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Heart studies needed for obesity drugs, FDA advisers say

Obesity drugs should be tested for cardiovascular safety, advisers to the US Food and Drug Administration (FDA) said Thursday.

In a 17–6 vote, members of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee said that drug developers should conduct the tests regardless of whether cardiovascular risks were deemed theoretically likely or had shown up in early testing.

Depending on whether and how the FDA chooses to implement the guidance, the decision could boost the expense and duration of clinical testing for obesity drugs. Such a move would probably be controversial, given the paucity of such drugs on the market and the size of the obesity epidemic in the United States. “If the FDA follows through with this vote, we’ve just added another disincentive to the drug companies to come up with obesity drugs,” said committee member Ed Hendricks, medical director of the Center for Weight Management in Roseville and Sacramento, California. “And we desperately need some drugs.”

But others on the committee argued that the history of cardiovascular risks associated with obesity drugs and the large population that would probably take them — about 35% of US adults are obese — warrant added scrutiny. “Attempts to reverse obesity are to some degree blocking key components of metabolism,” added Peter Savage, a senior adviser at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland. “It seems to me there is a deficit of information in this area and we need to learn more.”

It is a situation that highlights the tightrope that the FDA, tasked with ensuring safety and pressured to expedite the path of new therapies to the clinic, faces with nearly all of its drug approvals. The pressure on regulators is particularly intense when it comes to obesity drugs. In 2010, the FDA rejected three such  drugs (see ‘Slim spoils for obesity drugs‘), prompting a hailstorm of criticism from industry, the public, and Congress. One of the rejected drugs — Contrave, made by Orexigen Therapeutics — had been endorsed by FDA advisers, but the FDA ordered Orexigen to complete an additional long-term cardiovascular safety study before approval.

There is precedent for FDA to follow this week’s recommendations: in 2008, the same committee offered similar advice regarding diabetes drugs in the wake of the scandal over rosiglitazone (Avandia), a once popular diabetes drug made by GlaxoSmithKline. Years after the drug was approved, some analyses of clinical-trial data showed an increased risk of heart attack and stroke among diabetics taking the drug. The FDA instituted new guidelines requiring a combination of pre- and post-approval assurances of cardiovascular safety for all diabetes drugs.

It is too early to fully gauge the impact of those requirements on the size and duration of clinical trials, Jean-Marc Guettier of the FDA’s Division of Metabolism and Endocrinology Products told the advisers this week. But he provided some data suggesting that clinical-trial sizes had markedly increased and that there was a shift in the demographics of patients enrolled in the trials. Both factors are to be expected: cardiovascular effects such as heart attacks and strokes are typically so rare that to achieve statistical rigour, researchers need to enrol more patients and enrich their sample for those most at risk for heart trouble, such as older patients and patients with a history of cardiovascular events.


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