In advance of a US Food and Drug Administration expert panel meeting on Wednesday, agency reviewers found that the drug may not have properly noted all adverse events in a trial that Pfizer was ordered to undertake.
In briefing documents released today on the FDA web site, agency staffers wrote that “the trial was designed in a well-intentioned attempt to capture somewhat ill-defined and complex neuropsychiatric phenomena. However, many problems in the implementation were apparent upon review of the collected data.”
Among the problems cited by the FDA: trial investigators did not always make appropriate use of a side effect index; investigators inconsistently assessed the severity of side effects; there was inconsistent handling of cases involving suicidal behaviors; and a lack of information about the circumstances surrounding side effects. In some cases, investigators downgraded side effects by coding anger as irritability, according to the FDA review.
Pfizer has been angling for two years to alter the warnings on Chantix, and, more specifically, remove a so-called Black Box warning — the most serious type of health alert — on its product labeling. The warning refers to side effects such as psychiatric risks, aggressiveness, suicidal thoughts, and hostility.
An earlier attempt failed. In 2014, the drug maker cited a meta-analysis of five studies and four observational studies showing its drug did not show an increase in suicidal activity. An FDA advisory panel, however, voted to recommend that the warning remain intact.
The side effects have haunted the drug maker since Chantix was approved a decade ago, spawning horrendous publicity and numerous lawsuits, which the drug maker spent hundreds of millions of dollars to settle. Meanwhile, sales are sputtering, sliding from $846 million in 2008 to $671 million in 2015.
Earlier this year, Pfizer released the study results, which were published in the Lancet, and touted the findings, which claimed Chantix and GlaxoSmithKline’s Zyban drug, do not increase the risk of suicide.
The study found that, among patients already diagnosed with a psychiatric disorder, 6.5 percent of those on Chantix and 6.7 percent on Zyban had a neuropsychiatric side effect, compared to 4.9 percent on a placebo. Of those not diagnosed with a psychiatric disorder, 1.3 percent of those given Chantix experienced a neuropsychiatric side effect compared to 2.2 percent on Zyban and 2.4 percent on a placebo.
As we previously noted, the study involved 8,144 adult participants between the ages of 18 and 75 who, on average, smoked more than 10 cigarettes a day. And 82 percent had previously made at least one attempt to quit smoking. Of these, about half — or 4,116 participants — had a history of a previous or current stable psychiatric condition. About half of these people were taking a psychotropic medicine.
The FDA reviewers also noted that seven investigators at six trial sites disclosed financial arrangements or payments from Pfizer exceeding the $25,000 threshold for reporting to the agency. At two sites, the investigators reported multiple — as many as 60 — separate honoraria for speaking engagements and consulting fees, the reviewers wrote.
The FDA team also noted that a number of investigators received ongoing payments from Pfizer for involvement in speaking engagements or other activities not necessarily related to Chantix that did not meet the $25,000 threshold. This included 39 investigators at 27 sites outside the United States and four investigators at four US sites. No investigators had any financial relationships with Glaxo that met the threshold for reporting.
UPDATE: A Pfizer spokesman later sent us a note saying the trial is “a randomized, placebo-controlled, triple-dummy, blinded study; therefore any potential perceived bias would be equally distributed across all four treatment groups because the investigators were blinded. As a result, there is no preferential bias towards Chantix or any other treatment group.”
This post was updated to include a comment from Pfizer.