FDA Panelists Vote to Ease Restrictions on Avandia

Silver Springs, COIf anyone was curious as to the severity of the “hit” suffered by GlaxoSmithKline when its one-time superstar diabetes drug Avandia descended into a sea of concern over Avandia side effects, one needs only to look at the numbers. At its peak, more than 117,000 Americans were prescribed Avandia for Type 2 Diabetes. Following severe restrictions mandated by the US Food and Drug Administration (FDA) three years ago, that number fell to just 3,400.

But that may soon change, in view of a recent meeting of FDA panelists, the majority of whom voted to ease severe restrictions brought in by the FDA in 2010 over concerns regarding Avandia risks.

According to The Gupta Guide (6/6/13), the regular column appearing on medpagetoday.com and edited by the venerable Dr. Sanjay Gupta, an important aspect of the placement of severe restrictions on Avandia in 2010 was the requirement to revisit the RECORD trial - the lone large, randomized outcomes trial of rosiglitazone (Avandia). Following an independent review of the outcomes and methodology of RECORD by Duke Clinical Research Institute (DCRI), it was determined the original findings were largely accurate. It was also determined that while myocardial infarction (MI, or Avandia heart attack) remained worse when compared with rival Actos (pioglitazone), stroke outcomes were better with Avandia.

Avandia was at one time the darling of the Type 2 diabetes industry, until the GlaxoSmithKline drug was felled by research released in 2007 that suggested an unreasonably high risk for Avandia heart attack and other Avandia side effects. Doctors shifted their diabetic patients to Actos in droves, and Avandia was banned entirely from the European market.

Following a gathering of FDA panelists in 2010 debating the severity and implications of Avandia side effects, the federal drug agency severely tightened Avandia’s risk evaluation and mitigation strategy (REMS), making Avandia the option of last resort for patients whose diabetes would not respond to any other suitable drug. What’s more, only doctors with certain classifications were allowed to prescribe Avandia, and pharmacists required specific credentials to dispense rosiglitazone.

The FDA decided to leave Avandia on the market, pending the outcome of a re-evaluation of the RECORD trial.

Earlier this month in Silver Springs, a combined meeting of separate FDA advisory panels gathered to consider the results of the DCRI analysis, and debate Avandia’s future going forward. On June 6th, 20 out of 26 panelists on the FDA’s Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees voted to remove or modify the current restricitons on Avandia.

DCRI found that the hazard ratio for cardiovascular death, myocardial infarction (MI), and stroke to be 0.95 (95% CI 0.78-1.17) - roughly the same as the result of 0.93 (95% CI, 0.74-1.15) from the original study.

Previously, Avandia risks have included associations with Avandia liver failure as well as Avandia fracture. The risk for Avandia heart attack (MI) remains, together with the potential for Avandia death. However, given that risk for stroke associated with Avandia is less than that of Actos, the majority of panelists voting in Silver Springs held that Avandia, in 2013, is no more unsafe than any other diabetes drug on the market.

What happens now is up to the FDA. The agency could lift some or all of the severe restrictions. Avandia’s status as a treatment of last resort could be modified, or restrictions on who can prescribe Avandia and the dispensation of same, could be removed.

Or the FDA can do nothing, although that rarely happens. In most instances, the FDA follows the lead of its expert panels, according to the report.

While the majority of panelists voted to ease or modify restrictions, concerns remain.

According to The Gupta Guide, one panelist sought a Phase IV trial of the 3,400 Type 2 diabetes patients currently taking Avandia. Several other panelists called for an additional randomized, controlled trial to address once and for all the issues surrounding Avandia heart attack and cardiovascular safety.

But given the public awareness of Avandia side effects in recent years - together with those filing an Avandia lawsuit - such a trial may no longer be possible. “It may well not be feasible to conduct a trial that answers the questions we have,” said Susan Heckbert, MD, PhD, epidemiology professor at the University of Washington in Seattle, in comments appearing in The Gupta Guide.

All eyes are now on the FDA to see what the agency decides, and if they follow the lead of their expert panelists, as most expect. An easing of restrictions would come as good news for Actos patients, who now deal with the potential for Actos bladder cancer. In spite of greater risk for heart attack with Avandia, stroke outcomes are better than those of Actos and there does not appear to be a link to bladder cancer with rosiglitazone (Avandia), as there is with pioglitazone (Actos).

As such, until the FDA weighs in (and there is no mandated timeline to do so), the Avandia file remains in a state of flux.