Clinical trials of new drugs and biologics for type 2 diabetes should put more emphasis on showing that the therapies do not increase the risk of cardiovascular events such as heart attacks, the US Food and Drug Administration has recommended.

The FDA’s new Guidance for Industry on Diabetes Mellitus – Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes, which takes effect immediately, “defines more robust and adequate design and data collection approaches for Phase II and Phase III clinical trials than were previously required”, the agency explained.

Specifically, the guidance recommends these studies demonstrate that new antidiabetic therapies do not raise cardiovascular risk in comparison with existing treatments, particularly when the products are used by “patients of advanced age or by those with advanced diabetes or renal impairment”.

It also advises manufacturers to have any cardiovascular events in their clinical trials analysed by a committee of outside cardiologists (i.e., an independent cardiovascular endpoints committee) “who are unaware of which patients received the tested products and which were on placebo”.

Based on these evaluations, “the FDA can better ensure that product labelling includes comprehensive information on safety and effectiveness”, it stated. “This will enable prescribers and patients to make better-informed decisions on the management of type 2 diabetes.”

Committee recommendations

Last July, the agency’s Endocrinologic and Metabolic Drugs Advisory Committee voted 14-2 in favour of pharmaceutical companies with new diabetes treatments in development carrying out long-term studies of cardiovascular effects or providing equivalent evidence to rule out what the panel felt was an unacceptable risk of heart problems.

According to the FDA, its guidance “has benefited” from the advisory committee’s recommendations. Part of the new thinking is that Phase II and III trials should be “appropriately designed and conducted so that a meta-analysis can be performed at the time of completion of these studies that appropriately accounts for important study design features and patient or study level covariates”

To obtain sufficient endpoints to allow a meaningful estimate of risk, these trials should include patients at higher risk of cardiovascular events, “such as patients with relatively advanced disease, elderly patients, and patients with some degree of renal impairment”, the guidance notes. Sponsors should also supply a protocol describing the statistical methods for the proposed meta-analysis, including the endpoints that will be assessed.

“At this time, we believe it would be reasonable to include in a meta-analysis all placebo-controlled trials, add-on trials (i.e., drug versus placebo, each added to standard therapy), and active-controlled trials, and to preserve the study-level randomised comparison but include, when possible in the meta-analysis, important identifiers of study differences or other factors (e.g., dose, duration of exposure, add-on drugs),” the FDA says.

It is likely, the guidance adds, “that the controlled trials will need to last more than the typical three to six months’ duration to obtain enough events and to provide data on longer-term cardiovascular risk (e.g., minimum two years) for these chronically used therapies”.

Analysts believe the guidance could lead to delayed market entry for some diabetes therapies in late-stage development or awaiting FDA approval. The agency provided written notice of the recommendations to more than 100 manufacturers who have submitted investigational new drug applications for type 2 diabetes treatments.

The FDA continues to evaluate how the guidance will apply to already approved antidiabetic drugs and expects to publish further recommendations on marketed products at a future date. The agency “remains confident that currently marketed antidiabetic therapies are safe and effective when used according to approved labelling and advises patients to work with their healthcare professionals to select the most appropriate therapy to achieve adequate blood glucose control”, it declared.

At the same time, the FDA also pointed out that people with diabetes have a two- to four-times greater risk of heart disease than their non-diabetic counterparts, while “none of the currently approved antidiabetic therapies has been convincingly proven to reduce that risk”.

Because diabetes often requires life-long treatment, “prescribers and patients need to know more about whether their antidiabetic therapies put patients at increased risk of heart attack”, the agency commented.