FDA advisory panel re-reviews Avandia's cardiovascular safety

by Deborah Toscano 25 Jun 2013
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Earlier this month, a joint meeting of the FDA Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) and Drug Safety and Risk Management Advisory Committee (DSaRM) was held to re-visit the cardiovascular risk profile of Avandia (rosiglitazone). This high profile meeting was held to discuss the readjudication of the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial. The initial analysis of this trial in 2010, which indicated an unacceptable increased risk of major cardiovascular events with Avandia treatment, led to the placement of severe restrictions on the prescription of Avandia in the United States, and the market withdrawal in Europe. An independent readjudication of the trial data was conducted by Duke University and presented to the joint committee. Following the data review, although the panel was divided, the majority said they felt that the cardiovascular risks were not as serious as previously thought, with thirteen of 26 panelists voted to ease restrictions and seven more wanting the restrictions removed entirely. Five members wanted restrictions unchanged, and one panelist wanted the drug pulled from the U.S. market.

While the results could have minor implications for the drug in question, it could have even wider implications for all diabetes drugs, particularly those still in development. The finding at that time from a meta-analysis of 42 trials that Avandia posed a significant cardiovascular risk was a strong influential factor in the FDA’s decision to impose a major change in the regulatory requirements for all new diabetes drugs, that being the conduct of a proper cardiovascular outcomes trial to rule out cardiovascular risk (see briefing documents here). This requirement changed the whole face of the industry, as these trials are enormously expensive and time consuming since it can take many years to follow patients long enough to see the required number of events in order to conclude cardiovascular safety (or lack thereof).   Many potential players got cold feet and dropped out in light of the increased investment required for approval, while others were significantly delayed in their approval as a result, notably Takeda’s Nesina (alogliptin). Takeda submitted the original application back in January 2008; just one month after the new guidance requiring cardiovascular outcomes trials was released. In June of 2009 the FDA informed Takeda that approval would be considered after conducting an additional cardiovascular safety trial. The trial was initiated two months later, and in January 2013, five years from the original application, approval was finally granted. At the time alogliptin was submitted, it had the potential to be the second DPP-IV to market, behind Merck’s Januvia (first to market in 2006) in a close race with AstraZeneca/Bristol-Myers Squibb’s Onglyza (submitted July 2008 and approved July 2009). However, in the meantime, a third DPP-IV, Boehringer’s Tradjenta (linagliptin) received approval, pushing alogliptin back to fourth place.

While it remains to be seen if the FDA will in fact lift some, or all, of the restrictions on Avandia, the bigger question will be the fate of those yet to come. While conclusive clinical evidence of a clean cardiovascular safety profile for any drug is a significant positive, it is especially so for diabetes drugs since these patients are already at increased risk of heart attack or stroke, and this requirement is not likely to go away as long as there are so many unknowns with regard to heart disease. However, in light of this development, the possibility exists that the FDA may have a “change of heart” in approval requirements for new diabetes drugs that do not show any predisposing signal of cardiovascular toxicity, particularly so if the drug also shows evidence of long term clinical benefit beyond simple glucose lowering, with potentially a higher likelihood of pushing the cardiovascular outcomes trial requirement to a post-marketing commitment in such cases. With cardiovascular risk/benefit being a grey area that is extremely difficult to conclusively determine, the results of the 16 or so outcomes trials still ongoing will hopefully provide some valuable information to support evidence based medicine, rather than adding more fuel to this controversial fire. Only time will tell…

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