Glaxo's Avandia Causes Heart Attacks -- NEJM

There’s just one word for fading drug industry hopes that the House discussion over reauthorizing user fees for the Food and Drug Administration will ignore safety reforms. That word is “Fuhgeddaboudit.”

The New England Journal of Medicine this afternoon released a pooled analysis by Steven Nissen of the Cleveland Clinic showing that the heavily marketed diabetes drug Avandia from GlaxoSmithKline increases heart attack risk in the millions of patients who have taken it since it was approved in 1999. In fact, it increased that risk by 43 percent over other drugs or placebo.

Nissen was one of the first doctors to raise similar concerns about Vioxx.

The impact was immediate. The House vowed to hold hearings. Here’s Energy and Commerce chairman John Dingell’s (D-MI) quote, taken from Reuters:

"It is incredible that the agency charged with protecting the public health has such a poor record when it comes to post market drug safety. Regrettably it is incidents like this that demand legislative changes in the way FDA deals with drug safety. The Committee will address these dangerous shortcomings while writing legislation to reauthorize PDUFA."

Indeed, the outlook now is that the House will pass much tougher legislation than the Senate, which passed its version two weeks ago.

Nissen and his colleague Kathy Wolski looked at 42 studies that tested Avandia (rosiglitazone), which reduces blood-sugar levels in diabetics. Some studies compared it to metformin, a generic commonly used for glycemic control. Others compared is to sulfonylurea, insulin or placebo. In every case, Avandia increased the risk of heart attacks or deaths from cardiovascular disease, although not all reached statistical significance. Pooled together, though, and the pattern was clear.

“In view of the potential cardiovascular risks and in the absence of evidence of other health advantages, except for laboratory measures of glycemic control, the rationale for prescribing rosiglitazone at this time is unclear,” wrote Bruce Psaty of the University of Washington and Curt Furberg of Wake Forest in an accompanying editorial. “Unless new data provide a different picture of the risk-benefit profile, regulatory action by the Food and Drug Administration is now warranted.”

The FDA issued a mild warning late Monday afternoon. "There is inherent risk associated with switching patients with diabetes from one treatment to another even in the absence of specific risks associated with particular treatments. For these reasons, FDA is not asking GlaxoSmithKline, the drug's sponsor, to take any specific action at this time. FDA is providing this emerging information to prescribers so that they, and their patients, can make individualized treatment decisions," the agency statement said.

Once again, millions of Americans have been subjected to unwarranted risks from a drug that had no real benefits over other, cheaper drugs already on the market. And now that they're on this more expensive drug, they face additional risk if they decide to get off because of what they just learned. Thanks a lot, FDA.

Where should the House go with this? Here’s some of the things that should be put in their bill that were left out of the Senate legislation:

• Anytime a drug is approved on a surrogate end point (like glycemic control), the FDA needs to demand that the company conduct a comprehensive post-marketing trial large enough to identify all risks and benefits associated with the drug. And if the company doesn’t complete the study in a timely manner, the FDA should immediately withdraw it from the market.

• All clinical trials must not only be registered at the outset of the trial, but there results must be posted. Moreover, researchers need to have access to the data, right down to patient level whether or not that information was sent to the FDA.

• The FDA needs to make all of its data available to outside researchers. “Further analyses of data available to the FDA and the manufacturer would enable a more robust assessment of the risks of this drug,” they wrote.

Moreover, the bill should include a total ban on conflicts of interest on the advisory committees that consider these drugs. In February, Glaxo sent a letter to physicians warning them about increased bone fractures in women who take Avandia. This finding was an outgrowth of a company-funded study released in December – also in NEJM -- that claimed Avandia used as monotherapy for newly diagnosed diabetics lengthened the time until patients need a second drug or insulin. The authors of that study, all of whom had some type of financial tie to Glaxo, admitted that it was “not designed to evaluate cardiovascular disease outcomes.” How did the Glaxo-funded physicians get their result? Their trial had a shorter follow-up period and younger patients who had better glycemic control when entering the study, they admitted.

Does Congress want those doctors on the advisory committee that will inevitably be called to consider this latest analysis of Avandia?

Posted by gooznews at May 21, 2007 05:04 PM