Clinical trials were run at 139 sites in 16 countries, treating a total of 8,058 patients. Despite Pfizer’s extensive efforts to standardize adverse event categorization and reporting, the FDA and some panelists remained concerned that language difficulty and cultural variation in interpreting neuropsychiatric symptoms may have resulted in miscategorization or underreporting of such events. In addition, Pfizer’s own surveillance revealed data reporting problems at two overseas sites that resulted in those sites’ data being eliminated from analysis.
All of the trial data, together with a review of several observational studies, had to be weighed against the individual and public health risks of smoking. Individuals with serious mental illness are significantly more likely to smoke heavily and to relapse after quitting compared with the general population. Yet, those individuals are less likely to be prescribed medication to help stop smoking, Anne Eden Evins, MD, director of the Center for Addiction Medicine at Massachusetts General Hospital, Boston, said in her testimony on Pfizer’s behalf.
“The implication of EAGLES is that we can offer treatment to all smokers, including those with stable mental illness,” she said. “It is imperative we find ways to increase use of the most effective smoking cessation treatment for our patients who try time and again to quit smoking.”
Many committee members agreed, providing anecdotal evidence that the current boxed warning deters both prescribers and patients from considering varenicline for smoking cessation in patients with mental illness.
For David Pickar, MD, who voted to remove the warning, the decision was easy. “I have no ambivalence, whatsoever,” he said. “The risk-benefit ratio to me is as clear as anything I have seen. I have never, ever, ever seen a schizophrenia patient on this drug,” said Dr. Pickar, a psychiatrist affiliated with the Uniformed Services University of the Health Sciences, Bethesda, Md.
However, many panelists were disturbed by the variability seen between sites during the clinical trials and by the lack of depth in Pfizer’s adverse events reporting. Said Rajesh Narendran, MD, professor of radiology and psychiatry at the University of Pittsburgh: “I don’t think the trial was conducted with the same cleanliness and elegance” of a trial for a new drug application. “I wasn’t fully reassured, and I think that removing the black box does send the wrong message that this is now a safe drug,” he said.
Although the joint committees’ chair, Ruth Murphey Parker, MD, voted for modification of the boxed warning, she agreed. “I also felt that removal of the black box would be a signal for safety,” she said.
Others who voted for modification felt that prescribers should talk to their patients about risks and benefits. Said Christianne Roumie, MD, professor of internal medicine and pediatrics at Vanderbilt University, Nashville, Tenn., and a staff physician at Veterans Affairs Tennessee Valley Healthcare System, also in Nashville: “As a clinician, I always have the discussion. This should be a conversation and not ... carte blanche.”
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