recommended

Etoposide

Not prohibited; IV drip recommended

Ifosfamide

Not prohibited; IV drip recommended

Mitoxantrone

Not prohibited; IV drip recommended

Paclitaxel

Not prohibited; IV drip recommended

Teniposide

Not prohibited; IV drip recommended

Vinorelbine

Not prohibited; IV drip recommended

Daunorubicin

Prohibited

Doxorubicin

Prohibited

1 Wilkes & Barton-Burke, 2008 Oncology Nursing Drug Handbook 27–33 (2008) (Table 1.6).

2 IV-push information is derived from the “dosage and administration” sections of individual drug labels (available in Clerk of Court’s case file).


Notes

1 Indeed, respondent conceded below that Wyeth did propose an adequate warning of Phenergan’s risks. See Plaintiff Diana Levine’s Memorandum in Opposition to Wyeth’s Motion for Summary Judgment in Levine v. American Home Products Corp. (now Wyeth), No. 670–12–01 Wncv (Super. Ct. Washington Cty., Vt.), ¶7, p. 26. Specifically, respondent noted: “In 1988, Wyeth proposed language that would have prevented this accident by requiring a running IV and explaining why a running IV will address and reduce the risk [of intra-arterial injection].” Ibid. See also id., at 24 (“Although not strong enough, this improved the labeling instruction, if followed, would have prevented the inadvertent administration of Phenergan into an artery …”). The FDA rejected Wyeth’s proposal. See App. 359.

2 Moreover, in the trial judge’s final charge, he told the jury that “the critical factual issue which you must decide” is whether Phenergan’s FDA-mandated label reflects a proper balance between “the risks and benefits of intravenous administration and the potential for injury to patients.” Id., at 220. See also ___ Vt. ___, ___, 944 A. 2d 179, 182 (2006) (recognizing that respondent’s argument is that Phenergan’s “label should not have allowed IV push as a means of administration”).

3 Respondent sued her physician, physician’s assistant, and hospital for malpractice. After the parties settled that suit for an undisclosed sum, respondent’s physician sent her a letter in which he admitted “responsibility” for her injury and expressed his “profoun[d] regre[t]” and “remors[e]” for his actions. 1 Tr. 178–179 (Mar. 8, 2004) (testimony of Dr. John Matthew); see also App. 102–103 (testimony of physician’s assistant Jessica Fisch) (noting that her “sense of grief” was so “great” that she “would have gladly cut off [her own] arm” and given it to respondent). Thereafter, both the physician and the physician’s assistant agreed to testify on respondent’s behalf in her suit against Wyeth.

4 To be sure, Congress recognized the principles of conflict pre-emption in the FDCA. See Drug Amendments of 1962, §202, 76Stat. 793 (“Nothing in the amendments made by this Act to the Federal Food, Drug, and Cosmetic Act shall be construed as invalidating any provision of State law … unless there is a direct and positive conflict between such amendments and such provision of State law”). But a provision that simply recognizes the background principles of conflict pre-emption is not a traditional “saving clause,” and even if it were, it would not displace our conflict-pre-emption analysis. See Geier v. American Honda Motor Co., 529 U. S. 861, 869 (2000) (“[T]he saving clause … does not bar the ordinary working of conflict pre-emption principles”); id., at 873–874 (“The Court has … refused to read general ‘saving’ provisions to tolerate actual conflict both in cases involving impossibility and in ‘frustration-of-purpose’ cases” (emphasis deleted and citation omitted)).

5 The FDA cited numerous articles that generally discuss the costs and benefits associated with IV push. See, e.g., Nahrwold & Phelps, Inadvertent Intra-Arterial Injection of Mephenteramine, 70 Rocky Mountain Medical J. 38 (Sept. 1973) (cited in App. 314, no. 14); Albo, Cheung, Ruth, Snyder, & Beemtsma, Effect of Intra-Arterial Injections of Barbituates, 120 Am. J. of Surgery 676 (1970) (cited in App. 314, no. 12); Corser, Masey, Jacob, Kernoff, & Browne, Ischaemia Following Self-administered Intra-arterial Injection of Methylphenidate and Diamorphine, 40 Anesthesiology 51 (1985) (cited in App. 314, no. 9); Correspondence Regarding Thiopental and Thiamylal (3 letters), 59 Anesthesiology 153 (1983) (cited in App. 314, no. 11); Miller, Arthur, & Stratigos, Intra-arterial Injection of a Barbituate, 23 Anesthesia Progress 25 (1976) (cited in App. 315, no. 19).

6 See Webb & Lampert, Accidental Arterial Injections, 101 Am. J. Obstetrics & Gynecology 365 (1968) (cited in App. 313, no. 5).

7 See Hager & Wilson, Gangrene of the Hand Following Intra-arterial Injection, 94 Archives of Surgery 86 (1967) (cited in App. 313, no. 7); Enloe, Sylvester, & Morris, Hazards of Intra-Arterial Injection of Hydroxyzine, 16 Canadian Anaesthetists’ Society J. 425 (1969) (hereinafter Enloe) (noting “recent reports” of “the occurrence of severe necrosis and gangrene following [administration of] promethazine (Phenergan)” (cited in App. 314, no. 15)). See also Mostafavi & Samimi, Accidental Intra-arterial Injection of Promethazine HCl During General Anesthesia, 35 Anesthesiology 645 (1971) (reporting a case of gangrene, which required partial amputation of three fingers, after Phenergan was inadvertently pushed into an artery in the “antecubital” area); Promethazine, p. 7, in Clinical Pharmacology (Gold Standard Multimedia Inc. CD–ROM, version 1.16 (1998) (noting that “[i]nadvertent intra-arterial injection [of Phenergan] can result in arteriospasm … and development of gangrene”)).

8 Hager and Wilson noted that the most common reactions to intra-arterial injections of drugs like Phenergan include “[i]mmediate, severe, burning pain,” as well as “blanching.” 94 Archives of Surgery, at 87–88. The FDA required Wyeth to include Hager and Wilson’s observations on Phenergan’s label. See App. 311 (requiring the label to warn that “ ‘[t]he first sign [of an intra-arterial injection] may be the patient’s reaction to a sensation of fiery burning’ ” pain and “ ‘[b]lanching’ ”).

9 See Enloe 427 (discussing hydroxyzine—an antihistamine with chemical properties similar to those of Phenergan—and suggesting its “temporary” benefits can never outweigh the risks of intra-arterial injection); see also Goldsmith & Trieger, Accidental Intra-Arterial Injection: A Medical Emergency, 22 Anesthesia Progress 180 (1975) (noting the risks of intra-arterial administration of hydroxyzine) (cited in App. 315, no. 18); Klatte, Brooks, & Rhamy, Toxicity of Intra-Arterial Barbituates and Tranquilizing Drugs, 92 Radiology 700 (1969) (same) (cited in App. 314, no. 13). With full knowledge of those risks, FDA retained IV push for Phenergan, although the agency required Wyeth to incorporate observations from the Enloe article into Phenergan’s label. Compare Enloe 427 (arguing that “every precaution should be taken to avoid inadvertent intra-arterial injection,” including the use of “an obviously well-functioning venoclysis”), with App. 312 (FDA’s 1987 changes to Phenergan’s label). In contrast, at some time around 1970, the FDA prohibited all intravenous use of hydroxyzine. See id., at 79 (testimony of Dr. Harold Green). The FDA’s decision to regulate the two drugs differently—notwithstanding (1) the agency’s knowledge of the risks associated with both drugs and (2) the agency’s recognition of the relevance of hydroxyzine-related articles and case reports in its regulation of Phenergan—further demonstrates that the FDA intentionally preserved IV-push administration for Phenergan. See also Haas, Correspondence, 33 Anesthesia Progress 281 (1986) (“[Hydroxyzine’s] restriction does not lie with the medicine itself, but in the practice and malpractice of intravenous techniques. Unfortunately, the practitioner who knows how to treat injection technique problems is usually not the practitioner with the intravenous technique problems”).

10 See also Engler, Freeman, Kanavage, Ogden, & Moretz, Production of Gangrenous Extremities by Intra-Arterial Injections, 30 Am. Surgeon 602 (1964) (“Accidental arterial injection most often occurs in the antecubital region because this is a favorite site for venopuncture and in this area the ulnar and brachial arteries are superficial and easily entered” (cited in App. 313, no. 6)); Engler, Gangrenous Extremities Resulting from Intra-arterial Injections, 94 Archives of Surgery 644 (1966) (similar) (cited in App. 314, no. 16); Lynas & Bisset, Intra-arterial Thiopentone, 24 Anaesthesia 257 (1969) (“Most [anesthesiologists] agree that injections on the medial aspect of the antecubital fossa are best avoided” (cited in App. 314, no. 8)); Waters, Intra-arterial Thiopentone, 21 Anesthesia 346 (1966) (“The risk of producing gangrene of the forearm by accidental injection of sodium thiopentone into an artery at the elbow has been recognised for many years” (cited in App. 314, no. 10)); see also Hager & Wilson, 94 Archives of Surgery, at 88 (emphasizing that one of the best ways to prevent inadvertent intra-arterial injections is to be aware of “aberrant or superficial arteries at the antecubital, forearm, wrist, and hand level”); Mostafavi & Samimi, supra (warning against antecubital injections).

11 See App. 311 (requiring Phenergan’s label to warn that practitioners should “ ‘[b]eware of the close proximity of arteries and veins at commonly used injection sites and consider the possibility of aberrant arteries’ ”).

12 “Aspiration” refers to drawing a small amount of blood back into the needle to determine whether the needle is in an artery or a vein. Ordinarily, arterial blood is brighter than venous blood—but contact with Phenergan causes discoloration, which makes aspiration an unreliable method of protecting against intra-arterial injection. See id., at 282. Therefore, the label warned that when using IV push, a medical professional should beware that “[a]spiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with Phenergan Injection.” Id., at 390.

13 In addition, respondent’s own medical expert testified at trial that it is a principle of “basic anatomy” that the antecubital fossa contains aberrant arteries. See 2 Tr. 34–35 (Mar. 9, 2004) (testimony of Dr. Daniel O’Brien); see also ibid. (noting that Gray’s Anatomy, which is “the Bible of anatomy,” also warns of arteries in the antecubital space).

14 Thus, it is not true that “this Court has long” applied a presumption against pre-emption in conflict pre-emption cases. Ante, at 9, n. 3 (majority opinion). As long ago as Gibbons v. Ogden, 9 Wheat. 1, 210 (1824), the Court inquired whether a state law “interfer[ed] with,” was “contrary to,” or “c[a]me into collision with” federal law—and it did so without ever invoking a “presumption.” See also Davis, Unmasking the Presumption in Favor of Preemption, 53 S. C. L. Rev. 967, 974 (2002) (noting that many of the Court’s early pre-emption cases “resulted in almost automatic preemption of concurrent state regulation”). In subsequent years the Court has sometimes acknowledged a limited “presumption against pre-emption,” but it nonetheless remained an open question—before today—whether that presumption applied in conflict pre-emption cases. See Crosby v. National Foreign Trade Council, 530 U. S. 363, n. 8 (2000) (“We leave for another day a consideration in this context of a presumption against preemption”). Moreover, this Court has never held that the “presumption” applies in an area—such as drug labeling—that has long been “reserved for federal regulation.” United States v. Locke, 529 U. S. 89, 111 (2000) . See also Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 347–348 (2001) .

15 Vesicants may cause “blistering, severe tissue injury, or tissue necrosis” upon extravasation—even if the drug is not injected into an artery. See, e.g., Schulmeister, Administering Vesicants, 9 Clinical J. of Oncology Nursing 469, 469–470 (2005). See also ante, at 4 (majority opinion) (noting that Phenergan is labeled as an “irritant”); cf. Brief for Anju Budhwani et al. as Amici Curiae 15 (suggesting Phenergan should be considered a “vesicant”).

16 FDA, Oncology Tools Product Label Details, online at http://www.accessdata.fda.gov/scripts/cder/onctools/labels.cfm?GN=meclorethamine, nitrogen mustard (as visited Mar. 2, 2009, and available in Clerk of Court’s case file).

17 Ibid.

18 The same is true of FDA’s regulation of hydroxyzine. See n. 9,supra.


TOP

Dissent

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Alito, with whom The Chief Justice and Justice Scalia join, dissenting.

This case illustrates that tragic facts make bad law. The Court holds that a state tort jury, rather than the Food and Drug Administration (FDA), is ultimately responsible for regulating warning labels for prescription drugs. That result cannot be reconciled with Geier v. American Honda Motor Co., 529 U. S. 861 (2000) , or general principles of conflict pre-emption. I respectfully dissent.

I

The Court frames the question presented as a “narro[w]” one—namely, whether Wyeth has a duty to provide “an adequate warning about using the IV-push method” to administer Phenergan. Ante, at 8. But that ignores the antecedent question of who—the FDA or a jury in Vermont—has the authority and responsibility for determining the “adequacy” of Phenergan’s warnings. Moreover, it is unclear how a “stronger” warning could have helped respondent, see ante, at 16; after all, the physician’s assistant who treated her disregarded at least six separate warnings that are already on Phenergan’s labeling, so respondent would be hard pressed to prove that a seventh would have made a difference. 1

More to the point, the question presented by this case is not a “narrow” one, and it does not concern whether Phenergan’s label should bear a “stronger” warning. Rather, the real issue is whether a state tort jury can countermand the FDA’s considered judgment that Phenergan’s FDA-mandated warning label renders its intravenous (IV) use “safe.” Indeed, respondent’s amended complaint alleged that Phenergan is “not reasonably safe for intravenous administration,” App. 15, ¶6; respondent’s attorney told the jury that Phenergan’s label should say, “ ‘Do not use this drug intravenously,’ ” id., at 32; respondent’s expert told the jury, “I think the drug should be labeled ‘Not for IV use,’ ” id., at 59; and during his closing argument, respondent’s attorney told the jury, “Thank God we don’t rely on the FDA to … make the safe[ty] decision. You will make the decision. … The FDA doesn’t make the decision, you do,” id., at 211–212. 2

Federal law, however, does rely on the FDA to make safety determinations like the one it made here. The FDA has long known about the risks associated with IV push in general and its use to administer Phenergan in particular. Whether wisely or not, the FDA has concluded—over the course of extensive, 54-year-long regulatory proceedings—that the drug is “safe” and “effective” when used in accordance with its FDA-mandated labeling. The unfortunate fact that respondent’s healthcare providers ignored Phenergan’s labeling may make this an ideal medical-malpractice case. 3 But turning a common-law tort suit into a “frontal assault” on the FDA’s regulatory regime for drug labeling upsets the well-settled meaning of the Supremacy Clause and our conflict pre-emption jurisprudence. Brief for United States as Amicus Curiae 21.

II

A

To the extent that “[t]he purpose of Congress is the ultimate touchstone in every pre-emption case,” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) (internal quotation marks omitted), Congress made its “purpose” plain in authorizing the FDA—not state tort juries—to determine when and under what circumstances a drug is “safe.” “[T]he process for approving new drugs is at least as rigorous as the premarket approval process for medical devices,” Riegel v. Medtronic, Inc., 552 U. S. ___, ___ (2008) (slip op., at 11) (Ginsburg, J., dissenting), and we held that the latter pre-empted a state-law tort suit that conflicted with the FDA’s determination that a medical device was “safe,” id., at ___ (slip op., at 11) (opinion of the Court).

Under the Federal Food, Drug, and Cosmetic Act (FDCA), a drug manufacturer may not market a new drug before first submitting a new drug application (NDA) to the FDA and receiving the agency’s approval. See 21 U. S. C. §355(a). An NDA must contain, among other things, “the labeling proposed to be used for such drug,” §355(b)(1)(F), “full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use,” §355(b)(1)(A), and “a discussion of why the benefits exceed the risks [of the drug] under the conditions stated in the labeling,” 21 CFR §314.50(d)(5)(viii) (2008). The FDA will approve an NDA only if the agency finds, among other things, that the drug is “safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof,” there is “substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof,” and the proposed labeling is not “false or misleading in any particular.” 21 U. S. C. §355(d).

After the FDA approves a drug, the manufacturer remains under an obligation to investigate and report any adverse events associated with the drug, see 21 CFR §314.80, and must periodically submit any new information that may affect the FDA’s previous conclusions about the safety, effectiveness, or labeling of the drug, 21 U. S. C. §355(k). If the FDA finds that the drug is not “safe” when used in accordance with its labeling, the agency “shall” withdraw its approval of the drug. §355(e). The FDA also “shall” deem a drug “misbranded” if “it is dangerous to health when used in the dosage or manner, or with the frequency or duration prescribed, recommended, or suggested in the labeling thereof.” §352(j).

Thus, a drug’s warning label “serves as the standard under which the FDA determines whether a product is safe and effective.” 50Fed. Reg. 7470 (1985). Labeling is “[t]he centerpiece of risk management,” as it “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively.” 71Fed. Reg. 3934 (2006). The FDA has underscored the importance it places on drug labels by promulgating comprehensive regulations—spanning an entire part of the Code of Federal Regulations, see 21 CFR pt. 201, with seven subparts and 70 separate sections—that set forth drug manufacturers’ labeling obligations. Under those regulations, the FDA must be satisfied that a drug’s warning label contains, among other things, “a summary of the essential scientific information needed for the safe and effective use of the drug,” §201.56(1), including a description of “clinically significant adverse reactions,” “other potential safety hazards,” “limitations in use imposed by them, … and steps that should be taken if they occur,” §201.57(c)(6)(i). Neither the FDCA nor its implementing regulations suggest that juries may second-guess the FDA’s labeling decisions.

B

1

Where the FDA determines, in accordance with its statutory mandate, that a drug is on balance “safe,” our conflict pre-emption cases prohibit any State from countermanding that determination. See, e.g., Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 348 (2001) (after the FDA has struck “a somewhat delicate balance of statutory objectives” and determined that petitioner submitted a valid application to manufacture a medical device, a State may not use common law to negate it); International Paper Co. v. Ouellette, 479 U. S. 481, 494 (1987) (after the EPA has struck “the balance of public and private interests so carefully addressed by” the federal permitting regime for water pollution, a State may not use nuisance law to “upse[t]” it); Chicago & North Western Transp. Co. v. Kalo Brick & Tile Co., 450 U. S. 311, 321 (1981) (after the Interstate Commerce Commission has struck a “balance” between competing interests in permitting the abandonment of a railroad line, a State may not use statutory or common law to negate it).

Thus, as the Court itself recognizes, it is irrelevant in conflict pre-emption cases whether Congress “enacted an express pre-emption provision at some point during the FDCA’s 70-year history.” Ante, at 18; see also Geier, 529 U. S., at 869 (holding the absence of an express pre-emption clause “does not bar the ordinary working of conflict pre-emption principles”). Rather, the ordinary principles of conflict pre-emption turn solely on whether a State has upset the regulatory balance struck by the federal agency. Id., at 884–885; see also Chicago & North Western Transp. Co., supra, at 317 (describing conflict pre-emption as “a two-step process of first ascertaining the construction of the [federal and state laws] and then determining the constitutional question whether they are actually in conflict” (internal quotation marks omitted)).

2

A faithful application of this Court’s conflict pre-emption cases compels the conclusion that the FDA’s 40-year-long effort to regulate the safety and efficacy of Phenergan pre-empts respondent’s tort suit. Indeed, that result follows directly from our conclusion in Geier.

Geier arose under the National Traffic and Motor Safety Vehicle Act of 1966, which directs the Secretary of the Department of Transportation (DOT) to “establish by order … motor vehicle safety standards,” 15 U. S. C. §1392(a) (1988 ed.), which are defined as “minimum standard[s] for motor vehicle performance, or motor vehicle equipment performance,” §1391(2). Acting pursuant to that statutory mandate, the Secretary of Transportation promulgated Federal Motor Vehicle Safety Standard 208, which required car manufacturers to include passive restraint systems (i.e., devices that work automatically to protect occupants from injury during a collision) in a certain percentage of their cars built in or after 1987. See 49 CFR §571.208 (1999). Standard 208 did not require installation of any particular type of passive restraint; instead, it gave manufacturers the option to install automatic seatbelts, airbags, or any other suitable technology that they might develop, provided the restraint(s) met the performance requirements specified in the rule. Ibid.

Alexis Geier drove her 1987 Honda Accord into a tree, and although she was wearing her seatbelt, she nonetheless suffered serious injuries. She then sued Honda under state tort law, alleging that her car was negligently and defectively designed because it lacked a driver’s-side airbag. She argued that Congress had empowered the Secretary to set only “minimum standard[s]” for vehicle safety. 15 U. S. C. §1391(2). She also emphasized that the National Traffic and Motor Safety Vehicle Act contains a saving clause, which provides that “[c]ompliance with any Federal motor vehicle safety standard issued under this subchapter does not exempt any person from any liability under common law.” §1397(k).

Notwithstanding the statute’s saving clause, and notwithstanding the fact that Congress gave the Secretary authority to set only “minimum” safety standards, we held Geier’s state tort suit pre-empted. In reaching that result, we relied heavily on the view of the Secretary of Transportation—expressed in an amicus brief—that Standard 208 “ ‘embodies the Secretary’s policy judgment that safety would best be promoted if manufacturers installed alternative protection systems in their fleets rather than one particular system in every car.’ ” 529 U. S., at 881 (quoting Brief for United States as Amicus Curiae,O. T. 1999, No. 98–1811, p. 25). Because the Secretary determined that a menu of alternative technologies was “safe,” the doctrine of conflict pre-emption barred Geier’s efforts to deem some of those federally approved alternatives “unsafe” under state tort law.

The same rationale applies here. Through Phenergan’s label, the FDA offered medical professionals a menu of federally approved, “safe” and “effective” alternatives—including IV push—for administering the drug. Through a state tort suit, respondent attempted to deem IV push “unsafe” and “ineffective.” To be sure, federal law does not prohibit Wyeth from contraindicating IV push, just as federal law did not prohibit Honda from installing airbags in all its cars. But just as we held that States may not compel the latter, so, too, are States precluded from compelling the former. See also Fidelity Fed. Sav. & Loan Assn. v. De la Cuesta, 458 U. S. 141, 155 (1982) (“The conflict does not evaporate because the [agency’s] regulation simply permits, but does not compel,” the action forbidden by state law). If anything, a finding of pre-emption is even more appropriate here because the FDCA—unlike the National Traffic and Motor Safety Vehicle Act—contains no evidence that Congress intended the FDA to set only “minimum standards,” and the FDCA does not contain a saving clause. 4 See also ante, at 18 (conceding Congress’ “silence” on the issue).

III

In its attempt to evade Geier’s applicability to this case, the Court commits both factual and legal errors. First, as a factual matter, it is demonstrably untrue that the FDA failed to consider (and strike a “balance” between) the specific costs and benefits associated with IV push. Second, as a legal matter, Geier does not stand for the legal propositions espoused by the dissenters (and specifically rejected by the majority) in that case. Third, drug labeling by jury verdict undermines both our broader pre-emption jurisprudence and the broader workability of the federal drug-labeling regime.

A

Phenergan’s warning label has been subject to the FDA’s strict regulatory oversight since the 1950’s. For at least the last 34 years, the FDA has focused specifically on whether IV-push administration of Phenergan is “safe” and “effective” when performed in accordance with Phenergan’s label. The agency’s ultimate decision—to retain IV push as one means for administering Phenergan, albeit subject to stringent warnings—is reflected in the plain text of Phenergan’s label (sometimes in boldfaced font and all-capital letters). And the record contains ample evidence that the FDA specifically considered and reconsidered the strength of Phenergan’s IV-push-related warnings in light of new scientific and medical data. The majority’s factual assertions to the contrary are mistaken.

1

The FDA’s focus on IV push as a means of administering Phenergan dates back at least to 1975. In August of that year, several representatives from both the FDA and Wyeth met to discuss Phenergan’s warning label. At that meeting, the FDA specifically proposed “that Phenergan Injection should not be used in Tubex.” 2 Record 583, 586 (Plaintiff’s Trial Exh. 17, Internal Correspondence from W. E. Langeland to File (Sept. 5, 1975) (hereinafter 1975 Memo)). “Tubex” is a syringe system used exclusively for IV push. See App. 43. An FDA official explained that the agency’s concerns arose from medical-malpractice lawsuits involving IV push of the drug, see 1975 Memo 586, and that the FDA was aware of “5 cases involving amputation where the drug had been administered by Tubex together with several additional cases involving necrosis,” id., at 586–587. Rather than contraindicating Phenergan for IV push, however, the agency and Wyeth agreed “that there was a need for better instruction regarding the problems of intraarterial injection.” Id., at 587.

The next year, the FDA convened an advisory committee to study, among other things, the risks associated with the Tubex system and IV push. App. 294. At the conclusion of its study, the committee recommended an additional IV-push-specific warning for Phenergan’s label, see ibid., but did not recommend eliminating IV push from the drug label altogether. In response to the committee’s recommendations, the FDA instructed Wyeth to make several changes to strengthen Phenergan’s label, including the addition of upper case warnings related to IV push. See id., at 279–280, 282–283.

In 1987, the FDA directed Wyeth to amend its label to include the following text:

“ ‘[1] When used intravenously, [Phenergan] should be given in a concentration no greater than 25 mg/ml and at a rate not to exceed 25 mg/minute. [2] Injection through a properly running intravenous infusion may enhance the possibility of detecting arterial placement.’ ” Id., at 311–312.

The first of the two quoted sentences refers specifically to IV push; as respondent’s medical expert testified at trial, the label’s recommended rate of administration (not to exceed 25 mg per minute) refers to “IV push, as opposed to say being in a bag and dripped over a couple of hours.” Id., at 52. The second of the two quoted sentences refers to IV drip. See id., at 15–16 (emphasizing that a “running IV” is the same thing as “IV drip”).

In its 1987 labeling order, the FDA cited voluminous materials to “suppor[t]” its new and stronger warnings related to IV push and the preferability of IV drip. 5 Id., at 313. One of those articles specifically discussed the relative advantages and disadvantages of IV drip compared to IV push, as well as the costs and benefits of administering Phenergan via IV push. 6 The FDA also cited published case reports from the 1960’s of gangrene caused by the intra-arterial injection of Phenergan, 7 and the FDA instructed Wyeth to amend Phenergan’s label in accordance with the latest medical research. 8 The FDA also studied drugs similar to Phenergan and cited numerous cautionary articles—one of which urged the agency to consider contraindicating such drugs for IV use altogether. 9

In “support” of its labeling order, the FDA also cited numerous articles that singled out the inner crook of the elbow—known as the “antecubital fossa” in the medical community—whichis both a commonly used injection site, see id., at 70 (noting that respondent’s injection was pushed into “the antecubital space”), and a universally recognized high-risk area for inadvertent intra-arterial injections. One of the articles explained:

“Because of the numerous superficial positions the ulnar artery might occupy, it has often been entered during attempted venipuncture [of the antecubital fossa]. … However, the brachial and the radial arteries might also be quite superficial in the elbow region… . The arterial variations of the arm, especially in and about the cubital fossa, are common and numerous. If venipuncture must be performed in this area, a higher index of suspicion must be maintained to forestall misdirected injections.” Stone & Donnelly, The Accidental Intra-arterial Injection of Thiopental, 22 Anesthesiology 995, 996 (1961) (footnote omitted; cited in App. 315, no. 20). 10

Based on this and other research, the FDA ordered Wyeth to include a specific warning related to the use of the antecubital space for IV push. 11

2

When respondent was injured in 2000, Phenergan’s label specifically addressed IV push in several passages (sometimes in lieu of and sometimes in addition to those discussed above). For example, the label warned of the risks of intra-arterial injection associated with “aspiration,” which is a technique used only in conjunction with IV push. 12 The label also cautioned against the use of “syringes with rigid plungers,” App. 390, which are used onlyto administer the drug via IV push. As respondent’s medical expert testified at trial, “by talking plungers and rigid needles, that’s the way you do it, to push it with the plunger.” Id., at 53 (testimony of Dr. John Matthew). Moreover, Phenergan’s 2000 label devoted almost a full page to discussing the “Tubex system,” see id., at 391, which, as noted above, is used only to administer the drug via IV push.

While Phenergan’s label very clearly authorized the use of IV push, it also made clear that IV push is the delivery method of last resort. The label specified that “[t]he preferred parenteral route of administration is by deep intramuscular injection.” Id., at 390. If an intramuscular injection is ineffective, then “it is usually preferable to inject [Phenergan] through the tubing of an intravenous infusion set that is known to be functioning satisfactorily.” Ibid. See also id., at 50–51 (testimony of respondent’s medical expert, Dr. John Matthew) (conceding that the best way to determine that an IV set is functioning satisfactorily is to use IV drip). Finally, if for whatever reason a medical professional chooses to use IV push, he or she is on notice that “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY.” Id., at 391; see also id., at 390 (“Under no circumstances should Phenergan Injection be given by intra-arterial injection due to the likelihood of severe arteriospasm and the possibility of resultant gangrene”).

Phenergan’s label also directs medical practitioners to choose veins wisely when using IV push:

“Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or inadvertent intra-arterial injection. Reports compatible with inadvertent intra-arterial injection of Phenergan Injection, usually in conjunction with other drugs intended for intravenous use, suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances.” Ibid.

Thus, it is demonstrably untrue that, as of 2000, Phenergan’s “labeling did not contain a specific warning about the risks of IV-push administration.” Ante, at 4. And whatever else might be said about the extensive medical authorities and case reports that the FDA cited in “support” of its approval of IV-push administration of Phenergan, it cannot be said that the FDA “paid no more than passing attention to” IV push, ante, at 6; nor can it be said that the FDA failed to weigh its costs and benefits, Brief for Respondent 50.

3

For her part, respondent does not dispute the FDA’s conclusion that IV push has certain benefits. At trial, her medical practitioners testified that they used IV push in order to help her “in a swift and timely way” when she showed up at the hospital for the second time in one day complaining of “intractable” migraines, “terrible pain,” inability to “bear light or sound,” sleeplessness, hours-long spasms of “retching” and “vomiting,” and when “every possible” alternative treatment had “failed.” App. 40 (testimony of Dr. John Matthew); id., at 103, 106, 109 (testimony of physician’s assistant Jessica Fisch).

Rather than disputing the benefits of IV push, respondent complains that the FDA and Wyeth underestimated its costs (and hence did not provide sufficient warnings regarding its risks). But when the FDA mandated that Phenergan’s label read, “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY,” id., at 391, and when the FDA required Wyeth to warn that “[u]nder no circumstances should Phenergan Injection be given by intra-arterial injection,” id., at 390, the agency could reasonably assume that medical professionals would take care not to inject Phenergan intra-arterially. See also 71 Fed. Reg. 3934 (noting that a drug’s warning label “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively”). Unfortunately, the physician’s assistant who treated respondent in this case disregarded Phenergan’s label and pushed the drug into the single spot on her arm that is most likely to cause an inadvertent intra-arterial injection.

As noted above, when the FDA approved Phenergan’s label, it was textbook medical knowledge that the “antecubital fossa” creates a high risk of inadvertent intra-arterial injection, given the close proximity of veins and arteries. See supra, at 13–14; see also The Lippincott Manual of Nursing Practice 99 (7th ed. 2001) (noting, in a red-text “NURSING ALERT,” that the antecubital fossa is “not recommended” for administering dangerous drugs, “due to the potential for extravasation”). 13 According to the physician’s assistant who injured respondent, however, “[i]t never crossed my mind” that an antecubital injection of Phenergan could hit an artery. App. 110; see also ibid. (“[It] just wasn’t something that I was aware of at the time”). Oblivious to the risks emphasized in Phenergan’s warnings, the physician’s assistant pushed a double dose of the drug into an antecubital artery over the course of “[p]robably about three to four minutes,” id., at 111; id., at 105, notwithstanding respondent’s complaints of a “ ‘burn[ing]’ ” sensation that she subsequently described as “ ‘one of the most extreme pains that I’ve ever felt,’ ” id., at 110, 180–181. And when asked why she ignored Phenergan’s label and failed to stop pushing the drug after respondent complained of burning pains, the physician’s assistant explained that it would have been “just crazy” to “worr[y] about an [intra-arterial] injection” under the circumstances, id., at 111.

The FDA, however, did not think that the risks associated with IV push—especially in the antecubital space—were “just crazy.” That is why Phenergan’s label so clearly warns against them.

B

Given the “balance” that the FDA struck between the costs and benefits of administering Phenergan via IV push, Geier compels the pre-emption of tort suits (like this one) that would upset that balance. The contrary conclusion requires turning yesterday’s dissent into today’s majority opinion.

First, the Court denies the existence of a federal-state conflict in this case because Vermont merely countermanded the FDA’s determination that IV push is “safe” when performed in accordance with Phenergan’s warning label; the Court concludes that there is no conflict because Vermont did not “mandate a particular” label as a “replacement” for the one that the jury nullified, and because the State stopped short of altogether “contraindicating IV-push administration.” Ante, at 8. But as we emphasized in Geier (over the dissent’s assertions to the contrary), the degree of a State’s intrusion upon federal law is irrelevant—the Supremacy Clause applies with equal force to a state tort law that merely countermands a federal safety determination and to a state law that altogether prohibits car manufacturers from selling cars without airbags. Compare 529 U. S., at 881–882, with id., at 902 (Stevens, J., dissenting). Indeed, as recently as last Term, we held that the Supremacy Clause pre-empts a “[s]tate tort law that requires a manufacturer’s catheters to be safer, but hence less effective, than the model the FDA has approved … .” Riegel, 552 U. S., at ___ (slip op., at 11). It did not matter there that the State stopped short of altogether prohibiting the use of FDA-approved catheters—just as it does not matter here that Vermont stopped short of altogether prohibiting an FDA-approved method for administering Phenergan. See also Lohr, 518 U. S., at 504 (Breyer, J., concurring in part and concurring in judgment) (noting it would be an “anomalous result” if pre-emption applied differently to a state tort suit premised on the inadequacy of the FDA’s safety regulations and a state law that specifically prohibited an FDA-approved design).

Second, the Court today distinguishes Geier because the FDA articulated its pre-emptive intent “without offering States or other interested parties notice or opportunity for comment. Ante, at 21; see also ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that conflict pre-emption is appropriate only where the agency expresses its pre-emptive intent through notice-and-comment rulemaking. Compare 529 U. S., at 885 (“To insist on a specific expression of agency intent to pre-empt, made after notice-and-comment rulemaking, would be in certain cases to tolerate conflicts that an agency, and therefore Congress, is most unlikely to have intended. The dissent, as we have said, apparently welcomes that result … . We do not”), with id., at 908–910 (Stevens, J., dissenting) (emphasizing that “we generally expect an administrative regulation to declare any intention to pre-empt state law with some specificity,” and that “[t]his expectation … serves to ensurethat States will be able to have a dialog with agencies regarding pre-emption decisions ex ante through the normal notice-and-comment procedures of the Administrative Procedure Act” (internal quotation marks omitted)). Indeed, pre-emption is arguably more appropriate here than in Geier because the FDA (unlike the DOT) declared its pre-emptive intent in the Federal Register. See 71 Fed. Reg. 3933–3936. Yet the majority dismisses the FDA’s published preamble as “inherently suspect,” ante, at 21, and an afterthought that is entitled to “no weight,” ante, at 25. Compare Lohr, supra, at 506 (opinion of Breyer, J.) (emphasizing that the FDA has a “special understanding of the likely impact of both state and federal requirements, as well as an understanding of whether (or the extent to which) state requirements may interfere with federal objectives,” and that “[t]he FDA can translate these understandings into particularized pre-emptive intentions … through statements in ‘regulations, pre-ambles, interpretive statements, and responses tocomments’ ”).

Third, the Court distinguishes Geier because the DOT’s regulation “bear[s] the force of law,” whereas the FDA’s preamble does not. Ante, at 24; see also ante, at 19. But it is irrelevant that the FDA’s preamble does not “bear the force of law” because the FDA’s labeling decisions surely do. See 21 U. S. C. §355. It is well within the FDA’s discretion to make its labeling decisions through administrative adjudications rather than through less-formal and less-flexible rulemaking proceedings, see SEC v. Chenery Corp., 332 U. S. 194 (1947) , and we have never previously held that our pre-emption analysis turns on the agency’s choice of the latter over the former. Moreover, it cannot be said that Geier’s outcome hinged on the agency’s choice to promulgate a rule. See ante, at 19, 24. The Geier Court relied—again over the dissenters’ protestations—on materials other than the Secretary’s regulation to explain the conflict between state and federal law. Compare 529 U. S., at 881, with id., at 899–900 (Stevens, J., dissenting), and ante, at 1–2 (Breyer, J., concurring).

Fourth, the Court sandwiches its discussion of Geier between the “presumption against pre-emption,” ante, at 18, and heavy emphasis on “the longstanding coexistence of state and federal law and the FDA’s traditional recognition of state-law remedies,” ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that the “presumption against pre-emption” is relevant to the conflict pre-emption analysis. See 529 U. S., at 906–907 (Stevens, J., dissenting) (“[T]he Court simply ignores the presumption [against pre-emption]”). Rather than invoking such a “presumption,” the Court emphasized that it was applying “ordinary,” “longstanding,” and “experience-proved principles of conflict pre-emption.” Id., at 874. Under these principles, the sole question is whether there is an “actual conflict” between state and federal law; if so, then pre-emption follows automatically by operation of the Supremacy Clause. Id., at 871–872. See also Buckman, 531 U. S., at 347–348 (“[P]etitioner’s dealings with the FDA were prompted by [federal law], and the very subject matter of petitioner’s statements [to the FDA] were dictated by [federal law]. Accordingly—and in contrast to situations implicating ‘federalism concerns and the historic primacy of state regulation of matters of health and safety’—no presumption against pre-emption obtains in this case” (citation omitted)). 14

Finally, the Geier Court went out of its way to emphasize (yet again over the dissenters’ objections) that it placed “some weight” on the DOT’s amicus brief, which explained the agency’s regulatory objectives and the effects of state tort suits on the federal regulatory regime. 529 U. S., at 883; compare id., at 910–911 (Stevens, J., dissenting) (criticizing the majority for “uph[olding] a regulatory claim of frustration-of-purposes implied conflict pre-emption based on nothing more than an ex post administrative litigating position and inferences from regulatory history and final commentary”). See also Lohr, 518 U. S., at 496 (recognizing that the FDA is “uniquely qualified” to explain whether state law conflicts with the FDA’s objectives). Yet today, the FDA’s explanation of the conflict between state tort suits and the federal labeling regime, set forth in the agency’s amicus brief, is not even mentioned in the Court’s opinion. Instead of relying on the FDA’s explanation of its own regulatory purposes, the Court relies on a decade-old and now-repudiated statement, which the majority finds preferable. See ante, at 21–22, 24, n. 13. Cf. Riegel, 552 U. S., at ___ (slip op., at 13) (noting that “the agency’s earlier position (which the dissent describes at some length and finds preferable) is … compromised, indeed deprived of all claim to deference, by the fact that it is no longer the agency’s position” (citation omitted)); Altria Group, Inc. v. Good, 555 U. S. ___, ___ (2008) (slip op., at 16–17) (rejecting petitioners’ reliance on the pre-emptive effect of the agency’s “longstanding policy” because it is inconsistent with the agency’s current one). And Justice Breyer suggests that state tort suits may “help the [FDA],” ante, at 1 (concurring opinion), notwithstanding the FDA’s insistence that state tort suits will “disrupt the agency’s balancing of health risks and benefits,” Brief for United States as Amicus Curiae 9.

Geier does not countenance the use of state tort suits to second-guess the FDA’s labeling decisions. And the Court’s contrary conclusion has potentially far-reaching consequences.

C

By their very nature, juries are ill-equipped to perform the FDA’s cost-benefit-balancing function. As we explained in Riegel, juries tend to focus on the risk of a particular product’s design or warning label that arguably contributed to a particular plaintiff’s injury, not on the overall benefits of that design or label; “the patients who reaped those benefits are not represented in court.” 552 U. S., at ___ (slip op., at 12). Indeed, patients like respondent are the only ones whom tort juries ever see, and for a patient like respondent—who has already suffered a tragic accident—Phenergan’s risks are no longer a matter of probabilities and potentialities.

In contrast, the FDA has the benefit of the long view. Its drug-approval determinations consider the interests of all potential users of a drug, including “those who would suffer without new medical [products]” if juries in all 50 States were free to contradict the FDA’s expert determinations. Id., at ___ (slip op., at 13). And the FDA conveys its warnings with one voice, rather than whipsawing the medical community with 50 (or more) potentially conflicting ones. After today’s ruling, however, parochialism may prevail.

The problem is well illustrated by the labels borne by “vesicant” drugs, many of which are used for chemotherapy. As a class, vesicants are much more dangerous than drugs like Phenergan, 15 but the vast majority of vesicant labels—like Phenergan’s—either allow or do not disallow IV push. See Appendix, infra. Because vesicant extravasation can have devastating consequences, and because the potentially lifesaving benefits of these drugs offer hollow solace to the victim of such a tragedy, a jury’s cost-benefit analysis in a particular case may well differ from the FDA’s.

For example, consider Mustargen (mechlorethamine HCl)—the injectable form of mustard gas—which can be used as an anticancer drug. Mustargen’s FDA-approved label warns in several places that “This drug is HIGHLY TOXIC.” 16 Indeed, the drug is so highly toxic:

“Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water, for at least 15 minutes while removing contaminated clothing and shoes, followed by 2% sodium thiosulfate solution. Medical attention should be sought immediately. Contaminated clothing should be destroyed.” 17

Yet when it comes to administering this highly toxic drug, the label provides that “the drug may be injected directly into any suitable vein, [but] it is injected preferably into the rubber or plastic tubing of a flowing intravenous infusion set. This reduces the possibility of severe local reactions due to extravasation or high concentration of the drug.” (Emphasis added.) Similarly, the FDA-approved labels for other powerful chemotherapeutic vesicants—including Dactinomycin, Oxaliplatin, Vinblastine, and Vincristine—specifically allow IV push, notwithstanding their devastating effects when extravasated.

The fact that the labels for such drugs allow IV push is striking—both because vesicants are much more dangerous than Phenergan, and also because they are so frequently extravasated, see Boyle & Engelking, Vesicant Extravasation: Myths and Realities, 22 Oncology Nursing Forum 57, 58 (1995) (arguing that the rate of extravasation is “considerably higher” than 6.4% of all vesicant administrations). Regardless of the FDA’s reasons for not contraindicating IV push for these drugs, it is odd (to say the least) that a jury in Vermont can now order for Phenergan what the FDA has chosen not to order for mustard gas. 18

***

To be sure, state tort suits can peacefully coexist with the FDA’s labeling regime, and they have done so for decades. Ante, at 17–18. But this case is far from peaceful coexistence. The FDA told Wyeth that Phenergan’s label renders its use “safe.” But the State of Vermont, through its tort law, said: “Not so.”

The state-law rule at issue here is squarely pre-empted. Therefore, I would reverse the judgment of the Supreme Court of Vermont.

Appendix TO OPINION OF ALITO, J.

Vesicant1

IV Push2

Dactinomycin

Specifically allowed

Mechlorethamine (Mustargen)

Specifically allowed

Oxaliplatin

Specifically allowed

Vinblastine

Specifically allowed

Vincristine

Specifically allowed

Bleomycin

Neither mentioned nor prohibited

Carboplatin

Neither mentioned nor prohibited

Dacarbazine

Neither mentioned nor prohibited

Mitomycin

Neither mentioned nor prohibited

Carmustine

Not prohibited; IV drip recommended

Cisplatin

Not prohibited; IV drip recommended

Epirubicin

Not prohibited; IV drip recommended

Etoposide

Not prohibited; IV drip recommended

Ifosfamide

Not prohibited; IV drip recommended

Mitoxantrone

Not prohibited; IV drip recommended

Paclitaxel

Not prohibited; IV drip recommended

Teniposide

Not prohibited; IV drip recommended

Vinorelbine

Not prohibited; IV drip recommended

Daunorubicin

Prohibited

Doxorubicin

Prohibited

1 Wilkes & Barton-Burke, 2008 Oncology Nursing Drug Handbook 27–33 (2008) (Table 1.6).

2 IV-push information is derived from the “dosage and administration” sections of individual drug labels (available in Clerk of Court’s case file).


Notes

1 Indeed, respondent conceded below that Wyeth did propose an adequate warning of Phenergan’s risks. See Plaintiff Diana Levine’s Memorandum in Opposition to Wyeth’s Motion for Summary Judgment in Levine v. American Home Products Corp. (now Wyeth), No. 670–12–01 Wncv (Super. Ct. Washington Cty., Vt.), ¶7, p. 26. Specifically, respondent noted: “In 1988, Wyeth proposed language that would have prevented this accident by requiring a running IV and explaining why a running IV will address and reduce the risk [of intra-arterial injection].” Ibid. See also id., at 24 (“Although not strong enough, this improved the labeling instruction, if followed, would have prevented the inadvertent administration of Phenergan into an artery …”). The FDA rejected Wyeth’s proposal. See App. 359.

2 Moreover, in the trial judge’s final charge, he told the jury that “the critical factual issue which you must decide” is whether Phenergan’s FDA-mandated label reflects a proper balance between “the risks and benefits of intravenous administration and the potential for injury to patients.” Id., at 220. See also ___ Vt. ___, ___, 944 A. 2d 179, 182 (2006) (recognizing that respondent’s argument is that Phenergan’s “label should not have allowed IV push as a means of administration”).

3 Respondent sued her physician, physician’s assistant, and hospital for malpractice. After the parties settled that suit for an undisclosed sum, respondent’s physician sent her a letter in which he admitted “responsibility” for her injury and expressed his “profoun[d] regre[t]” and “remors[e]” for his actions. 1 Tr. 178–179 (Mar. 8, 2004) (testimony of Dr. John Matthew); see also App. 102–103 (testimony of physician’s assistant Jessica Fisch) (noting that her “sense of grief” was so “great” that she “would have gladly cut off [her own] arm” and given it to respondent). Thereafter, both the physician and the physician’s assistant agreed to testify on respondent’s behalf in her suit against Wyeth.

4 To be sure, Congress recognized the principles of conflict pre-emption in the FDCA. See Drug Amendments of 1962, §202, 76Stat. 793 (“Nothing in the amendments made by this Act to the Federal Food, Drug, and Cosmetic Act shall be construed as invalidating any provision of State law … unless there is a direct and positive conflict between such amendments and such provision of State law”). But a provision that simply recognizes the background principles of conflict pre-emption is not a traditional “saving clause,” and even if it were, it would not displace our conflict-pre-emption analysis. See Geier v. American Honda Motor Co., 529 U. S. 861, 869 (2000) (“[T]he saving clause … does not bar the ordinary working of conflict pre-emption principles”); id., at 873–874 (“The Court has … refused to read general ‘saving’ provisions to tolerate actual conflict both in cases involving impossibility and in ‘frustration-of-purpose’ cases” (emphasis deleted and citation omitted)).

5 The FDA cited numerous articles that generally discuss the costs and benefits associated with IV push. See, e.g., Nahrwold & Phelps, Inadvertent Intra-Arterial Injection of Mephenteramine, 70 Rocky Mountain Medical J. 38 (Sept. 1973) (cited in App. 314, no. 14); Albo, Cheung, Ruth, Snyder, & Beemtsma, Effect of Intra-Arterial Injections of Barbituates, 120 Am. J. of Surgery 676 (1970) (cited in App. 314, no. 12); Corser, Masey, Jacob, Kernoff, & Browne, Ischaemia Following Self-administered Intra-arterial Injection of Methylphenidate and Diamorphine, 40 Anesthesiology 51 (1985) (cited in App. 314, no. 9); Correspondence Regarding Thiopental and Thiamylal (3 letters), 59 Anesthesiology 153 (1983) (cited in App. 314, no. 11); Miller, Arthur, & Stratigos, Intra-arterial Injection of a Barbituate, 23 Anesthesia Progress 25 (1976) (cited in App. 315, no. 19).

6 See Webb & Lampert, Accidental Arterial Injections, 101 Am. J. Obstetrics & Gynecology 365 (1968) (cited in App. 313, no. 5).

7 See Hager & Wilson, Gangrene of the Hand Following Intra-arterial Injection, 94 Archives of Surgery 86 (1967) (cited in App. 313, no. 7); Enloe, Sylvester, & Morris, Hazards of Intra-Arterial Injection of Hydroxyzine, 16 Canadian Anaesthetists’ Society J. 425 (1969) (hereinafter Enloe) (noting “recent reports” of “the occurrence of severe necrosis and gangrene following [administration of] promethazine (Phenergan)” (cited in App. 314, no. 15)). See also Mostafavi & Samimi, Accidental Intra-arterial Injection of Promethazine HCl During General Anesthesia, 35 Anesthesiology 645 (1971) (reporting a case of gangrene, which required partial amputation of three fingers, after Phenergan was inadvertently pushed into an artery in the “antecubital” area); Promethazine, p. 7, in Clinical Pharmacology (Gold Standard Multimedia Inc. CD–ROM, version 1.16 (1998) (noting that “[i]nadvertent intra-arterial injection [of Phenergan] can result in arteriospasm … and development of gangrene”)).

8 Hager and Wilson noted that the most common reactions to intra-arterial injections of drugs like Phenergan include “[i]mmediate, severe, burning pain,” as well as “blanching.” 94 Archives of Surgery, at 87–88. The FDA required Wyeth to include Hager and Wilson’s observations on Phenergan’s label. See App. 311 (requiring the label to warn that “ ‘[t]he first sign [of an intra-arterial injection] may be the patient’s reaction to a sensation of fiery burning’ ” pain and “ ‘[b]lanching’ ”).

9 See Enloe 427 (discussing hydroxyzine—an antihistamine with chemical properties similar to those of Phenergan—and suggesting its “temporary” benefits can never outweigh the risks of intra-arterial injection); see also Goldsmith & Trieger, Accidental Intra-Arterial Injection: A Medical Emergency, 22 Anesthesia Progress 180 (1975) (noting the risks of intra-arterial administration of hydroxyzine) (cited in App. 315, no. 18); Klatte, Brooks, & Rhamy, Toxicity of Intra-Arterial Barbituates and Tranquilizing Drugs, 92 Radiology 700 (1969) (same) (cited in App. 314, no. 13). With full knowledge of those risks, FDA retained IV push for Phenergan, although the agency required Wyeth to incorporate observations from the Enloe article into Phenergan’s label. Compare Enloe 427 (arguing that “every precaution should be taken to avoid inadvertent intra-arterial injection,” including the use of “an obviously well-functioning venoclysis”), with App. 312 (FDA’s 1987 changes to Phenergan’s label). In contrast, at some time around 1970, the FDA prohibited all intravenous use of hydroxyzine. See id., at 79 (testimony of Dr. Harold Green). The FDA’s decision to regulate the two drugs differently—notwithstanding (1) the agency’s knowledge of the risks associated with both drugs and (2) the agency’s recognition of the relevance of hydroxyzine-related articles and case reports in its regulation of Phenergan—further demonstrates that the FDA intentionally preserved IV-push administration for Phenergan. See also Haas, Correspondence, 33 Anesthesia Progress 281 (1986) (“[Hydroxyzine’s] restriction does not lie with the medicine itself, but in the practice and malpractice of intravenous techniques. Unfortunately, the practitioner who knows how to treat injection technique problems is usually not the practitioner with the intravenous technique problems”).

10 See also Engler, Freeman, Kanavage, Ogden, & Moretz, Production of Gangrenous Extremities by Intra-Arterial Injections, 30 Am. Surgeon 602 (1964) (“Accidental arterial injection most often occurs in the antecubital region because this is a favorite site for venopuncture and in this area the ulnar and brachial arteries are superficial and easily entered” (cited in App. 313, no. 6)); Engler, Gangrenous Extremities Resulting from Intra-arterial Injections, 94 Archives of Surgery 644 (1966) (similar) (cited in App. 314, no. 16); Lynas & Bisset, Intra-arterial Thiopentone, 24 Anaesthesia 257 (1969) (“Most [anesthesiologists] agree that injections on the medial aspect of the antecubital fossa are best avoided” (cited in App. 314, no. 8)); Waters, Intra-arterial Thiopentone, 21 Anesthesia 346 (1966) (“The risk of producing gangrene of the forearm by accidental injection of sodium thiopentone into an artery at the elbow has been recognised for many years” (cited in App. 314, no. 10)); see also Hager & Wilson, 94 Archives of Surgery, at 88 (emphasizing that one of the best ways to prevent inadvertent intra-arterial injections is to be aware of “aberrant or superficial arteries at the antecubital, forearm, wrist, and hand level”); Mostafavi & Samimi, supra (warning against antecubital injections).

11 See App. 311 (requiring Phenergan’s label to warn that practitioners should “ ‘[b]eware of the close proximity of arteries and veins at commonly used injection sites and consider the possibility of aberrant arteries’ ”).

12 “Aspiration” refers to drawing a small amount of blood back into the needle to determine whether the needle is in an artery or a vein. Ordinarily, arterial blood is brighter than venous blood—but contact with Phenergan causes discoloration, which makes aspiration an unreliable method of protecting against intra-arterial injection. See id., at 282. Therefore, the label warned that when using IV push, a medical professional should beware that “[a]spiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with Phenergan Injection.” Id., at 390.

13 In addition, respondent’s own medical expert testified at trial that it is a principle of “basic anatomy” that the antecubital fossa contains aberrant arteries. See 2 Tr. 34–35 (Mar. 9, 2004) (testimony of Dr. Daniel O’Brien); see also ibid. (noting that Gray’s Anatomy, which is “the Bible of anatomy,” also warns of arteries in the antecubital space).

14 Thus, it is not true that “this Court has long” applied a presumption against pre-emption in conflict pre-emption cases. Ante, at 9, n. 3 (majority opinion). As long ago as Gibbons v. Ogden, 9 Wheat. 1, 210 (1824), the Court inquired whether a state law “interfer[ed] with,” was “contrary to,” or “c[a]me into collision with” federal law—and it did so without ever invoking a “presumption.” See also Davis, Unmasking the Presumption in Favor of Preemption, 53 S. C. L. Rev. 967, 974 (2002) (noting that many of the Court’s early pre-emption cases “resulted in almost automatic preemption of concurrent state regulation”). In subsequent years the Court has sometimes acknowledged a limited “presumption against pre-emption,” but it nonetheless remained an open question—before today—whether that presumption applied in conflict pre-emption cases. See Crosby v. National Foreign Trade Council, 530 U. S. 363, n. 8 (2000) (“We leave for another day a consideration in this context of a presumption against preemption”). Moreover, this Court has never held that the “presumption” applies in an area—such as drug labeling—that has long been “reserved for federal regulation.” United States v. Locke, 529 U. S. 89, 111 (2000) . See also Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 347–348 (2001) .

15 Vesicants may cause “blistering, severe tissue injury, or tissue necrosis” upon extravasation—even if the drug is not injected into an artery. See, e.g., Schulmeister, Administering Vesicants, 9 Clinical J. of Oncology Nursing 469, 469–470 (2005). See also ante, at 4 (majority opinion) (noting that Phenergan is labeled as an “irritant”); cf. Brief for Anju Budhwani et al. as Amici Curiae 15 (suggesting Phenergan should be considered a “vesicant”).

16 FDA, Oncology Tools Product Label Details, online at http://www.accessdata.fda.gov/scripts/cder/onctools/labels.cfm?GN=meclorethamine, nitrogen mustard (as visited Mar. 2, 2009, and available in Clerk of Court’s case file).

17 Ibid.

18 The same is true of FDA’s regulation of hydroxyzine. See n. 9,supra.


TOP

Dissent

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Alito, with whom The Chief Justice and Justice Scalia join, dissenting.

This case illustrates that tragic facts make bad law. The Court holds that a state tort jury, rather than the Food and Drug Administration (FDA), is ultimately responsible for regulating warning labels for prescription drugs. That result cannot be reconciled with Geier v. American Honda Motor Co., 529 U. S. 861 (2000) , or general principles of conflict pre-emption. I respectfully dissent.

I

The Court frames the question presented as a “narro[w]” one—namely, whether Wyeth has a duty to provide “an adequate warning about using the IV-push method” to administer Phenergan. Ante, at 8. But that ignores the antecedent question of who—the FDA or a jury in Vermont—has the authority and responsibility for determining the “adequacy” of Phenergan’s warnings. Moreover, it is unclear how a “stronger” warning could have helped respondent, see ante, at 16; after all, the physician’s assistant who treated her disregarded at least six separate warnings that are already on Phenergan’s labeling, so respondent would be hard pressed to prove that a seventh would have made a difference. 1

More to the point, the question presented by this case is not a “narrow” one, and it does not concern whether Phenergan’s label should bear a “stronger” warning. Rather, the real issue is whether a state tort jury can countermand the FDA’s considered judgment that Phenergan’s FDA-mandated warning label renders its intravenous (IV) use “safe.” Indeed, respondent’s amended complaint alleged that Phenergan is “not reasonably safe for intravenous administration,” App. 15, ¶6; respondent’s attorney told the jury that Phenergan’s label should say, “ ‘Do not use this drug intravenously,’ ” id., at 32; respondent’s expert told the jury, “I think the drug should be labeled ‘Not for IV use,’ ” id., at 59; and during his closing argument, respondent’s attorney told the jury, “Thank God we don’t rely on the FDA to … make the safe[ty] decision. You will make the decision. … The FDA doesn’t make the decision, you do,” id., at 211–212. 2

Federal law, however, does rely on the FDA to make safety determinations like the one it made here. The FDA has long known about the risks associated with IV push in general and its use to administer Phenergan in particular. Whether wisely or not, the FDA has concluded—over the course of extensive, 54-year-long regulatory proceedings—that the drug is “safe” and “effective” when used in accordance with its FDA-mandated labeling. The unfortunate fact that respondent’s healthcare providers ignored Phenergan’s labeling may make this an ideal medical-malpractice case. 3 But turning a common-law tort suit into a “frontal assault” on the FDA’s regulatory regime for drug labeling upsets the well-settled meaning of the Supremacy Clause and our conflict pre-emption jurisprudence. Brief for United States as Amicus Curiae 21.

II

A

To the extent that “[t]he purpose of Congress is the ultimate touchstone in every pre-emption case,” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) (internal quotation marks omitted), Congress made its “purpose” plain in authorizing the FDA—not state tort juries—to determine when and under what circumstances a drug is “safe.” “[T]he process for approving new drugs is at least as rigorous as the premarket approval process for medical devices,” Riegel v. Medtronic, Inc., 552 U. S. ___, ___ (2008) (slip op., at 11) (Ginsburg, J., dissenting), and we held that the latter pre-empted a state-law tort suit that conflicted with the FDA’s determination that a medical device was “safe,” id., at ___ (slip op., at 11) (opinion of the Court).

Under the Federal Food, Drug, and Cosmetic Act (FDCA), a drug manufacturer may not market a new drug before first submitting a new drug application (NDA) to the FDA and receiving the agency’s approval. See 21 U. S. C. §355(a). An NDA must contain, among other things, “the labeling proposed to be used for such drug,” §355(b)(1)(F), “full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use,” §355(b)(1)(A), and “a discussion of why the benefits exceed the risks [of the drug] under the conditions stated in the labeling,” 21 CFR §314.50(d)(5)(viii) (2008). The FDA will approve an NDA only if the agency finds, among other things, that the drug is “safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof,” there is “substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof,” and the proposed labeling is not “false or misleading in any particular.” 21 U. S. C. §355(d).

After the FDA approves a drug, the manufacturer remains under an obligation to investigate and report any adverse events associated with the drug, see 21 CFR §314.80, and must periodically submit any new information that may affect the FDA’s previous conclusions about the safety, effectiveness, or labeling of the drug, 21 U. S. C. §355(k). If the FDA finds that the drug is not “safe” when used in accordance with its labeling, the agency “shall” withdraw its approval of the drug. §355(e). The FDA also “shall” deem a drug “misbranded” if “it is dangerous to health when used in the dosage or manner, or with the frequency or duration prescribed, recommended, or suggested in the labeling thereof.” §352(j).

Thus, a drug’s warning label “serves as the standard under which the FDA determines whether a product is safe and effective.” 50Fed. Reg. 7470 (1985). Labeling is “[t]he centerpiece of risk management,” as it “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively.” 71Fed. Reg. 3934 (2006). The FDA has underscored the importance it places on drug labels by promulgating comprehensive regulations—spanning an entire part of the Code of Federal Regulations, see 21 CFR pt. 201, with seven subparts and 70 separate sections—that set forth drug manufacturers’ labeling obligations. Under those regulations, the FDA must be satisfied that a drug’s warning label contains, among other things, “a summary of the essential scientific information needed for the safe and effective use of the drug,” §201.56(1), including a description of “clinically significant adverse reactions,” “other potential safety hazards,” “limitations in use imposed by them, … and steps that should be taken if they occur,” §201.57(c)(6)(i). Neither the FDCA nor its implementing regulations suggest that juries may second-guess the FDA’s labeling decisions.

B

1

Where the FDA determines, in accordance with its statutory mandate, that a drug is on balance “safe,” our conflict pre-emption cases prohibit any State from countermanding that determination. See, e.g., Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 348 (2001) (after the FDA has struck “a somewhat delicate balance of statutory objectives” and determined that petitioner submitted a valid application to manufacture a medical device, a State may not use common law to negate it); International Paper Co. v. Ouellette, 479 U. S. 481, 494 (1987) (after the EPA has struck “the balance of public and private interests so carefully addressed by” the federal permitting regime for water pollution, a State may not use nuisance law to “upse[t]” it); Chicago & North Western Transp. Co. v. Kalo Brick & Tile Co., 450 U. S. 311, 321 (1981) (after the Interstate Commerce Commission has struck a “balance” between competing interests in permitting the abandonment of a railroad line, a State may not use statutory or common law to negate it).

Thus, as the Court itself recognizes, it is irrelevant in conflict pre-emption cases whether Congress “enacted an express pre-emption provision at some point during the FDCA’s 70-year history.” Ante, at 18; see also Geier, 529 U. S., at 869 (holding the absence of an express pre-emption clause “does not bar the ordinary working of conflict pre-emption principles”). Rather, the ordinary principles of conflict pre-emption turn solely on whether a State has upset the regulatory balance struck by the federal agency. Id., at 884–885; see also Chicago & North Western Transp. Co., supra, at 317 (describing conflict pre-emption as “a two-step process of first ascertaining the construction of the [federal and state laws] and then determining the constitutional question whether they are actually in conflict” (internal quotation marks omitted)).

2

A faithful application of this Court’s conflict pre-emption cases compels the conclusion that the FDA’s 40-year-long effort to regulate the safety and efficacy of Phenergan pre-empts respondent’s tort suit. Indeed, that result follows directly from our conclusion in Geier.

Geier arose under the National Traffic and Motor Safety Vehicle Act of 1966, which directs the Secretary of the Department of Transportation (DOT) to “establish by order … motor vehicle safety standards,” 15 U. S. C. §1392(a) (1988 ed.), which are defined as “minimum standard[s] for motor vehicle performance, or motor vehicle equipment performance,” §1391(2). Acting pursuant to that statutory mandate, the Secretary of Transportation promulgated Federal Motor Vehicle Safety Standard 208, which required car manufacturers to include passive restraint systems (i.e., devices that work automatically to protect occupants from injury during a collision) in a certain percentage of their cars built in or after 1987. See 49 CFR §571.208 (1999). Standard 208 did not require installation of any particular type of passive restraint; instead, it gave manufacturers the option to install automatic seatbelts, airbags, or any other suitable technology that they might develop, provided the restraint(s) met the performance requirements specified in the rule. Ibid.

Alexis Geier drove her 1987 Honda Accord into a tree, and although she was wearing her seatbelt, she nonetheless suffered serious injuries. She then sued Honda under state tort law, alleging that her car was negligently and defectively designed because it lacked a driver’s-side airbag. She argued that Congress had empowered the Secretary to set only “minimum standard[s]” for vehicle safety. 15 U. S. C. §1391(2). She also emphasized that the National Traffic and Motor Safety Vehicle Act contains a saving clause, which provides that “[c]ompliance with any Federal motor vehicle safety standard issued under this subchapter does not exempt any person from any liability under common law.” §1397(k).

Notwithstanding the statute’s saving clause, and notwithstanding the fact that Congress gave the Secretary authority to set only “minimum” safety standards, we held Geier’s state tort suit pre-empted. In reaching that result, we relied heavily on the view of the Secretary of Transportation—expressed in an amicus brief—that Standard 208 “ ‘embodies the Secretary’s policy judgment that safety would best be promoted if manufacturers installed alternative protection systems in their fleets rather than one particular system in every car.’ ” 529 U. S., at 881 (quoting Brief for United States as Amicus Curiae,O. T. 1999, No. 98–1811, p. 25). Because the Secretary determined that a menu of alternative technologies was “safe,” the doctrine of conflict pre-emption barred Geier’s efforts to deem some of those federally approved alternatives “unsafe” under state tort law.

The same rationale applies here. Through Phenergan’s label, the FDA offered medical professionals a menu of federally approved, “safe” and “effective” alternatives—including IV push—for administering the drug. Through a state tort suit, respondent attempted to deem IV push “unsafe” and “ineffective.” To be sure, federal law does not prohibit Wyeth from contraindicating IV push, just as federal law did not prohibit Honda from installing airbags in all its cars. But just as we held that States may not compel the latter, so, too, are States precluded from compelling the former. See also Fidelity Fed. Sav. & Loan Assn. v. De la Cuesta, 458 U. S. 141, 155 (1982) (“The conflict does not evaporate because the [agency’s] regulation simply permits, but does not compel,” the action forbidden by state law). If anything, a finding of pre-emption is even more appropriate here because the FDCA—unlike the National Traffic and Motor Safety Vehicle Act—contains no evidence that Congress intended the FDA to set only “minimum standards,” and the FDCA does not contain a saving clause. 4 See also ante, at 18 (conceding Congress’ “silence” on the issue).

III

In its attempt to evade Geier’s applicability to this case, the Court commits both factual and legal errors. First, as a factual matter, it is demonstrably untrue that the FDA failed to consider (and strike a “balance” between) the specific costs and benefits associated with IV push. Second, as a legal matter, Geier does not stand for the legal propositions espoused by the dissenters (and specifically rejected by the majority) in that case. Third, drug labeling by jury verdict undermines both our broader pre-emption jurisprudence and the broader workability of the federal drug-labeling regime.

A

Phenergan’s warning label has been subject to the FDA’s strict regulatory oversight since the 1950’s. For at least the last 34 years, the FDA has focused specifically on whether IV-push administration of Phenergan is “safe” and “effective” when performed in accordance with Phenergan’s label. The agency’s ultimate decision—to retain IV push as one means for administering Phenergan, albeit subject to stringent warnings—is reflected in the plain text of Phenergan’s label (sometimes in boldfaced font and all-capital letters). And the record contains ample evidence that the FDA specifically considered and reconsidered the strength of Phenergan’s IV-push-related warnings in light of new scientific and medical data. The majority’s factual assertions to the contrary are mistaken.

1

The FDA’s focus on IV push as a means of administering Phenergan dates back at least to 1975. In August of that year, several representatives from both the FDA and Wyeth met to discuss Phenergan’s warning label. At that meeting, the FDA specifically proposed “that Phenergan Injection should not be used in Tubex.” 2 Record 583, 586 (Plaintiff’s Trial Exh. 17, Internal Correspondence from W. E. Langeland to File (Sept. 5, 1975) (hereinafter 1975 Memo)). “Tubex” is a syringe system used exclusively for IV push. See App. 43. An FDA official explained that the agency’s concerns arose from medical-malpractice lawsuits involving IV push of the drug, see 1975 Memo 586, and that the FDA was aware of “5 cases involving amputation where the drug had been administered by Tubex together with several additional cases involving necrosis,” id., at 586–587. Rather than contraindicating Phenergan for IV push, however, the agency and Wyeth agreed “that there was a need for better instruction regarding the problems of intraarterial injection.” Id., at 587.

The next year, the FDA convened an advisory committee to study, among other things, the risks associated with the Tubex system and IV push. App. 294. At the conclusion of its study, the committee recommended an additional IV-push-specific warning for Phenergan’s label, see ibid., but did not recommend eliminating IV push from the drug label altogether. In response to the committee’s recommendations, the FDA instructed Wyeth to make several changes to strengthen Phenergan’s label, including the addition of upper case warnings related to IV push. See id., at 279–280, 282–283.

In 1987, the FDA directed Wyeth to amend its label to include the following text:

“ ‘[1] When used intravenously, [Phenergan] should be given in a concentration no greater than 25 mg/ml and at a rate not to exceed 25 mg/minute. [2] Injection through a properly running intravenous infusion may enhance the possibility of detecting arterial placement.’ ” Id., at 311–312.

The first of the two quoted sentences refers specifically to IV push; as respondent’s medical expert testified at trial, the label’s recommended rate of administration (not to exceed 25 mg per minute) refers to “IV push, as opposed to say being in a bag and dripped over a couple of hours.” Id., at 52. The second of the two quoted sentences refers to IV drip. See id., at 15–16 (emphasizing that a “running IV” is the same thing as “IV drip”).

In its 1987 labeling order, the FDA cited voluminous materials to “suppor[t]” its new and stronger warnings related to IV push and the preferability of IV drip. 5 Id., at 313. One of those articles specifically discussed the relative advantages and disadvantages of IV drip compared to IV push, as well as the costs and benefits of administering Phenergan via IV push. 6 The FDA also cited published case reports from the 1960’s of gangrene caused by the intra-arterial injection of Phenergan, 7 and the FDA instructed Wyeth to amend Phenergan’s label in accordance with the latest medical research. 8 The FDA also studied drugs similar to Phenergan and cited numerous cautionary articles—one of which urged the agency to consider contraindicating such drugs for IV use altogether. 9

In “support” of its labeling order, the FDA also cited numerous articles that singled out the inner crook of the elbow—known as the “antecubital fossa” in the medical community—whichis both a commonly used injection site, see id., at 70 (noting that respondent’s injection was pushed into “the antecubital space”), and a universally recognized high-risk area for inadvertent intra-arterial injections. One of the articles explained:

“Because of the numerous superficial positions the ulnar artery might occupy, it has often been entered during attempted venipuncture [of the antecubital fossa]. … However, the brachial and the radial arteries might also be quite superficial in the elbow region… . The arterial variations of the arm, especially in and about the cubital fossa, are common and numerous. If venipuncture must be performed in this area, a higher index of suspicion must be maintained to forestall misdirected injections.” Stone & Donnelly, The Accidental Intra-arterial Injection of Thiopental, 22 Anesthesiology 995, 996 (1961) (footnote omitted; cited in App. 315, no. 20). 10

Based on this and other research, the FDA ordered Wyeth to include a specific warning related to the use of the antecubital space for IV push. 11

2

When respondent was injured in 2000, Phenergan’s label specifically addressed IV push in several passages (sometimes in lieu of and sometimes in addition to those discussed above). For example, the label warned of the risks of intra-arterial injection associated with “aspiration,” which is a technique used only in conjunction with IV push. 12 The label also cautioned against the use of “syringes with rigid plungers,” App. 390, which are used onlyto administer the drug via IV push. As respondent’s medical expert testified at trial, “by talking plungers and rigid needles, that’s the way you do it, to push it with the plunger.” Id., at 53 (testimony of Dr. John Matthew). Moreover, Phenergan’s 2000 label devoted almost a full page to discussing the “Tubex system,” see id., at 391, which, as noted above, is used only to administer the drug via IV push.

While Phenergan’s label very clearly authorized the use of IV push, it also made clear that IV push is the delivery method of last resort. The label specified that “[t]he preferred parenteral route of administration is by deep intramuscular injection.” Id., at 390. If an intramuscular injection is ineffective, then “it is usually preferable to inject [Phenergan] through the tubing of an intravenous infusion set that is known to be functioning satisfactorily.” Ibid. See also id., at 50–51 (testimony of respondent’s medical expert, Dr. John Matthew) (conceding that the best way to determine that an IV set is functioning satisfactorily is to use IV drip). Finally, if for whatever reason a medical professional chooses to use IV push, he or she is on notice that “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY.” Id., at 391; see also id., at 390 (“Under no circumstances should Phenergan Injection be given by intra-arterial injection due to the likelihood of severe arteriospasm and the possibility of resultant gangrene”).

Phenergan’s label also directs medical practitioners to choose veins wisely when using IV push:

“Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or inadvertent intra-arterial injection. Reports compatible with inadvertent intra-arterial injection of Phenergan Injection, usually in conjunction with other drugs intended for intravenous use, suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances.” Ibid.

Thus, it is demonstrably untrue that, as of 2000, Phenergan’s “labeling did not contain a specific warning about the risks of IV-push administration.” Ante, at 4. And whatever else might be said about the extensive medical authorities and case reports that the FDA cited in “support” of its approval of IV-push administration of Phenergan, it cannot be said that the FDA “paid no more than passing attention to” IV push, ante, at 6; nor can it be said that the FDA failed to weigh its costs and benefits, Brief for Respondent 50.

3

For her part, respondent does not dispute the FDA’s conclusion that IV push has certain benefits. At trial, her medical practitioners testified that they used IV push in order to help her “in a swift and timely way” when she showed up at the hospital for the second time in one day complaining of “intractable” migraines, “terrible pain,” inability to “bear light or sound,” sleeplessness, hours-long spasms of “retching” and “vomiting,” and when “every possible” alternative treatment had “failed.” App. 40 (testimony of Dr. John Matthew); id., at 103, 106, 109 (testimony of physician’s assistant Jessica Fisch).

Rather than disputing the benefits of IV push, respondent complains that the FDA and Wyeth underestimated its costs (and hence did not provide sufficient warnings regarding its risks). But when the FDA mandated that Phenergan’s label read, “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY,” id., at 391, and when the FDA required Wyeth to warn that “[u]nder no circumstances should Phenergan Injection be given by intra-arterial injection,” id., at 390, the agency could reasonably assume that medical professionals would take care not to inject Phenergan intra-arterially. See also 71 Fed. Reg. 3934 (noting that a drug’s warning label “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively”). Unfortunately, the physician’s assistant who treated respondent in this case disregarded Phenergan’s label and pushed the drug into the single spot on her arm that is most likely to cause an inadvertent intra-arterial injection.

As noted above, when the FDA approved Phenergan’s label, it was textbook medical knowledge that the “antecubital fossa” creates a high risk of inadvertent intra-arterial injection, given the close proximity of veins and arteries. See supra, at 13–14; see also The Lippincott Manual of Nursing Practice 99 (7th ed. 2001) (noting, in a red-text “NURSING ALERT,” that the antecubital fossa is “not recommended” for administering dangerous drugs, “due to the potential for extravasation”). 13 According to the physician’s assistant who injured respondent, however, “[i]t never crossed my mind” that an antecubital injection of Phenergan could hit an artery. App. 110; see also ibid. (“[It] just wasn’t something that I was aware of at the time”). Oblivious to the risks emphasized in Phenergan’s warnings, the physician’s assistant pushed a double dose of the drug into an antecubital artery over the course of “[p]robably about three to four minutes,” id., at 111; id., at 105, notwithstanding respondent’s complaints of a “ ‘burn[ing]’ ” sensation that she subsequently described as “ ‘one of the most extreme pains that I’ve ever felt,’ ” id., at 110, 180–181. And when asked why she ignored Phenergan’s label and failed to stop pushing the drug after respondent complained of burning pains, the physician’s assistant explained that it would have been “just crazy” to “worr[y] about an [intra-arterial] injection” under the circumstances, id., at 111.

The FDA, however, did not think that the risks associated with IV push—especially in the antecubital space—were “just crazy.” That is why Phenergan’s label so clearly warns against them.

B

Given the “balance” that the FDA struck between the costs and benefits of administering Phenergan via IV push, Geier compels the pre-emption of tort suits (like this one) that would upset that balance. The contrary conclusion requires turning yesterday’s dissent into today’s majority opinion.

First, the Court denies the existence of a federal-state conflict in this case because Vermont merely countermanded the FDA’s determination that IV push is “safe” when performed in accordance with Phenergan’s warning label; the Court concludes that there is no conflict because Vermont did not “mandate a particular” label as a “replacement” for the one that the jury nullified, and because the State stopped short of altogether “contraindicating IV-push administration.” Ante, at 8. But as we emphasized in Geier (over the dissent’s assertions to the contrary), the degree of a State’s intrusion upon federal law is irrelevant—the Supremacy Clause applies with equal force to a state tort law that merely countermands a federal safety determination and to a state law that altogether prohibits car manufacturers from selling cars without airbags. Compare 529 U. S., at 881–882, with id., at 902 (Stevens, J., dissenting). Indeed, as recently as last Term, we held that the Supremacy Clause pre-empts a “[s]tate tort law that requires a manufacturer’s catheters to be safer, but hence less effective, than the model the FDA has approved … .” Riegel, 552 U. S., at ___ (slip op., at 11). It did not matter there that the State stopped short of altogether prohibiting the use of FDA-approved catheters—just as it does not matter here that Vermont stopped short of altogether prohibiting an FDA-approved method for administering Phenergan. See also Lohr, 518 U. S., at 504 (Breyer, J., concurring in part and concurring in judgment) (noting it would be an “anomalous result” if pre-emption applied differently to a state tort suit premised on the inadequacy of the FDA’s safety regulations and a state law that specifically prohibited an FDA-approved design).

Second, the Court today distinguishes Geier because the FDA articulated its pre-emptive intent “without offering States or other interested parties notice or opportunity for comment. Ante, at 21; see also ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that conflict pre-emption is appropriate only where the agency expresses its pre-emptive intent through notice-and-comment rulemaking. Compare 529 U. S., at 885 (“To insist on a specific expression of agency intent to pre-empt, made after notice-and-comment rulemaking, would be in certain cases to tolerate conflicts that an agency, and therefore Congress, is most unlikely to have intended. The dissent, as we have said, apparently welcomes that result … . We do not”), with id., at 908–910 (Stevens, J., dissenting) (emphasizing that “we generally expect an administrative regulation to declare any intention to pre-empt state law with some specificity,” and that “[t]his expectation … serves to ensurethat States will be able to have a dialog with agencies regarding pre-emption decisions ex ante through the normal notice-and-comment procedures of the Administrative Procedure Act” (internal quotation marks omitted)). Indeed, pre-emption is arguably more appropriate here than in Geier because the FDA (unlike the DOT) declared its pre-emptive intent in the Federal Register. See 71 Fed. Reg. 3933–3936. Yet the majority dismisses the FDA’s published preamble as “inherently suspect,” ante, at 21, and an afterthought that is entitled to “no weight,” ante, at 25. Compare Lohr, supra, at 506 (opinion of Breyer, J.) (emphasizing that the FDA has a “special understanding of the likely impact of both state and federal requirements, as well as an understanding of whether (or the extent to which) state requirements may interfere with federal objectives,” and that “[t]he FDA can translate these understandings into particularized pre-emptive intentions … through statements in ‘regulations, pre-ambles, interpretive statements, and responses tocomments’ ”).

Third, the Court distinguishes Geier because the DOT’s regulation “bear[s] the force of law,” whereas the FDA’s preamble does not. Ante, at 24; see also ante, at 19. But it is irrelevant that the FDA’s preamble does not “bear the force of law” because the FDA’s labeling decisions surely do. See 21 U. S. C. §355. It is well within the FDA’s discretion to make its labeling decisions through administrative adjudications rather than through less-formal and less-flexible rulemaking proceedings, see SEC v. Chenery Corp., 332 U. S. 194 (1947) , and we have never previously held that our pre-emption analysis turns on the agency’s choice of the latter over the former. Moreover, it cannot be said that Geier’s outcome hinged on the agency’s choice to promulgate a rule. See ante, at 19, 24. The Geier Court relied—again over the dissenters’ protestations—on materials other than the Secretary’s regulation to explain the conflict between state and federal law. Compare 529 U. S., at 881, with id., at 899–900 (Stevens, J., dissenting), and ante, at 1–2 (Breyer, J., concurring).

Fourth, the Court sandwiches its discussion of Geier between the “presumption against pre-emption,” ante, at 18, and heavy emphasis on “the longstanding coexistence of state and federal law and the FDA’s traditional recognition of state-law remedies,” ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that the “presumption against pre-emption” is relevant to the conflict pre-emption analysis. See 529 U. S., at 906–907 (Stevens, J., dissenting) (“[T]he Court simply ignores the presumption [against pre-emption]”). Rather than invoking such a “presumption,” the Court emphasized that it was applying “ordinary,” “longstanding,” and “experience-proved principles of conflict pre-emption.” Id., at 874. Under these principles, the sole question is whether there is an “actual conflict” between state and federal law; if so, then pre-emption follows automatically by operation of the Supremacy Clause. Id., at 871–872. See also Buckman, 531 U. S., at 347–348 (“[P]etitioner’s dealings with the FDA were prompted by [federal law], and the very subject matter of petitioner’s statements [to the FDA] were dictated by [federal law]. Accordingly—and in contrast to situations implicating ‘federalism concerns and the historic primacy of state regulation of matters of health and safety’—no presumption against pre-emption obtains in this case” (citation omitted)). 14

Finally, the Geier Court went out of its way to emphasize (yet again over the dissenters’ objections) that it placed “some weight” on the DOT’s amicus brief, which explained the agency’s regulatory objectives and the effects of state tort suits on the federal regulatory regime. 529 U. S., at 883; compare id., at 910–911 (Stevens, J., dissenting) (criticizing the majority for “uph[olding] a regulatory claim of frustration-of-purposes implied conflict pre-emption based on nothing more than an ex post administrative litigating position and inferences from regulatory history and final commentary”). See also Lohr, 518 U. S., at 496 (recognizing that the FDA is “uniquely qualified” to explain whether state law conflicts with the FDA’s objectives). Yet today, the FDA’s explanation of the conflict between state tort suits and the federal labeling regime, set forth in the agency’s amicus brief, is not even mentioned in the Court’s opinion. Instead of relying on the FDA’s explanation of its own regulatory purposes, the Court relies on a decade-old and now-repudiated statement, which the majority finds preferable. See ante, at 21–22, 24, n. 13. Cf. Riegel, 552 U. S., at ___ (slip op., at 13) (noting that “the agency’s earlier position (which the dissent describes at some length and finds preferable) is … compromised, indeed deprived of all claim to deference, by the fact that it is no longer the agency’s position” (citation omitted)); Altria Group, Inc. v. Good, 555 U. S. ___, ___ (2008) (slip op., at 16–17) (rejecting petitioners’ reliance on the pre-emptive effect of the agency’s “longstanding policy” because it is inconsistent with the agency’s current one). And Justice Breyer suggests that state tort suits may “help the [FDA],” ante, at 1 (concurring opinion), notwithstanding the FDA’s insistence that state tort suits will “disrupt the agency’s balancing of health risks and benefits,” Brief for United States as Amicus Curiae 9.

Geier does not countenance the use of state tort suits to second-guess the FDA’s labeling decisions. And the Court’s contrary conclusion has potentially far-reaching consequences.

C

By their very nature, juries are ill-equipped to perform the FDA’s cost-benefit-balancing function. As we explained in Riegel, juries tend to focus on the risk of a particular product’s design or warning label that arguably contributed to a particular plaintiff’s injury, not on the overall benefits of that design or label; “the patients who reaped those benefits are not represented in court.” 552 U. S., at ___ (slip op., at 12). Indeed, patients like respondent are the only ones whom tort juries ever see, and for a patient like respondent—who has already suffered a tragic accident—Phenergan’s risks are no longer a matter of probabilities and potentialities.

In contrast, the FDA has the benefit of the long view. Its drug-approval determinations consider the interests of all potential users of a drug, including “those who would suffer without new medical [products]” if juries in all 50 States were free to contradict the FDA’s expert determinations. Id., at ___ (slip op., at 13). And the FDA conveys its warnings with one voice, rather than whipsawing the medical community with 50 (or more) potentially conflicting ones. After today’s ruling, however, parochialism may prevail.

The problem is well illustrated by the labels borne by “vesicant” drugs, many of which are used for chemotherapy. As a class, vesicants are much more dangerous than drugs like Phenergan, 15 but the vast majority of vesicant labels—like Phenergan’s—either allow or do not disallow IV push. See Appendix, infra. Because vesicant extravasation can have devastating consequences, and because the potentially lifesaving benefits of these drugs offer hollow solace to the victim of such a tragedy, a jury’s cost-benefit analysis in a particular case may well differ from the FDA’s.

For example, consider Mustargen (mechlorethamine HCl)—the injectable form of mustard gas—which can be used as an anticancer drug. Mustargen’s FDA-approved label warns in several places that “This drug is HIGHLY TOXIC.” 16 Indeed, the drug is so highly toxic:

“Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water, for at least 15 minutes while removing contaminated clothing and shoes, followed by 2% sodium thiosulfate solution. Medical attention should be sought immediately. Contaminated clothing should be destroyed.” 17

Yet when it comes to administering this highly toxic drug, the label provides that “the drug may be injected directly into any suitable vein, [but] it is injected preferably into the rubber or plastic tubing of a flowing intravenous infusion set. This reduces the possibility of severe local reactions due to extravasation or high concentration of the drug.” (Emphasis added.) Similarly, the FDA-approved labels for other powerful chemotherapeutic vesicants—including Dactinomycin, Oxaliplatin, Vinblastine, and Vincristine—specifically allow IV push, notwithstanding their devastating effects when extravasated.

The fact that the labels for such drugs allow IV push is striking—both because vesicants are much more dangerous than Phenergan, and also because they are so frequently extravasated, see Boyle & Engelking, Vesicant Extravasation: Myths and Realities, 22 Oncology Nursing Forum 57, 58 (1995) (arguing that the rate of extravasation is “considerably higher” than 6.4% of all vesicant administrations). Regardless of the FDA’s reasons for not contraindicating IV push for these drugs, it is odd (to say the least) that a jury in Vermont can now order for Phenergan what the FDA has chosen not to order for mustard gas. 18

***

To be sure, state tort suits can peacefully coexist with the FDA’s labeling regime, and they have done so for decades. Ante, at 17–18. But this case is far from peaceful coexistence. The FDA told Wyeth that Phenergan’s label renders its use “safe.” But the State of Vermont, through its tort law, said: “Not so.”

The state-law rule at issue here is squarely pre-empted. Therefore, I would reverse the judgment of the Supreme Court of Vermont.

Appendix TO OPINION OF ALITO, J.

Vesicant1

IV Push2

Dactinomycin

Specifically allowed

Mechlorethamine (Mustargen)

Specifically allowed

Oxaliplatin

Specifically allowed

Vinblastine

Specifically allowed

Vincristine

Specifically allowed

Bleomycin

Neither mentioned nor prohibited

Carboplatin

Neither mentioned nor prohibited

Dacarbazine

Neither mentioned nor prohibited

Mitomycin

Neither mentioned nor prohibited

Carmustine

Not prohibited; IV drip recommended

Cisplatin

Not prohibited; IV drip recommended

Epirubicin

Not prohibited; IV drip recommended

Etoposide

Not prohibited; IV drip recommended

Ifosfamide

Not prohibited; IV drip recommended

Mitoxantrone

Not prohibited; IV drip recommended

Paclitaxel

Not prohibited; IV drip recommended

Teniposide

Not prohibited; IV drip recommended

Vinorelbine

Not prohibited; IV drip recommended

Daunorubicin

Prohibited

Doxorubicin

Prohibited

1 Wilkes & Barton-Burke, 2008 Oncology Nursing Drug Handbook 27–33 (2008) (Table 1.6).

2 IV-push information is derived from the “dosage and administration” sections of individual drug labels (available in Clerk of Court’s case file).


Notes

1 Indeed, respondent conceded below that Wyeth did propose an adequate warning of Phenergan’s risks. See Plaintiff Diana Levine’s Memorandum in Opposition to Wyeth’s Motion for Summary Judgment in Levine v. American Home Products Corp. (now Wyeth), No. 670–12–01 Wncv (Super. Ct. Washington Cty., Vt.), ¶7, p. 26. Specifically, respondent noted: “In 1988, Wyeth proposed language that would have prevented this accident by requiring a running IV and explaining why a running IV will address and reduce the risk [of intra-arterial injection].” Ibid. See also id., at 24 (“Although not strong enough, this improved the labeling instruction, if followed, would have prevented the inadvertent administration of Phenergan into an artery …”). The FDA rejected Wyeth’s proposal. See App. 359.

2 Moreover, in the trial judge’s final charge, he told the jury that “the critical factual issue which you must decide” is whether Phenergan’s FDA-mandated label reflects a proper balance between “the risks and benefits of intravenous administration and the potential for injury to patients.” Id., at 220. See also ___ Vt. ___, ___, 944 A. 2d 179, 182 (2006) (recognizing that respondent’s argument is that Phenergan’s “label should not have allowed IV push as a means of administration”).

3 Respondent sued her physician, physician’s assistant, and hospital for malpractice. After the parties settled that suit for an undisclosed sum, respondent’s physician sent her a letter in which he admitted “responsibility” for her injury and expressed his “profoun[d] regre[t]” and “remors[e]” for his actions. 1 Tr. 178–179 (Mar. 8, 2004) (testimony of Dr. John Matthew); see also App. 102–103 (testimony of physician’s assistant Jessica Fisch) (noting that her “sense of grief” was so “great” that she “would have gladly cut off [her own] arm” and given it to respondent). Thereafter, both the physician and the physician’s assistant agreed to testify on respondent’s behalf in her suit against Wyeth.

4 To be sure, Congress recognized the principles of conflict pre-emption in the FDCA. See Drug Amendments of 1962, §202, 76Stat. 793 (“Nothing in the amendments made by this Act to the Federal Food, Drug, and Cosmetic Act shall be construed as invalidating any provision of State law … unless there is a direct and positive conflict between such amendments and such provision of State law”). But a provision that simply recognizes the background principles of conflict pre-emption is not a traditional “saving clause,” and even if it were, it would not displace our conflict-pre-emption analysis. See Geier v. American Honda Motor Co., 529 U. S. 861, 869 (2000) (“[T]he saving clause … does not bar the ordinary working of conflict pre-emption principles”); id., at 873–874 (“The Court has … refused to read general ‘saving’ provisions to tolerate actual conflict both in cases involving impossibility and in ‘frustration-of-purpose’ cases” (emphasis deleted and citation omitted)).

5 The FDA cited numerous articles that generally discuss the costs and benefits associated with IV push. See, e.g., Nahrwold & Phelps, Inadvertent Intra-Arterial Injection of Mephenteramine, 70 Rocky Mountain Medical J. 38 (Sept. 1973) (cited in App. 314, no. 14); Albo, Cheung, Ruth, Snyder, & Beemtsma, Effect of Intra-Arterial Injections of Barbituates, 120 Am. J. of Surgery 676 (1970) (cited in App. 314, no. 12); Corser, Masey, Jacob, Kernoff, & Browne, Ischaemia Following Self-administered Intra-arterial Injection of Methylphenidate and Diamorphine, 40 Anesthesiology 51 (1985) (cited in App. 314, no. 9); Correspondence Regarding Thiopental and Thiamylal (3 letters), 59 Anesthesiology 153 (1983) (cited in App. 314, no. 11); Miller, Arthur, & Stratigos, Intra-arterial Injection of a Barbituate, 23 Anesthesia Progress 25 (1976) (cited in App. 315, no. 19).

6 See Webb & Lampert, Accidental Arterial Injections, 101 Am. J. Obstetrics & Gynecology 365 (1968) (cited in App. 313, no. 5).

7 See Hager & Wilson, Gangrene of the Hand Following Intra-arterial Injection, 94 Archives of Surgery 86 (1967) (cited in App. 313, no. 7); Enloe, Sylvester, & Morris, Hazards of Intra-Arterial Injection of Hydroxyzine, 16 Canadian Anaesthetists’ Society J. 425 (1969) (hereinafter Enloe) (noting “recent reports” of “the occurrence of severe necrosis and gangrene following [administration of] promethazine (Phenergan)” (cited in App. 314, no. 15)). See also Mostafavi & Samimi, Accidental Intra-arterial Injection of Promethazine HCl During General Anesthesia, 35 Anesthesiology 645 (1971) (reporting a case of gangrene, which required partial amputation of three fingers, after Phenergan was inadvertently pushed into an artery in the “antecubital” area); Promethazine, p. 7, in Clinical Pharmacology (Gold Standard Multimedia Inc. CD–ROM, version 1.16 (1998) (noting that “[i]nadvertent intra-arterial injection [of Phenergan] can result in arteriospasm … and development of gangrene”)).

8 Hager and Wilson noted that the most common reactions to intra-arterial injections of drugs like Phenergan include “[i]mmediate, severe, burning pain,” as well as “blanching.” 94 Archives of Surgery, at 87–88. The FDA required Wyeth to include Hager and Wilson’s observations on Phenergan’s label. See App. 311 (requiring the label to warn that “ ‘[t]he first sign [of an intra-arterial injection] may be the patient’s reaction to a sensation of fiery burning’ ” pain and “ ‘[b]lanching’ ”).

9 See Enloe 427 (discussing hydroxyzine—an antihistamine with chemical properties similar to those of Phenergan—and suggesting its “temporary” benefits can never outweigh the risks of intra-arterial injection); see also Goldsmith & Trieger, Accidental Intra-Arterial Injection: A Medical Emergency, 22 Anesthesia Progress 180 (1975) (noting the risks of intra-arterial administration of hydroxyzine) (cited in App. 315, no. 18); Klatte, Brooks, & Rhamy, Toxicity of Intra-Arterial Barbituates and Tranquilizing Drugs, 92 Radiology 700 (1969) (same) (cited in App. 314, no. 13). With full knowledge of those risks, FDA retained IV push for Phenergan, although the agency required Wyeth to incorporate observations from the Enloe article into Phenergan’s label. Compare Enloe 427 (arguing that “every precaution should be taken to avoid inadvertent intra-arterial injection,” including the use of “an obviously well-functioning venoclysis”), with App. 312 (FDA’s 1987 changes to Phenergan’s label). In contrast, at some time around 1970, the FDA prohibited all intravenous use of hydroxyzine. See id., at 79 (testimony of Dr. Harold Green). The FDA’s decision to regulate the two drugs differently—notwithstanding (1) the agency’s knowledge of the risks associated with both drugs and (2) the agency’s recognition of the relevance of hydroxyzine-related articles and case reports in its regulation of Phenergan—further demonstrates that the FDA intentionally preserved IV-push administration for Phenergan. See also Haas, Correspondence, 33 Anesthesia Progress 281 (1986) (“[Hydroxyzine’s] restriction does not lie with the medicine itself, but in the practice and malpractice of intravenous techniques. Unfortunately, the practitioner who knows how to treat injection technique problems is usually not the practitioner with the intravenous technique problems”).

10 See also Engler, Freeman, Kanavage, Ogden, & Moretz, Production of Gangrenous Extremities by Intra-Arterial Injections, 30 Am. Surgeon 602 (1964) (“Accidental arterial injection most often occurs in the antecubital region because this is a favorite site for venopuncture and in this area the ulnar and brachial arteries are superficial and easily entered” (cited in App. 313, no. 6)); Engler, Gangrenous Extremities Resulting from Intra-arterial Injections, 94 Archives of Surgery 644 (1966) (similar) (cited in App. 314, no. 16); Lynas & Bisset, Intra-arterial Thiopentone, 24 Anaesthesia 257 (1969) (“Most [anesthesiologists] agree that injections on the medial aspect of the antecubital fossa are best avoided” (cited in App. 314, no. 8)); Waters, Intra-arterial Thiopentone, 21 Anesthesia 346 (1966) (“The risk of producing gangrene of the forearm by accidental injection of sodium thiopentone into an artery at the elbow has been recognised for many years” (cited in App. 314, no. 10)); see also Hager & Wilson, 94 Archives of Surgery, at 88 (emphasizing that one of the best ways to prevent inadvertent intra-arterial injections is to be aware of “aberrant or superficial arteries at the antecubital, forearm, wrist, and hand level”); Mostafavi & Samimi, supra (warning against antecubital injections).

11 See App. 311 (requiring Phenergan’s label to warn that practitioners should “ ‘[b]eware of the close proximity of arteries and veins at commonly used injection sites and consider the possibility of aberrant arteries’ ”).

12 “Aspiration” refers to drawing a small amount of blood back into the needle to determine whether the needle is in an artery or a vein. Ordinarily, arterial blood is brighter than venous blood—but contact with Phenergan causes discoloration, which makes aspiration an unreliable method of protecting against intra-arterial injection. See id., at 282. Therefore, the label warned that when using IV push, a medical professional should beware that “[a]spiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with Phenergan Injection.” Id., at 390.

13 In addition, respondent’s own medical expert testified at trial that it is a principle of “basic anatomy” that the antecubital fossa contains aberrant arteries. See 2 Tr. 34–35 (Mar. 9, 2004) (testimony of Dr. Daniel O’Brien); see also ibid. (noting that Gray’s Anatomy, which is “the Bible of anatomy,” also warns of arteries in the antecubital space).

14 Thus, it is not true that “this Court has long” applied a presumption against pre-emption in conflict pre-emption cases. Ante, at 9, n. 3 (majority opinion). As long ago as Gibbons v. Ogden, 9 Wheat. 1, 210 (1824), the Court inquired whether a state law “interfer[ed] with,” was “contrary to,” or “c[a]me into collision with” federal law—and it did so without ever invoking a “presumption.” See also Davis, Unmasking the Presumption in Favor of Preemption, 53 S. C. L. Rev. 967, 974 (2002) (noting that many of the Court’s early pre-emption cases “resulted in almost automatic preemption of concurrent state regulation”). In subsequent years the Court has sometimes acknowledged a limited “presumption against pre-emption,” but it nonetheless remained an open question—before today—whether that presumption applied in conflict pre-emption cases. See Crosby v. National Foreign Trade Council, 530 U. S. 363, n. 8 (2000) (“We leave for another day a consideration in this context of a presumption against preemption”). Moreover, this Court has never held that the “presumption” applies in an area—such as drug labeling—that has long been “reserved for federal regulation.” United States v. Locke, 529 U. S. 89, 111 (2000) . See also Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 347–348 (2001) .

15 Vesicants may cause “blistering, severe tissue injury, or tissue necrosis” upon extravasation—even if the drug is not injected into an artery. See, e.g., Schulmeister, Administering Vesicants, 9 Clinical J. of Oncology Nursing 469, 469–470 (2005). See also ante, at 4 (majority opinion) (noting that Phenergan is labeled as an “irritant”); cf. Brief for Anju Budhwani et al. as Amici Curiae 15 (suggesting Phenergan should be considered a “vesicant”).

16 FDA, Oncology Tools Product Label Details, online at http://www.accessdata.fda.gov/scripts/cder/onctools/labels.cfm?GN=meclorethamine, nitrogen mustard (as visited Mar. 2, 2009, and available in Clerk of Court’s case file).

17 Ibid.

18 The same is true of FDA’s regulation of hydroxyzine. See n. 9,supra.


TOP

Dissent

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Alito, with whom The Chief Justice and Justice Scalia join, dissenting.

This case illustrates that tragic facts make bad law. The Court holds that a state tort jury, rather than the Food and Drug Administration (FDA), is ultimately responsible for regulating warning labels for prescription drugs. That result cannot be reconciled with Geier v. American Honda Motor Co., 529 U. S. 861 (2000) , or general principles of conflict pre-emption. I respectfully dissent.

I

The Court frames the question presented as a “narro[w]” one—namely, whether Wyeth has a duty to provide “an adequate warning about using the IV-push method” to administer Phenergan. Ante, at 8. But that ignores the antecedent question of who—the FDA or a jury in Vermont—has the authority and responsibility for determining the “adequacy” of Phenergan’s warnings. Moreover, it is unclear how a “stronger” warning could have helped respondent, see ante, at 16; after all, the physician’s assistant who treated her disregarded at least six separate warnings that are already on Phenergan’s labeling, so respondent would be hard pressed to prove that a seventh would have made a difference. 1

More to the point, the question presented by this case is not a “narrow” one, and it does not concern whether Phenergan’s label should bear a “stronger” warning. Rather, the real issue is whether a state tort jury can countermand the FDA’s considered judgment that Phenergan’s FDA-mandated warning label renders its intravenous (IV) use “safe.” Indeed, respondent’s amended complaint alleged that Phenergan is “not reasonably safe for intravenous administration,” App. 15, ¶6; respondent’s attorney told the jury that Phenergan’s label should say, “ ‘Do not use this drug intravenously,’ ” id., at 32; respondent’s expert told the jury, “I think the drug should be labeled ‘Not for IV use,’ ” id., at 59; and during his closing argument, respondent’s attorney told the jury, “Thank God we don’t rely on the FDA to … make the safe[ty] decision. You will make the decision. … The FDA doesn’t make the decision, you do,” id., at 211–212. 2

Federal law, however, does rely on the FDA to make safety determinations like the one it made here. The FDA has long known about the risks associated with IV push in general and its use to administer Phenergan in particular. Whether wisely or not, the FDA has concluded—over the course of extensive, 54-year-long regulatory proceedings—that the drug is “safe” and “effective” when used in accordance with its FDA-mandated labeling. The unfortunate fact that respondent’s healthcare providers ignored Phenergan’s labeling may make this an ideal medical-malpractice case. 3 But turning a common-law tort suit into a “frontal assault” on the FDA’s regulatory regime for drug labeling upsets the well-settled meaning of the Supremacy Clause and our conflict pre-emption jurisprudence. Brief for United States as Amicus Curiae 21.

II

A

To the extent that “[t]he purpose of Congress is the ultimate touchstone in every pre-emption case,” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) (internal quotation marks omitted), Congress made its “purpose” plain in authorizing the FDA—not state tort juries—to determine when and under what circumstances a drug is “safe.” “[T]he process for approving new drugs is at least as rigorous as the premarket approval process for medical devices,” Riegel v. Medtronic, Inc., 552 U. S. ___, ___ (2008) (slip op., at 11) (Ginsburg, J., dissenting), and we held that the latter pre-empted a state-law tort suit that conflicted with the FDA’s determination that a medical device was “safe,” id., at ___ (slip op., at 11) (opinion of the Court).

Under the Federal Food, Drug, and Cosmetic Act (FDCA), a drug manufacturer may not market a new drug before first submitting a new drug application (NDA) to the FDA and receiving the agency’s approval. See 21 U. S. C. §355(a). An NDA must contain, among other things, “the labeling proposed to be used for such drug,” §355(b)(1)(F), “full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use,” §355(b)(1)(A), and “a discussion of why the benefits exceed the risks [of the drug] under the conditions stated in the labeling,” 21 CFR §314.50(d)(5)(viii) (2008). The FDA will approve an NDA only if the agency finds, among other things, that the drug is “safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof,” there is “substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof,” and the proposed labeling is not “false or misleading in any particular.” 21 U. S. C. §355(d).

After the FDA approves a drug, the manufacturer remains under an obligation to investigate and report any adverse events associated with the drug, see 21 CFR §314.80, and must periodically submit any new information that may affect the FDA’s previous conclusions about the safety, effectiveness, or labeling of the drug, 21 U. S. C. §355(k). If the FDA finds that the drug is not “safe” when used in accordance with its labeling, the agency “shall” withdraw its approval of the drug. §355(e). The FDA also “shall” deem a drug “misbranded” if “it is dangerous to health when used in the dosage or manner, or with the frequency or duration prescribed, recommended, or suggested in the labeling thereof.” §352(j).

Thus, a drug’s warning label “serves as the standard under which the FDA determines whether a product is safe and effective.” 50Fed. Reg. 7470 (1985). Labeling is “[t]he centerpiece of risk management,” as it “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively.” 71Fed. Reg. 3934 (2006). The FDA has underscored the importance it places on drug labels by promulgating comprehensive regulations—spanning an entire part of the Code of Federal Regulations, see 21 CFR pt. 201, with seven subparts and 70 separate sections—that set forth drug manufacturers’ labeling obligations. Under those regulations, the FDA must be satisfied that a drug’s warning label contains, among other things, “a summary of the essential scientific information needed for the safe and effective use of the drug,” §201.56(1), including a description of “clinically significant adverse reactions,” “other potential safety hazards,” “limitations in use imposed by them, … and steps that should be taken if they occur,” §201.57(c)(6)(i). Neither the FDCA nor its implementing regulations suggest that juries may second-guess the FDA’s labeling decisions.

B

1

Where the FDA determines, in accordance with its statutory mandate, that a drug is on balance “safe,” our conflict pre-emption cases prohibit any State from countermanding that determination. See, e.g., Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 348 (2001) (after the FDA has struck “a somewhat delicate balance of statutory objectives” and determined that petitioner submitted a valid application to manufacture a medical device, a State may not use common law to negate it); International Paper Co. v. Ouellette, 479 U. S. 481, 494 (1987) (after the EPA has struck “the balance of public and private interests so carefully addressed by” the federal permitting regime for water pollution, a State may not use nuisance law to “upse[t]” it); Chicago & North Western Transp. Co. v. Kalo Brick & Tile Co., 450 U. S. 311, 321 (1981) (after the Interstate Commerce Commission has struck a “balance” between competing interests in permitting the abandonment of a railroad line, a State may not use statutory or common law to negate it).

Thus, as the Court itself recognizes, it is irrelevant in conflict pre-emption cases whether Congress “enacted an express pre-emption provision at some point during the FDCA’s 70-year history.” Ante, at 18; see also Geier, 529 U. S., at 869 (holding the absence of an express pre-emption clause “does not bar the ordinary working of conflict pre-emption principles”). Rather, the ordinary principles of conflict pre-emption turn solely on whether a State has upset the regulatory balance struck by the federal agency. Id., at 884–885; see also Chicago & North Western Transp. Co., supra, at 317 (describing conflict pre-emption as “a two-step process of first ascertaining the construction of the [federal and state laws] and then determining the constitutional question whether they are actually in conflict” (internal quotation marks omitted)).

2

A faithful application of this Court’s conflict pre-emption cases compels the conclusion that the FDA’s 40-year-long effort to regulate the safety and efficacy of Phenergan pre-empts respondent’s tort suit. Indeed, that result follows directly from our conclusion in Geier.

Geier arose under the National Traffic and Motor Safety Vehicle Act of 1966, which directs the Secretary of the Department of Transportation (DOT) to “establish by order … motor vehicle safety standards,” 15 U. S. C. §1392(a) (1988 ed.), which are defined as “minimum standard[s] for motor vehicle performance, or motor vehicle equipment performance,” §1391(2). Acting pursuant to that statutory mandate, the Secretary of Transportation promulgated Federal Motor Vehicle Safety Standard 208, which required car manufacturers to include passive restraint systems (i.e., devices that work automatically to protect occupants from injury during a collision) in a certain percentage of their cars built in or after 1987. See 49 CFR §571.208 (1999). Standard 208 did not require installation of any particular type of passive restraint; instead, it gave manufacturers the option to install automatic seatbelts, airbags, or any other suitable technology that they might develop, provided the restraint(s) met the performance requirements specified in the rule. Ibid.

Alexis Geier drove her 1987 Honda Accord into a tree, and although she was wearing her seatbelt, she nonetheless suffered serious injuries. She then sued Honda under state tort law, alleging that her car was negligently and defectively designed because it lacked a driver’s-side airbag. She argued that Congress had empowered the Secretary to set only “minimum standard[s]” for vehicle safety. 15 U. S. C. §1391(2). She also emphasized that the National Traffic and Motor Safety Vehicle Act contains a saving clause, which provides that “[c]ompliance with any Federal motor vehicle safety standard issued under this subchapter does not exempt any person from any liability under common law.” §1397(k).

Notwithstanding the statute’s saving clause, and notwithstanding the fact that Congress gave the Secretary authority to set only “minimum” safety standards, we held Geier’s state tort suit pre-empted. In reaching that result, we relied heavily on the view of the Secretary of Transportation—expressed in an amicus brief—that Standard 208 “ ‘embodies the Secretary’s policy judgment that safety would best be promoted if manufacturers installed alternative protection systems in their fleets rather than one particular system in every car.’ ” 529 U. S., at 881 (quoting Brief for United States as Amicus Curiae,O. T. 1999, No. 98–1811, p. 25). Because the Secretary determined that a menu of alternative technologies was “safe,” the doctrine of conflict pre-emption barred Geier’s efforts to deem some of those federally approved alternatives “unsafe” under state tort law.

The same rationale applies here. Through Phenergan’s label, the FDA offered medical professionals a menu of federally approved, “safe” and “effective” alternatives—including IV push—for administering the drug. Through a state tort suit, respondent attempted to deem IV push “unsafe” and “ineffective.” To be sure, federal law does not prohibit Wyeth from contraindicating IV push, just as federal law did not prohibit Honda from installing airbags in all its cars. But just as we held that States may not compel the latter, so, too, are States precluded from compelling the former. See also Fidelity Fed. Sav. & Loan Assn. v. De la Cuesta, 458 U. S. 141, 155 (1982) (“The conflict does not evaporate because the [agency’s] regulation simply permits, but does not compel,” the action forbidden by state law). If anything, a finding of pre-emption is even more appropriate here because the FDCA—unlike the National Traffic and Motor Safety Vehicle Act—contains no evidence that Congress intended the FDA to set only “minimum standards,” and the FDCA does not contain a saving clause. 4 See also ante, at 18 (conceding Congress’ “silence” on the issue).

III

In its attempt to evade Geier’s applicability to this case, the Court commits both factual and legal errors. First, as a factual matter, it is demonstrably untrue that the FDA failed to consider (and strike a “balance” between) the specific costs and benefits associated with IV push. Second, as a legal matter, Geier does not stand for the legal propositions espoused by the dissenters (and specifically rejected by the majority) in that case. Third, drug labeling by jury verdict undermines both our broader pre-emption jurisprudence and the broader workability of the federal drug-labeling regime.

A

Phenergan’s warning label has been subject to the FDA’s strict regulatory oversight since the 1950’s. For at least the last 34 years, the FDA has focused specifically on whether IV-push administration of Phenergan is “safe” and “effective” when performed in accordance with Phenergan’s label. The agency’s ultimate decision—to retain IV push as one means for administering Phenergan, albeit subject to stringent warnings—is reflected in the plain text of Phenergan’s label (sometimes in boldfaced font and all-capital letters). And the record contains ample evidence that the FDA specifically considered and reconsidered the strength of Phenergan’s IV-push-related warnings in light of new scientific and medical data. The majority’s factual assertions to the contrary are mistaken.

1

The FDA’s focus on IV push as a means of administering Phenergan dates back at least to 1975. In August of that year, several representatives from both the FDA and Wyeth met to discuss Phenergan’s warning label. At that meeting, the FDA specifically proposed “that Phenergan Injection should not be used in Tubex.” 2 Record 583, 586 (Plaintiff’s Trial Exh. 17, Internal Correspondence from W. E. Langeland to File (Sept. 5, 1975) (hereinafter 1975 Memo)). “Tubex” is a syringe system used exclusively for IV push. See App. 43. An FDA official explained that the agency’s concerns arose from medical-malpractice lawsuits involving IV push of the drug, see 1975 Memo 586, and that the FDA was aware of “5 cases involving amputation where the drug had been administered by Tubex together with several additional cases involving necrosis,” id., at 586–587. Rather than contraindicating Phenergan for IV push, however, the agency and Wyeth agreed “that there was a need for better instruction regarding the problems of intraarterial injection.” Id., at 587.

The next year, the FDA convened an advisory committee to study, among other things, the risks associated with the Tubex system and IV push. App. 294. At the conclusion of its study, the committee recommended an additional IV-push-specific warning for Phenergan’s label, see ibid., but did not recommend eliminating IV push from the drug label altogether. In response to the committee’s recommendations, the FDA instructed Wyeth to make several changes to strengthen Phenergan’s label, including the addition of upper case warnings related to IV push. See id., at 279–280, 282–283.

In 1987, the FDA directed Wyeth to amend its label to include the following text:

“ ‘[1] When used intravenously, [Phenergan] should be given in a concentration no greater than 25 mg/ml and at a rate not to exceed 25 mg/minute. [2] Injection through a properly running intravenous infusion may enhance the possibility of detecting arterial placement.’ ” Id., at 311–312.

The first of the two quoted sentences refers specifically to IV push; as respondent’s medical expert testified at trial, the label’s recommended rate of administration (not to exceed 25 mg per minute) refers to “IV push, as opposed to say being in a bag and dripped over a couple of hours.” Id., at 52. The second of the two quoted sentences refers to IV drip. See id., at 15–16 (emphasizing that a “running IV” is the same thing as “IV drip”).

In its 1987 labeling order, the FDA cited voluminous materials to “suppor[t]” its new and stronger warnings related to IV push and the preferability of IV drip. 5 Id., at 313. One of those articles specifically discussed the relative advantages and disadvantages of IV drip compared to IV push, as well as the costs and benefits of administering Phenergan via IV push. 6 The FDA also cited published case reports from the 1960’s of gangrene caused by the intra-arterial injection of Phenergan, 7 and the FDA instructed Wyeth to amend Phenergan’s label in accordance with the latest medical research. 8 The FDA also studied drugs similar to Phenergan and cited numerous cautionary articles—one of which urged the agency to consider contraindicating such drugs for IV use altogether. 9

In “support” of its labeling order, the FDA also cited numerous articles that singled out the inner crook of the elbow—known as the “antecubital fossa” in the medical community—whichis both a commonly used injection site, see id., at 70 (noting that respondent’s injection was pushed into “the antecubital space”), and a universally recognized high-risk area for inadvertent intra-arterial injections. One of the articles explained:

“Because of the numerous superficial positions the ulnar artery might occupy, it has often been entered during attempted venipuncture [of the antecubital fossa]. … However, the brachial and the radial arteries might also be quite superficial in the elbow region… . The arterial variations of the arm, especially in and about the cubital fossa, are common and numerous. If venipuncture must be performed in this area, a higher index of suspicion must be maintained to forestall misdirected injections.” Stone & Donnelly, The Accidental Intra-arterial Injection of Thiopental, 22 Anesthesiology 995, 996 (1961) (footnote omitted; cited in App. 315, no. 20). 10

Based on this and other research, the FDA ordered Wyeth to include a specific warning related to the use of the antecubital space for IV push. 11

2

When respondent was injured in 2000, Phenergan’s label specifically addressed IV push in several passages (sometimes in lieu of and sometimes in addition to those discussed above). For example, the label warned of the risks of intra-arterial injection associated with “aspiration,” which is a technique used only in conjunction with IV push. 12 The label also cautioned against the use of “syringes with rigid plungers,” App. 390, which are used onlyto administer the drug via IV push. As respondent’s medical expert testified at trial, “by talking plungers and rigid needles, that’s the way you do it, to push it with the plunger.” Id., at 53 (testimony of Dr. John Matthew). Moreover, Phenergan’s 2000 label devoted almost a full page to discussing the “Tubex system,” see id., at 391, which, as noted above, is used only to administer the drug via IV push.

While Phenergan’s label very clearly authorized the use of IV push, it also made clear that IV push is the delivery method of last resort. The label specified that “[t]he preferred parenteral route of administration is by deep intramuscular injection.” Id., at 390. If an intramuscular injection is ineffective, then “it is usually preferable to inject [Phenergan] through the tubing of an intravenous infusion set that is known to be functioning satisfactorily.” Ibid. See also id., at 50–51 (testimony of respondent’s medical expert, Dr. John Matthew) (conceding that the best way to determine that an IV set is functioning satisfactorily is to use IV drip). Finally, if for whatever reason a medical professional chooses to use IV push, he or she is on notice that “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY.” Id., at 391; see also id., at 390 (“Under no circumstances should Phenergan Injection be given by intra-arterial injection due to the likelihood of severe arteriospasm and the possibility of resultant gangrene”).

Phenergan’s label also directs medical practitioners to choose veins wisely when using IV push:

“Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or inadvertent intra-arterial injection. Reports compatible with inadvertent intra-arterial injection of Phenergan Injection, usually in conjunction with other drugs intended for intravenous use, suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances.” Ibid.

Thus, it is demonstrably untrue that, as of 2000, Phenergan’s “labeling did not contain a specific warning about the risks of IV-push administration.” Ante, at 4. And whatever else might be said about the extensive medical authorities and case reports that the FDA cited in “support” of its approval of IV-push administration of Phenergan, it cannot be said that the FDA “paid no more than passing attention to” IV push, ante, at 6; nor can it be said that the FDA failed to weigh its costs and benefits, Brief for Respondent 50.

3

For her part, respondent does not dispute the FDA’s conclusion that IV push has certain benefits. At trial, her medical practitioners testified that they used IV push in order to help her “in a swift and timely way” when she showed up at the hospital for the second time in one day complaining of “intractable” migraines, “terrible pain,” inability to “bear light or sound,” sleeplessness, hours-long spasms of “retching” and “vomiting,” and when “every possible” alternative treatment had “failed.” App. 40 (testimony of Dr. John Matthew); id., at 103, 106, 109 (testimony of physician’s assistant Jessica Fisch).

Rather than disputing the benefits of IV push, respondent complains that the FDA and Wyeth underestimated its costs (and hence did not provide sufficient warnings regarding its risks). But when the FDA mandated that Phenergan’s label read, “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY,” id., at 391, and when the FDA required Wyeth to warn that “[u]nder no circumstances should Phenergan Injection be given by intra-arterial injection,” id., at 390, the agency could reasonably assume that medical professionals would take care not to inject Phenergan intra-arterially. See also 71 Fed. Reg. 3934 (noting that a drug’s warning label “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively”). Unfortunately, the physician’s assistant who treated respondent in this case disregarded Phenergan’s label and pushed the drug into the single spot on her arm that is most likely to cause an inadvertent intra-arterial injection.

As noted above, when the FDA approved Phenergan’s label, it was textbook medical knowledge that the “antecubital fossa” creates a high risk of inadvertent intra-arterial injection, given the close proximity of veins and arteries. See supra, at 13–14; see also The Lippincott Manual of Nursing Practice 99 (7th ed. 2001) (noting, in a red-text “NURSING ALERT,” that the antecubital fossa is “not recommended” for administering dangerous drugs, “due to the potential for extravasation”). 13 According to the physician’s assistant who injured respondent, however, “[i]t never crossed my mind” that an antecubital injection of Phenergan could hit an artery. App. 110; see also ibid. (“[It] just wasn’t something that I was aware of at the time”). Oblivious to the risks emphasized in Phenergan’s warnings, the physician’s assistant pushed a double dose of the drug into an antecubital artery over the course of “[p]robably about three to four minutes,” id., at 111; id., at 105, notwithstanding respondent’s complaints of a “ ‘burn[ing]’ ” sensation that she subsequently described as “ ‘one of the most extreme pains that I’ve ever felt,’ ” id., at 110, 180–181. And when asked why she ignored Phenergan’s label and failed to stop pushing the drug after respondent complained of burning pains, the physician’s assistant explained that it would have been “just crazy” to “worr[y] about an [intra-arterial] injection” under the circumstances, id., at 111.

The FDA, however, did not think that the risks associated with IV push—especially in the antecubital space—were “just crazy.” That is why Phenergan’s label so clearly warns against them.

B

Given the “balance” that the FDA struck between the costs and benefits of administering Phenergan via IV push, Geier compels the pre-emption of tort suits (like this one) that would upset that balance. The contrary conclusion requires turning yesterday’s dissent into today’s majority opinion.

First, the Court denies the existence of a federal-state conflict in this case because Vermont merely countermanded the FDA’s determination that IV push is “safe” when performed in accordance with Phenergan’s warning label; the Court concludes that there is no conflict because Vermont did not “mandate a particular” label as a “replacement” for the one that the jury nullified, and because the State stopped short of altogether “contraindicating IV-push administration.” Ante, at 8. But as we emphasized in Geier (over the dissent’s assertions to the contrary), the degree of a State’s intrusion upon federal law is irrelevant—the Supremacy Clause applies with equal force to a state tort law that merely countermands a federal safety determination and to a state law that altogether prohibits car manufacturers from selling cars without airbags. Compare 529 U. S., at 881–882, with id., at 902 (Stevens, J., dissenting). Indeed, as recently as last Term, we held that the Supremacy Clause pre-empts a “[s]tate tort law that requires a manufacturer’s catheters to be safer, but hence less effective, than the model the FDA has approved … .” Riegel, 552 U. S., at ___ (slip op., at 11). It did not matter there that the State stopped short of altogether prohibiting the use of FDA-approved catheters—just as it does not matter here that Vermont stopped short of altogether prohibiting an FDA-approved method for administering Phenergan. See also Lohr, 518 U. S., at 504 (Breyer, J., concurring in part and concurring in judgment) (noting it would be an “anomalous result” if pre-emption applied differently to a state tort suit premised on the inadequacy of the FDA’s safety regulations and a state law that specifically prohibited an FDA-approved design).

Second, the Court today distinguishes Geier because the FDA articulated its pre-emptive intent “without offering States or other interested parties notice or opportunity for comment. Ante, at 21; see also ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that conflict pre-emption is appropriate only where the agency expresses its pre-emptive intent through notice-and-comment rulemaking. Compare 529 U. S., at 885 (“To insist on a specific expression of agency intent to pre-empt, made after notice-and-comment rulemaking, would be in certain cases to tolerate conflicts that an agency, and therefore Congress, is most unlikely to have intended. The dissent, as we have said, apparently welcomes that result … . We do not”), with id., at 908–910 (Stevens, J., dissenting) (emphasizing that “we generally expect an administrative regulation to declare any intention to pre-empt state law with some specificity,” and that “[t]his expectation … serves to ensurethat States will be able to have a dialog with agencies regarding pre-emption decisions ex ante through the normal notice-and-comment procedures of the Administrative Procedure Act” (internal quotation marks omitted)). Indeed, pre-emption is arguably more appropriate here than in Geier because the FDA (unlike the DOT) declared its pre-emptive intent in the Federal Register. See 71 Fed. Reg. 3933–3936. Yet the majority dismisses the FDA’s published preamble as “inherently suspect,” ante, at 21, and an afterthought that is entitled to “no weight,” ante, at 25. Compare Lohr, supra, at 506 (opinion of Breyer, J.) (emphasizing that the FDA has a “special understanding of the likely impact of both state and federal requirements, as well as an understanding of whether (or the extent to which) state requirements may interfere with federal objectives,” and that “[t]he FDA can translate these understandings into particularized pre-emptive intentions … through statements in ‘regulations, pre-ambles, interpretive statements, and responses tocomments’ ”).

Third, the Court distinguishes Geier because the DOT’s regulation “bear[s] the force of law,” whereas the FDA’s preamble does not. Ante, at 24; see also ante, at 19. But it is irrelevant that the FDA’s preamble does not “bear the force of law” because the FDA’s labeling decisions surely do. See 21 U. S. C. §355. It is well within the FDA’s discretion to make its labeling decisions through administrative adjudications rather than through less-formal and less-flexible rulemaking proceedings, see SEC v. Chenery Corp., 332 U. S. 194 (1947) , and we have never previously held that our pre-emption analysis turns on the agency’s choice of the latter over the former. Moreover, it cannot be said that Geier’s outcome hinged on the agency’s choice to promulgate a rule. See ante, at 19, 24. The Geier Court relied—again over the dissenters’ protestations—on materials other than the Secretary’s regulation to explain the conflict between state and federal law. Compare 529 U. S., at 881, with id., at 899–900 (Stevens, J., dissenting), and ante, at 1–2 (Breyer, J., concurring).

Fourth, the Court sandwiches its discussion of Geier between the “presumption against pre-emption,” ante, at 18, and heavy emphasis on “the longstanding coexistence of state and federal law and the FDA’s traditional recognition of state-law remedies,” ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that the “presumption against pre-emption” is relevant to the conflict pre-emption analysis. See 529 U. S., at 906–907 (Stevens, J., dissenting) (“[T]he Court simply ignores the presumption [against pre-emption]”). Rather than invoking such a “presumption,” the Court emphasized that it was applying “ordinary,” “longstanding,” and “experience-proved principles of conflict pre-emption.” Id., at 874. Under these principles, the sole question is whether there is an “actual conflict” between state and federal law; if so, then pre-emption follows automatically by operation of the Supremacy Clause. Id., at 871–872. See also Buckman, 531 U. S., at 347–348 (“[P]etitioner’s dealings with the FDA were prompted by [federal law], and the very subject matter of petitioner’s statements [to the FDA] were dictated by [federal law]. Accordingly—and in contrast to situations implicating ‘federalism concerns and the historic primacy of state regulation of matters of health and safety’—no presumption against pre-emption obtains in this case” (citation omitted)). 14

Finally, the Geier Court went out of its way to emphasize (yet again over the dissenters’ objections) that it placed “some weight” on the DOT’s amicus brief, which explained the agency’s regulatory objectives and the effects of state tort suits on the federal regulatory regime. 529 U. S., at 883; compare id., at 910–911 (Stevens, J., dissenting) (criticizing the majority for “uph[olding] a regulatory claim of frustration-of-purposes implied conflict pre-emption based on nothing more than an ex post administrative litigating position and inferences from regulatory history and final commentary”). See also Lohr, 518 U. S., at 496 (recognizing that the FDA is “uniquely qualified” to explain whether state law conflicts with the FDA’s objectives). Yet today, the FDA’s explanation of the conflict between state tort suits and the federal labeling regime, set forth in the agency’s amicus brief, is not even mentioned in the Court’s opinion. Instead of relying on the FDA’s explanation of its own regulatory purposes, the Court relies on a decade-old and now-repudiated statement, which the majority finds preferable. See ante, at 21–22, 24, n. 13. Cf. Riegel, 552 U. S., at ___ (slip op., at 13) (noting that “the agency’s earlier position (which the dissent describes at some length and finds preferable) is … compromised, indeed deprived of all claim to deference, by the fact that it is no longer the agency’s position” (citation omitted)); Altria Group, Inc. v. Good, 555 U. S. ___, ___ (2008) (slip op., at 16–17) (rejecting petitioners’ reliance on the pre-emptive effect of the agency’s “longstanding policy” because it is inconsistent with the agency’s current one). And Justice Breyer suggests that state tort suits may “help the [FDA],” ante, at 1 (concurring opinion), notwithstanding the FDA’s insistence that state tort suits will “disrupt the agency’s balancing of health risks and benefits,” Brief for United States as Amicus Curiae 9.

Geier does not countenance the use of state tort suits to second-guess the FDA’s labeling decisions. And the Court’s contrary conclusion has potentially far-reaching consequences.

C

By their very nature, juries are ill-equipped to perform the FDA’s cost-benefit-balancing function. As we explained in Riegel, juries tend to focus on the risk of a particular product’s design or warning label that arguably contributed to a particular plaintiff’s injury, not on the overall benefits of that design or label; “the patients who reaped those benefits are not represented in court.” 552 U. S., at ___ (slip op., at 12). Indeed, patients like respondent are the only ones whom tort juries ever see, and for a patient like respondent—who has already suffered a tragic accident—Phenergan’s risks are no longer a matter of probabilities and potentialities.

In contrast, the FDA has the benefit of the long view. Its drug-approval determinations consider the interests of all potential users of a drug, including “those who would suffer without new medical [products]” if juries in all 50 States were free to contradict the FDA’s expert determinations. Id., at ___ (slip op., at 13). And the FDA conveys its warnings with one voice, rather than whipsawing the medical community with 50 (or more) potentially conflicting ones. After today’s ruling, however, parochialism may prevail.

The problem is well illustrated by the labels borne by “vesicant” drugs, many of which are used for chemotherapy. As a class, vesicants are much more dangerous than drugs like Phenergan, 15 but the vast majority of vesicant labels—like Phenergan’s—either allow or do not disallow IV push. See Appendix, infra. Because vesicant extravasation can have devastating consequences, and because the potentially lifesaving benefits of these drugs offer hollow solace to the victim of such a tragedy, a jury’s cost-benefit analysis in a particular case may well differ from the FDA’s.

For example, consider Mustargen (mechlorethamine HCl)—the injectable form of mustard gas—which can be used as an anticancer drug. Mustargen’s FDA-approved label warns in several places that “This drug is HIGHLY TOXIC.” 16 Indeed, the drug is so highly toxic:

“Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water, for at least 15 minutes while removing contaminated clothing and shoes, followed by 2% sodium thiosulfate solution. Medical attention should be sought immediately. Contaminated clothing should be destroyed.” 17

Yet when it comes to administering this highly toxic drug, the label provides that “the drug may be injected directly into any suitable vein, [but] it is injected preferably into the rubber or plastic tubing of a flowing intravenous infusion set. This reduces the possibility of severe local reactions due to extravasation or high concentration of the drug.” (Emphasis added.) Similarly, the FDA-approved labels for other powerful chemotherapeutic vesicants—including Dactinomycin, Oxaliplatin, Vinblastine, and Vincristine—specifically allow IV push, notwithstanding their devastating effects when extravasated.

The fact that the labels for such drugs allow IV push is striking—both because vesicants are much more dangerous than Phenergan, and also because they are so frequently extravasated, see Boyle & Engelking, Vesicant Extravasation: Myths and Realities, 22 Oncology Nursing Forum 57, 58 (1995) (arguing that the rate of extravasation is “considerably higher” than 6.4% of all vesicant administrations). Regardless of the FDA’s reasons for not contraindicating IV push for these drugs, it is odd (to say the least) that a jury in Vermont can now order for Phenergan what the FDA has chosen not to order for mustard gas. 18

***

To be sure, state tort suits can peacefully coexist with the FDA’s labeling regime, and they have done so for decades. Ante, at 17–18. But this case is far from peaceful coexistence. The FDA told Wyeth that Phenergan’s label renders its use “safe.” But the State of Vermont, through its tort law, said: “Not so.”

The state-law rule at issue here is squarely pre-empted. Therefore, I would reverse the judgment of the Supreme Court of Vermont.

Appendix TO OPINION OF ALITO, J.

Vesicant1

IV Push2

Dactinomycin

Specifically allowed

Mechlorethamine (Mustargen)

Specifically allowed

Oxaliplatin

Specifically allowed

Vinblastine

Specifically allowed

Vincristine

Specifically allowed

Bleomycin

Neither mentioned nor prohibited

Carboplatin

Neither mentioned nor prohibited

Dacarbazine

Neither mentioned nor prohibited

Mitomycin

Neither mentioned nor prohibited

Carmustine

Not prohibited; IV drip recommended

Cisplatin

Not prohibited; IV drip recommended

Epirubicin

Not prohibited; IV drip recommended

Etoposide

Not prohibited; IV drip recommended

Ifosfamide

Not prohibited; IV drip recommended

Mitoxantrone

Not prohibited; IV drip recommended

Paclitaxel

Not prohibited; IV drip recommended

Teniposide

Not prohibited; IV drip recommended

Vinorelbine

Not prohibited; IV drip recommended

Daunorubicin

Prohibited

Doxorubicin

Prohibited

1 Wilkes & Barton-Burke, 2008 Oncology Nursing Drug Handbook 27–33 (2008) (Table 1.6).

2 IV-push information is derived from the “dosage and administration” sections of individual drug labels (available in Clerk of Court’s case file).


Notes

1 Indeed, respondent conceded below that Wyeth did propose an adequate warning of Phenergan’s risks. See Plaintiff Diana Levine’s Memorandum in Opposition to Wyeth’s Motion for Summary Judgment in Levine v. American Home Products Corp. (now Wyeth), No. 670–12–01 Wncv (Super. Ct. Washington Cty., Vt.), ¶7, p. 26. Specifically, respondent noted: “In 1988, Wyeth proposed language that would have prevented this accident by requiring a running IV and explaining why a running IV will address and reduce the risk [of intra-arterial injection].” Ibid. See also id., at 24 (“Although not strong enough, this improved the labeling instruction, if followed, would have prevented the inadvertent administration of Phenergan into an artery …”). The FDA rejected Wyeth’s proposal. See App. 359.

2 Moreover, in the trial judge’s final charge, he told the jury that “the critical factual issue which you must decide” is whether Phenergan’s FDA-mandated label reflects a proper balance between “the risks and benefits of intravenous administration and the potential for injury to patients.” Id., at 220. See also ___ Vt. ___, ___, 944 A. 2d 179, 182 (2006) (recognizing that respondent’s argument is that Phenergan’s “label should not have allowed IV push as a means of administration”).

3 Respondent sued her physician, physician’s assistant, and hospital for malpractice. After the parties settled that suit for an undisclosed sum, respondent’s physician sent her a letter in which he admitted “responsibility” for her injury and expressed his “profoun[d] regre[t]” and “remors[e]” for his actions. 1 Tr. 178–179 (Mar. 8, 2004) (testimony of Dr. John Matthew); see also App. 102–103 (testimony of physician’s assistant Jessica Fisch) (noting that her “sense of grief” was so “great” that she “would have gladly cut off [her own] arm” and given it to respondent). Thereafter, both the physician and the physician’s assistant agreed to testify on respondent’s behalf in her suit against Wyeth.

4 To be sure, Congress recognized the principles of conflict pre-emption in the FDCA. See Drug Amendments of 1962, §202, 76Stat. 793 (“Nothing in the amendments made by this Act to the Federal Food, Drug, and Cosmetic Act shall be construed as invalidating any provision of State law … unless there is a direct and positive conflict between such amendments and such provision of State law”). But a provision that simply recognizes the background principles of conflict pre-emption is not a traditional “saving clause,” and even if it were, it would not displace our conflict-pre-emption analysis. See Geier v. American Honda Motor Co., 529 U. S. 861, 869 (2000) (“[T]he saving clause … does not bar the ordinary working of conflict pre-emption principles”); id., at 873–874 (“The Court has … refused to read general ‘saving’ provisions to tolerate actual conflict both in cases involving impossibility and in ‘frustration-of-purpose’ cases” (emphasis deleted and citation omitted)).

5 The FDA cited numerous articles that generally discuss the costs and benefits associated with IV push. See, e.g., Nahrwold & Phelps, Inadvertent Intra-Arterial Injection of Mephenteramine, 70 Rocky Mountain Medical J. 38 (Sept. 1973) (cited in App. 314, no. 14); Albo, Cheung, Ruth, Snyder, & Beemtsma, Effect of Intra-Arterial Injections of Barbituates, 120 Am. J. of Surgery 676 (1970) (cited in App. 314, no. 12); Corser, Masey, Jacob, Kernoff, & Browne, Ischaemia Following Self-administered Intra-arterial Injection of Methylphenidate and Diamorphine, 40 Anesthesiology 51 (1985) (cited in App. 314, no. 9); Correspondence Regarding Thiopental and Thiamylal (3 letters), 59 Anesthesiology 153 (1983) (cited in App. 314, no. 11); Miller, Arthur, & Stratigos, Intra-arterial Injection of a Barbituate, 23 Anesthesia Progress 25 (1976) (cited in App. 315, no. 19).

6 See Webb & Lampert, Accidental Arterial Injections, 101 Am. J. Obstetrics & Gynecology 365 (1968) (cited in App. 313, no. 5).

7 See Hager & Wilson, Gangrene of the Hand Following Intra-arterial Injection, 94 Archives of Surgery 86 (1967) (cited in App. 313, no. 7); Enloe, Sylvester, & Morris, Hazards of Intra-Arterial Injection of Hydroxyzine, 16 Canadian Anaesthetists’ Society J. 425 (1969) (hereinafter Enloe) (noting “recent reports” of “the occurrence of severe necrosis and gangrene following [administration of] promethazine (Phenergan)” (cited in App. 314, no. 15)). See also Mostafavi & Samimi, Accidental Intra-arterial Injection of Promethazine HCl During General Anesthesia, 35 Anesthesiology 645 (1971) (reporting a case of gangrene, which required partial amputation of three fingers, after Phenergan was inadvertently pushed into an artery in the “antecubital” area); Promethazine, p. 7, in Clinical Pharmacology (Gold Standard Multimedia Inc. CD–ROM, version 1.16 (1998) (noting that “[i]nadvertent intra-arterial injection [of Phenergan] can result in arteriospasm … and development of gangrene”)).

8 Hager and Wilson noted that the most common reactions to intra-arterial injections of drugs like Phenergan include “[i]mmediate, severe, burning pain,” as well as “blanching.” 94 Archives of Surgery, at 87–88. The FDA required Wyeth to include Hager and Wilson’s observations on Phenergan’s label. See App. 311 (requiring the label to warn that “ ‘[t]he first sign [of an intra-arterial injection] may be the patient’s reaction to a sensation of fiery burning’ ” pain and “ ‘[b]lanching’ ”).

9 See Enloe 427 (discussing hydroxyzine—an antihistamine with chemical properties similar to those of Phenergan—and suggesting its “temporary” benefits can never outweigh the risks of intra-arterial injection); see also Goldsmith & Trieger, Accidental Intra-Arterial Injection: A Medical Emergency, 22 Anesthesia Progress 180 (1975) (noting the risks of intra-arterial administration of hydroxyzine) (cited in App. 315, no. 18); Klatte, Brooks, & Rhamy, Toxicity of Intra-Arterial Barbituates and Tranquilizing Drugs, 92 Radiology 700 (1969) (same) (cited in App. 314, no. 13). With full knowledge of those risks, FDA retained IV push for Phenergan, although the agency required Wyeth to incorporate observations from the Enloe article into Phenergan’s label. Compare Enloe 427 (arguing that “every precaution should be taken to avoid inadvertent intra-arterial injection,” including the use of “an obviously well-functioning venoclysis”), with App. 312 (FDA’s 1987 changes to Phenergan’s label). In contrast, at some time around 1970, the FDA prohibited all intravenous use of hydroxyzine. See id., at 79 (testimony of Dr. Harold Green). The FDA’s decision to regulate the two drugs differently—notwithstanding (1) the agency’s knowledge of the risks associated with both drugs and (2) the agency’s recognition of the relevance of hydroxyzine-related articles and case reports in its regulation of Phenergan—further demonstrates that the FDA intentionally preserved IV-push administration for Phenergan. See also Haas, Correspondence, 33 Anesthesia Progress 281 (1986) (“[Hydroxyzine’s] restriction does not lie with the medicine itself, but in the practice and malpractice of intravenous techniques. Unfortunately, the practitioner who knows how to treat injection technique problems is usually not the practitioner with the intravenous technique problems”).

10 See also Engler, Freeman, Kanavage, Ogden, & Moretz, Production of Gangrenous Extremities by Intra-Arterial Injections, 30 Am. Surgeon 602 (1964) (“Accidental arterial injection most often occurs in the antecubital region because this is a favorite site for venopuncture and in this area the ulnar and brachial arteries are superficial and easily entered” (cited in App. 313, no. 6)); Engler, Gangrenous Extremities Resulting from Intra-arterial Injections, 94 Archives of Surgery 644 (1966) (similar) (cited in App. 314, no. 16); Lynas & Bisset, Intra-arterial Thiopentone, 24 Anaesthesia 257 (1969) (“Most [anesthesiologists] agree that injections on the medial aspect of the antecubital fossa are best avoided” (cited in App. 314, no. 8)); Waters, Intra-arterial Thiopentone, 21 Anesthesia 346 (1966) (“The risk of producing gangrene of the forearm by accidental injection of sodium thiopentone into an artery at the elbow has been recognised for many years” (cited in App. 314, no. 10)); see also Hager & Wilson, 94 Archives of Surgery, at 88 (emphasizing that one of the best ways to prevent inadvertent intra-arterial injections is to be aware of “aberrant or superficial arteries at the antecubital, forearm, wrist, and hand level”); Mostafavi & Samimi, supra (warning against antecubital injections).

11 See App. 311 (requiring Phenergan’s label to warn that practitioners should “ ‘[b]eware of the close proximity of arteries and veins at commonly used injection sites and consider the possibility of aberrant arteries’ ”).

12 “Aspiration” refers to drawing a small amount of blood back into the needle to determine whether the needle is in an artery or a vein. Ordinarily, arterial blood is brighter than venous blood—but contact with Phenergan causes discoloration, which makes aspiration an unreliable method of protecting against intra-arterial injection. See id., at 282. Therefore, the label warned that when using IV push, a medical professional should beware that “[a]spiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with Phenergan Injection.” Id., at 390.

13 In addition, respondent’s own medical expert testified at trial that it is a principle of “basic anatomy” that the antecubital fossa contains aberrant arteries. See 2 Tr. 34–35 (Mar. 9, 2004) (testimony of Dr. Daniel O’Brien); see also ibid. (noting that Gray’s Anatomy, which is “the Bible of anatomy,” also warns of arteries in the antecubital space).

14 Thus, it is not true that “this Court has long” applied a presumption against pre-emption in conflict pre-emption cases. Ante, at 9, n. 3 (majority opinion). As long ago as Gibbons v. Ogden, 9 Wheat. 1, 210 (1824), the Court inquired whether a state law “interfer[ed] with,” was “contrary to,” or “c[a]me into collision with” federal law—and it did so without ever invoking a “presumption.” See also Davis, Unmasking the Presumption in Favor of Preemption, 53 S. C. L. Rev. 967, 974 (2002) (noting that many of the Court’s early pre-emption cases “resulted in almost automatic preemption of concurrent state regulation”). In subsequent years the Court has sometimes acknowledged a limited “presumption against pre-emption,” but it nonetheless remained an open question—before today—whether that presumption applied in conflict pre-emption cases. See Crosby v. National Foreign Trade Council, 530 U. S. 363, n. 8 (2000) (“We leave for another day a consideration in this context of a presumption against preemption”). Moreover, this Court has never held that the “presumption” applies in an area—such as drug labeling—that has long been “reserved for federal regulation.” United States v. Locke, 529 U. S. 89, 111 (2000) . See also Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 347–348 (2001) .

15 Vesicants may cause “blistering, severe tissue injury, or tissue necrosis” upon extravasation—even if the drug is not injected into an artery. See, e.g., Schulmeister, Administering Vesicants, 9 Clinical J. of Oncology Nursing 469, 469–470 (2005). See also ante, at 4 (majority opinion) (noting that Phenergan is labeled as an “irritant”); cf. Brief for Anju Budhwani et al. as Amici Curiae 15 (suggesting Phenergan should be considered a “vesicant”).

16 FDA, Oncology Tools Product Label Details, online at http://www.accessdata.fda.gov/scripts/cder/onctools/labels.cfm?GN=meclorethamine, nitrogen mustard (as visited Mar. 2, 2009, and available in Clerk of Court’s case file).

17 Ibid.

18 The same is true of FDA’s regulation of hydroxyzine. See n. 9,supra.


TOP

Dissent

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Alito, with whom The Chief Justice and Justice Scalia join, dissenting.

This case illustrates that tragic facts make bad law. The Court holds that a state tort jury, rather than the Food and Drug Administration (FDA), is ultimately responsible for regulating warning labels for prescription drugs. That result cannot be reconciled with Geier v. American Honda Motor Co., 529 U. S. 861 (2000) , or general principles of conflict pre-emption. I respectfully dissent.

I

The Court frames the question presented as a “narro[w]” one—namely, whether Wyeth has a duty to provide “an adequate warning about using the IV-push method” to administer Phenergan. Ante, at 8. But that ignores the antecedent question of who—the FDA or a jury in Vermont—has the authority and responsibility for determining the “adequacy” of Phenergan’s warnings. Moreover, it is unclear how a “stronger” warning could have helped respondent, see ante, at 16; after all, the physician’s assistant who treated her disregarded at least six separate warnings that are already on Phenergan’s labeling, so respondent would be hard pressed to prove that a seventh would have made a difference. 1

More to the point, the question presented by this case is not a “narrow” one, and it does not concern whether Phenergan’s label should bear a “stronger” warning. Rather, the real issue is whether a state tort jury can countermand the FDA’s considered judgment that Phenergan’s FDA-mandated warning label renders its intravenous (IV) use “safe.” Indeed, respondent’s amended complaint alleged that Phenergan is “not reasonably safe for intravenous administration,” App. 15, ¶6; respondent’s attorney told the jury that Phenergan’s label should say, “ ‘Do not use this drug intravenously,’ ” id., at 32; respondent’s expert told the jury, “I think the drug should be labeled ‘Not for IV use,’ ” id., at 59; and during his closing argument, respondent’s attorney told the jury, “Thank God we don’t rely on the FDA to … make the safe[ty] decision. You will make the decision. … The FDA doesn’t make the decision, you do,” id., at 211–212. 2

Federal law, however, does rely on the FDA to make safety determinations like the one it made here. The FDA has long known about the risks associated with IV push in general and its use to administer Phenergan in particular. Whether wisely or not, the FDA has concluded—over the course of extensive, 54-year-long regulatory proceedings—that the drug is “safe” and “effective” when used in accordance with its FDA-mandated labeling. The unfortunate fact that respondent’s healthcare providers ignored Phenergan’s labeling may make this an ideal medical-malpractice case. 3 But turning a common-law tort suit into a “frontal assault” on the FDA’s regulatory regime for drug labeling upsets the well-settled meaning of the Supremacy Clause and our conflict pre-emption jurisprudence. Brief for United States as Amicus Curiae 21.

II

A

To the extent that “[t]he purpose of Congress is the ultimate touchstone in every pre-emption case,” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) (internal quotation marks omitted), Congress made its “purpose” plain in authorizing the FDA—not state tort juries—to determine when and under what circumstances a drug is “safe.” “[T]he process for approving new drugs is at least as rigorous as the premarket approval process for medical devices,” Riegel v. Medtronic, Inc., 552 U. S. ___, ___ (2008) (slip op., at 11) (Ginsburg, J., dissenting), and we held that the latter pre-empted a state-law tort suit that conflicted with the FDA’s determination that a medical device was “safe,” id., at ___ (slip op., at 11) (opinion of the Court).

Under the Federal Food, Drug, and Cosmetic Act (FDCA), a drug manufacturer may not market a new drug before first submitting a new drug application (NDA) to the FDA and receiving the agency’s approval. See 21 U. S. C. §355(a). An NDA must contain, among other things, “the labeling proposed to be used for such drug,” §355(b)(1)(F), “full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use,” §355(b)(1)(A), and “a discussion of why the benefits exceed the risks [of the drug] under the conditions stated in the labeling,” 21 CFR §314.50(d)(5)(viii) (2008). The FDA will approve an NDA only if the agency finds, among other things, that the drug is “safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof,” there is “substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof,” and the proposed labeling is not “false or misleading in any particular.” 21 U. S. C. §355(d).

After the FDA approves a drug, the manufacturer remains under an obligation to investigate and report any adverse events associated with the drug, see 21 CFR §314.80, and must periodically submit any new information that may affect the FDA’s previous conclusions about the safety, effectiveness, or labeling of the drug, 21 U. S. C. §355(k). If the FDA finds that the drug is not “safe” when used in accordance with its labeling, the agency “shall” withdraw its approval of the drug. §355(e). The FDA also “shall” deem a drug “misbranded” if “it is dangerous to health when used in the dosage or manner, or with the frequency or duration prescribed, recommended, or suggested in the labeling thereof.” §352(j).

Thus, a drug’s warning label “serves as the standard under which the FDA determines whether a product is safe and effective.” 50Fed. Reg. 7470 (1985). Labeling is “[t]he centerpiece of risk management,” as it “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively.” 71Fed. Reg. 3934 (2006). The FDA has underscored the importance it places on drug labels by promulgating comprehensive regulations—spanning an entire part of the Code of Federal Regulations, see 21 CFR pt. 201, with seven subparts and 70 separate sections—that set forth drug manufacturers’ labeling obligations. Under those regulations, the FDA must be satisfied that a drug’s warning label contains, among other things, “a summary of the essential scientific information needed for the safe and effective use of the drug,” §201.56(1), including a description of “clinically significant adverse reactions,” “other potential safety hazards,” “limitations in use imposed by them, … and steps that should be taken if they occur,” §201.57(c)(6)(i). Neither the FDCA nor its implementing regulations suggest that juries may second-guess the FDA’s labeling decisions.

B

1

Where the FDA determines, in accordance with its statutory mandate, that a drug is on balance “safe,” our conflict pre-emption cases prohibit any State from countermanding that determination. See, e.g., Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 348 (2001) (after the FDA has struck “a somewhat delicate balance of statutory objectives” and determined that petitioner submitted a valid application to manufacture a medical device, a State may not use common law to negate it); International Paper Co. v. Ouellette, 479 U. S. 481, 494 (1987) (after the EPA has struck “the balance of public and private interests so carefully addressed by” the federal permitting regime for water pollution, a State may not use nuisance law to “upse[t]” it); Chicago & North Western Transp. Co. v. Kalo Brick & Tile Co., 450 U. S. 311, 321 (1981) (after the Interstate Commerce Commission has struck a “balance” between competing interests in permitting the abandonment of a railroad line, a State may not use statutory or common law to negate it).

Thus, as the Court itself recognizes, it is irrelevant in conflict pre-emption cases whether Congress “enacted an express pre-emption provision at some point during the FDCA’s 70-year history.” Ante, at 18; see also Geier, 529 U. S., at 869 (holding the absence of an express pre-emption clause “does not bar the ordinary working of conflict pre-emption principles”). Rather, the ordinary principles of conflict pre-emption turn solely on whether a State has upset the regulatory balance struck by the federal agency. Id., at 884–885; see also Chicago & North Western Transp. Co., supra, at 317 (describing conflict pre-emption as “a two-step process of first ascertaining the construction of the [federal and state laws] and then determining the constitutional question whether they are actually in conflict” (internal quotation marks omitted)).

2

A faithful application of this Court’s conflict pre-emption cases compels the conclusion that the FDA’s 40-year-long effort to regulate the safety and efficacy of Phenergan pre-empts respondent’s tort suit. Indeed, that result follows directly from our conclusion in Geier.

Geier arose under the National Traffic and Motor Safety Vehicle Act of 1966, which directs the Secretary of the Department of Transportation (DOT) to “establish by order … motor vehicle safety standards,” 15 U. S. C. §1392(a) (1988 ed.), which are defined as “minimum standard[s] for motor vehicle performance, or motor vehicle equipment performance,” §1391(2). Acting pursuant to that statutory mandate, the Secretary of Transportation promulgated Federal Motor Vehicle Safety Standard 208, which required car manufacturers to include passive restraint systems (i.e., devices that work automatically to protect occupants from injury during a collision) in a certain percentage of their cars built in or after 1987. See 49 CFR §571.208 (1999). Standard 208 did not require installation of any particular type of passive restraint; instead, it gave manufacturers the option to install automatic seatbelts, airbags, or any other suitable technology that they might develop, provided the restraint(s) met the performance requirements specified in the rule. Ibid.

Alexis Geier drove her 1987 Honda Accord into a tree, and although she was wearing her seatbelt, she nonetheless suffered serious injuries. She then sued Honda under state tort law, alleging that her car was negligently and defectively designed because it lacked a driver’s-side airbag. She argued that Congress had empowered the Secretary to set only “minimum standard[s]” for vehicle safety. 15 U. S. C. §1391(2). She also emphasized that the National Traffic and Motor Safety Vehicle Act contains a saving clause, which provides that “[c]ompliance with any Federal motor vehicle safety standard issued under this subchapter does not exempt any person from any liability under common law.” §1397(k).

Notwithstanding the statute’s saving clause, and notwithstanding the fact that Congress gave the Secretary authority to set only “minimum” safety standards, we held Geier’s state tort suit pre-empted. In reaching that result, we relied heavily on the view of the Secretary of Transportation—expressed in an amicus brief—that Standard 208 “ ‘embodies the Secretary’s policy judgment that safety would best be promoted if manufacturers installed alternative protection systems in their fleets rather than one particular system in every car.’ ” 529 U. S., at 881 (quoting Brief for United States as Amicus Curiae,O. T. 1999, No. 98–1811, p. 25). Because the Secretary determined that a menu of alternative technologies was “safe,” the doctrine of conflict pre-emption barred Geier’s efforts to deem some of those federally approved alternatives “unsafe” under state tort law.

The same rationale applies here. Through Phenergan’s label, the FDA offered medical professionals a menu of federally approved, “safe” and “effective” alternatives—including IV push—for administering the drug. Through a state tort suit, respondent attempted to deem IV push “unsafe” and “ineffective.” To be sure, federal law does not prohibit Wyeth from contraindicating IV push, just as federal law did not prohibit Honda from installing airbags in all its cars. But just as we held that States may not compel the latter, so, too, are States precluded from compelling the former. See also Fidelity Fed. Sav. & Loan Assn. v. De la Cuesta, 458 U. S. 141, 155 (1982) (“The conflict does not evaporate because the [agency’s] regulation simply permits, but does not compel,” the action forbidden by state law). If anything, a finding of pre-emption is even more appropriate here because the FDCA—unlike the National Traffic and Motor Safety Vehicle Act—contains no evidence that Congress intended the FDA to set only “minimum standards,” and the FDCA does not contain a saving clause. 4 See also ante, at 18 (conceding Congress’ “silence” on the issue).

III

In its attempt to evade Geier’s applicability to this case, the Court commits both factual and legal errors. First, as a factual matter, it is demonstrably untrue that the FDA failed to consider (and strike a “balance” between) the specific costs and benefits associated with IV push. Second, as a legal matter, Geier does not stand for the legal propositions espoused by the dissenters (and specifically rejected by the majority) in that case. Third, drug labeling by jury verdict undermines both our broader pre-emption jurisprudence and the broader workability of the federal drug-labeling regime.

A

Phenergan’s warning label has been subject to the FDA’s strict regulatory oversight since the 1950’s. For at least the last 34 years, the FDA has focused specifically on whether IV-push administration of Phenergan is “safe” and “effective” when performed in accordance with Phenergan’s label. The agency’s ultimate decision—to retain IV push as one means for administering Phenergan, albeit subject to stringent warnings—is reflected in the plain text of Phenergan’s label (sometimes in boldfaced font and all-capital letters). And the record contains ample evidence that the FDA specifically considered and reconsidered the strength of Phenergan’s IV-push-related warnings in light of new scientific and medical data. The majority’s factual assertions to the contrary are mistaken.

1

The FDA’s focus on IV push as a means of administering Phenergan dates back at least to 1975. In August of that year, several representatives from both the FDA and Wyeth met to discuss Phenergan’s warning label. At that meeting, the FDA specifically proposed “that Phenergan Injection should not be used in Tubex.” 2 Record 583, 586 (Plaintiff’s Trial Exh. 17, Internal Correspondence from W. E. Langeland to File (Sept. 5, 1975) (hereinafter 1975 Memo)). “Tubex” is a syringe system used exclusively for IV push. See App. 43. An FDA official explained that the agency’s concerns arose from medical-malpractice lawsuits involving IV push of the drug, see 1975 Memo 586, and that the FDA was aware of “5 cases involving amputation where the drug had been administered by Tubex together with several additional cases involving necrosis,” id., at 586–587. Rather than contraindicating Phenergan for IV push, however, the agency and Wyeth agreed “that there was a need for better instruction regarding the problems of intraarterial injection.” Id., at 587.

The next year, the FDA convened an advisory committee to study, among other things, the risks associated with the Tubex system and IV push. App. 294. At the conclusion of its study, the committee recommended an additional IV-push-specific warning for Phenergan’s label, see ibid., but did not recommend eliminating IV push from the drug label altogether. In response to the committee’s recommendations, the FDA instructed Wyeth to make several changes to strengthen Phenergan’s label, including the addition of upper case warnings related to IV push. See id., at 279–280, 282–283.

In 1987, the FDA directed Wyeth to amend its label to include the following text:

“ ‘[1] When used intravenously, [Phenergan] should be given in a concentration no greater than 25 mg/ml and at a rate not to exceed 25 mg/minute. [2] Injection through a properly running intravenous infusion may enhance the possibility of detecting arterial placement.’ ” Id., at 311–312.

The first of the two quoted sentences refers specifically to IV push; as respondent’s medical expert testified at trial, the label’s recommended rate of administration (not to exceed 25 mg per minute) refers to “IV push, as opposed to say being in a bag and dripped over a couple of hours.” Id., at 52. The second of the two quoted sentences refers to IV drip. See id., at 15–16 (emphasizing that a “running IV” is the same thing as “IV drip”).

In its 1987 labeling order, the FDA cited voluminous materials to “suppor[t]” its new and stronger warnings related to IV push and the preferability of IV drip. 5 Id., at 313. One of those articles specifically discussed the relative advantages and disadvantages of IV drip compared to IV push, as well as the costs and benefits of administering Phenergan via IV push. 6 The FDA also cited published case reports from the 1960’s of gangrene caused by the intra-arterial injection of Phenergan, 7 and the FDA instructed Wyeth to amend Phenergan’s label in accordance with the latest medical research. 8 The FDA also studied drugs similar to Phenergan and cited numerous cautionary articles—one of which urged the agency to consider contraindicating such drugs for IV use altogether. 9

In “support” of its labeling order, the FDA also cited numerous articles that singled out the inner crook of the elbow—known as the “antecubital fossa” in the medical community—whichis both a commonly used injection site, see id., at 70 (noting that respondent’s injection was pushed into “the antecubital space”), and a universally recognized high-risk area for inadvertent intra-arterial injections. One of the articles explained:

“Because of the numerous superficial positions the ulnar artery might occupy, it has often been entered during attempted venipuncture [of the antecubital fossa]. … However, the brachial and the radial arteries might also be quite superficial in the elbow region… . The arterial variations of the arm, especially in and about the cubital fossa, are common and numerous. If venipuncture must be performed in this area, a higher index of suspicion must be maintained to forestall misdirected injections.” Stone & Donnelly, The Accidental Intra-arterial Injection of Thiopental, 22 Anesthesiology 995, 996 (1961) (footnote omitted; cited in App. 315, no. 20). 10

Based on this and other research, the FDA ordered Wyeth to include a specific warning related to the use of the antecubital space for IV push. 11

2

When respondent was injured in 2000, Phenergan’s label specifically addressed IV push in several passages (sometimes in lieu of and sometimes in addition to those discussed above). For example, the label warned of the risks of intra-arterial injection associated with “aspiration,” which is a technique used only in conjunction with IV push. 12 The label also cautioned against the use of “syringes with rigid plungers,” App. 390, which are used onlyto administer the drug via IV push. As respondent’s medical expert testified at trial, “by talking plungers and rigid needles, that’s the way you do it, to push it with the plunger.” Id., at 53 (testimony of Dr. John Matthew). Moreover, Phenergan’s 2000 label devoted almost a full page to discussing the “Tubex system,” see id., at 391, which, as noted above, is used only to administer the drug via IV push.

While Phenergan’s label very clearly authorized the use of IV push, it also made clear that IV push is the delivery method of last resort. The label specified that “[t]he preferred parenteral route of administration is by deep intramuscular injection.” Id., at 390. If an intramuscular injection is ineffective, then “it is usually preferable to inject [Phenergan] through the tubing of an intravenous infusion set that is known to be functioning satisfactorily.” Ibid. See also id., at 50–51 (testimony of respondent’s medical expert, Dr. John Matthew) (conceding that the best way to determine that an IV set is functioning satisfactorily is to use IV drip). Finally, if for whatever reason a medical professional chooses to use IV push, he or she is on notice that “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY.” Id., at 391; see also id., at 390 (“Under no circumstances should Phenergan Injection be given by intra-arterial injection due to the likelihood of severe arteriospasm and the possibility of resultant gangrene”).

Phenergan’s label also directs medical practitioners to choose veins wisely when using IV push:

“Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or inadvertent intra-arterial injection. Reports compatible with inadvertent intra-arterial injection of Phenergan Injection, usually in conjunction with other drugs intended for intravenous use, suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances.” Ibid.

Thus, it is demonstrably untrue that, as of 2000, Phenergan’s “labeling did not contain a specific warning about the risks of IV-push administration.” Ante, at 4. And whatever else might be said about the extensive medical authorities and case reports that the FDA cited in “support” of its approval of IV-push administration of Phenergan, it cannot be said that the FDA “paid no more than passing attention to” IV push, ante, at 6; nor can it be said that the FDA failed to weigh its costs and benefits, Brief for Respondent 50.

3

For her part, respondent does not dispute the FDA’s conclusion that IV push has certain benefits. At trial, her medical practitioners testified that they used IV push in order to help her “in a swift and timely way” when she showed up at the hospital for the second time in one day complaining of “intractable” migraines, “terrible pain,” inability to “bear light or sound,” sleeplessness, hours-long spasms of “retching” and “vomiting,” and when “every possible” alternative treatment had “failed.” App. 40 (testimony of Dr. John Matthew); id., at 103, 106, 109 (testimony of physician’s assistant Jessica Fisch).

Rather than disputing the benefits of IV push, respondent complains that the FDA and Wyeth underestimated its costs (and hence did not provide sufficient warnings regarding its risks). But when the FDA mandated that Phenergan’s label read, “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY,” id., at 391, and when the FDA required Wyeth to warn that “[u]nder no circumstances should Phenergan Injection be given by intra-arterial injection,” id., at 390, the agency could reasonably assume that medical professionals would take care not to inject Phenergan intra-arterially. See also 71 Fed. Reg. 3934 (noting that a drug’s warning label “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively”). Unfortunately, the physician’s assistant who treated respondent in this case disregarded Phenergan’s label and pushed the drug into the single spot on her arm that is most likely to cause an inadvertent intra-arterial injection.

As noted above, when the FDA approved Phenergan’s label, it was textbook medical knowledge that the “antecubital fossa” creates a high risk of inadvertent intra-arterial injection, given the close proximity of veins and arteries. See supra, at 13–14; see also The Lippincott Manual of Nursing Practice 99 (7th ed. 2001) (noting, in a red-text “NURSING ALERT,” that the antecubital fossa is “not recommended” for administering dangerous drugs, “due to the potential for extravasation”). 13 According to the physician’s assistant who injured respondent, however, “[i]t never crossed my mind” that an antecubital injection of Phenergan could hit an artery. App. 110; see also ibid. (“[It] just wasn’t something that I was aware of at the time”). Oblivious to the risks emphasized in Phenergan’s warnings, the physician’s assistant pushed a double dose of the drug into an antecubital artery over the course of “[p]robably about three to four minutes,” id., at 111; id., at 105, notwithstanding respondent’s complaints of a “ ‘burn[ing]’ ” sensation that she subsequently described as “ ‘one of the most extreme pains that I’ve ever felt,’ ” id., at 110, 180–181. And when asked why she ignored Phenergan’s label and failed to stop pushing the drug after respondent complained of burning pains, the physician’s assistant explained that it would have been “just crazy” to “worr[y] about an [intra-arterial] injection” under the circumstances, id., at 111.

The FDA, however, did not think that the risks associated with IV push—especially in the antecubital space—were “just crazy.” That is why Phenergan’s label so clearly warns against them.

B

Given the “balance” that the FDA struck between the costs and benefits of administering Phenergan via IV push, Geier compels the pre-emption of tort suits (like this one) that would upset that balance. The contrary conclusion requires turning yesterday’s dissent into today’s majority opinion.

First, the Court denies the existence of a federal-state conflict in this case because Vermont merely countermanded the FDA’s determination that IV push is “safe” when performed in accordance with Phenergan’s warning label; the Court concludes that there is no conflict because Vermont did not “mandate a particular” label as a “replacement” for the one that the jury nullified, and because the State stopped short of altogether “contraindicating IV-push administration.” Ante, at 8. But as we emphasized in Geier (over the dissent’s assertions to the contrary), the degree of a State’s intrusion upon federal law is irrelevant—the Supremacy Clause applies with equal force to a state tort law that merely countermands a federal safety determination and to a state law that altogether prohibits car manufacturers from selling cars without airbags. Compare 529 U. S., at 881–882, with id., at 902 (Stevens, J., dissenting). Indeed, as recently as last Term, we held that the Supremacy Clause pre-empts a “[s]tate tort law that requires a manufacturer’s catheters to be safer, but hence less effective, than the model the FDA has approved … .” Riegel, 552 U. S., at ___ (slip op., at 11). It did not matter there that the State stopped short of altogether prohibiting the use of FDA-approved catheters—just as it does not matter here that Vermont stopped short of altogether prohibiting an FDA-approved method for administering Phenergan. See also Lohr, 518 U. S., at 504 (Breyer, J., concurring in part and concurring in judgment) (noting it would be an “anomalous result” if pre-emption applied differently to a state tort suit premised on the inadequacy of the FDA’s safety regulations and a state law that specifically prohibited an FDA-approved design).

Second, the Court today distinguishes Geier because the FDA articulated its pre-emptive intent “without offering States or other interested parties notice or opportunity for comment. Ante, at 21; see also ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that conflict pre-emption is appropriate only where the agency expresses its pre-emptive intent through notice-and-comment rulemaking. Compare 529 U. S., at 885 (“To insist on a specific expression of agency intent to pre-empt, made after notice-and-comment rulemaking, would be in certain cases to tolerate conflicts that an agency, and therefore Congress, is most unlikely to have intended. The dissent, as we have said, apparently welcomes that result … . We do not”), with id., at 908–910 (Stevens, J., dissenting) (emphasizing that “we generally expect an administrative regulation to declare any intention to pre-empt state law with some specificity,” and that “[t]his expectation … serves to ensurethat States will be able to have a dialog with agencies regarding pre-emption decisions ex ante through the normal notice-and-comment procedures of the Administrative Procedure Act” (internal quotation marks omitted)). Indeed, pre-emption is arguably more appropriate here than in Geier because the FDA (unlike the DOT) declared its pre-emptive intent in the Federal Register. See 71 Fed. Reg. 3933–3936. Yet the majority dismisses the FDA’s published preamble as “inherently suspect,” ante, at 21, and an afterthought that is entitled to “no weight,” ante, at 25. Compare Lohr, supra, at 506 (opinion of Breyer, J.) (emphasizing that the FDA has a “special understanding of the likely impact of both state and federal requirements, as well as an understanding of whether (or the extent to which) state requirements may interfere with federal objectives,” and that “[t]he FDA can translate these understandings into particularized pre-emptive intentions … through statements in ‘regulations, pre-ambles, interpretive statements, and responses tocomments’ ”).

Third, the Court distinguishes Geier because the DOT’s regulation “bear[s] the force of law,” whereas the FDA’s preamble does not. Ante, at 24; see also ante, at 19. But it is irrelevant that the FDA’s preamble does not “bear the force of law” because the FDA’s labeling decisions surely do. See 21 U. S. C. §355. It is well within the FDA’s discretion to make its labeling decisions through administrative adjudications rather than through less-formal and less-flexible rulemaking proceedings, see SEC v. Chenery Corp., 332 U. S. 194 (1947) , and we have never previously held that our pre-emption analysis turns on the agency’s choice of the latter over the former. Moreover, it cannot be said that Geier’s outcome hinged on the agency’s choice to promulgate a rule. See ante, at 19, 24. The Geier Court relied—again over the dissenters’ protestations—on materials other than the Secretary’s regulation to explain the conflict between state and federal law. Compare 529 U. S., at 881, with id., at 899–900 (Stevens, J., dissenting), and ante, at 1–2 (Breyer, J., concurring).

Fourth, the Court sandwiches its discussion of Geier between the “presumption against pre-emption,” ante, at 18, and heavy emphasis on “the longstanding coexistence of state and federal law and the FDA’s traditional recognition of state-law remedies,” ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that the “presumption against pre-emption” is relevant to the conflict pre-emption analysis. See 529 U. S., at 906–907 (Stevens, J., dissenting) (“[T]he Court simply ignores the presumption [against pre-emption]”). Rather than invoking such a “presumption,” the Court emphasized that it was applying “ordinary,” “longstanding,” and “experience-proved principles of conflict pre-emption.” Id., at 874. Under these principles, the sole question is whether there is an “actual conflict” between state and federal law; if so, then pre-emption follows automatically by operation of the Supremacy Clause. Id., at 871–872. See also Buckman, 531 U. S., at 347–348 (“[P]etitioner’s dealings with the FDA were prompted by [federal law], and the very subject matter of petitioner’s statements [to the FDA] were dictated by [federal law]. Accordingly—and in contrast to situations implicating ‘federalism concerns and the historic primacy of state regulation of matters of health and safety’—no presumption against pre-emption obtains in this case” (citation omitted)). 14

Finally, the Geier Court went out of its way to emphasize (yet again over the dissenters’ objections) that it placed “some weight” on the DOT’s amicus brief, which explained the agency’s regulatory objectives and the effects of state tort suits on the federal regulatory regime. 529 U. S., at 883; compare id., at 910–911 (Stevens, J., dissenting) (criticizing the majority for “uph[olding] a regulatory claim of frustration-of-purposes implied conflict pre-emption based on nothing more than an ex post administrative litigating position and inferences from regulatory history and final commentary”). See also Lohr, 518 U. S., at 496 (recognizing that the FDA is “uniquely qualified” to explain whether state law conflicts with the FDA’s objectives). Yet today, the FDA’s explanation of the conflict between state tort suits and the federal labeling regime, set forth in the agency’s amicus brief, is not even mentioned in the Court’s opinion. Instead of relying on the FDA’s explanation of its own regulatory purposes, the Court relies on a decade-old and now-repudiated statement, which the majority finds preferable. See ante, at 21–22, 24, n. 13. Cf. Riegel, 552 U. S., at ___ (slip op., at 13) (noting that “the agency’s earlier position (which the dissent describes at some length and finds preferable) is … compromised, indeed deprived of all claim to deference, by the fact that it is no longer the agency’s position” (citation omitted)); Altria Group, Inc. v. Good, 555 U. S. ___, ___ (2008) (slip op., at 16–17) (rejecting petitioners’ reliance on the pre-emptive effect of the agency’s “longstanding policy” because it is inconsistent with the agency’s current one). And Justice Breyer suggests that state tort suits may “help the [FDA],” ante, at 1 (concurring opinion), notwithstanding the FDA’s insistence that state tort suits will “disrupt the agency’s balancing of health risks and benefits,” Brief for United States as Amicus Curiae 9.

Geier does not countenance the use of state tort suits to second-guess the FDA’s labeling decisions. And the Court’s contrary conclusion has potentially far-reaching consequences.

C

By their very nature, juries are ill-equipped to perform the FDA’s cost-benefit-balancing function. As we explained in Riegel, juries tend to focus on the risk of a particular product’s design or warning label that arguably contributed to a particular plaintiff’s injury, not on the overall benefits of that design or label; “the patients who reaped those benefits are not represented in court.” 552 U. S., at ___ (slip op., at 12). Indeed, patients like respondent are the only ones whom tort juries ever see, and for a patient like respondent—who has already suffered a tragic accident—Phenergan’s risks are no longer a matter of probabilities and potentialities.

In contrast, the FDA has the benefit of the long view. Its drug-approval determinations consider the interests of all potential users of a drug, including “those who would suffer without new medical [products]” if juries in all 50 States were free to contradict the FDA’s expert determinations. Id., at ___ (slip op., at 13). And the FDA conveys its warnings with one voice, rather than whipsawing the medical community with 50 (or more) potentially conflicting ones. After today’s ruling, however, parochialism may prevail.

The problem is well illustrated by the labels borne by “vesicant” drugs, many of which are used for chemotherapy. As a class, vesicants are much more dangerous than drugs like Phenergan, 15 but the vast majority of vesicant labels—like Phenergan’s—either allow or do not disallow IV push. See Appendix, infra. Because vesicant extravasation can have devastating consequences, and because the potentially lifesaving benefits of these drugs offer hollow solace to the victim of such a tragedy, a jury’s cost-benefit analysis in a particular case may well differ from the FDA’s.

For example, consider Mustargen (mechlorethamine HCl)—the injectable form of mustard gas—which can be used as an anticancer drug. Mustargen’s FDA-approved label warns in several places that “This drug is HIGHLY TOXIC.” 16 Indeed, the drug is so highly toxic:

“Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water, for at least 15 minutes while removing contaminated clothing and shoes, followed by 2% sodium thiosulfate solution. Medical attention should be sought immediately. Contaminated clothing should be destroyed.” 17

Yet when it comes to administering this highly toxic drug, the label provides that “the drug may be injected directly into any suitable vein, [but] it is injected preferably into the rubber or plastic tubing of a flowing intravenous infusion set. This reduces the possibility of severe local reactions due to extravasation or high concentration of the drug.” (Emphasis added.) Similarly, the FDA-approved labels for other powerful chemotherapeutic vesicants—including Dactinomycin, Oxaliplatin, Vinblastine, and Vincristine—specifically allow IV push, notwithstanding their devastating effects when extravasated.

The fact that the labels for such drugs allow IV push is striking—both because vesicants are much more dangerous than Phenergan, and also because they are so frequently extravasated, see Boyle & Engelking, Vesicant Extravasation: Myths and Realities, 22 Oncology Nursing Forum 57, 58 (1995) (arguing that the rate of extravasation is “considerably higher” than 6.4% of all vesicant administrations). Regardless of the FDA’s reasons for not contraindicating IV push for these drugs, it is odd (to say the least) that a jury in Vermont can now order for Phenergan what the FDA has chosen not to order for mustard gas. 18

***

To be sure, state tort suits can peacefully coexist with the FDA’s labeling regime, and they have done so for decades. Ante, at 17–18. But this case is far from peaceful coexistence. The FDA told Wyeth that Phenergan’s label renders its use “safe.” But the State of Vermont, through its tort law, said: “Not so.”

The state-law rule at issue here is squarely pre-empted. Therefore, I would reverse the judgment of the Supreme Court of Vermont.

Appendix TO OPINION OF ALITO, J.

Vesicant1

IV Push2

Dactinomycin

Specifically allowed

Mechlorethamine (Mustargen)

Specifically allowed

Oxaliplatin

Specifically allowed

Vinblastine

Specifically allowed

Vincristine

Specifically allowed

Bleomycin

Neither mentioned nor prohibited

Carboplatin

Neither mentioned nor prohibited

Dacarbazine

Neither mentioned nor prohibited

Mitomycin

Neither mentioned nor prohibited

Carmustine

Not prohibited; IV drip recommended

Cisplatin

Not prohibited; IV drip recommended

Epirubicin

Not prohibited; IV drip recommended

Etoposide

Not prohibited; IV drip recommended

Ifosfamide

Not prohibited; IV drip recommended

Mitoxantrone

Not prohibited; IV drip recommended

Paclitaxel

Not prohibited; IV drip recommended

Teniposide

Not prohibited; IV drip recommended

Vinorelbine

Not prohibited; IV drip recommended

Daunorubicin

Prohibited

Doxorubicin

Prohibited

1 Wilkes & Barton-Burke, 2008 Oncology Nursing Drug Handbook 27–33 (2008) (Table 1.6).

2 IV-push information is derived from the “dosage and administration” sections of individual drug labels (available in Clerk of Court’s case file).


Notes

1 Indeed, respondent conceded below that Wyeth did propose an adequate warning of Phenergan’s risks. See Plaintiff Diana Levine’s Memorandum in Opposition to Wyeth’s Motion for Summary Judgment in Levine v. American Home Products Corp. (now Wyeth), No. 670–12–01 Wncv (Super. Ct. Washington Cty., Vt.), ¶7, p. 26. Specifically, respondent noted: “In 1988, Wyeth proposed language that would have prevented this accident by requiring a running IV and explaining why a running IV will address and reduce the risk [of intra-arterial injection].” Ibid. See also id., at 24 (“Although not strong enough, this improved the labeling instruction, if followed, would have prevented the inadvertent administration of Phenergan into an artery …”). The FDA rejected Wyeth’s proposal. See App. 359.

2 Moreover, in the trial judge’s final charge, he told the jury that “the critical factual issue which you must decide” is whether Phenergan’s FDA-mandated label reflects a proper balance between “the risks and benefits of intravenous administration and the potential for injury to patients.” Id., at 220. See also ___ Vt. ___, ___, 944 A. 2d 179, 182 (2006) (recognizing that respondent’s argument is that Phenergan’s “label should not have allowed IV push as a means of administration”).

3 Respondent sued her physician, physician’s assistant, and hospital for malpractice. After the parties settled that suit for an undisclosed sum, respondent’s physician sent her a letter in which he admitted “responsibility” for her injury and expressed his “profoun[d] regre[t]” and “remors[e]” for his actions. 1 Tr. 178–179 (Mar. 8, 2004) (testimony of Dr. John Matthew); see also App. 102–103 (testimony of physician’s assistant Jessica Fisch) (noting that her “sense of grief” was so “great” that she “would have gladly cut off [her own] arm” and given it to respondent). Thereafter, both the physician and the physician’s assistant agreed to testify on respondent’s behalf in her suit against Wyeth.

4 To be sure, Congress recognized the principles of conflict pre-emption in the FDCA. See Drug Amendments of 1962, §202, 76Stat. 793 (“Nothing in the amendments made by this Act to the Federal Food, Drug, and Cosmetic Act shall be construed as invalidating any provision of State law … unless there is a direct and positive conflict between such amendments and such provision of State law”). But a provision that simply recognizes the background principles of conflict pre-emption is not a traditional “saving clause,” and even if it were, it would not displace our conflict-pre-emption analysis. See Geier v. American Honda Motor Co., 529 U. S. 861, 869 (2000) (“[T]he saving clause … does not bar the ordinary working of conflict pre-emption principles”); id., at 873–874 (“The Court has … refused to read general ‘saving’ provisions to tolerate actual conflict both in cases involving impossibility and in ‘frustration-of-purpose’ cases” (emphasis deleted and citation omitted)).

5 The FDA cited numerous articles that generally discuss the costs and benefits associated with IV push. See, e.g., Nahrwold & Phelps, Inadvertent Intra-Arterial Injection of Mephenteramine, 70 Rocky Mountain Medical J. 38 (Sept. 1973) (cited in App. 314, no. 14); Albo, Cheung, Ruth, Snyder, & Beemtsma, Effect of Intra-Arterial Injections of Barbituates, 120 Am. J. of Surgery 676 (1970) (cited in App. 314, no. 12); Corser, Masey, Jacob, Kernoff, & Browne, Ischaemia Following Self-administered Intra-arterial Injection of Methylphenidate and Diamorphine, 40 Anesthesiology 51 (1985) (cited in App. 314, no. 9); Correspondence Regarding Thiopental and Thiamylal (3 letters), 59 Anesthesiology 153 (1983) (cited in App. 314, no. 11); Miller, Arthur, & Stratigos, Intra-arterial Injection of a Barbituate, 23 Anesthesia Progress 25 (1976) (cited in App. 315, no. 19).

6 See Webb & Lampert, Accidental Arterial Injections, 101 Am. J. Obstetrics & Gynecology 365 (1968) (cited in App. 313, no. 5).

7 See Hager & Wilson, Gangrene of the Hand Following Intra-arterial Injection, 94 Archives of Surgery 86 (1967) (cited in App. 313, no. 7); Enloe, Sylvester, & Morris, Hazards of Intra-Arterial Injection of Hydroxyzine, 16 Canadian Anaesthetists’ Society J. 425 (1969) (hereinafter Enloe) (noting “recent reports” of “the occurrence of severe necrosis and gangrene following [administration of] promethazine (Phenergan)” (cited in App. 314, no. 15)). See also Mostafavi & Samimi, Accidental Intra-arterial Injection of Promethazine HCl During General Anesthesia, 35 Anesthesiology 645 (1971) (reporting a case of gangrene, which required partial amputation of three fingers, after Phenergan was inadvertently pushed into an artery in the “antecubital” area); Promethazine, p. 7, in Clinical Pharmacology (Gold Standard Multimedia Inc. CD–ROM, version 1.16 (1998) (noting that “[i]nadvertent intra-arterial injection [of Phenergan] can result in arteriospasm … and development of gangrene”)).

8 Hager and Wilson noted that the most common reactions to intra-arterial injections of drugs like Phenergan include “[i]mmediate, severe, burning pain,” as well as “blanching.” 94 Archives of Surgery, at 87–88. The FDA required Wyeth to include Hager and Wilson’s observations on Phenergan’s label. See App. 311 (requiring the label to warn that “ ‘[t]he first sign [of an intra-arterial injection] may be the patient’s reaction to a sensation of fiery burning’ ” pain and “ ‘[b]lanching’ ”).

9 See Enloe 427 (discussing hydroxyzine—an antihistamine with chemical properties similar to those of Phenergan—and suggesting its “temporary” benefits can never outweigh the risks of intra-arterial injection); see also Goldsmith & Trieger, Accidental Intra-Arterial Injection: A Medical Emergency, 22 Anesthesia Progress 180 (1975) (noting the risks of intra-arterial administration of hydroxyzine) (cited in App. 315, no. 18); Klatte, Brooks, & Rhamy, Toxicity of Intra-Arterial Barbituates and Tranquilizing Drugs, 92 Radiology 700 (1969) (same) (cited in App. 314, no. 13). With full knowledge of those risks, FDA retained IV push for Phenergan, although the agency required Wyeth to incorporate observations from the Enloe article into Phenergan’s label. Compare Enloe 427 (arguing that “every precaution should be taken to avoid inadvertent intra-arterial injection,” including the use of “an obviously well-functioning venoclysis”), with App. 312 (FDA’s 1987 changes to Phenergan’s label). In contrast, at some time around 1970, the FDA prohibited all intravenous use of hydroxyzine. See id., at 79 (testimony of Dr. Harold Green). The FDA’s decision to regulate the two drugs differently—notwithstanding (1) the agency’s knowledge of the risks associated with both drugs and (2) the agency’s recognition of the relevance of hydroxyzine-related articles and case reports in its regulation of Phenergan—further demonstrates that the FDA intentionally preserved IV-push administration for Phenergan. See also Haas, Correspondence, 33 Anesthesia Progress 281 (1986) (“[Hydroxyzine’s] restriction does not lie with the medicine itself, but in the practice and malpractice of intravenous techniques. Unfortunately, the practitioner who knows how to treat injection technique problems is usually not the practitioner with the intravenous technique problems”).

10 See also Engler, Freeman, Kanavage, Ogden, & Moretz, Production of Gangrenous Extremities by Intra-Arterial Injections, 30 Am. Surgeon 602 (1964) (“Accidental arterial injection most often occurs in the antecubital region because this is a favorite site for venopuncture and in this area the ulnar and brachial arteries are superficial and easily entered” (cited in App. 313, no. 6)); Engler, Gangrenous Extremities Resulting from Intra-arterial Injections, 94 Archives of Surgery 644 (1966) (similar) (cited in App. 314, no. 16); Lynas & Bisset, Intra-arterial Thiopentone, 24 Anaesthesia 257 (1969) (“Most [anesthesiologists] agree that injections on the medial aspect of the antecubital fossa are best avoided” (cited in App. 314, no. 8)); Waters, Intra-arterial Thiopentone, 21 Anesthesia 346 (1966) (“The risk of producing gangrene of the forearm by accidental injection of sodium thiopentone into an artery at the elbow has been recognised for many years” (cited in App. 314, no. 10)); see also Hager & Wilson, 94 Archives of Surgery, at 88 (emphasizing that one of the best ways to prevent inadvertent intra-arterial injections is to be aware of “aberrant or superficial arteries at the antecubital, forearm, wrist, and hand level”); Mostafavi & Samimi, supra (warning against antecubital injections).

11 See App. 311 (requiring Phenergan’s label to warn that practitioners should “ ‘[b]eware of the close proximity of arteries and veins at commonly used injection sites and consider the possibility of aberrant arteries’ ”).

12 “Aspiration” refers to drawing a small amount of blood back into the needle to determine whether the needle is in an artery or a vein. Ordinarily, arterial blood is brighter than venous blood—but contact with Phenergan causes discoloration, which makes aspiration an unreliable method of protecting against intra-arterial injection. See id., at 282. Therefore, the label warned that when using IV push, a medical professional should beware that “[a]spiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with Phenergan Injection.” Id., at 390.

13 In addition, respondent’s own medical expert testified at trial that it is a principle of “basic anatomy” that the antecubital fossa contains aberrant arteries. See 2 Tr. 34–35 (Mar. 9, 2004) (testimony of Dr. Daniel O’Brien); see also ibid. (noting that Gray’s Anatomy, which is “the Bible of anatomy,” also warns of arteries in the antecubital space).

14 Thus, it is not true that “this Court has long” applied a presumption against pre-emption in conflict pre-emption cases. Ante, at 9, n. 3 (majority opinion). As long ago as Gibbons v. Ogden, 9 Wheat. 1, 210 (1824), the Court inquired whether a state law “interfer[ed] with,” was “contrary to,” or “c[a]me into collision with” federal law—and it did so without ever invoking a “presumption.” See also Davis, Unmasking the Presumption in Favor of Preemption, 53 S. C. L. Rev. 967, 974 (2002) (noting that many of the Court’s early pre-emption cases “resulted in almost automatic preemption of concurrent state regulation”). In subsequent years the Court has sometimes acknowledged a limited “presumption against pre-emption,” but it nonetheless remained an open question—before today—whether that presumption applied in conflict pre-emption cases. See Crosby v. National Foreign Trade Council, 530 U. S. 363, n. 8 (2000) (“We leave for another day a consideration in this context of a presumption against preemption”). Moreover, this Court has never held that the “presumption” applies in an area—such as drug labeling—that has long been “reserved for federal regulation.” United States v. Locke, 529 U. S. 89, 111 (2000) . See also Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 347–348 (2001) .

15 Vesicants may cause “blistering, severe tissue injury, or tissue necrosis” upon extravasation—even if the drug is not injected into an artery. See, e.g., Schulmeister, Administering Vesicants, 9 Clinical J. of Oncology Nursing 469, 469–470 (2005). See also ante, at 4 (majority opinion) (noting that Phenergan is labeled as an “irritant”); cf. Brief for Anju Budhwani et al. as Amici Curiae 15 (suggesting Phenergan should be considered a “vesicant”).

16 FDA, Oncology Tools Product Label Details, online at http://www.accessdata.fda.gov/scripts/cder/onctools/labels.cfm?GN=meclorethamine, nitrogen mustard (as visited Mar. 2, 2009, and available in Clerk of Court’s case file).

17 Ibid.

18 The same is true of FDA’s regulation of hydroxyzine. See n. 9,supra.


TOP

Dissent

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Alito, with whom The Chief Justice and Justice Scalia join, dissenting.

This case illustrates that tragic facts make bad law. The Court holds that a state tort jury, rather than the Food and Drug Administration (FDA), is ultimately responsible for regulating warning labels for prescription drugs. That result cannot be reconciled with Geier v. American Honda Motor Co., 529 U. S. 861 (2000) , or general principles of conflict pre-emption. I respectfully dissent.

I

The Court frames the question presented as a “narro[w]” one—namely, whether Wyeth has a duty to provide “an adequate warning about using the IV-push method” to administer Phenergan. Ante, at 8. But that ignores the antecedent question of who—the FDA or a jury in Vermont—has the authority and responsibility for determining the “adequacy” of Phenergan’s warnings. Moreover, it is unclear how a “stronger” warning could have helped respondent, see ante, at 16; after all, the physician’s assistant who treated her disregarded at least six separate warnings that are already on Phenergan’s labeling, so respondent would be hard pressed to prove that a seventh would have made a difference. 1

More to the point, the question presented by this case is not a “narrow” one, and it does not concern whether Phenergan’s label should bear a “stronger” warning. Rather, the real issue is whether a state tort jury can countermand the FDA’s considered judgment that Phenergan’s FDA-mandated warning label renders its intravenous (IV) use “safe.” Indeed, respondent’s amended complaint alleged that Phenergan is “not reasonably safe for intravenous administration,” App. 15, ¶6; respondent’s attorney told the jury that Phenergan’s label should say, “ ‘Do not use this drug intravenously,’ ” id., at 32; respondent’s expert told the jury, “I think the drug should be labeled ‘Not for IV use,’ ” id., at 59; and during his closing argument, respondent’s attorney told the jury, “Thank God we don’t rely on the FDA to … make the safe[ty] decision. You will make the decision. … The FDA doesn’t make the decision, you do,” id., at 211–212. 2

Federal law, however, does rely on the FDA to make safety determinations like the one it made here. The FDA has long known about the risks associated with IV push in general and its use to administer Phenergan in particular. Whether wisely or not, the FDA has concluded—over the course of extensive, 54-year-long regulatory proceedings—that the drug is “safe” and “effective” when used in accordance with its FDA-mandated labeling. The unfortunate fact that respondent’s healthcare providers ignored Phenergan’s labeling may make this an ideal medical-malpractice case. 3 But turning a common-law tort suit into a “frontal assault” on the FDA’s regulatory regime for drug labeling upsets the well-settled meaning of the Supremacy Clause and our conflict pre-emption jurisprudence. Brief for United States as Amicus Curiae 21.

II

A

To the extent that “[t]he purpose of Congress is the ultimate touchstone in every pre-emption case,” Medtronic, Inc. v. Lohr, 518 U. S. 470, 485 (1996) (internal quotation marks omitted), Congress made its “purpose” plain in authorizing the FDA—not state tort juries—to determine when and under what circumstances a drug is “safe.” “[T]he process for approving new drugs is at least as rigorous as the premarket approval process for medical devices,” Riegel v. Medtronic, Inc., 552 U. S. ___, ___ (2008) (slip op., at 11) (Ginsburg, J., dissenting), and we held that the latter pre-empted a state-law tort suit that conflicted with the FDA’s determination that a medical device was “safe,” id., at ___ (slip op., at 11) (opinion of the Court).

Under the Federal Food, Drug, and Cosmetic Act (FDCA), a drug manufacturer may not market a new drug before first submitting a new drug application (NDA) to the FDA and receiving the agency’s approval. See 21 U. S. C. §355(a). An NDA must contain, among other things, “the labeling proposed to be used for such drug,” §355(b)(1)(F), “full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use,” §355(b)(1)(A), and “a discussion of why the benefits exceed the risks [of the drug] under the conditions stated in the labeling,” 21 CFR §314.50(d)(5)(viii) (2008). The FDA will approve an NDA only if the agency finds, among other things, that the drug is “safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof,” there is “substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof,” and the proposed labeling is not “false or misleading in any particular.” 21 U. S. C. §355(d).

After the FDA approves a drug, the manufacturer remains under an obligation to investigate and report any adverse events associated with the drug, see 21 CFR §314.80, and must periodically submit any new information that may affect the FDA’s previous conclusions about the safety, effectiveness, or labeling of the drug, 21 U. S. C. §355(k). If the FDA finds that the drug is not “safe” when used in accordance with its labeling, the agency “shall” withdraw its approval of the drug. §355(e). The FDA also “shall” deem a drug “misbranded” if “it is dangerous to health when used in the dosage or manner, or with the frequency or duration prescribed, recommended, or suggested in the labeling thereof.” §352(j).

Thus, a drug’s warning label “serves as the standard under which the FDA determines whether a product is safe and effective.” 50Fed. Reg. 7470 (1985). Labeling is “[t]he centerpiece of risk management,” as it “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively.” 71Fed. Reg. 3934 (2006). The FDA has underscored the importance it places on drug labels by promulgating comprehensive regulations—spanning an entire part of the Code of Federal Regulations, see 21 CFR pt. 201, with seven subparts and 70 separate sections—that set forth drug manufacturers’ labeling obligations. Under those regulations, the FDA must be satisfied that a drug’s warning label contains, among other things, “a summary of the essential scientific information needed for the safe and effective use of the drug,” §201.56(1), including a description of “clinically significant adverse reactions,” “other potential safety hazards,” “limitations in use imposed by them, … and steps that should be taken if they occur,” §201.57(c)(6)(i). Neither the FDCA nor its implementing regulations suggest that juries may second-guess the FDA’s labeling decisions.

B

1

Where the FDA determines, in accordance with its statutory mandate, that a drug is on balance “safe,” our conflict pre-emption cases prohibit any State from countermanding that determination. See, e.g., Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 348 (2001) (after the FDA has struck “a somewhat delicate balance of statutory objectives” and determined that petitioner submitted a valid application to manufacture a medical device, a State may not use common law to negate it); International Paper Co. v. Ouellette, 479 U. S. 481, 494 (1987) (after the EPA has struck “the balance of public and private interests so carefully addressed by” the federal permitting regime for water pollution, a State may not use nuisance law to “upse[t]” it); Chicago & North Western Transp. Co. v. Kalo Brick & Tile Co., 450 U. S. 311, 321 (1981) (after the Interstate Commerce Commission has struck a “balance” between competing interests in permitting the abandonment of a railroad line, a State may not use statutory or common law to negate it).

Thus, as the Court itself recognizes, it is irrelevant in conflict pre-emption cases whether Congress “enacted an express pre-emption provision at some point during the FDCA’s 70-year history.” Ante, at 18; see also Geier, 529 U. S., at 869 (holding the absence of an express pre-emption clause “does not bar the ordinary working of conflict pre-emption principles”). Rather, the ordinary principles of conflict pre-emption turn solely on whether a State has upset the regulatory balance struck by the federal agency. Id., at 884–885; see also Chicago & North Western Transp. Co., supra, at 317 (describing conflict pre-emption as “a two-step process of first ascertaining the construction of the [federal and state laws] and then determining the constitutional question whether they are actually in conflict” (internal quotation marks omitted)).

2

A faithful application of this Court’s conflict pre-emption cases compels the conclusion that the FDA’s 40-year-long effort to regulate the safety and efficacy of Phenergan pre-empts respondent’s tort suit. Indeed, that result follows directly from our conclusion in Geier.

Geier arose under the National Traffic and Motor Safety Vehicle Act of 1966, which directs the Secretary of the Department of Transportation (DOT) to “establish by order … motor vehicle safety standards,” 15 U. S. C. §1392(a) (1988 ed.), which are defined as “minimum standard[s] for motor vehicle performance, or motor vehicle equipment performance,” §1391(2). Acting pursuant to that statutory mandate, the Secretary of Transportation promulgated Federal Motor Vehicle Safety Standard 208, which required car manufacturers to include passive restraint systems (i.e., devices that work automatically to protect occupants from injury during a collision) in a certain percentage of their cars built in or after 1987. See 49 CFR §571.208 (1999). Standard 208 did not require installation of any particular type of passive restraint; instead, it gave manufacturers the option to install automatic seatbelts, airbags, or any other suitable technology that they might develop, provided the restraint(s) met the performance requirements specified in the rule. Ibid.

Alexis Geier drove her 1987 Honda Accord into a tree, and although she was wearing her seatbelt, she nonetheless suffered serious injuries. She then sued Honda under state tort law, alleging that her car was negligently and defectively designed because it lacked a driver’s-side airbag. She argued that Congress had empowered the Secretary to set only “minimum standard[s]” for vehicle safety. 15 U. S. C. §1391(2). She also emphasized that the National Traffic and Motor Safety Vehicle Act contains a saving clause, which provides that “[c]ompliance with any Federal motor vehicle safety standard issued under this subchapter does not exempt any person from any liability under common law.” §1397(k).

Notwithstanding the statute’s saving clause, and notwithstanding the fact that Congress gave the Secretary authority to set only “minimum” safety standards, we held Geier’s state tort suit pre-empted. In reaching that result, we relied heavily on the view of the Secretary of Transportation—expressed in an amicus brief—that Standard 208 “ ‘embodies the Secretary’s policy judgment that safety would best be promoted if manufacturers installed alternative protection systems in their fleets rather than one particular system in every car.’ ” 529 U. S., at 881 (quoting Brief for United States as Amicus Curiae,O. T. 1999, No. 98–1811, p. 25). Because the Secretary determined that a menu of alternative technologies was “safe,” the doctrine of conflict pre-emption barred Geier’s efforts to deem some of those federally approved alternatives “unsafe” under state tort law.

The same rationale applies here. Through Phenergan’s label, the FDA offered medical professionals a menu of federally approved, “safe” and “effective” alternatives—including IV push—for administering the drug. Through a state tort suit, respondent attempted to deem IV push “unsafe” and “ineffective.” To be sure, federal law does not prohibit Wyeth from contraindicating IV push, just as federal law did not prohibit Honda from installing airbags in all its cars. But just as we held that States may not compel the latter, so, too, are States precluded from compelling the former. See also Fidelity Fed. Sav. & Loan Assn. v. De la Cuesta, 458 U. S. 141, 155 (1982) (“The conflict does not evaporate because the [agency’s] regulation simply permits, but does not compel,” the action forbidden by state law). If anything, a finding of pre-emption is even more appropriate here because the FDCA—unlike the National Traffic and Motor Safety Vehicle Act—contains no evidence that Congress intended the FDA to set only “minimum standards,” and the FDCA does not contain a saving clause. 4 See also ante, at 18 (conceding Congress’ “silence” on the issue).

III

In its attempt to evade Geier’s applicability to this case, the Court commits both factual and legal errors. First, as a factual matter, it is demonstrably untrue that the FDA failed to consider (and strike a “balance” between) the specific costs and benefits associated with IV push. Second, as a legal matter, Geier does not stand for the legal propositions espoused by the dissenters (and specifically rejected by the majority) in that case. Third, drug labeling by jury verdict undermines both our broader pre-emption jurisprudence and the broader workability of the federal drug-labeling regime.

A

Phenergan’s warning label has been subject to the FDA’s strict regulatory oversight since the 1950’s. For at least the last 34 years, the FDA has focused specifically on whether IV-push administration of Phenergan is “safe” and “effective” when performed in accordance with Phenergan’s label. The agency’s ultimate decision—to retain IV push as one means for administering Phenergan, albeit subject to stringent warnings—is reflected in the plain text of Phenergan’s label (sometimes in boldfaced font and all-capital letters). And the record contains ample evidence that the FDA specifically considered and reconsidered the strength of Phenergan’s IV-push-related warnings in light of new scientific and medical data. The majority’s factual assertions to the contrary are mistaken.

1

The FDA’s focus on IV push as a means of administering Phenergan dates back at least to 1975. In August of that year, several representatives from both the FDA and Wyeth met to discuss Phenergan’s warning label. At that meeting, the FDA specifically proposed “that Phenergan Injection should not be used in Tubex.” 2 Record 583, 586 (Plaintiff’s Trial Exh. 17, Internal Correspondence from W. E. Langeland to File (Sept. 5, 1975) (hereinafter 1975 Memo)). “Tubex” is a syringe system used exclusively for IV push. See App. 43. An FDA official explained that the agency’s concerns arose from medical-malpractice lawsuits involving IV push of the drug, see 1975 Memo 586, and that the FDA was aware of “5 cases involving amputation where the drug had been administered by Tubex together with several additional cases involving necrosis,” id., at 586–587. Rather than contraindicating Phenergan for IV push, however, the agency and Wyeth agreed “that there was a need for better instruction regarding the problems of intraarterial injection.” Id., at 587.

The next year, the FDA convened an advisory committee to study, among other things, the risks associated with the Tubex system and IV push. App. 294. At the conclusion of its study, the committee recommended an additional IV-push-specific warning for Phenergan’s label, see ibid., but did not recommend eliminating IV push from the drug label altogether. In response to the committee’s recommendations, the FDA instructed Wyeth to make several changes to strengthen Phenergan’s label, including the addition of upper case warnings related to IV push. See id., at 279–280, 282–283.

In 1987, the FDA directed Wyeth to amend its label to include the following text:

“ ‘[1] When used intravenously, [Phenergan] should be given in a concentration no greater than 25 mg/ml and at a rate not to exceed 25 mg/minute. [2] Injection through a properly running intravenous infusion may enhance the possibility of detecting arterial placement.’ ” Id., at 311–312.

The first of the two quoted sentences refers specifically to IV push; as respondent’s medical expert testified at trial, the label’s recommended rate of administration (not to exceed 25 mg per minute) refers to “IV push, as opposed to say being in a bag and dripped over a couple of hours.” Id., at 52. The second of the two quoted sentences refers to IV drip. See id., at 15–16 (emphasizing that a “running IV” is the same thing as “IV drip”).

In its 1987 labeling order, the FDA cited voluminous materials to “suppor[t]” its new and stronger warnings related to IV push and the preferability of IV drip. 5 Id., at 313. One of those articles specifically discussed the relative advantages and disadvantages of IV drip compared to IV push, as well as the costs and benefits of administering Phenergan via IV push. 6 The FDA also cited published case reports from the 1960’s of gangrene caused by the intra-arterial injection of Phenergan, 7 and the FDA instructed Wyeth to amend Phenergan’s label in accordance with the latest medical research. 8 The FDA also studied drugs similar to Phenergan and cited numerous cautionary articles—one of which urged the agency to consider contraindicating such drugs for IV use altogether. 9

In “support” of its labeling order, the FDA also cited numerous articles that singled out the inner crook of the elbow—known as the “antecubital fossa” in the medical community—whichis both a commonly used injection site, see id., at 70 (noting that respondent’s injection was pushed into “the antecubital space”), and a universally recognized high-risk area for inadvertent intra-arterial injections. One of the articles explained:

“Because of the numerous superficial positions the ulnar artery might occupy, it has often been entered during attempted venipuncture [of the antecubital fossa]. … However, the brachial and the radial arteries might also be quite superficial in the elbow region… . The arterial variations of the arm, especially in and about the cubital fossa, are common and numerous. If venipuncture must be performed in this area, a higher index of suspicion must be maintained to forestall misdirected injections.” Stone & Donnelly, The Accidental Intra-arterial Injection of Thiopental, 22 Anesthesiology 995, 996 (1961) (footnote omitted; cited in App. 315, no. 20). 10

Based on this and other research, the FDA ordered Wyeth to include a specific warning related to the use of the antecubital space for IV push. 11

2

When respondent was injured in 2000, Phenergan’s label specifically addressed IV push in several passages (sometimes in lieu of and sometimes in addition to those discussed above). For example, the label warned of the risks of intra-arterial injection associated with “aspiration,” which is a technique used only in conjunction with IV push. 12 The label also cautioned against the use of “syringes with rigid plungers,” App. 390, which are used onlyto administer the drug via IV push. As respondent’s medical expert testified at trial, “by talking plungers and rigid needles, that’s the way you do it, to push it with the plunger.” Id., at 53 (testimony of Dr. John Matthew). Moreover, Phenergan’s 2000 label devoted almost a full page to discussing the “Tubex system,” see id., at 391, which, as noted above, is used only to administer the drug via IV push.

While Phenergan’s label very clearly authorized the use of IV push, it also made clear that IV push is the delivery method of last resort. The label specified that “[t]he preferred parenteral route of administration is by deep intramuscular injection.” Id., at 390. If an intramuscular injection is ineffective, then “it is usually preferable to inject [Phenergan] through the tubing of an intravenous infusion set that is known to be functioning satisfactorily.” Ibid. See also id., at 50–51 (testimony of respondent’s medical expert, Dr. John Matthew) (conceding that the best way to determine that an IV set is functioning satisfactorily is to use IV drip). Finally, if for whatever reason a medical professional chooses to use IV push, he or she is on notice that “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY.” Id., at 391; see also id., at 390 (“Under no circumstances should Phenergan Injection be given by intra-arterial injection due to the likelihood of severe arteriospasm and the possibility of resultant gangrene”).

Phenergan’s label also directs medical practitioners to choose veins wisely when using IV push:

“Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or inadvertent intra-arterial injection. Reports compatible with inadvertent intra-arterial injection of Phenergan Injection, usually in conjunction with other drugs intended for intravenous use, suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances.” Ibid.

Thus, it is demonstrably untrue that, as of 2000, Phenergan’s “labeling did not contain a specific warning about the risks of IV-push administration.” Ante, at 4. And whatever else might be said about the extensive medical authorities and case reports that the FDA cited in “support” of its approval of IV-push administration of Phenergan, it cannot be said that the FDA “paid no more than passing attention to” IV push, ante, at 6; nor can it be said that the FDA failed to weigh its costs and benefits, Brief for Respondent 50.

3

For her part, respondent does not dispute the FDA’s conclusion that IV push has certain benefits. At trial, her medical practitioners testified that they used IV push in order to help her “in a swift and timely way” when she showed up at the hospital for the second time in one day complaining of “intractable” migraines, “terrible pain,” inability to “bear light or sound,” sleeplessness, hours-long spasms of “retching” and “vomiting,” and when “every possible” alternative treatment had “failed.” App. 40 (testimony of Dr. John Matthew); id., at 103, 106, 109 (testimony of physician’s assistant Jessica Fisch).

Rather than disputing the benefits of IV push, respondent complains that the FDA and Wyeth underestimated its costs (and hence did not provide sufficient warnings regarding its risks). But when the FDA mandated that Phenergan’s label read, “INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY,” id., at 391, and when the FDA required Wyeth to warn that “[u]nder no circumstances should Phenergan Injection be given by intra-arterial injection,” id., at 390, the agency could reasonably assume that medical professionals would take care not to inject Phenergan intra-arterially. See also 71 Fed. Reg. 3934 (noting that a drug’s warning label “communicates to health care practitioners the agency’s formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively”). Unfortunately, the physician’s assistant who treated respondent in this case disregarded Phenergan’s label and pushed the drug into the single spot on her arm that is most likely to cause an inadvertent intra-arterial injection.

As noted above, when the FDA approved Phenergan’s label, it was textbook medical knowledge that the “antecubital fossa” creates a high risk of inadvertent intra-arterial injection, given the close proximity of veins and arteries. See supra, at 13–14; see also The Lippincott Manual of Nursing Practice 99 (7th ed. 2001) (noting, in a red-text “NURSING ALERT,” that the antecubital fossa is “not recommended” for administering dangerous drugs, “due to the potential for extravasation”). 13 According to the physician’s assistant who injured respondent, however, “[i]t never crossed my mind” that an antecubital injection of Phenergan could hit an artery. App. 110; see also ibid. (“[It] just wasn’t something that I was aware of at the time”). Oblivious to the risks emphasized in Phenergan’s warnings, the physician’s assistant pushed a double dose of the drug into an antecubital artery over the course of “[p]robably about three to four minutes,” id., at 111; id., at 105, notwithstanding respondent’s complaints of a “ ‘burn[ing]’ ” sensation that she subsequently described as “ ‘one of the most extreme pains that I’ve ever felt,’ ” id., at 110, 180–181. And when asked why she ignored Phenergan’s label and failed to stop pushing the drug after respondent complained of burning pains, the physician’s assistant explained that it would have been “just crazy” to “worr[y] about an [intra-arterial] injection” under the circumstances, id., at 111.

The FDA, however, did not think that the risks associated with IV push—especially in the antecubital space—were “just crazy.” That is why Phenergan’s label so clearly warns against them.

B

Given the “balance” that the FDA struck between the costs and benefits of administering Phenergan via IV push, Geier compels the pre-emption of tort suits (like this one) that would upset that balance. The contrary conclusion requires turning yesterday’s dissent into today’s majority opinion.

First, the Court denies the existence of a federal-state conflict in this case because Vermont merely countermanded the FDA’s determination that IV push is “safe” when performed in accordance with Phenergan’s warning label; the Court concludes that there is no conflict because Vermont did not “mandate a particular” label as a “replacement” for the one that the jury nullified, and because the State stopped short of altogether “contraindicating IV-push administration.” Ante, at 8. But as we emphasized in Geier (over the dissent’s assertions to the contrary), the degree of a State’s intrusion upon federal law is irrelevant—the Supremacy Clause applies with equal force to a state tort law that merely countermands a federal safety determination and to a state law that altogether prohibits car manufacturers from selling cars without airbags. Compare 529 U. S., at 881–882, with id., at 902 (Stevens, J., dissenting). Indeed, as recently as last Term, we held that the Supremacy Clause pre-empts a “[s]tate tort law that requires a manufacturer’s catheters to be safer, but hence less effective, than the model the FDA has approved … .” Riegel, 552 U. S., at ___ (slip op., at 11). It did not matter there that the State stopped short of altogether prohibiting the use of FDA-approved catheters—just as it does not matter here that Vermont stopped short of altogether prohibiting an FDA-approved method for administering Phenergan. See also Lohr, 518 U. S., at 504 (Breyer, J., concurring in part and concurring in judgment) (noting it would be an “anomalous result” if pre-emption applied differently to a state tort suit premised on the inadequacy of the FDA’s safety regulations and a state law that specifically prohibited an FDA-approved design).

Second, the Court today distinguishes Geier because the FDA articulated its pre-emptive intent “without offering States or other interested parties notice or opportunity for comment. Ante, at 21; see also ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that conflict pre-emption is appropriate only where the agency expresses its pre-emptive intent through notice-and-comment rulemaking. Compare 529 U. S., at 885 (“To insist on a specific expression of agency intent to pre-empt, made after notice-and-comment rulemaking, would be in certain cases to tolerate conflicts that an agency, and therefore Congress, is most unlikely to have intended. The dissent, as we have said, apparently welcomes that result … . We do not”), with id., at 908–910 (Stevens, J., dissenting) (emphasizing that “we generally expect an administrative regulation to declare any intention to pre-empt state law with some specificity,” and that “[t]his expectation … serves to ensurethat States will be able to have a dialog with agencies regarding pre-emption decisions ex ante through the normal notice-and-comment procedures of the Administrative Procedure Act” (internal quotation marks omitted)). Indeed, pre-emption is arguably more appropriate here than in Geier because the FDA (unlike the DOT) declared its pre-emptive intent in the Federal Register. See 71 Fed. Reg. 3933–3936. Yet the majority dismisses the FDA’s published preamble as “inherently suspect,” ante, at 21, and an afterthought that is entitled to “no weight,” ante, at 25. Compare Lohr, supra, at 506 (opinion of Breyer, J.) (emphasizing that the FDA has a “special understanding of the likely impact of both state and federal requirements, as well as an understanding of whether (or the extent to which) state requirements may interfere with federal objectives,” and that “[t]he FDA can translate these understandings into particularized pre-emptive intentions … through statements in ‘regulations, pre-ambles, interpretive statements, and responses tocomments’ ”).

Third, the Court distinguishes Geier because the DOT’s regulation “bear[s] the force of law,” whereas the FDA’s preamble does not. Ante, at 24; see also ante, at 19. But it is irrelevant that the FDA’s preamble does not “bear the force of law” because the FDA’s labeling decisions surely do. See 21 U. S. C. §355. It is well within the FDA’s discretion to make its labeling decisions through administrative adjudications rather than through less-formal and less-flexible rulemaking proceedings, see SEC v. Chenery Corp., 332 U. S. 194 (1947) , and we have never previously held that our pre-emption analysis turns on the agency’s choice of the latter over the former. Moreover, it cannot be said that Geier’s outcome hinged on the agency’s choice to promulgate a rule. See ante, at 19, 24. The Geier Court relied—again over the dissenters’ protestations—on materials other than the Secretary’s regulation to explain the conflict between state and federal law. Compare 529 U. S., at 881, with id., at 899–900 (Stevens, J., dissenting), and ante, at 1–2 (Breyer, J., concurring).

Fourth, the Court sandwiches its discussion of Geier between the “presumption against pre-emption,” ante, at 18, and heavy emphasis on “the longstanding coexistence of state and federal law and the FDA’s traditional recognition of state-law remedies,” ante, at 24. But the Geier Court specifically rejected the argument (again made by the dissenters in that case) that the “presumption against pre-emption” is relevant to the conflict pre-emption analysis. See 529 U. S., at 906–907 (Stevens, J., dissenting) (“[T]he Court simply ignores the presumption [against pre-emption]”). Rather than invoking such a “presumption,” the Court emphasized that it was applying “ordinary,” “longstanding,” and “experience-proved principles of conflict pre-emption.” Id., at 874. Under these principles, the sole question is whether there is an “actual conflict” between state and federal law; if so, then pre-emption follows automatically by operation of the Supremacy Clause. Id., at 871–872. See also Buckman, 531 U. S., at 347–348 (“[P]etitioner’s dealings with the FDA were prompted by [federal law], and the very subject matter of petitioner’s statements [to the FDA] were dictated by [federal law]. Accordingly—and in contrast to situations implicating ‘federalism concerns and the historic primacy of state regulation of matters of health and safety’—no presumption against pre-emption obtains in this case” (citation omitted)). 14

Finally, the Geier Court went out of its way to emphasize (yet again over the dissenters’ objections) that it placed “some weight” on the DOT’s amicus brief, which explained the agency’s regulatory objectives and the effects of state tort suits on the federal regulatory regime. 529 U. S., at 883; compare id., at 910–911 (Stevens, J., dissenting) (criticizing the majority for “uph[olding] a regulatory claim of frustration-of-purposes implied conflict pre-emption based on nothing more than an ex post administrative litigating position and inferences from regulatory history and final commentary”). See also Lohr, 518 U. S., at 496 (recognizing that the FDA is “uniquely qualified” to explain whether state law conflicts with the FDA’s objectives). Yet today, the FDA’s explanation of the conflict between state tort suits and the federal labeling regime, set forth in the agency’s amicus brief, is not even mentioned in the Court’s opinion. Instead of relying on the FDA’s explanation of its own regulatory purposes, the Court relies on a decade-old and now-repudiated statement, which the majority finds preferable. See ante, at 21–22, 24, n. 13. Cf. Riegel, 552 U. S., at ___ (slip op., at 13) (noting that “the agency’s earlier position (which the dissent describes at some length and finds preferable) is … compromised, indeed deprived of all claim to deference, by the fact that it is no longer the agency’s position” (citation omitted)); Altria Group, Inc. v. Good, 555 U. S. ___, ___ (2008) (slip op., at 16–17) (rejecting petitioners’ reliance on the pre-emptive effect of the agency’s “longstanding policy” because it is inconsistent with the agency’s current one). And Justice Breyer suggests that state tort suits may “help the [FDA],” ante, at 1 (concurring opinion), notwithstanding the FDA’s insistence that state tort suits will “disrupt the agency’s balancing of health risks and benefits,” Brief for United States as Amicus Curiae 9.

Geier does not countenance the use of state tort suits to second-guess the FDA’s labeling decisions. And the Court’s contrary conclusion has potentially far-reaching consequences.

C

By their very nature, juries are ill-equipped to perform the FDA’s cost-benefit-balancing function. As we explained in Riegel, juries tend to focus on the risk of a particular product’s design or warning label that arguably contributed to a particular plaintiff’s injury, not on the overall benefits of that design or label; “the patients who reaped those benefits are not represented in court.” 552 U. S., at ___ (slip op., at 12). Indeed, patients like respondent are the only ones whom tort juries ever see, and for a patient like respondent—who has already suffered a tragic accident—Phenergan’s risks are no longer a matter of probabilities and potentialities.

In contrast, the FDA has the benefit of the long view. Its drug-approval determinations consider the interests of all potential users of a drug, including “those who would suffer without new medical [products]” if juries in all 50 States were free to contradict the FDA’s expert determinations. Id., at ___ (slip op., at 13). And the FDA conveys its warnings with one voice, rather than whipsawing the medical community with 50 (or more) potentially conflicting ones. After today’s ruling, however, parochialism may prevail.

The problem is well illustrated by the labels borne by “vesicant” drugs, many of which are used for chemotherapy. As a class, vesicants are much more dangerous than drugs like Phenergan, 15 but the vast majority of vesicant labels—like Phenergan’s—either allow or do not disallow IV push. See Appendix, infra. Because vesicant extravasation can have devastating consequences, and because the potentially lifesaving benefits of these drugs offer hollow solace to the victim of such a tragedy, a jury’s cost-benefit analysis in a particular case may well differ from the FDA’s.

For example, consider Mustargen (mechlorethamine HCl)—the injectable form of mustard gas—which can be used as an anticancer drug. Mustargen’s FDA-approved label warns in several places that “This drug is HIGHLY TOXIC.” 16 Indeed, the drug is so highly toxic:

“Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water, for at least 15 minutes while removing contaminated clothing and shoes, followed by 2% sodium thiosulfate solution. Medical attention should be sought immediately. Contaminated clothing should be destroyed.” 17

Yet when it comes to administering this highly toxic drug, the label provides that “the drug may be injected directly into any suitable vein, [but] it is injected preferably into the rubber or plastic tubing of a flowing intravenous infusion set. This reduces the possibility of severe local reactions due to extravasation or high concentration of the drug.” (Emphasis added.) Similarly, the FDA-approved labels for other powerful chemotherapeutic vesicants—including Dactinomycin, Oxaliplatin, Vinblastine, and Vincristine—specifically allow IV push, notwithstanding their devastating effects when extravasated.

The fact that the labels for such drugs allow IV push is striking—both because vesicants are much more dangerous than Phenergan, and also because they are so frequently extravasated, see Boyle & Engelking, Vesicant Extravasation: Myths and Realities, 22 Oncology Nursing Forum 57, 58 (1995) (arguing that the rate of extravasation is “considerably higher” than 6.4% of all vesicant administrations). Regardless of the FDA’s reasons for not contraindicating IV push for these drugs, it is odd (to say the least) that a jury in Vermont can now order for Phenergan what the FDA has chosen not to order for mustard gas. 18

***

To be sure, state tort suits can peacefully coexist with the FDA’s labeling regime, and they have done so for decades. Ante, at 17–18. But this case is far from peaceful coexistence. The FDA told Wyeth that Phenergan’s label renders its use “safe.” But the State of Vermont, through its tort law, said: “Not so.”

The state-law rule at issue here is squarely pre-empted. Therefore, I would reverse the judgment of the Supreme Court of Vermont.

Appendix TO OPINION OF ALITO, J.

Vesicant1

IV Push2

Dactinomycin

Specifically allowed

Mechlorethamine (Mustargen)

Specifically allowed

Oxaliplatin

Specifically allowed

Vinblastine

Specifically allowed

Vincristine

Specifically allowed

Bleomycin

Neither mentioned nor prohibited

Carboplatin

Neither mentioned nor prohibited

Dacarbazine

Neither mentioned nor prohibited

Mitomycin

Neither mentioned nor prohibited

Carmustine

Not prohibited; IV drip recommended

Cisplatin

Not prohibited; IV drip recommended

Epirubicin

Not prohibited; IV drip recommended

Etoposide

Not prohibited; IV drip recommended

Ifosfamide

Not prohibited; IV drip recommended

Mitoxantrone

Not prohibited; IV drip recommended

Paclitaxel

Not prohibited; IV drip recommended

Teniposide

Not prohibited; IV drip recommended

Vinorelbine

Not prohibited; IV drip recommended

Daunorubicin

Prohibited

Doxorubicin

Prohibited

1 Wilkes & Barton-Burke, 2008 Oncology Nursing Drug Handbook 27–33 (2008) (Table 1.6).

2 IV-push information is derived from the “dosage and administration” sections of individual drug labels (available in Clerk of Court’s case file).


Notes

1 Indeed, respondent conceded below that Wyeth did propose an adequate warning of Phenergan’s risks. See Plaintiff Diana Levine’s Memorandum in Opposition to Wyeth’s Motion for Summary Judgment in Levine v. American Home Products Corp. (now Wyeth), No. 670–12–01 Wncv (Super. Ct. Washington Cty., Vt.), ¶7, p. 26. Specifically, respondent noted: “In 1988, Wyeth proposed language that would have prevented this accident by requiring a running IV and explaining why a running IV will address and reduce the risk [of intra-arterial injection].” Ibid. See also id., at 24 (“Although not strong enough, this improved the labeling instruction, if followed, would have prevented the inadvertent administration of Phenergan into an artery …”). The FDA rejected Wyeth’s proposal. See App. 359.

2 Moreover, in the trial judge’s final charge, he told the jury that “the critical factual issue which you must decide” is whether Phenergan’s FDA-mandated label reflects a proper balance between “the risks and benefits of intravenous administration and the potential for injury to patients.” Id., at 220. See also ___ Vt. ___, ___, 944 A. 2d 179, 182 (2006) (recognizing that respondent’s argument is that Phenergan’s “label should not have allowed IV push as a means of administration”).

3 Respondent sued her physician, physician’s assistant, and hospital for malpractice. After the parties settled that suit for an undisclosed sum, respondent’s physician sent her a letter in which he admitted “responsibility” for her injury and expressed his “profoun[d] regre[t]” and “remors[e]” for his actions. 1 Tr. 178–179 (Mar. 8, 2004) (testimony of Dr. John Matthew); see also App. 102–103 (testimony of physician’s assistant Jessica Fisch) (noting that her “sense of grief” was so “great” that she “would have gladly cut off [her own] arm” and given it to respondent). Thereafter, both the physician and the physician’s assistant agreed to testify on respondent’s behalf in her suit against Wyeth.

4 To be sure, Congress recognized the principles of conflict pre-emption in the FDCA. See Drug Amendments of 1962, §202, 76Stat. 793 (“Nothing in the amendments made by this Act to the Federal Food, Drug, and Cosmetic Act shall be construed as invalidating any provision of State law … unless there is a direct and positive conflict between such amendments and such provision of State law”). But a provision that simply recognizes the background principles of conflict pre-emption is not a traditional “saving clause,” and even if it were, it would not displace our conflict-pre-emption analysis. See Geier v. American Honda Motor Co., 529 U. S. 861, 869 (2000) (“[T]he saving clause … does not bar the ordinary working of conflict pre-emption principles”); id., at 873–874 (“The Court has … refused to read general ‘saving’ provisions to tolerate actual conflict both in cases involving impossibility and in ‘frustration-of-purpose’ cases” (emphasis deleted and citation omitted)).

5 The FDA cited numerous articles that generally discuss the costs and benefits associated with IV push. See, e.g., Nahrwold & Phelps, Inadvertent Intra-Arterial Injection of Mephenteramine, 70 Rocky Mountain Medical J. 38 (Sept. 1973) (cited in App. 314, no. 14); Albo, Cheung, Ruth, Snyder, & Beemtsma, Effect of Intra-Arterial Injections of Barbituates, 120 Am. J. of Surgery 676 (1970) (cited in App. 314, no. 12); Corser, Masey, Jacob, Kernoff, & Browne, Ischaemia Following Self-administered Intra-arterial Injection of Methylphenidate and Diamorphine, 40 Anesthesiology 51 (1985) (cited in App. 314, no. 9); Correspondence Regarding Thiopental and Thiamylal (3 letters), 59 Anesthesiology 153 (1983) (cited in App. 314, no. 11); Miller, Arthur, & Stratigos, Intra-arterial Injection of a Barbituate, 23 Anesthesia Progress 25 (1976) (cited in App. 315, no. 19).

6 See Webb & Lampert, Accidental Arterial Injections, 101 Am. J. Obstetrics & Gynecology 365 (1968) (cited in App. 313, no. 5).

7 See Hager & Wilson, Gangrene of the Hand Following Intra-arterial Injection, 94 Archives of Surgery 86 (1967) (cited in App. 313, no. 7); Enloe, Sylvester, & Morris, Hazards of Intra-Arterial Injection of Hydroxyzine, 16 Canadian Anaesthetists’ Society J. 425 (1969) (hereinafter Enloe) (noting “recent reports” of “the occurrence of severe necrosis and gangrene following [administration of] promethazine (Phenergan)” (cited in App. 314, no. 15)). See also Mostafavi & Samimi, Accidental Intra-arterial Injection of Promethazine HCl During General Anesthesia, 35 Anesthesiology 645 (1971) (reporting a case of gangrene, which required partial amputation of three fingers, after Phenergan was inadvertently pushed into an artery in the “antecubital” area); Promethazine, p. 7, in Clinical Pharmacology (Gold Standard Multimedia Inc. CD–ROM, version 1.16 (1998) (noting that “[i]nadvertent intra-arterial injection [of Phenergan] can result in arteriospasm … and development of gangrene”)).

8 Hager and Wilson noted that the most common reactions to intra-arterial injections of drugs like Phenergan include “[i]mmediate, severe, burning pain,” as well as “blanching.” 94 Archives of Surgery, at 87–88. The FDA required Wyeth to include Hager and Wilson’s observations on Phenergan’s label. See App. 311 (requiring the label to warn that “ ‘[t]he first sign [of an intra-arterial injection] may be the patient’s reaction to a sensation of fiery burning’ ” pain and “ ‘[b]lanching’ ”).

9 See Enloe 427 (discussing hydroxyzine—an antihistamine with chemical properties similar to those of Phenergan—and suggesting its “temporary” benefits can never outweigh the risks of intra-arterial injection); see also Goldsmith & Trieger, Accidental Intra-Arterial Injection: A Medical Emergency, 22 Anesthesia Progress 180 (1975) (noting the risks of intra-arterial administration of hydroxyzine) (cited in App. 315, no. 18); Klatte, Brooks, & Rhamy, Toxicity of Intra-Arterial Barbituates and Tranquilizing Drugs, 92 Radiology 700 (1969) (same) (cited in App. 314, no. 13). With full knowledge of those risks, FDA retained IV push for Phenergan, although the agency required Wyeth to incorporate observations from the Enloe article into Phenergan’s label. Compare Enloe 427 (arguing that “every precaution should be taken to avoid inadvertent intra-arterial injection,” including the use of “an obviously well-functioning venoclysis”), with App. 312 (FDA’s 1987 changes to Phenergan’s label). In contrast, at some time around 1970, the FDA prohibited all intravenous use of hydroxyzine. See id., at 79 (testimony of Dr. Harold Green). The FDA’s decision to regulate the two drugs differently—notwithstanding (1) the agency’s knowledge of the risks associated with both drugs and (2) the agency’s recognition of the relevance of hydroxyzine-related articles and case reports in its regulation of Phenergan—further demonstrates that the FDA intentionally preserved IV-push administration for Phenergan. See also Haas, Correspondence, 33 Anesthesia Progress 281 (1986) (“[Hydroxyzine’s] restriction does not lie with the medicine itself, but in the practice and malpractice of intravenous techniques. Unfortunately, the practitioner who knows how to treat injection technique problems is usually not the practitioner with the intravenous technique problems”).

10 See also Engler, Freeman, Kanavage, Ogden, & Moretz, Production of Gangrenous Extremities by Intra-Arterial Injections, 30 Am. Surgeon 602 (1964) (“Accidental arterial injection most often occurs in the antecubital region because this is a favorite site for venopuncture and in this area the ulnar and brachial arteries are superficial and easily entered” (cited in App. 313, no. 6)); Engler, Gangrenous Extremities Resulting from Intra-arterial Injections, 94 Archives of Surgery 644 (1966) (similar) (cited in App. 314, no. 16); Lynas & Bisset, Intra-arterial Thiopentone, 24 Anaesthesia 257 (1969) (“Most [anesthesiologists] agree that injections on the medial aspect of the antecubital fossa are best avoided” (cited in App. 314, no. 8)); Waters, Intra-arterial Thiopentone, 21 Anesthesia 346 (1966) (“The risk of producing gangrene of the forearm by accidental injection of sodium thiopentone into an artery at the elbow has been recognised for many years” (cited in App. 314, no. 10)); see also Hager & Wilson, 94 Archives of Surgery, at 88 (emphasizing that one of the best ways to prevent inadvertent intra-arterial injections is to be aware of “aberrant or superficial arteries at the antecubital, forearm, wrist, and hand level”); Mostafavi & Samimi, supra (warning against antecubital injections).

11 See App. 311 (requiring Phenergan’s label to warn that practitioners should “ ‘[b]eware of the close proximity of arteries and veins at commonly used injection sites and consider the possibility of aberrant arteries’ ”).

12 “Aspiration” refers to drawing a small amount of blood back into the needle to determine whether the needle is in an artery or a vein. Ordinarily, arterial blood is brighter than venous blood—but contact with Phenergan causes discoloration, which makes aspiration an unreliable method of protecting against intra-arterial injection. See id., at 282. Therefore, the label warned that when using IV push, a medical professional should beware that “[a]spiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with Phenergan Injection.” Id., at 390.

13 In addition, respondent’s own medical expert testified at trial that it is a principle of “basic anatomy” that the antecubital fossa contains aberrant arteries. See 2 Tr. 34–35 (Mar. 9, 2004) (testimony of Dr. Daniel O’Brien); see also ibid. (noting that Gray’s Anatomy, which is “the Bible of anatomy,” also warns of arteries in the antecubital space).

14 Thus, it is not true that “this Court has long” applied a presumption against pre-emption in conflict pre-emption cases. Ante, at 9, n. 3 (majority opinion). As long ago as Gibbons v. Ogden, 9 Wheat. 1, 210 (1824), the Court inquired whether a state law “interfer[ed] with,” was “contrary to,” or “c[a]me into collision with” federal law—and it did so without ever invoking a “presumption.” See also Davis, Unmasking the Presumption in Favor of Preemption, 53 S. C. L. Rev. 967, 974 (2002) (noting that many of the Court’s early pre-emption cases “resulted in almost automatic preemption of concurrent state regulation”). In subsequent years the Court has sometimes acknowledged a limited “presumption against pre-emption,” but it nonetheless remained an open question—before today—whether that presumption applied in conflict pre-emption cases. See Crosby v. National Foreign Trade Council, 530 U. S. 363, n. 8 (2000) (“We leave for another day a consideration in this context of a presumption against preemption”). Moreover, this Court has never held that the “presumption” applies in an area—such as drug labeling—that has long been “reserved for federal regulation.” United States v. Locke, 529 U. S. 89, 111 (2000) . See also Buckman Co. v. Plaintiffs’ Legal Comm., 531 U. S. 341, 347–348 (2001) .

15 Vesicants may cause “blistering, severe tissue injury, or tissue necrosis” upon extravasation—even if the drug is not injected into an artery. See, e.g., Schulmeister, Administering Vesicants, 9 Clinical J. of Oncology Nursing 469, 469–470 (2005). See also ante, at 4 (majority opinion) (noting that Phenergan is labeled as an “irritant”); cf. Brief for Anju Budhwani et al. as Amici Curiae 15 (suggesting Phenergan should be considered a “vesicant”).

16 FDA, Oncology Tools Product Label Details, online at http://www.accessdata.fda.gov/scripts/cder/onctools/labels.cfm?GN=meclorethamine, nitrogen mustard (as visited Mar. 2, 2009, and available in Clerk of Court’s case file).

17 Ibid.

18 The same is true of FDA’s regulation of hydroxyzine. See n. 9,supra.


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Dissent

WYETH, PETITIONER v. DIANA LEVINE

on writ of certiorari to the supreme court ofvermont


[March 4, 2009]

Justice Alito, with whom The Chief Justice and Justice Scalia join, dissenting.

This case illustrates that tragic facts make bad law. The Court holds that a state tort jury, rather than the Food and Drug Administration (FDA), is ultimately responsible for regulating warning labels for prescription drugs. That result cannot be reconciled with Geier v. American Honda Motor Co., 529 U. S. 861 (2000) , or general principles of conflict pre-emption. I respectfully dissent.

I

The Court frames the question presented as a “narro[w]” one—namely, whether Wyeth has a duty to provide “an adequate warning about using the IV-push method” to administer Phenergan. Ante, at 8. But that ignores the antecedent question of who—the FDA or a jury in Vermont—has the authority and responsibility for determining the “adequacy” of Phenergan’s warnings. Moreover, it is unclear how a “stronger” warning could have helped respondent, see ante, at 16; after all, the physician’s assistant who treated her disregarded at least six separate warnings that are already on Phenergan’s labeling, so respondent would be hard pressed to prove that a seventh would have made a difference. 1

More to the point, the question presented by this case is not a “narrow” one, and it does not concern whether Phenergan’s label should bear a “stronger” warning. Rather, the real issue is whether a state tort jury can countermand the FDA’s considered judgment that Phenergan’s FDA-mandated warning label renders its intravenous (IV) use “safe.” Indeed, respondent’s amended complaint alleged that Phenergan is “not reasonably safe for intravenous administration,” App. 15, ¶6; respondent’s attorney told the jury that Phenergan’s label should say, “ ‘Do not use this drug intravenously,’ ” id., at 32; respondent’s expert told the jury, “I think the drug should be labeled ‘Not for IV use,’ ” id., at 59; and during his closing argument, respondent’s attorney told the jury, “Thank God we don’t rely on the FDA to … make the safe[ty] decision. You will make the decision. … The FDA doesn’t make the decision, you do,” id., at 211–212. 2

Federal law, however, does rely on the FDA to make safety determinations like the one it made he