The effect of poor compliance and treatment side effects on sample size requirements in randomized clinical trials.
Treatment side effects and associated noncompliance have methodological implications vital to the testing of new drugs. In this paper, we quantify the impact of these factors on sample size requirements in clinical trials. In the Lipid Research Clinics Trial, side effects caused treatment group compliance (50.8%) to be lower than placebo compliance (67.3%). Cholesterol reduction among treatment noncompliers was 35.2% of the reduction among compliers. Had treatment group compliance been as high as placebo compliance, 41% fewer patients would have been required to achieve the same statistical power and an expected 31% more coronary events would have been prevented. We conclude: Because they discourage patient compliance, treatment side effects can (1) cause large sample size increases, (2) lead to underestimates of true efficacy, and (3) contribute to potentially invalid negative conclusions in clinical trials. The impact of side effects goes well beyond the complications and patient discomforts with which they are associated.
Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri 63110.
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Schechtman
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Gordon
D002792:Cholestyramine Resin / Q000009:adverse effects / Q000627:therapeutic use; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy; D016032:Randomized Controlled Trials as Topic / Q000379:methods* / Q000706:statistics & numerical data; D012494:Sampling Studies; D016312:Treatment Refusal
D002792:Cholestyramine Resin