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:
- issuance of the FDA’s February 2014 assessment of pancreatic safety in the New England Journal of Medicine;
- 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.