Patient compliance and the conduct and interpretation of therapeutic trials.

Low patient compliance with prescribed treatments is a very common problem in clinical care and can seriously distort the generalizability and validity of controlled clinical trials. Aside from undermining the benefit of any treatment, noncompliance is often, but unpredictably, a marker for adverse patient outcomes independent of any treatment effect. The proper management of compliance in therapeutic trials depends in part on the objectives of the trial. If the purpose of the study is to determine whether a treatment does more good than harm to those who take it ("efficacy"), then noncompliers should be prevented from entering the trial. In a study of "effectiveness" (to determine whether a treatment does more good than harm to those to whom it is offered), quite the opposite approach is required. Regardless of the purpose of the trial, efforts should be made to balance the numbers of low compliers across the treatment groups, compliance should be monitored, and compliance improving strategies should be employed unless the main objective of the trial is to observe natural compliance. In all studies, because of the bias that noncompliance can have on results, the main analysis should include all those entered, whether or not compliant with the treatment regimen.