The Food and Drug Administration's meeting next week to decide the fate of the blockbuster diabetes drug Avandia promises to be a nail-biter—on a par with last night's ESPN special to reveal which lucky team basketball star LeBron James had chosen. But just like ESPN's LeBron prognosticators, I'll make a prediction: I'm guessing Avandia's fate may already be decided—if the meeting materials posted by the FDA today are any indication. While some prominent researchers (including those at the FDA) have demonstrated that Avandia is associated with an increased risk of strokes, heart attacks, and heart-related deaths, clinical trials conducted by manufacturer GlaxoSmithKline have found no increase in cardiovascular risks.
But here's the rub: When Thomas Marciniak, an FDA medical team leader, analyzed one of the recent GSK-sponsored trials, he discovered that the company had made mistakes in its data analysis and that increased heart risks were indeed present in Avandia users. In some cases, the researchers who conducted the so-called "Record" study, one of the trials cited by GSK, failed to count heart attacks and hospitalizations as heart-related conditions and didn't investigate some deaths in Avandia users to see whether they may have been caused by the drug. In a memo posted today on the FDA website, Marciniak called the study "inadequately designed" and alleged it was conducted to reassure the public of the drug's safety even though the data suggested otherwise. Another analysis comparing Avandia with Actos, the only other diabetes drug in the same class, found that the likelihood of major heart events like heart attacks or strokes "tended to be less" with Actos and "tended to be greater" with Avandia, according to FDA statistician Bradley McEvoy.
In a statement issued today, GSK maintained that results from six controlled clinical trials together show that Avandia "does not increase the overall risk of heart attack, stroke or death." Company executives will have a chance to make their case at the FDA meeting on July 13 for keeping Avandia on the market.
The bigger story here may be the lack of good safety studies in the years after Avandia hit the market to assess the risks of the diabetes drug—a criticism that applies to the entire pharmaceutical industry, public health experts contend. None of the Avandia studies conducted after the drug gained FDA approval were specifically designed to look at heart risks, the FDA materials pointed out. This is despite the fact that the agency's drug reviewers had concerns about Avandia's possible link to heart problems when it was initially approved back in 1999. Even with all the studies that have been conducted since then, FDA scientists had a tough time assessing the true safety risks of Avandia compared to Actos since the two manufacturers didn't conduct their research the same way. Plans to compare Avandia and Actos in a head-to-head safety trial could be cancelled if Avandia is yanked off the market.
The Institute of Medicine today released a set of recommendations to help the FDA determine an ethical framework for ordering manufacturers to conduct clinical safety studies when a drug poses a possible safety hazard after it's put on the market. The IOM's full set of recommendations to the FDA for conducting post-marketing studies, which an expert panel is slated to issue next year, will be more telling. Will the FDA begin to require companies to perform specific safety trials quickly following a drug's approval? Will these trials be standardized so that one drug can be compared against another? Just how much authority will the FDA exert over drug companies in the studies it requires after a drug is approved? Answers to those questions may prove to be more suspenseful than the decision to take Avandia off the market, since the odds seem pretty stacked against the drug.