Sponsors of new type 2 diabetes therapies should be required to provide clinical data that can exclude an unacceptable cardiovascular risk prior to approval, FDA's Endocrinologic and Metabolic Drugs Advisory Committee concluded at a July 1-2 meeting.

The committee expressed concern that the current clinical development process for diabetes therapies does not rigorously assess potential cardiovascular risk, voting 14-2 that long-term clinical data should be required for all anti-diabetic drugs or biologics - even those that have not shown any cardiovascular risk during Phase II/III development.

"The current pre-approval process is insufficient to rule out cardiovascular risk in a disease where cardiovascular morbidity and mortality is so prevalent," temporary member Eric Holmboe, American Board of Internal Medicine, said.

"This makes good clinical sense that you would want to [know] this because, if it causes harm, it could definitely change the risk/benefit ratio."

The committee emphasized, however, that sponsors should only be required to show a lack of cardiovascular risk commensurate with the product's microvascular benefits - rather than demonstrate cardiovascular benefit.

To date, all type 2 diabetes agents have been approved on the basis of glycemic control; none have clearly demonstrated improvement in macrovascular outcomes.

Nonetheless, the expectation that sponsors address the potential for cardiovascular risk pre-approval represents a significant shift from FDA's current regulatory standards for diabetes applications.

"It is a higher level of understanding and a higher level of assurance that you have excluded an unacceptable cardiovascular risk," Office of New Drugs Director John Jenkins said after the meeting.

"The committee didn't specifically define what an unacceptable risk would be, but they clearly voted that they wanted us to require studies that would give us that assurance."

Office of Medical Policy Director Robert Temple added that such a requirement was rare. "There are not a lot of drugs where you need large-scale cardiovascular outcome data at the time of approval," he said. "You can see that people developing non-steroidal anti-inflammatory drugs are getting that kind of data for obvious reasons - because there has been nervousness about that."

The emergence of cardiovascular problems with anti-diabetics like GlaxoSmithKline's Avandia (rosiglitazone) and Bristol-Myers Squibb's Pargluva (muraglitazar) raised safety concerns and even called into question the approval standards for a disease where the majority of patients die from heart problems (¹ Also see "Avandia Concerns Highlight Need To Change Diabetes Approval Standards" - Pink Sheet, 13 August, 2007., p. 7).

Temporary member Peter Savage, National Institute of Diabetes and Digestive and Kidney Diseases, emphasized that adding a more formal cardiovascular assessment to reviews is essential to obtaining the necessary information for conducting risk/benefit analyses in this therapeutic category.

"A more structured system is the only way we are going to really get the type of information we need to be sure that we don't at some time in the future make a serious mistake and let something slide through," he said.

While preferring that cardiovascular risk be characterized pre-approval, the panel recognized practical limitations to such an approach and suggested a variety of study types to evaluate a potential signal that would straddle both pre- and post-approval timeframes. Such approaches include conducting a screening trial followed by a full outcomes trial post-approval, doing an interim analysis of a full outcomes trial, or pooling data from similar trials.

If the pre-approval data sufficiently rule out a predetermined degree of risk, a post-approval confirmatory study may not be needed, the panel suggested.

Meeting participants generally agreed that cardiovascular outcomes trials should evaluate hard endpoints, such as myocardial infarction, death and stroke. They further suggested that trials should evaluate high-risk diabetes patients in order to increase the event rate and be long-term in nature, with several members suggesting that five-year confirmatory trials are reasonable.

- Brian Marson (b.marson@elsevier.com)

Diabetes Therapies Need Cardiovascular Safety Data For Approval, Panel Says

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