In a draft guidance issued on 09 March, the US Food and Drug administration (FDA) proposed a new, broader approach to conducting safety evaluations for new drugs to treat type 2 diabetes that looks beyond assessing cardiovascular (CV) risk.
Background
After a meta-analysis published in the New England Journal of Medicine in 2007 raised concerns that the widely-used diabetes drug Avandia (rosiglitazone) could increase the risk of myocardial infraction, FDA issued guidance in 2008 recommending drugmakers evaluate antidiabetic drugs for cardiovascular risk by conducting cardiovascular outcome trials (CVOTs).
In the ensuing years, none of the CVOTs have identified an increased risk of ischemic cardiovascular events. Some of the studies actually demonstrated a decreased risk for cardiovascular events, leading FDA to approve drugs such as Boehringer Ingelheim’s Jardiance (empagliflozin) and Novo Nordisk’s Victoza (liraglutide) to reduce the risk of cardiovascular death in patients with type 2 diabetes.
Draft Guidance
The new four-page draft guidance replaces the agency’s 2008 guidance on evaluating cardiovascular risk in type 2 diabetes drugs, as well as the agency’s 2008 draft guidance on developing drugs to treat or prevent diabetes.
“By following previous FDA recommendations, sponsors have shown that new type 2 diabetes drugs do not have excess ischemic cardiovascular risk, which has provided reassuring cardiovascular safety information for millions of diabetes patients. Now, with this proposed approach, we will have broader, valuable safety information for these medications,” said Lisa Yanoff, acting director of the Division for Metabolism and Endocrinology Products at the Center for Drug Evaluation and Research.
Unlike the agency’s previous guidance, the new draft guidance does not recommend sponsors “uniformly rule out a specific degree of risk for ischemic cardiovascular adverse outcomes.”
In the draft guidance, FDA says that the safety database to support the marketing application of a new drug for glycemic control should include at least 4,000 patient-years of exposure to the drug in Phase 3 studies, at least 1,500 patients exposed to the drug for one year and at least 500 patients exposed to the drug for two years.
The draft guidance also recommends sponsors enroll a broader range of patients with comorbidities and diabetes-associated conditions, including patients with chronic kidney disease and older patients.
Specifically, the guidance calls on sponsors to enroll at least 500 patients with stage 3 or 4 chronic kidney disease, 600 patients with establish cardiovascular disease and 600 patients over the age of 65 in Phase 3 studies. “Recognizing that a given patient could fall into more than one of these three categories, sponsors should aim for at least 1,200 patients with at least one of these conditions,” FDA says.
Despite the broader focus, FDA says sponsors should still pay close attention to cardiovascular events and assess any that occur during a study by adjudication.
Additionally, FDA says that in some cases sponsors may need to “accrue a minimum number of relevant adverse events to exclude a meaningful degree of risk,” and that sponsors should employ “data safety monitoring boards or committees to provide independent oversight of the safety findings from the clinical trials.”
