Multiple Co-primary Endpoints: Medical and Statistical Solutions: A Report from the Multiple Endpoints Expert Team of the Pharmaceutical Research and Manufacturers of America

Abstract

There are quite a few disorders for which regulatory agencies have required a treatment to demonstrate a statistically significant effect on multiple endpoints, each at the one-sided 2.5% level, before accepting the treatment's efficacy for the disorders. Depending on the correlation among the endpoints, this requirement could lead to a substantial reduction in the study's power to conclude the efficacy of a treatment. To investigate the prevalence of this requirement and propose possible solutions, a multiple-disciplinary Multiple Endpoints Expert Team sponsored by Pharmaceutical Research and Manufacturers of America was formed in November 2003. The team recognized early that many researchers were not fully aware of the implications of requiring multiple co-primary endpoints. The team proposes possible solutions from both the medical and the statistical perspectives. The optimal solution is to reduce the number of multiple co-primary endpoints. If after careful considerations, multiple co-primary endpoints remain a scientific requirement, the team proposes statistical solutions and encourages that regulatory agencies be receptive to approaches that adopt modest upward adjustments of the nominal significance levels for testing individual endpoints. Finally, the team hopes that this report will draw more attention to the problem of multiple co-primary endpoints and stimulate further research.

Power and sample size when multiple endpoints are considered

“…A particular type of testing problem that leads to multiplicity, that of repeated sequential analysis, will not be covered. For recent treatments of the question of multiplicity that cover similar ground to this paper, the reader is referred to Chuang-Stein et al [15] and Offen et al [16].…”

Group-Sequential Strategies in Clinical Trials with Multiple Co-Primary Outcomes

“…However, as the clinical benefit of an intervention is often characterized by a set of (potentially correlated) multiple outcomes, many recent clinical trials, especially in medical product development, have utilized more than one endpoint as co-primary (Often et al, 2007). “Co-primary” in this setting means that the trial is designed to evaluate if the intervention is superior to the control on all of the endpoints.…”

A critical assessment of composite and coprimary endpoints: A complex problem

“…6 In contrast, there are an increasing number of situations where regulatory agencies are requiring demonstration of efficacy in multiple endpoints, all at a 1-sided 2.5% level, where failure to achieve a positive result in any or multiple endpoints is considered treatment failure. 7 For clarity, we will call this the ''simultaneous'' type of multiple coprimary endpoints, because multiple independent outcomes are simultaneously required to be positive in order to establish effect (ie, an effect is demonstrated if there is a significant difference in endpoint 1 and endpoint 2 and endpoint 3). While the requirement that all endpoints be positive in order to establish efficacy means that there is no need to adjust the individual alpha significance levels downwards, adjusting significance levels upwards is also considered statistically unacceptable.…”

“…This problem has been termed ''reverse multiplicity'' to distinguish it from the multiplicity problem discussed above in regards to the single-sufficient coprimary endpoint, and several statistical solutions in this evolving area have recently been proposed. 4,7 For example, one proposed solution is to adjust significance levels as a function of the number of coprimary endpoints and the correlation between endpoints. Statisticians have An ''event'' is defined as the first occurrence following an intervention of one of several predesignated outcomes Example: Following interferon treatment for melanoma, ''disease-free survival'' is defined as the time from treatment to any of the following outcomes: d Melanoma recurrence d Diagnosis of a second primary melanoma d Any-cause mortality Scale/index Clinical signs and symptoms are synthesized into a single outcome measure.…”

“…4 Given the problematic coprimary endpoint, the 2005 recommendations of the Multiple Endpoints Expert Team suggest either trying to identify a single primary endpoint or developing a composite endpoint. 7 Although the term ''composite (or compound) endpoint'' has been used to refer to multiple variables that when combined forms the single primary endpoint of a trial, going forward the term should optimally be reserved for the specific circumstance in which multiple outcomes are synthesized to make a single assessment of each patient. On the other hand, the term ''coprimary endpoint'' best refers to multiple variables, individually assessed across the population under investigation (Fig 2).…”