SILVER SPRING, Md. -- Two FDA advisory committees delivered a split decision on whether or not to remove a black box warning label from two key smoking cessation drugs, with the final tally in favor of removal.
But the vote Wednesday was close with the Psychopharmacologic Drugs Advisory Committee, and Drug Safety and Risk management Advisory Committee members pretty evenly split: 10 voted to remove the warning, four voted to modify warning language to reflect results from a recently completed postmarketing trial and five wanted the warned to stay unchanged.
FDA does not have to honor the committees' vote, and a vote this close is often considered a null recommendation.
Pfizer, which makes varenicline (Chantix), is declaring a win: "We look forward to the FDA's decision on the CHANTIX labeling," Freda Lewis-Hall, MD, DFAPA, Chief Medical Officer and executive vice president at Pfizer, said in a statement e-mailed just after the vote. "We are pleased with the Committees' (sic) 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."
GlaxoSmithKline, which manufactures bupropion (Zyban), is being more cautious: “This was a committee recommendation which FDA can accept, reject or modify,” a spokeswoman wrote in an email Thurdsday. “For that reason, we’ll wait to hear from FDA about the Zyban label and then work closely with FDA to take necessary actions, if any.”
Varenicline, approved by FDA in 2006, and bupropion (Zyban) (1997) have been shown to help smokers quit better than nicotine patches and placebos. But because these drugs have also been linked to psychiatric reactions, FDA ordered the black box warning for varenicline and bupropion in 2009 based on reports of increased risk of suicidal ideation among users. At the same time the agency ordered manufacturers Pfizer and GlaxoSmithKline (Zyban) to complete a placebo-controlled postmarket safety trial.
"Because patients with a history of psychiatric illness did not participate in the initial clinical efficacy trials that supported approval of the NDA (new drug application), it was also important to ascertain whether the medications were effective in these patients, in order to understand the balance of risks and benefits," according to an FDA briefing document released publicly Monday.
Pfizer and GlaxoSmithKline funded the randomized, double blind, active- and placebo-controlled, multinational study (called EAGLES); they also employed several study authors.
The 3-year trial ended in January 2015 and results were published in Lancet in April this year, showing that patients with or without a history of psychiatric activity were not more likely to suffer psychiatric episodes when taking varenicline or bupropion than those taking a placebo. "Regarding efficacy, this trial provides clear confirmation that all three medications (including nicotine replacement therapies) are more effective than placebo in patients with and without histories of psychiatric diagnoses," the FDA reported in the new review.
"This is the largest randomized, controlled trial to date comparing these smoking-cessation medications directly and comparing them with placebo," researcher Robert Anthenelli, MD, told 鶹ý in April. "We are hoping that the recognition that these medications are safe for smokers with and without psychiatric disorders will encourage people to try and quit and feel comfortable that they can use any of the available medications."
Lingering Questions
But FDA reviewers had questioned the study's sample and how data were collected and analyzed: Patients with substance abuse issues were not included and investigators struggled to code reactions consistently. One researcher coded a patient who was hospitalized for depression after taking varenicline as having suffered a "mild" reaction, for example.
"Despite efforts to actively solicit information about the range of complex and ill-defined experiences that patients have reported in postmarketing cases, this trial did not seem to have identified many of the types of cases that had been previously identified to be of concern," FDA reported.
On Wednesday, many committee members raised other concerns with the trial's conduct, and with setting a precedent by removing the black box warning. Several committee members worried that removing the warning would signal to patients and providers that the drug has been proven safe, and would preclude them from mulling the potential drastic side effects.
"I don't really feel fully reassured that this trial captured the essence of what was being reported," said Rajesh Narendran, MD, a Pittsburgh psychiatrist. "I think removing the black box does send the wrong message. Keeping it in there in my opinion has very little harm."
Others questioned Pfizer and GlaxoSmithKline. “I felt more time was needed to complete a more robust sensitivity analysis,” said Elaine H. Morrato, DrPH, a public health dean with the University of Colorado, who voted to leave the warning untouched. “I had the sense that the sponsors were turning in new analyses one week ago. The FDA I’d imagine would want more time to complete analyses.”
The FDA itself may have had the harshest words for the companies, citing the yes-no data they turned in instead of the informative narratives about reactions to the drug that they had been asked to complete. “This is not the first time asking the company for informative narratives,” said Sharon Hertz, MD, director of anaesthesia, analgesia, and addiction. Speaking about FDA’s role reviewing such studies in general, she added: “We expect companies to identify problems and bring them forward.”
Words of Praise
But the majority of committee members praised the study's rigor; a few of those who voted to remove the warning said the study supplied the evidence needed to make them comfortable using Varenicline to address a major public health problem.
"The risk-benefit ratio is as clear as anything I have ever seen," said David Pickar, MD, a Johns Hopkins Medical School psychiatry professor who said he works with psychiatric patients. Looking at his fellow committee members, Pickar added: "For you, these are adverse events, but the benefit to these patients could be substantial in the most fundamental thing, which is being alive."
Many of the committee members who voted to modify the warning cited uncertainty about the drugs' effects, despite praising the trial overall. "My read of what we heard today is that I don't know," said acting chairperson Ruth M. Parker, MD, a professor at Emory University School of medicine. "I do think the label should be changed to reflect trial findings."
This is the second time the FDA is reviewing the black box warning on varenicline. In 2014 the agency declined to remove the box warning from Chantix when Pfizer submitted new data from other studies, because an advisory committee recommended waiting for the postmarketing study data.
GSK declined to participate in Wednesday's hearing, the committees reported.