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


METHODS
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.
Tugwell
Peter
P
Institute of Population Health, University of Ottawa, 1 Stewart Street, Room 312, Ottawa, Ontario K1N 6N5, Canada. elacasse@uottawa.ca
Judd
Maria G
MG
Fries
Jim F
JF
Singh
Gurkirpal
G
Wells
George A
GA
D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects; D004311:Double-Blind Method; D004341:Drug Evaluation / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D017063:Outcome Assessment, Health Care / Q000379:methods; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012107:Research Design; D018401:Sample Size; D013223:Statistics as Topic
D016861:Cyclooxygenase Inhibitors