FDA Questions Validity of Smoking Cessation Drug Research

Pauline Anderson

September 13, 2016

The US Food and Drug Administration (FDA) has raised concerns about a postmarketing study that examined adverse neuropsychiatric events in patients who used smoking cessation drugs varenicline (Chantix, Pfizer) and bupropion (multiple brands).

The FDA questions how researchers determined primary neuropsychiatric adverse event outcomes that affect the interpretation of the trial results.

The FDA released a report outlining its concerns ahead of a joint meeting of the Psychopharmacological Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee tomorrow.

At that meeting, advisory committee members will discuss the postmarketing trial of verenicline and bupropion to determine whether the findings support changes in product labeling.

Varenicline is a partial α4β2 acetylcholine nicotine receptor agonist that was approved in May 2006 as an aid to smoking cessation. Buproprion hydrochloride, an aminoketone antidepressant originally approved under the name Wellbutrin (GlaxoSmithKline), was approved for smoking cessation under the name Zyban (GlaxoSmithKline) in 1997.

On the basis of postmarketing adverse event reports, varenicline and bupropion carry boxed warnings on the risk for serious neuropsychiatric events, such as suicidal thoughts and suicide.

In 2008, the FDA required Pfizer and GlaxoSmithKline to conduct a placebo-controlled postmarketing safety trial to further characterize the risk for neuropsychiatric adverse events and to evaluate whether a prior history of psychiatric illness was a risk modifier (patients with a history of psychiatric illness did not participate in the initial clinical efficacy trials).

The study the FDA examined was a double-blind, active- and placebo-controlled, multicenter, parallel group study designed to assess the safety and efficacy of varenicline 1 mg BID and bupropion hydrochloride 150 mg BID for smoking cessation.

Many Problems

The primary comparisons were to be varenicline vs placebo and bupropion vs placebo. Nicotine replacement therapy (NRT) was included as an active control, and study medications were to be given via a triple-dummy design.

The treatment continued for 12 weeks and was followed by a nontreatment follow-up phase for another 12 weeks. About 2000 patients in each of four treatment arms were to be included, for a total of 8000 patients at some 200 sites.

Patients were classified into one of two cohorts ― those with an established and stable diagnosis of psychiatric disorder (PHx), and those without a diagnosis of a psychiatric disorder (non-PHx).

The trial was designed in a well-intentioned attempt to capture somewhat ill-defined and complex neuropsychiatric phenomena, the FDA says in its report.

"However, many problems in the implementation were apparent upon review of the collected data," the agency notes.

Among the FDA's concerns were that the interview tools developed to capture neuropsychiatric adverse events were not used to the extent intended "to get a nuanced understanding of such adverse events."

In addition, there was substantial variability among investigators in how the severity of adverse events was coded and how the adverse-event terms were applied. The FDA says there was also inconsistency in how suicidality cases were handled.

Side Effects Downplayed?

"All these factors likely served to lower the overall number of primary outcome events, which may result in biasing towards a null finding," the FDA notes.

According to the FDA, the rate of neuropsychiatric symptoms among those in the non-PHx cohort was lowest among patients randomly assocated to receive varenicline (1.3%) and was similar for patients who received bupropion, NRT, or placebo (2.2% to 2.5%).

The rate of neuropsychiatric symptoms in the PHx cohort was highest among patients who received varenicline and bupropion (6.5% and 6.7% respectively) and was lowest among patients who received placebo (4.9%).

The report also raises the question of whether researchers who had received substantial fees for speaking on behalf of varenicline may have underreported side effects in the trial.

Review of financial disclosures identified seven investigators at six sites who disclosed financial arrangements or payments from Pfizer that exceeded the $25,000 threshold for reporting to the FDA. At two sites, the investigators reported multiple (as many as 60) separate honoraria for speaking engagements and consulting fees.

None of the investigators had any financial relationships with GlaxoSmithKline that met the threshold for reporting.


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