The choice of a valid primary endpoint is crucial for a randomized controlled trial (RCT) designed to demonstrate efficacy of a new pharmaceutical drug. Recent improvements in medical management, however, have led to a continuous decline in mortality and morbidity for several common disorders, i.e., also in the incidence of clinically relevant outcomes that may be addressed in a drug trial as an endpoint. For example, secondary prevention after myocardial infarction with aspirin, β-blockers, ACE inhibitors, and statins has remarkably lowered the rate of a subsequent cardiovascular event,1 and combination antiretroviral therapy for HIV infection has made mortality even unfeasible as a clinical endpoint.2
As a solution to maintain feasibility of RCTs, particularly those facing low event rates, the investigation of composite endpoints has been introduced and become fashionable in the last few years.Why to use a composite endpoint
A composite endpoint in a RCT consists of multiple single endpoints that are combined in order to confront an investigational drug with a higher number of events expected during the trial. For instance, the primary composite endpoint may include mortality along with nonfatal endpoints such as hospitalization and cardiac arrest in chronic heart failure patients,6 or along with myocardial infarction and stroke in hypertensives.7
The major advantages in using a composite endpoint are: statistical precision and efficiency will be increased8 ; trials become smaller, less costly; and the results of promising new treatments will be available earlier. If more than one outcome is important for efficacy evaluation, a composite endpoint can efficiently deal with the issue of multiplicity.9 A summary measure for drug efficacy can be defined10 (e.g., the assessment of skeletal-related events [SREs] in trials for prevention or treatment of bone metastases).
The selection of composite endpoints has been regarded as "a useful strategy" for registration of pharmaceuticals in the ICH E9 guideline.9 A Points-to-consider document released by the European Agency for the Evaluation of Medicinal Products (EMEA) specifies regulatory requirements.11
Clinical and regulatory requirements
The use of a composite endpoint in a clinical trial is usually justified if the following assumptions are respected:
As a consequence of the third assumption, regulatory authorities require all components of a composite endpoint to be analyzed separately.9,11 One needs to be aware whether a treatment affects all components or just a single outcome.5