GlaxoSmithKline's Avandia Is Back Under FDA Scrutiny Over Cardiac Risks

On Tuesday, the Food and Drug Administration will convene a panel of experts -- again -- to discuss GlaxoSmithKline's (GSK) type II diabetes drug Avandia. Sales of Avandia, which topped $2.6 billion in 2006, fell to $1.2 billion in 2009 following a study that suggested the drug poses increased risk for serious heart problems and after the FDA added a black box label warning regarding the elevated cardiac risk in 2007.

Since then, more studies on Avandia's elevated risk have been published, and several researchers, medical professionals, regulatory officials and senators have called for the FDA to order the drug pulled from the market.

But Avandia (generic name rosiglitazone) continues to be prescribed, both in the U.S. and in Europe. The FDA panel is convening to assess the risks and benefits of the drug, and recommend action.

Some FDA Reviewers Criticize Safety Trial

Ahead of the meeting, the FDA released documents on Friday that harshly criticize a pivotal clinical trial conducted by Glaxo called Record, which supported the continued use of Avandia. In the 765-page document, Thomas Marciniak, the team leader of cardiovascular products says: "Our summary is that RECORD was inadequately designed and conducted to provide any reassurance about the CV [cardiovascular] safety of rosiglitazone."

In a damming slide show, Marciniak further concludes that "RECORD confirms and extends the recognized concerns regarding increased HF [heart failure] and HF deaths with rosiglitazone. RECORD suggests the rosiglitazone increases the risk for MI [myocardial infarction]."

Dr. Steven Nissen, a long-time advocate of pulling the drug from the market, also submitted material that concludes that with an alternative in the market that has favorable cardiovascular effects -- pioglitazone, or Actos, manufactured by Takeda -- the "continued marketing of rosiglitazone cannot be medically or ethically justified." Takeda's Actos had sales of over $4 billion last year.

Defending the Record Trial

But other documents submitted Friday show that some at the FDA, among them deputy director Ellis Unger, don't necessarily agree with Marciniak and Nissen, and see the Record results as "reassuring."

GlaxoSmithKline launched the Record trial in 2001 with nearly 4,447 patients. The company claimed in its own filings on Friday that "The results of the RECORD study demonstrated that RSG [rosiglitazone] does not increase the risk of overall cardiovascular morbidity or mortality compared with standard glucose-lowering drugs." The company concludes that "RSG is an important option for the treatment of type 2 diabetes with a favorable benefit risk in both women and men."

Meanwhile, GlaxoSmithKline is conducting another clinical trial called Tide, which compares Avandia to Actos. The study, which has been dubbed by critics as unethical, will also be discussed by the FDA's panel.

Glaxo Withheld Avandia Risk Data

However, perhaps more damning are comments made Monday by a former FDA official, who said GlaxoSmithKline withheld information from regulators that suggested that Avandia posed an increased risk for serious heart problems, both The Wall Street Journal and Bloomberg report.

The statements by the ex-FDA official, which were made in a deposition for lawsuits filed against Glaxo, are included in a letter sent by Sen. Charles Grassley (R-Iowa) and Sen. Max Baucus (D-Mont.) of the Senate Finance Committee sent to the agency. The two have been investigating Glaxo and Avandia for some time now. The letter includes additional information detailing internal company records about Avandia, according to sources.

GlaxoSmithKline's problems with Avandia may be just beginning, as the drug already is the target of extensive litigation. The Wall Street Journal reports that according to its sources, GlaxoSmithKline faces 11,000 suits in federal and state courts. Analysts estimate the total liability may be as much as $6 billion to resolve all Avandia litigation, Bloomberg reports. The British pharmaceutical had set aside 2.3 billion pounds ($3.5 billion) for "legal and other disputes" as of the end of March.

Reminiscent of Past Drug Failures?

As Mathew Herper of Forbes notes, the panel's decision will not be final. He also reminds us how in 2005, a similar FDA panel on Merck's (MRK) recalled drug Vioxx voted in favor of returning it to the market. Similarly, an FDA panel said Pfizer's (PFE) Bextra should remain on sale. Vioxx didn't come back, and Bextra was withdrawn, and both companies had to deal with lawsuits and billions in payouts.

As Jim Edwards of BNET said, it almost doesn't matter whether Glaxo withdraws Avandia from the market or not given all the bad publicity it has received. Still, within the context of the FDA recent push toward more transparency and a greater emphasis on safety, it will be interesting to see how much influence Obama appointee Margaret Hamburg has managed to accrue in her relatively short time as FDA commissioner.