FDA is presenting two advisory panels with a broad set of options for dealing with persistent reports of safety signals with GlaxoSmithKline's type 2 diabetes drug Avandia (rosiglitazone), ranging from taking it off the market to removing the boxed warning of ischemic cardiovascular events from its label, as well as three in-between options.

This set of five options was released to the media along with eight other questions relating to Avandia's safety at an unusual press conference July 8 that featured CDER Director Janet Woodcock, FDA Principal Deputy Commissioner Joshua Sharfstein and other agency officials.

The extremely high profile of this review is further underlined by the fact that FDA Commissioner Margaret Hamburg is slated to open the July 13-14 joint meeting of the Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees.

Of the three intermediate options the committees could recommend, only one seems to fit the profile of a Risk Evaluation and Mitigation Strategy - allowing the drug to remain on the market while adding new warnings to the label and instituting a prescriber certification program or requiring special patient and physician education.

The other two options include just adding new warnings to the label, or leaving the status quo completely unchanged.

FDA is also asking the joint advisory panels to assess the relative risks of Avandia, Takeda's Actos (pioglitazone) and non-thiazolidinedione diabetes drugs such as metformin and sulfonylureas with respect to two specific hazards - death and ischemic cardiovascular events (stroke or heart attack).

In addition, the agency is requesting an overall risk-benefit analysis for Avandia "in the context of other available anti-diabetic therapies," and, assuming Avandia remains on the market, whether GSK's ongoing TIDE (Thiazolidinedione Intervention in Vitamin D Evaluation) trial comparing Avandia and Actos should be continued or not.

For the post-marketing trial, a just-released study from the Institute of Medicine will also likely guide the panel's discussion (see Also see "IoM Report On Postmarketing Study Ethics Could Drive Broad Overhaul Of Informed Consent" - Pink Sheet, 9 July, 2010. ).

Public Citizen Health Research Group Director Sidney Wolfe and David Juurlink, a researcher at Sunnybrook Health Sciences Centre in Toronto, sent a May 11 letter to FDA Commissioner Margaret Hamburg requesting that the agency immediately halt the trial for safety reasons (Also see "GSK Settles Hundreds Of Avandia Suits Before FDA Advisory Cmte. Meeting" - Pink Sheet, 17 May, 2010.). That same day, Bloomberg reported that GSK had agreed to pay about $60 million to resolve more than 700 lawsuits that cited data that seem to show Avandia increases the risk of heart attacks.

High Stakes, No Prejudgment

The stakes remain high, and Woodcock was at pains to stress during the July 8 press conference that FDA has not prejudged the issue of the drug's safety and that there is still internal disagreement about it at the agency.

"The standards for determining efficacy are much stronger than the standards for determining whether there's a safety problem with a drug," Woodcock said. "There's disagreement within the scientific community, and that's why we've summoned the advisory committee, to decide whether there is a safety signal with the drug."

"Historically, there have been many cases where there were safety signals and calls to take a product off the market, and then when studies were done, it was found there was not a problem. ... There was a long controversy in the 1990s over calcium channel blockers, and concern that they might increase the risk of heart disease, cancer and suicide. But large-scale studies proved these risks didn't exist."

"Not every signal is true, and we have to find out which ones represent the potential for harm and take appropriate action," Woodcock said.

"We're going to try to make a decision as quickly as we can under the circumstances," Sharfstein said.

- Martin Berman-Gorvine (m.berman-gorvine@elsevier.com)

Avandia Committee Review: FDA Puts Five Options On Table For Advisory Panels

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