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Bad news for GSK: Two New Studies Cite Avandia Heart Risk

http://online.wsj.com/article/SB10001424052748703964104575334570859778764.html

›JUNE 28, 2010, 6:28 P.M. ET
By ALICIA MUNDY And JENNIFER CORBETT DOOREN

Two new studies released Monday said the diabetes drug Avandia is unsafe, heating up a controversy about a drug linked in a number of studies to an increased risk of heart attack and heart failure.

The reports were presented in the Journal of the American Medical Association and its sister publication, the Archives of Internal Medicine. They come two weeks before an important Food and Drug Administration meeting on Avandia's safety. In releasing the papers together, a JAMA spokeswoman said the editors "hope the peer-reviewed scientific studies will have some impact on the FDA's discussions about the safety of this medication."

The studies also coincided with the American Diabetes Association's annual meeting in Orlando.

Avandia manufacturer GlaxoSmithKline PLC said in a statement that the drug, which lowers blood glucose, is safe and effective. Glaxo said it looks forward to a "rigorous scientific discussion" about the new studies at the FDA meeting.

One study in JAMA is an update of a 2007 analysis of the clinical trials done on Avandia by Steven Nissen, a cardiologist at the Cleveland Clinic. The original analysis was based on 42 studies involving Avandia and showed a 43% increase in the risk of heart attacks. The new analysis looks at 56 clinical studies, including a Glaxo-funded study known as Record, and shows an increased heart attack risk of 28%. If the Record study is removed from the analysis, the risk of heart attacks rises to 39%.

The second study, published in the Archives of Internal Medicine, was led by FDA drug-safety scientist David Graham, and looked at the outcomes of nearly 230,000 Medicare patients who were treated with Avandia or Actos, a similar drug made by Takeda Pharmaceutical Co. The study looked at a combined endpoint of heart attack, stroke, heart failure or death and found that patients taking Avandia had an 18% increased risk compared to those taking Actos.

Dr. Graham has argued that it should be withdrawn from the market.

"I think these studies ought to weigh heavily on the advisory panel," Dr. Nissen said in an interview.

An analysis of data from a third study, called Bari 2D and funded by the government, didn't show cardiovascular risks. The results, which haven't been peer-viewed and published yet, were released early at the diabetes conference in response to the JAMA studies.

FDA Deputy Commissioner Joshua Sharfstein said Drs. Nissen and Graham have been asked to present their findings to the panel of experts when it meets for two days at the FDA in July. "They are making an important contribution to the discussion of the safety of Avandia," said Dr. Sharfstein, adding that the agency is taking the Avandia issue seriously.

The Avandia debate has widened a battle inside and outside the FDA about how it deals with information on a drug's safety, particularly involving a product already on the market. Pharmaceutical companies are closely following the Avandia controversy in Washington.

Scientists such as Dr. Graham, as well as congressional critics and outside researchers, say the FDA insists on too high a standard for withdrawing a drug from the market. They say the FDA should have a separate drug safety division independent of the drug-approval section.

In an interview, Dr. Graham said his FDA superiors "demand proof beyond a reasonable doubt that a drug is dangerous before they pull it. That is unreasonable, and not in the public health interest." Dr. Graham was an early critic of Vioxx, the Merck & Co. painkiller that was pulled from the market in 2004.

The head of the FDA's drug division, Janet Woodcock, has defended Avandia's safety and said its benefits still outweigh its risks. The FDA is now reviewing its drug approval and safety procedures.

A draft of Dr. Graham's study was reported in early June by several publications including The Wall Street Journal. JAMA said it bent its usual rules against publishing results that have appeared elsewhere because it didn't think Dr. Graham was responsible for the leak. The final study was peer-reviewed and revised.

The American Heart Association said in a statement that while the JAMA report didn't involve a clinical trial, it "deserves serious consideration." The medical group recommended that patients over 65 years old who are taking Avandia discuss the new findings with their physicians.

Avandia's safety came under renewed attack in February in the wake of a Senate Finance Committee report that was highly critical of both the FDA and Glaxo's handling of Avandia's potential cardiovascular impact.‹