Important Preemption Decision

Last week the Sixth Circuit issued a significant opinion in Yates v. Ortho-McNeil-Janssen Pharmaceuticals Inc., No. 15-3104, 2015 WL 8538119 (6th Cir. Dec. 11, 2015), upholding impossibility preemption of design defect claims against brand-name drug manufacturers.

Yates alleged she experienced a stroke while using the ORTHO EVRA® birth control patch, and sued the manufacturers of the patch.  Yates alleged five causes of action against defendants: (1) strict liability in tort—failure to warn; (2) strict liability in tort—manufacturing defect; (3) negligence; (4) breach of implied warranty; and (5) breach of express warranty.  The district court granted summary judgment as to Yates's failure to warn claim. 2014 WL 1369466 (N.D.Ohio Apr. 7, 2014). Thereafter, the district court granted summary judgment as to Yates's remaining claims and entered final judgment dismissing the case. 76 F.Supp.3d 680 (N.D.Ohio 2015). Yates timely appealed the district court's dismissal of all five of her causes of action.  The Sixth Circuit affirmed.

Failure to warn.

To establish a claim against a drug manufacturer for failure to warn under New York law, a plaintiff must demonstrate that the warning was inadequate and that the failure to adequately warn of the dangers of the drug was a proximate cause of his or her injuries. Krasnopolsky v. Warner–Lambert Co., 799 F.Supp. 1342, 1346 (E.D.N.Y.1992) (quoting Glucksman v. Halsey Drug Co., 160 A.D.2d 305, 553 N.Y.S.2d 724, 726 (1990)). The manufacturer's duty to warn extends to the treating physician, and not directly to the patient. Glucksman, 553 N.Y.S.2d at 726. It has long been the law in New York that prescription medicine warnings are adequate when information regarding the precise malady incurred was communicated in the prescribing information. Alston v. Caraco Pharm., Inc., 670 F.Supp.2d 279, 284 (S.D.N.Y.2009) (quoting Wolfgruber v. Upjohn Co., 72 A.D.2d 59, 423 N.Y.S.2d 95, 96–97 (1979)).  In this case, the “precise malady incurred” was a stroke, and the risk of stroke was communicated in the prescribing information. Defendants mentioned the risk of stroke several times in the package inserts. The label specifically stated there was an increased risk of several serious conditions including stroke. Thus, there was no genuine issue of material fact for a jury on the issue of whether defendants failed to adequately warn Yates, through her prescribing medical provider, of the risk of stroke associated with the product. 

Preemption

Readers know that state law claims can be preempted expressly in a federal statute or regulation, or impliedly, where congressional intent to preempt state law is inferred.  Congress may intend federal law to occupy the field,  or state law may conflict with a federal statute.  Conflict preemption exists where it is impossible for a private party to comply with both state and federal law, or when the state law is an obstacle to the accomplishment and execution of the full purposes and objectives of Congress. A court needs to ascertain whether federal law expressly prohibits the defendant from complying with state law, or there is sufficient, sometimes termed clear evidence, that the FDA would have prohibited the defendant from taking the necessary steps under state law.

The next issue in this case was whether defendants could have complied with their alleged duty under New York law to have designed a safer drug, given FDA approvals of the design. The court reviewed Supreme Court guidance in three recent opinions on federal preemption in pharmaceutical products liability suits: LevineMensing, and  Bartlett, in which plaintiff argued that the manufacturers could comply with both federal and state law by choosing not to make the drug at all. The Supreme Court reversed, holding that impossibility preemption barred the plaintiff's claims. As for drug redesign, the Court found that was impossible for two reasons: (1) the FDCA requires generic drugs to have the same active ingredients, route of administration, dosage form, strength, and labeling as the brand-name drug on which it is based; and thus the drug was “chemically incapable” of being redesigned. 

New York law provides that a product is defectively designed if  the product, as designed, was not reasonably safe because there was a substantial likelihood of harm and it was feasible to design the product in a safer manner. Doomes v. Best Transit Corp., 17 N.Y.3d 594, 608, 935 N.Y.S.2d 268, 958 N.E.2d 1183 (2011). New York follows a “risk-utility” approach to determining whether a product is not reasonably safe, which calls for consideration of several factors: (1) the utility of the product to the public as a whole and to the individual user; (2) the nature of the product—that is, the likelihood that it will cause injury; (3) the availability of a safer design; (4) the potential for designing and manufacturing the product so that it is safer but remains functional and reasonably priced; (5) the ability of the plaintiff to have avoided injury by careful use of the product; (6) the degree of awareness of the potential danger of the product which reasonably can be attributed to the plaintiff; and (7) the manufacturer's ability to spread any cost related to improving the safety of the design.

The court concluded that Yates's post-approval design defect claim was clearly preempted by federal law. FDA regulations provide that once a drug, whether generic or brand-name, is approved, the manufacturer is prohibited from making any major changes to the qualitative or quantitative formulation of the drug product, including inactive ingredients, or in the specifications provided in the approved application. 21 C.F.R. § 314.70(b)(2)(i). Moderate changes must be reported to the FDA at least 30 days prior to distribution of the drug product made using the change. Id. § 314.70(c).  Based on the plain meaning of the regulation,  defendants could not have altered the dosage of estrogen without submission to the FDA and the agency's approval prior to distribution of the product made using the change. Changing the dosage level of the active ingredient of ORTHO EVRA® constituted a “major change."  Quite simply, federal law prohibited defendants from decreasing the dosage of estrogen post-approval.

Readers should note the Sixth Circuit going out of its way to state that the FDA pre-approval requirement for design changes applied to all prescription drugs, with a reference to “branded or generic” drugs.  The court also rejected plaintiff's contention that there is no federal law that would have prohibited defendants from designing a different drug in the first instance, as opposed to altering an approved design. Yates's argument regarding defendants' pre-approval duty was too attenuated. To imagine such a pre-approval duty exists, a court would have to speculate that had defendants designed ORTHO EVRA® differently, the FDA would have approved the alternate design. Next, the court would have to assume that Yates would have selected this method of birth control from all the choices, and in the face of whatever warnings were on the label. Further the court would have to suppose that this alternate design would not have caused Yates to suffer a stroke. "This is several steps too far".  The argument was contingent upon whether the FDA would approve the alternate design in the first place, and this “never start selling” claim was also preempted because it mirrored the “stop selling” claim rejected in Bartlett.   

The Sixth Circuit affirmed the district court’s grant of summary judgment on all claims ( the others on fact-specific issues we won't get into here).

 

Preemption Found in Another Drug MDL

Implied preemption makes complete sense when it is evident that the FDA would not have permitted label changes that plaintiffs in private litigation say are required by state law. The latest example comes in the MDL litigation accusing various drug companies of failing to warn patients of alleged pancreas problems from Type 2 diabetes drugs; the California federal court recognized the FDA would have rejected the types of warnings plaintiffs demanded. See In re Incretin-Based Therapies Prods. Liab. Litig., No. 3:13-md-2452, 2015 WL 6912689 (S.D. Cal. Nov. 9, 2015).  The court concluded that defendants’ preemption defense was not only viable, but also dispositive of plaintiffs’ failure to warn claims. The record established that the FDA had specifically considered pancreatic cancer risk, commented publicly on the adequacy of drug labeling, and maintained its position that scientific evidence of a causal association between incretin mimetics and pancreatic cancer was indeterminate. Because an indeterminate causal association falls well below the federal regulatory standards required for labeling changes, clear evidence existed that the FDA would have rejected a reference to pancreatic cancer in product labeling.

This litigation involves claims that defendants failed to warn that four prescription drugs used to treat type 2 diabetes cause or increase the risk of pancreatic cancer. Plaintiffs are individuals with type 2 diabetes who were prescribed and consumed one or more of the prescription drugs in this group. The court first discussed Levine v. Wyeth, and its comment  that “absent clear evidence that the FDA would not have approved a change to Phenergan’s label” the Supreme Court would “not conclude that it was impossible for Wyeth to comply with both federal and state requirements.”  The court read Levine as providing the relevant conflict preemption standard (although there is an argument that the "clear evidence" notion arises from the unique procedural posture of the case, not as an evidentiary standard applicable in all preemption cases), but the case did not define what constitutes clear evidence. As such, application of the standard is necessarily fact-specific, said the court.  See Koho v. Forest Labs., Inc., 17 F. Supp. 3d 1109, 1118 (W.D. Wash. 2014) (“[T]he clear evidence standard is a fact based inquiry that depends on the express type of warning at issue and the particular facts of each case.”); Dobbs, 797 F. Supp. 2d at 1270 (explaining that ascertaining conflict preemption is “necessarily fact specific”).

Defendants cited multiple instances where the FDA had taken a position regarding pancreatic safety, including: (1) issuance of the FDA’s February 2014 assessment of pancreatic safety in the New England Journal of Medicine; (2) the FDA’s rejection of a citizen petition requesting the withdrawal of Victoza; (3) the FDA’s September 2014 conclusion that a causal association between incretin mimetics and pancreatic cancer is indeterminate; and (4) the subsequent approval of other incretin-based therapies without any reference to pancreatic cancer in the product labeling. Defendants argued that each instance represents the FDA’s opinion regarding pancreatic safety and its conclusion that current data does not support a pancreatic cancer label reference.
Plaintiffs argued that the evidence established the FDA has been aware of a pancreatic cancer safety "signal" for several years, and actively investigated the existence of a possible causal relationship between the drugs and pancreatic cancer.

It is worth noting, particularly, that in 2014, the FDA formally responded to a 2012 Victoza citizen petition. In doing so, the FDA again rejected adverse event data as evidence of a causal association between Victoza and pancreatic cancer. The FDA also concluded that any causal association between exposure to Victoza and pancreatic cancer is indeterminate at this time. Based on these conclusions, the FDA made no labeling change recommendations specific to pancreatic cancer. In September 2014, the FDA again reviewed pancreatic safety concerns in considering the safety of a higher dose of Victoza, marketed for weight loss. As part of a briefing document, the FDA acknowledged that pancreatic cancer had been “hypothesized but not proven” as a risk associated with incretin mimetics, and that “animal observations and clinical trial data reviewed by the FDA to date have not supported a causal association.” The FDA also reiterated its earlier conclusion that studies were “inconclusive” as to a causal association between incretin mimetics and pancreatic cancer.


These facts established that  the FDA has considered pancreatic cancer risk, the specific issue that plaintiffs allege defendants should have warned of or otherwise referenced in their product labeling. In addition to considering the specific issue raised by plaintiffs, the FDA had also  consistently concluded that a causal association between the drugs and pancreatic cancer was indeterminate. This falls below the science-based regulatory standards that govern what
must be included in product labeling. See 21 C.F.R. § 201.57(c)(6) (requiring reasonable evidence of a causal association); id. § 201.57(c)(7) (requiring sufficient basis to believe there is a causal association).  The FDA had also not required any of the defendants to add a pancreatic cancer warning, or required the inclusion of a warning in newly approved incretin-based therapies. That FDA inaction was "highly persuasive given the FDA’s comprehensive review of pancreatic safety and ability to mandate a labeling change if it concluded the regulatory standards were satisfied.

The court also rejected the standard plaintiff position that a defendant cannot establish preemption absent express rejection by the agency of a proposed labeling change it made. "Plaintiffs overstate the burden imposed by Levine."  While a CBE rejection would readily meet the clear evidence standard, it is not the only means by which a manufacturer can establish conflict preemption. The Supreme Court stated a manufacturer must demonstrate the FDA would have rejected a label change, not that the FDA did reject the labeling change.  Also, plaintiffs cannot establish the FDA’s substantial review of pancreatic safety in this posture was materially different from what the FDA would have done in response to a CBE, had one been submitted.  In fact, instead of reviewing data submitted by an individual manufacturer, the FDA considered a variety of data sources related to the entire class of incretin mimetics. Thus, "the facts of this matter are different in form only."

Notably, responding to citizen petitions is just as much within the FDA’s regulatory authority. The Victoza citizen petition rejection was written by the Director of the FDA’s Center for Drug Evaluation and Research, and constitutes the FDA’s official response to the request to withdraw Victoza from the market. Other courts to address conflict preemption have considered citizen petition responses as indicative of whether the FDA would reject a proposed labeling change. See, e.g., Mason, 596 F.3d at 395 (considering citizen petitions in clear evidence analysis); Koho, 17 F. Supp. 3d at 1117 (same); Dorsett, 699 F. Supp. 2d at 1157 (same).

The existence of an alleged "open safety signal" and the FDA’s ongoing review of pancreatic safety did not undermine the FDA’s previously articulated conclusions. The existence of a safety signal is not, without more, indicative of a causal association. FDA Guidance for Industry recognizes that signal generation is only the first step in pharmacovigilance and merely indicates the need for further investigation before any conclusions are drawn. Further investigation may or may not lead to the conclusion that the product caused the event. The existence of a hypothetical causal association is insufficient to satisfy the CBE standard. See Robinson, 615 F.3d at 869 (noting a label describing every serious disease that might or even arguably be caused by a drug would result in “information overload” making “label warnings worthless to consumers”); Mason, 596 F.3d at 392 (“While it is important for a manufacturer to warn of potential side effects, it is equally important that it not over-warn because over-warning can deter potentially beneficial uses of the drug by making it seem riskier than warranted and can dilute the effectiveness of valid warnings.”).

Thus, the FDA’s ongoing review of pancreatic safety, indeed any drug, is more indicative of the nature of drug surveillance than of the existence of a causal association. FDA continuously monitors every medication for new or evolving information as long as a drug is on the market. The potential for the FDA to reach a different conclusion in the future in light of new, future, scientific evidence or developments does not preclude a finding of preemption now. 

Sound analysis.

Administration Releases Memorandum On Preemption

The Democratic assault on the preemption doctrine has taken its next step with the release last week by the White House of a Presidential memorandum which restricts federal agency statements on preemption and directs those agencies to review preemption pronouncements made in the past decade under the Bush Administration.


Ironically, the directive ostensibly rests on the grounds of States rights: noting State law and national law often operate concurrently to provide independent safeguards for the public, and that throughout our history, State and local governments have frequently protected health, safety, and the environment more aggressively than has the national government.  “An understanding of the important role of State governments in our Federal system is reflected in longstanding practices by executive departments and agencies, which have shown respect for the traditional prerogatives of the States,” argues the memorandum.

The memorandum comes two months after the Supreme Court’s ruling on preemption in the context of drugs in Wyeth v. Levine, and concurrently with democratic efforts in Congress to overturn Medtronic v. Riegel in the medical device context.


The memorandum sets for the general policy of the new Administration that preemption of State law by executive departments and agencies should be undertaken only with full consideration of the “legitimate prerogatives of the States and with a sufficient legal basis for preemption.” Specifically, it orders that agencies should not include in regulatory preambles statements that the department intends to preempt State law through the regulation except where preemption provisions are also included in the codified regulation. Also, agencies should not include preemption provisions in codified regulations except where such provisions would be justified under the (presumably re-assessed) legal principles governing preemption.

Finally, departments should review regulations issued within the past 10 years that contain statements in regulatory preambles or codified provisions intended by the agency to preempt State law, in order to decide whether such statements or provisions are justified under (again, re-interpreted) applicable legal principles governing preemption. Where the head of a department or agency determines that a regulatory statement of preemption or codified regulatory provision cannot be so justified, the head of that department or agency should initiate appropriate action, which may include amendment of the relevant regulation.


The memorandum is a political statement as much as a legal document, and is consistent with President’s Obama’s comments while a candidate. As it eventually evolves into specific agency statements and policy, it promises to create a hodge-podge regulatory quilt, under which business will struggle with product safety decisions which will comply with federal, national standards, be upheld in some state jurisdictions, but nevertheless be subject to review by lay juries in others.

 

Preemption Decision in Wake of Levine

Much attention has been focused on what aspects of the preemption doctrine were restricted by the U.S. Supreme Court's recent decision in Wyeth v. Levine. A recent decision holds that claims that a drug was “unreasonably dangerous” and that no warning would have been adequate, are preempted. Longs v. Wyeth, 2009 WL 754524 (N.D. Ohio, 3/20/09). Plaintiff sued Wyeth and asserted strict liability and negligence claims concerning the diet drug Redux. Wyeth argued that plaintiff's claim that Redux was an unreasonably dangerous drug, for which no warning would have been adequate, directly conflicts with the FDA's authority to determine which drugs are sufficiently safe and effective to be marketed. The court affirmed its grant of summary judgment, finding that the strict liability and negligence claims related to pre-FDA approval were preempted by federal law, and that the claims that were not preempted failed on their merits.

The Court rejected plaintiff’s claim that Wyeth v. Levine called for reconsideration. In Wyeth, the Court considered the narrow issue of whether the FDA's drug labeling judgments preempt certain state law product liability claims premised on the theory that different labeling judgments were necessary to make drugs reasonably safe for use. The court noted that the Supreme Court emphasized that it was Congress' intent to have state law complement federal drug regulation because manufacturers may have superior access to information about their drugs, especially in the postmarketing phase as new risks emerge.

The instant case was distinguishable from Wyeth v. Levine because it did not involve a failure to warn claim, and because Levine arose out of the actions of the manufacturer post-FDA approval. A post-FDA approval duty is distinguishable from a manufacturer's duty prior to approval by the FDA, a circumstance that the Supreme Court did not explicitly address. Whatever Wyeth v. Levine may stand for regarding whether post-FDA approval claims are preempted, it does not purport to hold anything for pre-FDA approval claims, held the court.
 

Supreme Court Decides Levine v. Wyeth

The Supreme Court has issued its decision in the much-anticipated Levine preemption case.

Readers of MassTortDefense will recall that Wyeth manufactures the anti-nausea drug Phenergan. After a clinician injected plaintiff 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 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 musician. 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 FDA. The Vermont Supreme Court affirmed.


Today, the Supreme Court affirmed, 6-3, J. Stevens writing for the majority, holding that 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. 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 was 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, said the Court, as there was no good evidence that the FDA would ultimately have rejected such a labeling change. Wyeth’s reading of the CBE regulation and its 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.

The Court also rejected 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, because it relies on an overbroad view of an agency’s power to preempt state law. The history of the FDCA shows that Congress did not intend to pre-empt state law failure to warn actions, said the majority. The preamble to the 2006 FDA regulation declaring that state law failure to warn claims threaten the FDA’s statutorily prescribed is merely an agency’s assertion that state law is an obstacle to achieving its statutory objectives. 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. Skidmore v. Swift & Co., 323 U. S. 134. Under this standard, the FDA’s 2006 preamble did not merit much deference, said the Court. It was limited 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.

Quick reactions: The Court was able to get around some facts that made the case appear strong for Wyeth, noting the findings below that that a stronger warning would have made a factual difference (getting around the issues of possible medical malpractice), and that this was indeed a failure to warn and not a duty to contraindicate case. Second, it seems that congressional intent is the touchstone of not only express preemption, but also implied preemption. Third, the presumption against preemption, which some argued really applies only in express cases, also applies to implied preemption cases. Fourth, the Court recognized that some state-law claims might well frustrate the achievement of congressional objectives, but “this is not the case." Defendants will have to carefully explore that opening, develop a robust regulatory record, and see where that may take them.
 

Wyeth Files Reply Brief in Levine Preemption Case

Wyeth has filed its reply brief in the Levine case.

The reply stresses that this case is not a conventional failure to warn case, but an alleged failure to contraindicate case. Thus, plaintiff is directly challenging the FDA’s balancing of the risks and benefits of a labeled, warned-about indication. State law cannot obstruct federal regulation of pharmaceuticals by seeking to impose a different outcome to this balancing process than the one reached by the FDA.

When the FDA did address the risks and benefits of the particular method of drug delivery at issue, the agency told the defendant to use labeling which the state court jury held was inadequate under state law. 

Wyeth also stressed what the case was not: no allegations of concealment from the agency or of failure to make a label change in response to any new risk information. The FDA had all the important information, and made a regulatory decision, which plaintiffs told the jury they could, and should, simply reject.

Note also an interesting discussion of CBE issues, with the arguments that this was not a CBE case, especially where methods of use are at issue, and that the FDA's interpretation of the CBE is entitled to Auer- level deference. (As noted in a post by MassTortDefense, the CBE regulation was always intended to apply solely to new, emerging, significant information.) Finally the plaintiff’s argument that the defendant must prove that a CBE submission would have been unsuccessful before qualifying for preemption would create the untenable and frequently dis-approved situation in which juries are deciding hypothetical situations full of what-ifs.