Composite Endpoints for Clinical Trials

Abstract

advantages, such as smaller sample sizes, shorter completion times and the summary measure for a treatment effect if more than one outcome is important. However, they are also associated with risks and pitfalls, particularly if basic clinical and statistical requirements are not adequately respected. This article focuses on time-to-event composite endpoints that combine fatal and nonfatal events and aim to demonstrate efficacy of a treatment in long-term trials.The most important issues with the selection of individual endpoint components -the trial conduct, data analysis, interpretation and reporting -are discussed. Composite endpoints should be clinically meaningful and the expected effects on each component should be similar, based on biological plausibility. Surrogates as endpoint components must have been validated, i.e. a correlation to a hard clinical outcome must have been confirmed. Patients need to be followed up on assigned treatment (clinical status permitting) until death or end of planned follow-up in the absence of events, and must not be regarded as 'a trial completer' after occurrence of the first component event. Difficulties in interpretation arise when the results on single components of the composite endpoint go in opposite directions, and when hard clinical outcomes are combined with soft endpoints, particularly if the latter occur much more frequently but are of inferior relevance. Accordingly, all individual components of the composite need to be analysed separately. In this review, several examples from recently published trials are used to illustrate both the principal needs and the inherent problems of using a composite endpoint.More specific regulatory guidelines and better reporting standards are needed. The ultimate goals of a trial with a composite endpoint should be to solve a medical problem and to support clinical decision making, rather than just to provide statistical convenience.

Relative Effectiveness Assessment of Pharmaceuticals: Similarities and Differences in 29 Jurisdictions

“…Relative efficacy: the extent to which an intervention does more good than harm under ideal circumstances, compared to one or more alternative interventions [2] Relative effectiveness: the extent to which an intervention does more good than harm compared to one or more intervention alternatives for achieving the desired results when provided under the usual circumstances of health care practice [2] Surrogate endpoint: a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives [5] Composite endpoint: An endpoint that consists of multiple endpoints that are combined into a new single outcome measure by using a predefined algorithm [6] Health state utility: value assigned to the quality of life in a health state, normally on a scale of 0 (dead) to 1 (full health)…”

Modeling the Cumulative Effects of Social Exposures on Health: Moving beyond Disease-Specific Models

“…However, as the focus of this analysis is on understanding how socioeconomic position impacts the cumulative burden of disease, the number of health conditions described above were summed for each respondent to provide a nominal indicator of their compound health conditions categorized as: 0, 1, 2 or 3+ conditions [43,44,45,46]. …”

Data-driven desirability function to measure patients’ disease progression in a longitudinal study

“…Third, multiple outcomes are likely to have different levels of importance in terms of their relative contribution to the overall score and ascertaining the correct levels of importance can be problematic. Kleist [13] also cautioned that the components in the multiple outcomes should be carefully selected and based on biological plausibility and if surrogate outcomes are used, each one of them should have been properly validated that it correlates with a hard clinical outcome. Ideally, expected frequency of each component outcome should be somewhat similar with extra care in combining hard and soft outcomes, for example, fatal and non-fatal events.…”