We here at the DDL Blog try to stay on top of the goings on at the FDA. We’ve learned that on September 14, 2016, the FDA will hold an advisory committee meeting to review the results of a recently completed, randomized, placebo-controlled clinical trial (Evaluating Adverse Events in a Global Smoking Cessation Study or “EAGLES”), as well as findings from other studies that have assessed the neuropsychiatric effects of Chantix (varenicline). See September 14, 2016: Joint Meeting of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. The committee will consider whether data from these studies supports changing the Chantix product labeling, including potentially removing the boxed warning regarding serious neuropsychiatric events. The meeting comes approximately three years after Pfizer agreed to pay nearly $300 million to settle thousands of lawsuits filed by plaintiffs alleging that they experienced adverse neuropsychiatric effects while taking Chantix. See Pfizer 2012 Financial Report, at 107.

This chain of events seems to be a clear cut example of litigation marching ahead of the science, and at that cost, we thought we’d probe the situation a little deeper. Chantix was approved by FDA in May 2006. It was the first new smoking cessation medication to come to market in more than a decade, and was recognized at the time to be one of the most effective treatments available to help smokers break their addiction to nicotine. The following, year, however, a highly publicized incident involving a Texas musician named Carter Albrecht raised concerns about potential adverse neuropsychiatric effects of the medication. The musician, who was taking Chantix and was heavily intoxicated at the time, was shot and killed by a neighbor who thought that Mr. Albrecht was burglarizing his home. Mr. Albrecht’s girlfriend publicly blamed Mr. Albrecht’s behavior on his use of Chantix. See Girlfriend Believes Chantix Contributed to Texas Musician’s Death. The incident sparked national media attention, which led to an increasing number of anecdotal reports of patients experiencing neuropsychiatric events while taking Chantix.

Based largely on these anecdotal reports, the FDA instructed Pfizer to include warnings about potential neuropsychiatric effects in the Chantix product labeling, and, in July 2009, mandated the addition of a boxed warning. The boxed warning advised that patients being treated with Chantix should be monitored for neuropsychiatric symptoms “including changes in behavior, hostility, agitation, depressed mood, and suicide-related events, including ideation, behavior, and attempted suicide” and recommended stopping Chantix if any of these symptoms are observed. To further evaluate this issue, FDA also asked Pfizer to conduct a clinical trial—the recently completed EAGLES study—to assess the neuropsychiatric safety of Chantix.

Shortly after the boxed warning was added, thousands of lawsuits were filed by plaintiffs across the country alleging various neuropsychiatric injuries related to their Chantix use. The cases were coordinated in an MDL proceeding in the Northern District of Alabama. While the litigation was ongoing, several controlled studies, including EAGLES, were underway to answer questions raised by the anecdotal reports. See McClain v. Metabolife Int’l, Inc., 401 F.3d 1233, 1254 (11th Cir. 2005) (noting that anecdotal reports simply “raise questions” about potential adverse effects of a medication, but that those questions can be answered only with controlled studies). Defendant argued that the court should not allow the litigation to get ahead of this evolving science, but the court disagreed ruling that there was no need to suddenly halt the judicial process because of worries by the defendant that science was lagging behind the Chantix lawsuit litigation, noting that some studies may not be completed until 2017. See Order, Case No. 2:10-cv-01463, Doc. 232, Oct. 16, 2012, at 2-3. Not long after the ruling, Pfizer settled the majority of lawsuits, and the MDL was terminated in late 2014.

Two years after the litigation ended, Pfizer announced the results of the EAGLES study. According to the press release, EAGLES was the largest clinical trial of approved smoking cessation medicines—including 8,144 adult smokers—and was designed to compare the neuropsychiatric safety of Chantix and bupropion with placebo and nicotine patch. The authors concluded that the trial did not show a significant increase in the incidence of serious neuropsychiatric adverse events with Chantix compared to placebo and nicotine patch and, just as importantly, showed that patients taking Chantix had significantly higher continuous abstinence rates than patients treated with bupropion, nicotine patch, or placebo. These results were consistent with other controlled studies—including meta-analyses of clinical trials and large-scale observational studies involving tens of thousands of patients—which did not find evidence of an association between Chantix use and serious neuropsychiatric events.

While all of these studies have their limitations, the totality of this controlled data stands in stark contrast to the anecdotal reports that led to the addition of the boxed warning and served as the basis for thousands of lawsuits. Indeed, in light of this new data, leading researchers and clinicians have called for removal of the boxed warning from the Chantix label. See e.g., Davies and Thomas, The FDA and Varenicline: Should Risk Communication Be Improved?, Addiction 2016, doi: 10.1111/add.13592; Niaura, Ray. Varenicline and Suicide: Reconsidered and Reconciled, Nicotine & Tobacco Research 2016, doi:10.1093/ntr/ntv247. The FDA advisory committee will review the study results next week, and FDA is expected to make a final decision by the end of the year.

While we await the outcome of the advisory committee meeting and FDA’s ultimate decision on the labeling, it is worth taking a moment to reflect on the Chantix litigation moving forward while controlled studies were underway to fully evaluate the scientific question at hand. The court was certainly correct in recognizing that waiting for studies to be completed would have delayed resolution of cases that, in some instances, had been pending for years. But, as the Supreme Court explained in Daubert v. Merrell Dow Pharmaceuticals, Inc., 509 U.S. 579, 597 (1993), the goal of “reaching a quick, final, and binding legal judgment” on matters that are “often of great consequence” is not advanced by accepting hypotheses and conjectures in the place of reliable scientific evidence. That is why both the Sixth and Seventh Circuit have emphasized that the law must lag science, not lead it. See Rosen v. Ciba-Geigy Corp., 78 F.3d 316, 319 (7th Cir. 1996); Tamraz v. Lincoln Elec. Co., 620 F.3d 665, 677 (6th Cir. 2010).

The Chantix litigation ignored this admonition, and instead went forward based largely on anecdotal reports. The parties expended precious legal and financial resources, and the litigation result was at odds with subsequent evidence from the most reliable scientific studies. Worse still, the public perception of Chantix was adversely affected, and it is likely that use of a highly effective smoking cessation medication declined as a result. Considering that cigarette smoking is a factor in more than 480,000 deaths each year in the United States alone, that is certainly not a desirable outcome from a public health perspective. In a sense, this is all water under the bridge. We hope, however, that courts will look to the Chantix example, be reminded of the potential consequences of letting a litigation get ahead of the science, and avoid similar results in the future.