Powering our way to the elusive side effect: A composite outcome ‘basket’ of predefined designated endpoints in each organ system should be included in all controlled trials

Tugwell, Peter; Judd, Maria G.; Fries, Jim F.; Singh, Gurkirpal; Wells, George A.

doi:10.1016/j.jclinepi.2004.11.028

« Previous Next »Journal of Clinical Epidemiology
Volume 58, Issue 8 , Pages 785-790, August 2005

Powering our way to the elusive side effect: A composite outcome ‘basket’ of predefined designated endpoints in each organ system should be included in all controlled trials

Peter Tugwell
- Institute of Population Health, University of Ottawa, 1 Stewart Street, Room 312, Ottawa, Ontario K1N 6N5, Canada
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Corresponding author. Tel.: 613-562-5800 ext. 1945; fax: 613-562-5659.
Maria G. Judd
- Institute of Population Health, University of Ottawa, 1 Stewart Street, Room 312, Ottawa, Ontario K1N 6N5, Canada
Jim F. Fries
- Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA
Gurkirpal Singh
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
George A. Wells
- Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada

Accepted 30 November 2004.

Abstract

Objective

To review the methodological insights gained from the CLASS and VIGOR coxib trials and make suggestions for primary safety outcomes in future trials.

Study Design and Setting

We reviewed the methodology and findings of recent coxib trials and similar studies that have produced considerable controversy.

Results

There were statistical power problems with the primary and unexpected endpoints in both coxib trials. One approach for decreasing sample size requirements is using composite outcomes, wherein different clinically relevant endpoints are combined. By virtue of increasing the event rate fewer patients are required to detect a relative treatment effect of 50%.

Conclusions

The recent withdrawal from the market of rofecoxib took years; the approach proposed here could shorten this time. It is important to revisit the comprehensiveness of the ability to detect important outcomes. Composite outcomes can be more varied in content, including mortality and morbidity. The proposed basket would consist of predefined designated endpoints in each organ system that could be associated with the population one is treating, and not just expected to be related to treatment. The goal is to anticipate and have a reasonable chance of detecting the unexpected side effect.

Keywords: Outcome assessment, Composite endpoints, Clinical trials, Measurement, Responsiveness, COX-2