Thursday, July 03, 2008

The Avandia Effect

Type 2 diabetes just entered the new era of drug development.

FDA’s Endocrine & Metabolic Drugs Advisory Committee’s recommended (by a 14-2 vote) that cardiovascular safety become a standard requirement for type 2 diabetes drug candidates.

That pretty much guarantees that FDA will increase the approval requirements for type 2 diabetes drugs—making development of new products all the more expensive. (Read more coverage of the advisory committee meeting in today’s issue of “The Pink Sheet DAILY”.)

That in itself isn’t much of a surprise. As we’ve said previously, FDA was headed in that direction already, having released a post-Avandia draft guidance document much to that effect. Plus, as Office of New Drugs director John Jenkins pointed out after the advisory committee meeting, the recommendations are just an “extension” of what FDA already does for drugs with a safety signal.

But the advisory committee went even further, and recommended cardiovascular outcomes data for all investigational type 2 diabetes products—even those for which no evidence of a cardiovascular risk was seen in clinical development.

That kind of standard requirement for a prospective cardiovascular study is unprecedented in drug development—with the exception of non-steroidal anti-inflammatory drugs. That, in effect, makes diabetes drugs the next NSAIDs. Welcome to the new world of drug development.

Committee members did not agree on how best to study the cardiovascular risk, but threw out a number of options—ranging from a prospective “pooling” of all Phase III studies to a standalone long-term cardiovascular safety study. Other options included extending Phase III studies longer term or conducting pre-approval screening studies.

However FDA decides to move forward, it will be a change over current requirements for a diabetes drug approval, and a higher number of patients exposed to the drug prior to approval. Right now, FDA typically asks sponsors to enroll 2,500 patients in Phase II and III, with 1,500 patients studied for at least one year.

Drug developers did avoid a double-whammy on diabetes drug development: the advisory committee agreed that the surrogate endpoint of hemoglobin A1c levels should remain the standard for demonstrating glycemic control.

That efficacy endpoint was called into question when two long-term studies (ACCORD and ADVANCE) found that aggressively controlling blood glucose in type 2 diabetics at high risk for cardiovascular disease doesn’t result in a statistically significant reduction in either CV events like heart disease and stroke or CV-related death. (We wrote on that fun finding in an earlier post.)

Given all the talk about changing that endpoint, industry got lucky on that one. But when it comes to drug safety, it's not business as usual anymore.

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