FDA vs. Big Pharmaceuticals: Clinical Trials May Not Be Good Enough
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FDA vs. Big Pharmaceuticals: Clinical Trials May Not Be Good Enough

Avandia may be the poster drug for comparative effectiveness outcomes

There will be more at stake than just one drug’s future when the Food and Drug Administration opens a two-day hearing Tuesday on the safety of the diabetes drug Avandia.

The 30-member panel of outside experts will also be rendering judgment on research methods that are frequently used to compare effectiveness and are slated to become a pillar of the nation’s drug safety monitoring system. If the panel or the FDA leadership proves reluctant to rely on those methods, it could set back efforts to hold down health care costs and develop safer drugs.

For those not following the saga of GlaxoSmithKline’s Avandia (generic name rosiglitazone), the blood-sugar-lowering agent has been under a cloud since 2007 when Steven Nissen and Kathy Wolski of the Cleveland Clinic published a pooled analysis of more than 40 clinical trials that showed that compared to other drugs, Avandia raised the risk of heart attacks among already cardiovascular-compromised diabetes patients. But the drug stayed on market after an FDA panel gave it a green light despite agreeing with the negative findings. The agency added a warning to the drug’s label, but said the heart risks were inconclusive. 

The Trials
Why the mixed message? Pooling data from a large number of clinical trials can offer tantalizing hypotheses about the benefits and risks of drugs. But FDA officials are reluctant to rely on them. They believe pooled analyses don’t have the statistical heft of a well-designed randomized controlled clinical trial (RCT) – the so-called gold standard of medical research. (Both doctors and the patients in RCTs are randomly assigned to two arms of a trial without knowing who received the experimental therapy and who received the sugar pills.)

Glaxo’s defense of the drug rested on a fairly large RCT – dubbed the RECORD trial – that followed over 4,400 patients for five years. It showed patients on Avandia had fewer overall deaths and fewer heart attacks than patients randomly assigned to receive older diabetes drugs. 

Many physicians and patients were not convinced. They only heard the risk message that was endorsed by the committee, if not by the FDA itself. Avandia sales plunged by over two-thirds in the wake of the 2007 meeting (there are at least 13 other drugs, including one very similar to Avandia, for treating diabetics and pre-diabetics for high blood sugar). Last year, Glaxo sales to the nation’s 24 million diabetics dipped to a million prescriptions with $642 million in sales.

The Critics Weigh In
But Avandia’s critics were not assuaged. Earlier this year, the FDA decided to hold a second major hearing on the drug’s safety after the Senate Finance Committee charged in a report that Glaxo engaged in research misconduct during the RECORD trial.

After reviewing every patient record in the trial, one of the reviewers, Thomas Marciniak, found a number of instances where deaths that occurred while taking Avandia were inexplicably dropped from the final analysis. Moreover, the final health outcomes of hundreds of patients in both arms of the trial were never recorded.

Top FDA officials were still not convinced. “These issues leave much in doubt and thus undermine one’s ability to take much comfort from the safety findings,” Norman Strowbridge, Marciniak’s supervisor at the FDA, said in a note appended to the report. “It is less clear to me whether, despite its shortcomings, one can interpret RECORD as showing new evidence of the harm of rosiglitazone.”

Given the controversy over RECORD, the committee will have to base its judgment on the evidence presented in two other studies. An updated meta-analysis by Nissen, a cardiologist who has repeatedly called for removing the drug from the market, and Wolski in the Archives of Internal Medicine last month showed patients experienced an increased number of heart attacks but not an increased number of deaths from taking Avandia.

A more damning study will come from David Graham of the FDA’s drug safety office, whose pioneering use of electronic patient records from Kaiser Permanente helped bring to light the heart attack risks associated with Merck’s Vioxx. This time Graham worked with researchers at the Centers for Medicare and Medicaid Services to cull records of nearly a quarter million Medicare recipients. They found that elderly diabetics who used Avandia instead of Takeda’s Actos (pioglitazone), a diabetes drug that works the same way, experienced a 68 percent increase in risk of heart attack, stroke, heart failure or death.

“We estimate that about 48,000 excess cases of acute myocardial infarction (heart attack), stroke, heart failure, or death were attributable to the use of rosiglitazone rather than pioglitazone from 1999-2009,” Graham wrote in the briefing book for the committee. Glaxo officials rejected the conclusions of both studies, and their methods.

Ironically, though the FDA is reluctant to embrace epidemiological studies like Graham’s, it is compiling its own massive database of electronic patient records dubbed the Sentinel project to hunt for safety problems in already-approved drugs. 

More significantly for those concerned about cost control, the government is pouring a significant share of the $1.1 billion it has earmarked for comparative effectiveness research into large outcomes database research.  Once this research becomes public, arguments over the research methods are certain to come to the fore, raised by companies who rely on RCTs to show comparability or even superiority.

The elite committee that will evaluate the evidence is a marked difference from the similarly large committee that evaluated Vioxx in 2005, which was dominated by rheumatologists, many of whom had ties to drug manufacturers.  The FDA did not issue a single conflict-of-interest waiver for this week’s meeting.

Even before the committee is asked to assess the safety data, it will be asked to evaluate the strengths and weaknesses of its sources and their methods. The members’ answers to that question may in the long run have far more significance than the near-term fate of Avandia.