Food and Drug Administration Analysis of Ticagrelor: Using Data From an Enriched Trial to Evaluate Benefit-Risk Difference in an Unstudied Population.

Prognostic enrichment strategies are often used in cardiovascular outcome trials and enroll patients who are at higher risk for cardiovascular outcome events. By increasing the rate of outcome events, prognostic enrichment increases the absolute difference between treatment and control groups for a given risk reduction, making the demonstration of efficacy more efficient.1 However, this strategy poses an important practical question: Can the trial results be generalized to lower-risk individuals? This determination is particularly challenging when the drug poses a serious risk (eg, bleeding), because the benefit-risk balance for drug treatment could conceivably be considerably less favorable in the lower-risk patients than in the enriched populations, and preclude extrapolation of trial results to lower-risk individuals. We discuss here the Food and Drug Administration risk-benefit analysis to inform a regulatory decision regarding the scope of a new indication for ticagrelor (Brilinta, AstraZeneca), a platelet inhibitor originally approved in 2011 for the reduction of major adverse cardiac events (MACE; the composite of cardiovascular death, myocardial infarction [MI], or stroke) in patients with acute coronary syndrome. The new indication for secondary prevention of MACE in patients with a prior MI was approved without imposing any restrictions of use to high-risk patients.In 2015, the Food and Drug Administration received an efficacy supplement, proposing to expand the indication for ticagrelor beyond the acute setting; data submitted in support of this proposal came from the PEGASUS study (The Prevention of Cardiovascular Events in Patients with …