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

J Clin Epidemiol. 2005 Aug;58(8):785-90. doi: 10.1016/j.jclinepi.2004.11.028.


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.

MeSH terms

  • Cyclooxygenase Inhibitors / adverse effects
  • Double-Blind Method
  • Drug Evaluation / methods
  • Drug-Related Side Effects and Adverse Reactions*
  • Gastrointestinal Diseases / chemically induced
  • Humans
  • Outcome Assessment, Health Care / methods
  • Randomized Controlled Trials as Topic / methods*
  • Research Design
  • Sample Size
  • Statistics as Topic


  • Cyclooxygenase Inhibitors