Washington Editor

SILVER SPRING, Md. - Companies investigating new drugs and biologics to treat diabetes should be required to routinely conduct additional preapproval testing of their products to rule out cardiovascular risks, a panel of experts told the FDA Wednesday in a 14 to 2 vote.

However, the agency's Endocrinologic and Metabolic Drugs Advisory Committee was split on whether drugmakers should be required to conduct a single long-term preapproval trial or something like a two-step study, which would consist of a preapproval screening assessment followed by a postapproval confirmatory study.

All drugs currently approved by the FDA to treat diabetes are indicated to improve glycemic control and are approved on the basis of hemoglobin A1c.

But concerns have been raised in recent years about cardiovascular effects linked to the therapies, specifically to a class of drugs known as thiazolidinediones.

The focus on cardiovascular safety of antidiabetic drugs is further heightened by the fact that patients with Type II diabetes have a two- to fourfold greater risk of cardiovascular mortality compared with those without the disease.

A meta-analysis published last year in the New England Journal of Medicine showed that patients taking GlaxoSmithKline plc's thiazolidinedione drug Avandia (rosiglitazone) had a 43 percent greater risk of myocardial infarction than those taking other treatments for diabetes or a placebo.

In response to the Avandia safety concerns, lawmakers and consumer groups have pressed the FDA to require cardiovascular studies for all diabetes drugs before the products are approved.

Leading the charge has been Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic Foundation in Ohio, who co-authored the meta-analysis.

Avandia was approved in 1999 without any cardiovascular outcomes data, he noted. In fact, Nissen said, no robust cardiovascular outcomes data exist for any current diabetes therapies.

Researchers have been forced to rely on meta-analyses or post hoc data from randomized trials that were not designed to determine the cardiovascular benefits or risks of diabetes drugs, he said.

In the absence of randomized cardiovascular outcomes trials, Nissen lamented, researchers and regulators are left with unsatisfactory methods to assess the benefits and risks of diabetes drugs.

Nissen, who made a presentation Tuesday before the FDA committee, told reporters Wednesday that he supported the two-step process of a preapproval screening assessment and a postapproval confirmatory study, which he called a "rational" approach that would ensure safety while not delaying the entrance to the market of needed new therapies.

However, he said such studies must be conducted over a reasonable amount of time to rule out concerns.

But panelist Eric Felner, a pediatric endocrinologist at Emory University School of Medicine in Atlanta - one of the two panelists who voted against mandatory preapproval cardiovascular studies - argued that requiring drugmakers to conduct such trials could leave patients waiting several years for a product that is potentially "better that what we have now."

Even the two-step screening-confirmatory trial could delay a product by more than two years, he added. Requiring a single preapproval cardiovascular study, Felner asserted, could result in a five- to seven-year delay.

But Nissen contended that it is in drugmakers' best interests to conduct the cardiovascular trials because such studies not only could rule out the risks, but may in the end show that the drugs reduce cardiovascular events.

There currently is no conclusive evidence of such a reduction of those risks with the drugs in patients with Type II diabetes, regulators said. However, intensive glycemic control appears to reduce cardiovascular complications in patients with Type I disease.

Companies, Nissen said, "are going to be hell-bent to be the first to claim" their drug reduces cardiovascular risks.

Although they did not vote on requiring that preapproval studies show a benefit of reducing cardiovascular risks, most on the panel said they were against such a requirement.

The FDA is not required to follow the advice of its advisory panels, but generally does so.

John Jenkins, director of the FDA's Office of New Drugs, told reporters that the agency would consider all of the advice of the panel. He could not provide a timeline of how soon the agency would act on the advice.

Alan Moses, global chief medical officer for Novo Nordisk AS, one of the world's largest developers of diabetes treatments, urged regulators to carefully consider the implications of requiring large-scale outcomes studies prior to drug approval for drugs that do not have a signal of cardiovascular toxicity in preclinical and clinical testing.