FDA Advisory Committee Recommends Modifying Avandia Restrictions
After years of controversy that resulted in an independent re-adjudication of the RECORD Trial, the U.S. Food and Drug Administration’s (FDA) Metabolic Advisory Committee and the Drug Safety and Risk Management Advisory Committee have recommended modifying current restrictions on the diabetes drug rosiglitazone (Avandia).
Seven panelists voted to remove the Risk Evaluation and Mitigation Strategy (REMS) that is currently in place, five voted to leave it as is, thirteen were in favor of modification and one voted to remove rosiglitazone from the market. In addition to weighing the votes and the explanations for the votes, the FDA will take into consideration the discussion that unfolded during the two day meeting.
In general, panelists felt that the RECORD trial was fundamentally flawed, leaving unanswered questions, but recognized that the re-adjudication was not designed to critique or examine the clinical trial. That said, many of the panelists expressed a strong interest in a new trial that would address unanswered questions. However, they were aware of limitations on the feasibility of such a trial, including the likely disinterest of the drug’s manufacturer in sponsoring another trial in light of the expiration of the original patent and the numerous newer diabetes drugs on the market, coupled with a number currently in the development pipeline. That said, the re-adjudication of the trial by the Duke Clinical Research Institute gave this panel more confidence in the RECORD trial data than the 2010 panel had, as the panelists who served on both repeatedly expressed.
Over the course of two days, the committees examined results from the re-adjudication and heard from various stakeholders, including the drug’s manufacturer and public representatives. ACC Past President Ralph G. Brindis, MD, MPH, MACC, spoke on behalf of the ACC during the public portion of the meeting and shared ways stakeholders can come together and support the development of new cardiovascular safety assessment methodologies that improve efficiency and cost effectiveness. “The story of rosiglitazone is a cautionary tale that highlights some real shortcomings inherent in the life cycle of drug/device development, evaluation, approval and clinical use,” Brindis pointed out. “The FDA approved rosiglitazone 14 years ago yet we still are lacking conclusive evidence as to its cardiovascular safety. Rehashing the clinical trials data only goes so far. Establishing a real-time surveillance system is critical for ensuring our patients are safe when taking various medications.”
Several panel members referenced the comments ACC submitted ahead of the meeting that recommended the use of registries and trusted third parties and standardizing cardiovascular endpoints for drug safety assessment. The National Cardiovascular Data Registry (NCDR®) is an example of an existing clinical data infrastructure and is considered a trusted third party by both the FDA and industry. While the FDA’s involvement and support of the ACC’s registries to date has focused on medical devices, NCDR Registries, the PINNACLE Registry® in particular, collect a great deal of data pertaining to drugs that could be used to evaluate the safety of drugs taken by patients with cardiovascular disease.
This unique case has the potential to shape how the cardiac safety of drugs is studied and monitored, both before and after approval. “I think the future is bright,” said Brindis regarding next steps. “Hopefully instead of focusing on the controversy surrounding Avandia, this meeting will help us look to the future and how we can enhance our cardiovascular community. The ACC looks forward to working with the FDA, researchers and industry in harnessing the power of national registries along with improving methodologies to better assess cardiovascular safety of promising pharmaceuticals.”
The debate surrounding rosiglitazone began in 2007 when a New England Journal of Medicine article raised concerns about cardiovascular complications associated with rosiglitazone. The ACC, American Heart Association and American Diabetes Association released a statement following the publication of the article. In 2010, the ACC and the American Heart Association released a Science Alert on “Thiazolidinedione Drugs and Cardiovascular Risks” to help cardiologists provide high quality care to diabetes patients.
Keywords: Risk Management, Risk, Safety, United States Food and Drug Administration, Cardiovascular Diseases, Risk Factors, Advisory Committees, Diabetes Mellitus, Thiazolidinediones
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