Because patient safety is paramount, thorough assessment of the risks associated with any new therapy is vital. Nevertheless, in the case of diabetes drugs, a one-size-fits-all approach to evaluating cardiovascular risk may be hindering sorely needed treatments from making their way to market.
Under the FDA’s Guidance for Industry, drug developers must establish an independent cardiovascular (CV) endpoints committee to prospectively adjudicate, in a blinded fashion, CV events during all phase 2 and phase 3 trials.1
The guidance recommends that the cardiovascular (CV) events include CV mortality, myocardial infarction (MI) and stroke. In addition, it recommends the events include hospitalization for acute coronary syndrome, urgent revascularization procedures and possibly other endpoints.1
However, some new diabetes therapies in development may not have mechanisms of action or any early clinical indication of an elevated CV safety risk during phase 2 or phase 3 trials. The question then becomes whether the FDA guidance needs more flexibility in determining which specific CV safety concerns should be pursued in larger premarketing and postmarketing CV outcome trials.
“It is a big issue,” said William R. Hiatt, MD, who is a professor of medicine in the division of cardiology at the University of Colorado School of Medicine in Denver. “Not all diabetes drugs may have exactly the same cardiac risk. It is true that the initial concern on cardiac risk was driven by rosiglitazone, but subsequent independent analyses of the RECORD trial (a large cardiovascular outcome trial of rosiglitazone) resolved most of the cardiac ischemic risk concerns.”
A meta-analysis in 2007 suggested a 43% increase in MI and a 64% increase in death from CV causes with use of rosiglitazone.2 Following that study, the FDA required a black box warning for the drug. In 2010, the agency also restricted its use as part of a Risk Evaluation and Mitigation Strategy (REMS). In November 2013, after the release and discussion of an extensive, independent, FDA-requested readjudication of the RECORD data, the agency lifted some of its restrictions and modified the REMS.
Narrowing the Scope
The diabetes drug liraglutide was recently evaluated by the FDA for an additional indication to treat obesity at a higher dose, said Dr. Hiatt. Further review of the CV risk profile of that drug revealed no indication of increased risk for ischemic heart disease events, but it was associated with an increase in heart rate, suggesting the possibility for cardiac arrhythmias.
“The requirement for any new diabetes drug to undergo extensive pre- or postmarketing study for safety should focus the sponsor’s resources on the specific cardiac and non-cardiac risks to be elucidated. This will allow for the trial design and sample size to focus on the most important safety concerns,” said Dr. Hiatt.
Under the current guidance, the FDA urges drug developers to perform phase 2 and phase 3 clinical trials so that a meta-analysis can be conducted at the time of completion of these studies that accounts for important study design features and patient or study level covariates. It suggests the phase 2 and phase 3 programs include patients at higher risk for CV events, such as patients with relatively advanced disease, elderly patients and patients with some degree of renal impairment.1
“The FDA is motivated by patient safety and keeping it to the highest possible standards,” said Dr. Hiatt in an interview with Endocrinology Advisor. “There is no one single answer. I think we need to have smaller and more targeted studies that allow for investigation of a variety of potentially infrequent but serious adverse events.”