Avandia safety - The Healthcare Channel has some great insights

The U.S. Senate just released a 350-page report on the GlaxoSmithKline (GSK) drug Avandia (rosiglitazone). The report investigates whether the FDA and GSK acted properly to evaluate the safety risk of the drug. The conclusions are scathing to GSK. It asserts that GSK knew years before 2007 of the safety concerns and intentionally stifled doctors trying to make the concerns public.

Per the previous Healthcare Channel note on 2/19/2010, it does seem that the recent BARI 2D study was not part of the report, and the full RECORD data from 2009 are not incorporated into the analysis. Both studies supported the safety of Avandia, as did the ADOPT and DREAM trials.

However, the Senate report is worth reading and provides interesting insight into how Big Pharma handles a crisis threatening a blockbuster drug. On the PDF file of the report, search for the keyword “RECORD” and the internal dialogue at GSK on how to handle the underpowered nature of RECORD is revealed. The rest of the report on pages 1 through 17 is interesting as well.

The HCC continues to believe that the final verdict on Avandia safety is yet to be determined. Plenty of evidence, all insufficient alone, suggests that Avandia raises the risk for heart attack (MI), stroke and death. Also, more recent randomized controlled trials (BARI 2D and RECORD) seem to support that the drug is safe.

The Steve Nissen metanalysis that caused most of the public focus on Avandia in 2007 and the FDA advisory committee was poorly conducted and unable to make the conclusion that Avandia was unsafe. In a 2007 Annals of Internal Medicine paper, Drs. Kaul, Diamond, and Bax wrote, “A recent, widely publicized meta-analysis of 42 clinical trials concluded that rosiglitazone was associated with an approximately 43% increased risk for myocardial infarction and an approximately 64% increased risk for cardiovascular death. The sensitivity of these conclusions to several methodological choices was not assessed. The meta-analysis was not based on a comprehensive search for all studies that might yield evidence about rosiglitazone's cardiovascular effects. Studies were combined on the basis of a lack of statistical heterogeneity, despite substantial variability in study design and outcome assessment. The meta-analytic approach that was used required the exclusion of studies with zero events in the treatment and control groups. Alternative meta-analytic approaches that use continuity corrections show lower odds ratios that are not statistically significant. We conclude that the risk for myocardial infarction and death from cardiovascular disease for diabetic patients taking rosiglitazone is uncertain: Neither increased nor decreased risk is established.”

All of the individual trials have significant flaws given that detecting low event rates such as death from a drug requires massively large populations, or “N”, usually only found in observational registries. The FDA will likely reconvene an advisory panel to determine what to do. Recall, a previous advisory committee that analyzed the studies in the recent Senate report previously voted to keep Avandia on the market.

Multiple agendas are at play in the name of Avandia safety. On one hand, a powerful drug company was defending a cash cow. On the other, cardiologists trying to be relevant and famous were working the room, so to speak. During a Congressional oversight hearing, some members of congress scolded Dr. Nissen for his tactics and leaking his New England Journal of Medicine report to Congress before it was published.

Rep. Darrell Issa (R-CA), said, “Mr. Issa. OK. I am going to yield back to the gentleman. I just want to make sure something gets in the record, though. The American Enterprise Institute published something that I think says a lot about the author that we are going to hear from in a few minutes. The study's primary author, Cleveland Clinic cardiologist, Steven Nissen, admitted to the Wall Street Journal that he was in touch with Congress while preparing his analysis. Three days after the study was submitted to the New England Journal of Medicine and before it was published, the FDA Commissioner received a letter about Avandia from members of the House Energy and Commerce Committee that seemed to reference the New England Journal of Medicine study. I just want to make sure that is in the record, and I will yield back to the gentleman.”

The revenue for Avandia has already dropped dramatically. The impact of this Senate report will likely lead to another FDA advisory committee and the drug being pulled from the market, with little impact to GSK stock.

The important point raised by the Avandia scandal, according to Dr. Sanjay Kaul of Cedars Sinai, is the need for outcome based clinical trials for new drugs that target large populations. Currently, drugs are almost always approved based on surrogate markers, such as hemoglobin A1c or cholesterol levels, and not actual outcomes such as lower death rates or fewer heart attacks. The GAO issued a report last year on this topic. The HCC interviewed the author of the report, Marcia Crosse. The video interview may be viewed here.

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