WYETH v. LEVINE: FDA Approval of Drug Label Does Not Preempt State Law Failure to Warn Claims
March, 2009
by Edward M. Kay and Melinda S. Kollross
The United States Supreme Court affirms a Vermont jury verdict against Wyeth, manufacturer of the drug Phenergan, holding that FDA approval of Wyeth's labeling of Phenergan does not preempt state-law failure to warn claims brought by a musician who developed gangrene and had to have her forearm amputated after receiving an improperly administered injection of Phenergan by the "IV-push" method. Wyeth v. Levine, --- U.S. ---, 129 S. Ct. 1187 (Mar. 4, 2009).
FACTS
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.
On April 7, 2000, Levine visited a 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 sued 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, 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.
Wyeth moved for summary judgment, arguing that Levine's failure-to-warn claims were preempted by federal law. The court found no merit in either Wyeth's field preemption argument, which it later abandoned, or its conflict preemption argument. With respect to Wyeth's contention that there was an "actual conflict between a specific FDA order," and Levine's failure-to-warn action, the court found no evidence that Wyeth had "earnestly attempted" to strengthen the intra-arterial injection warning or that the FDA had "specifically disallowed" stronger language.
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. By contrast, even a careful and experienced clinician using the IV-push method will occasionally expose an artery to Phenergan. 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 functioning satisfactorily," the labeling did not contain a specific warning about the risks of IV-push administration.
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. 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.
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."
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. 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.
The trial court denied Wyeth's motion for judgment as a matter of law, rejecting Wyeth's preemption 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.
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." Dissenting 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 U.S. Supreme Court granted Wyeth's petition for certiorari based upon the importance of the preemption issue and because the FDA has changed its position on state tort law and now endorses the views expressed in Chief Justice Reiber's dissent. The question presented by the petition was 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."
ANALYSIS
The Majority Opinion
The majority opinion authored by Justice Stevens (with Justices Kennedy, Souter, Ginsburg, and Breyer, joining) rejected both preemption arguments made by Wyeth. Justice Thomas concurred in the judgment only.
1. No Impossibility of Compliance with Both State and Federal Law
Wyeth first argued that Levine's state-law claims are preempted because it is impossible for it to comply with both the state-law duties underlying those claims and its federal labeling duties. The Court disagreed. The FDA's pre-market approval of a new drug application includes the approval of the exact text in the proposed label. Generally speaking, a manufacturer may only change a drug label after the FDA approves a supplemental application. However, the FDA's "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.
Per 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. According to the Court, 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 were based on a fundamental misunderstanding that the FDA, rather than the manufacturer, bears primary responsibility for drug labeling. That is incorrect. 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.
Wyeth accordingly failed to demonstrate that it was impossible for it to comply with both federal and state requirements.
2. No Obstruction of Purposes/Objectives of Federal Drug Labeling Regulation
Wyeth also argued 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." 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 Court found no merit in this argument, which it characterized as relying on an untenable interpretation of congressional intent and an overbroad view of an agency's power to preempt state law. The 70-year history of the FDCA shows that Congress did not intend to preempt state-law failure-to-warn actions. There is no express preemption provision for prescription drugs - despite Congress' 1976 enactment of such a provision for medical devices. Wyeth's argument that the FDA must be presumed to have established a specific labeling standard that leaves no room for different state-law judgments, is based not on a 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 as the expert federal agency responsible for evaluating and regulating drugs. Although an agency regulation with the force of law can preempt conflicting state requirements, this case does not involve such a 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 preempt state law directly, the weight the Court accords the agency's explanation of state law's impact on the federal scheme depends on its thoroughness, consistency, and persuasiveness. 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 preemption 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.
Wyeth argued that this case presents a conflict between state and federal law analogous to that in Geier v. American Honda Motor Co., 529 U.S. 861, 120 S. Ct. 1913, 146 L.Ed.2d 914 (2000). Geier 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. 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. 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."
The majority distinguished Geier as follows. 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, the Court determined that state tort suits presented an obstacle to the federal scheme. After conducting its own preemption analysis, the Geier court considered the agency's explanation of how state law interfered with its regulation, regarding it as further support for the Court's independent conclusion that the plaintiff's tort claim obstructed the federal regime. Here, by contrast, the Court has no occasion to consider the preemptive effect of a specific agency regulation bearing the force of law and gives no deference to the FDA's newfound opinion, expressed in its 2006 preamble, that state law "frustrate[s] the agency's implementation of its statutory mandate.
Thus, the court was not persuaded that failure-to-warn claims like Levine's obstruct the federal regulation of drug labeling. Although recognizing that some state-law claims might well frustrate the achievement of congressional objectives, "this is not such a case."
The Dissent
The lengthy dissent (authored by Justice Alito with Chief Justice Roberts and Justice Scalia joining) begins by pronouncing that "[t]his case illustrates that tragic facts make bad law" and goes on to accuse the majority of committing both factual and legal errors in attempting to evade Geier.
While 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 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 Levine as the physician's assistant who treated her disregarded at least six separate warnings that are already on Phenergan's labeling, so Levine would be hard pressed to prove that a seventh would have made a difference. Indeed, Levine conceded below that Wyeth did propose an adequate warning of Phenergan's risks -- which the FDA rejected.
In the dissent's view, the question presented by this case is not a "narrow" one, and it does not concern whether Phenergan 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." Levine's amended complaint alleged that Phenergan is "not reasonably safe for intravenous administration;" her attorney told the jury that Phenergan's label should say, "[d]o not use this drug intravenously;" Levine's expert told the jury, "I think the drug should be labeled ‘Not for IV use"; and during his closing argument, Levine'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."
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 Levine's healthcare providers ignored Phenergan's labeling may make this an ideal medical-malpractice case. 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 longstanding conflict preemption jurisprudence. To the extent that "[t]he purpose of Congress is the ultimate touchstone in every pre-emption case," Congress made its "purpose" plain in authorizing the FDA -- not state tort juries -- to determine when and under what circumstances a drug is "safe."
Where the FDA determines, in accordance with its statutory mandate, that a drug is on balance "safe," the Court's conflict preemption cases prohibit any State from countermanding that determination. Thus, as the Court itself recognizes, it is irrelevant in conflict preemption cases whether Congress "enacted an express pre-emption provision at some point during the FDCA's 70-year history." Rather, the ordinary principles of conflict pre-emption turn solely on whether a State has upset the regulatory balance struck by the federal agency.
A faithful application of this Court's conflict preemption cases compels the conclusion that the FDA's 40-year-long effort to regulate the safety and efficacy of Phenergan preempts Levine's tort suit. Indeed, that result follows directly from Geier. 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, Levine 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 Geier held that States may not compel the latter, so, too, are States precluded from compelling the former. If anything, a finding of preemption 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.
In attempting to evade Geier's'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 preemption jurisprudence and the broader workability of the federal drug-labeling regime.
When the FDA mandated that Phenergan's label read, "INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY," and required Wyeth to warn that "[u]nder no circumstances should Phenergan Injection be given by intra-arterial injection," the agency could reasonably assume that medical professionals would take care not to inject Phenergan intra-arterially. Unfortunately, the physician's assistant who treated Levine 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. Given the "balance" that the FDA struck between the costs and benefits of administering Phenergan via IV push, Geier compels the preemption of tort suits (like this one) that would upset that balance. The contrary conclusion requires turning yesterday's dissent into today's majority opinion. Geir does not countenance the use of state tort suits to second-guess the FDA's labeling decisions.
Learning Point:
As the dissent explains, Wyeth has potentially far-reaching consequences. Juries are ill-equipped to perform the FDA's cost-benefit-balancing function. They 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 because "the patients who reaped those benefits are not represented in court." Indeed, patients like Levine are the only ones whom tort juries ever see, and for someone like Levine -- who has already suffered a tragic accident -- Phenergan's risks are no longer a matter of probabilities and potentialities. Levine sought treatment for a migraine headache and ended up losing her arm. The cost-benefit analysis seems almost absurd on these facts.
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. 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 FDA told Wyeth that Phenergan's label renders its use "safe." But the State of Vermont, through its tort law, said: "[n]ot so."
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