Bitter pills

8220;I do not think it8217;s wise to approve the drug or see the drug marketed until there8217;s a dedicated cardiovascular safety trial,8221; said Steven Nissen, of the Cleveland Clinic Foundation, who led the analysis. 8220;We have to put safety first.8221;

The Journal of the American Medical Association released the study online Thursday, five weeks ahead of its November 23 publication, because of the public health implications.

The FDA on Tuesday notified the company that the drug was 8220;approvable8221; pending additional information about the drug8217;s safety, but it did not specifically request a new study designed to examine the risk of cardiovascular problems.

The critique comes as the agency is struggling to restore its credibility in the wake of a series of embarrassing revelations and controversies, including the withdrawal of the blockbuster painkiller Vioxx last year because of safety concerns, a protracted battle over the Plan B morning-after contraceptive pill, and the sudden resignation of FDA Commissioner Lester Crawford, which remains shrouded in mystery.

The latest controversy underscores the heightened concern over drug safety, with the scrutiny this time on an earlier stage in the FDA approval process.

8220;We saw what happened with Vioxx. I don8217;t think we can afford to allow a drug without particularly important benefits to be approved when there is an apparent doubling of major cardiovascular events,8221; Nissen said.

Pargluva, also known as muraglitazar, is the first of a new class of diabetes drugs known as 8220;dual-action PPARs8221;. Several similar drugs are already on the market to lower levels of blood fats known as triglycerides, raise levels of 8220;good cholesterol8221; and increase the effectiveness of insulin for diabetics. Drugs like Pargluva were designed to combine those effects into a single pill.

As part of its standard drug-review process, the FDA convened a panel of experts to examine Pargluva on September 9. The committee voted 8-1 to recommend approval. The FDA usually follows the advice of its advisory panels.

Meanwhile, Nissen and two colleagues, alarmed that the only heart specialist on the FDA panel had recused himself because of a conflict of interest, independently reviewed the data from five studies involving 2,374 patients that Bristol-Myers Squib had submitted. The analysis found those taking the drug had more than twice the risk of death, heart attacks and strokes, and nearly triple the risk when all types of heart problems were included, such as congestive heart failure and a condition known as a transient ischemic attack.

While the number of patients available for the analysis was relatively small, the trends are so clear and consistent that it would be surprising if the higher risk was due to chance, Nissen said, especially given that patients in the studies tended to be healthier than the typical diabetic.

Neither the FDA, the chairman of the advisory panel nor Bristol-Myers Squibb had immediate comment on the report. An FDA spokeswoman said the agency could not discuss the study because it involves a pending drug application.