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.

SHB Products Liability Practice Recognized

Just a quick note that your humble blogger;s firm, Shook Hardy, was recently recognized by Law360 as having the largest product liability practices in the country.  

This practice area is of course a key part of the firm's identity, and the size of the practice reflects the trust our valued clients place in our ability to help them navigate individual, collective, class action, and mass tort product liability claims, on durable products, pharmaceuticals, consumer products, chemicals, medical devices and more.

FDA Seeks Comment on "Natural" Labels

Readers will recall our many posts about the "all natural" litigation and the spate of cases plaintiff firms have brought challenging such label claims on food, beverage, and other products.  Many of these cases have raised the issue of FDA guidance on the question, in contexts such as primary jurisdiction, agency deference, and preemption.

At least four citizen's petitions are currently in play, asking the agency to define or to prohibit the use of the term "natural" in food labels. The FDA continues to analyze the issue, and recently repeated its call for input on the use of the term “natural” in the labeling of food products, including foods that are genetically engineered. 

FDA also noted that some federal courts, as a result of litigation between private parties, have requested administrative determinations from FDA regarding whether food products containing ingredients produced using genetic engineering or foods containing high fructose corn syrup may be labeled as “natural.”  But it has so far declined several judges' requests to determine whether "natural" was a permissible labeling term in the context of those cases.

It is a fair question whether this step by the FDA means courts handling "natural" litigation should stay the suits pending FDA action.  Of course, under the primary jurisdiction doctrine, a court may stay proceedings or dismiss a complaint pending the resolution of an issue within the special competence of an administrative agency.

 

Stay in Amarin Extended

The court recently extended its stay of the proceedings in Amarin Pharma Inc.'s suit against the FDA challenging threatened agency action concerning the alleged promotion of drugs for off-label uses See Amarin Pharma, Inc. v. FDA, No. 15-cv-3588 (S.D.N.Y.,  order 10/30/15).  The stay to December 17th is reportedly to give the parties more time to engage in settlement discussions. This one remains a case to watch for those in the pharma practice area.

First Amendment doctrine, and its relationship to the FDCA, has changed dramatically since the FDCA and many of its implementing regulations were adopted.  And one may question whether the FDA has kept up with these changes.

Earlier this Summer, the district court granted a motion for preliminary injunction in favor of Amarin, reaching the merits of Amarin’s First Amendment claims.  The case concerned Vascepa , an omega-3 fatty acid obtained from fish oil. Vascepa was approved to reduce triglyceride levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia. Amarin was seeking a new indication pursuant to a Special Protocol Assessment (“SPA”) agreement with FDA, for patients with “persistently high” triglycerides (≥ 200 and ≤ 500 mg/dL).  While Amarin believed it had satisfied all of FDA’s requirements to obtain the new approval, FDA disagreed and rescinded the SPA. FDA went further to warn Amarin that any effort by Amarin to market Vascepa for the proposed supplemental use could constitute "misbranding" under the Federal Food, Drug, and Cosmetic Act.

Amarin filed a civil complaint against FDA, claiming that this threat of prosecution for misbranding had a chilling effect on its commercial speech.  Amarin proposed to engage in truthful, non-misleading speech about Vascepa directly with healthcare professionals, such as disseminating study results and reprints of peer-reviewed scientific publications. The company also proposed to make "contemporaneous disclosures” to ensure that the messages were not at all misleading.

The court noted that in contrast to FDA’s long-standing position that off-label promotion of drug products can constitute criminal misbranding, off-label use is not illegal and may even be the standard of care in some circumstances.  The company relied on the Second Circuit's First Amendment decision in Caronia, but the FDA argued Caronia was a narrow, fact-bound decision, turning on particular jury instructions given at the sales rep's  trial. At the least, it ought to be construed in harmony with FDA regulations distingusihing between directed off-label speech and requests by the practicioner for information. The court rejected FDA’s interpretation, finding the FDA may not bring such an action based on truthful promotional speech alone. “Where the speech at issue consists of truthful and non-misleading speech promoting the off-label use of an FDA-approved drug, such speech, under Caronia, cannot be the act upon which an action for misbranding is based.”

With this rule in mind, the court evaluated and ruled on each of Amarin’s proposed off-label statements concerning Vascepa along with FDA’s responses.  This included the “agreed-upon statements and disclosures,” which were found to be “based on current information, truthful and non-misleading.”  And then the additional “contested disclosures” (such as “not-approved for” use language). The court eventually crafted a revised hybrid disclosure on that.  The court also said the proposed cardiovascular disease claim, as revised during litigation, given its qualified phrasing and its acceptance in other contexts by the FDA, was presently truthful and non-misleading.

 

The court offered a few important caveats: a manufacturer that leaves its sales force at liberty to converse unscripted with doctors about off-label use of an approved drug invites a misbranding action if false or misleading (e.g., one-sided or incomplete) representations result.

And the dynamic nature of science and medicine is such that knowledge is ever-advancing. A statement that is fair and balanced today may become incomplete in the future as new studies are done or new data is acquired.

Again, one to keep an eye on.
 

 

SHB Recognized in Best Lawyers Firm Rankings

 

U.S. News & World Report and Best Lawyers have named Shook, Hardy & Bacon to their annual list of Best Law Firms.

Shook received two national Tier 1 rankings, for Commercial Litigation and Mass Tort Litigation/Class Action – Defendants (it is surely a coincidence that those are the primary areas of your humble blogger), and 12 total national rankings. 

In addition, seven of Shook’s offices received 21 Tier 1 metropolitan rankings and 42 total metropolitan rankings in the three-tiered list. Shook’s Metropolitan Tier 1 rankings include the office of your author, Philly, for FDA Law, and Mass Tort Litigation / Class Actions - Defendants.

The complete rankings appear in U.S. News & World Report’s  Best Law Firms report.

 

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