In a close, split vote, a panel of FDA advisors have recommended the removal of a black box warning that indicates side effects of the stop-smoking drug Chantix may cause suicidal thoughts and other psychological changes.
The vote, coming after a hearing of the FDA’s Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee this week, was 10 in favor of removing the warning, five against removing the warning, and four who wanted the warning modified to include new trial results. However, the recommendation came over the objections of a number of prominent consumer groups, as well as concerns expressed by the FDA’s own reviewers about removing the suicide warning.
Chantix (varenicline) is a prescription medication introduced by Pfizer in 2006, designed to help people quit smoking. However, in 2009, the FDA required Pfizer to add a “black box” warning for Chantix, alerting doctors and patients to a potential link between use of the drug and the emergence of unusual behavior, including suicidal or homicidal thoughts.
In recent years, Pfizer has tried to get that warning removed, arguing that new studies raise questions about whether there are any psychological side effects from Chantix.
The latest review came following a Pfizer-backed study on Chantix, Zyban and the nicotine patch, known as the EAGLES clinical trial, which seemed to clear the drugs of serious psychological side effects. However, FDA reviewers questioned those results in briefing materials (PDF) provided before the meeting.
“In brief, the interview tools that were developed to optimally capture the neuropsychiatric adverse events of concern were not utilized to the extent intended to get a nuanced understanding of such adverse events,” the reviewers wrote. “In some cases, lack of information about the circumstances of events limited FDA’s ability to determine whether they were primary outcome events. Additionally, there was substantial variability among investigators in how the adverse event severity was coded and how the adverse event terms were applied, leading to variability in the number of neuropsychiatric adverse events included in the primary outcome. Finally, there was inconsistency in how suicidality cases were handled, with the Columbia Suicide Severity Rating Scale (C-SSRS) results not being reconciled with the adverse event reporting.”
The reviewers concluded that all of the above factors probably lowered the number of psychological adverse events in the study’s findings, biasing it in favor of Chantix.
Removal of the black box warning was also challenged by the Institute for Safe Medication Practices (ISMP) and Public Citizen.
“ISMP believes it will cause preventable harm to patients if the prominent warnings about suicidal behavior and violence associated with varenicline (CHANTIX) are removed from the prescribing information and medication Guide,” the ISMP said in a statement (PDF). “Instead existing warnings should be clarified and strengthened.”
The ISMP pointed out that Chantix is the “primary suspect drug” in 17,900 psychiatric adverse events that resulted in serious injuries, with 43% of those reports coming from healthcare professionals.
In testimony (PDF) submitted by Public Citizen’s Health Research Group, Dr. Sammy Almashat warned about flaws in the EAGLES clinical trials.
In a trial investigating rare adverse events, the erroneous misclassification of – or failure to detect – a relatively small number of events can have a pivotal effect on final outcomes,” Almashat’s testimony states. “A few more events in the varenicline or bupropion arms not initially detected, or slightly fewer erroneously included events in the placebo arm, could have made these increased risks significant.”
Pfizer is heralding the split vote as a victory and defended the accuracy of the EAGLES trial, which included a number of researchers paid by Pfizer and GlaxoSmithKline, the makers of Zyban.
“The totality of available scientific evidence, including the outcomes of EAGLES, supports the safety and efficacy of CHANTIX, and we look forward to the FDA’s decision on the CHANTIX labeling,” Dr. Freda Lewis-Hall, Pfizer’s Chief Medical Officer, said in a press release. “We are pleased with the Committees’ recommendation to remove the boxed warning and believe this is an important step toward updating the CHANTIX labeling to more accurately reflect its neuropsychiatric safety profile and help patients and prescribers make informed decisions about treatment options.”
Committee members who voted for removal of the black box warning said they were confident in the clinical trial’s results and cited the health benefits of consumers quitting smoking. Those against the removal warned that the trial’s results were uncertain and that removing the warning could set a troubling precedence for the FDA and the safety of future drugs.
The advisory committee’s recommendations are non-binding on the FDA. However, the agency usually weighs those recommendations heavily. But it is unclear how the FDA will weigh such a closely split vote, and some observers say that in the past the agency has considered such votes a wash and went on to make its own determination.
Chantix Health Concerns
While Chantix was originally viewed as a potential blockbuster medication to help people quit smoking, sales have been slowed by concerns about the risk of severe psychological side effects and unusually violent or aggressive behavior among users.
The public first began to become aware of the potential Chantix side effects after the 2007 shooting death of Jeffrey Carter Albrecht, former keyboardist for the folk band Edie Brickell and the New Bohemians, who allegedly was suffering a violent psychotic episode sparked by Chantix when he was shot to death by a neighbor. Albrecht thought the neighbor’s house was his girlfriend’s, and was reportedly trying to kick the door down when he was shot.
Reports of Chantix rage ballooned after that, and some studies appeared to verify that the drug caused aggression, and sometimes homicidal tendencies, in some users. It also caused suicidal tendencies as well as vivid and horrific nightmares. There were skits on Saturday Night Live and the term Chantix Nightmare became a pop culture reference.
Pfizer was hit with nearly 3,000 Chantix lawsuits after the FDA added the black box warning. All of the claims alleged that inadequate warnings were provided for users of the medication prior to July 2009. Following several years of litigation, the drug maker agreed to pay about $300 million as part of a global Chantix settlement agreement reached in 2013, which resolved the litigation and avoided cases going to trial.