Complexity and contradiction in clinical trial research.

Randomized clinical trials have become the accepted scientific standard for evaluating therapeutic efficacy. Contradictory results from multiple randomized clinical trials on the same topic have been attributed either to methodologic deficiencies in the design of one of the trials or to small sample sizes that did not provide assurance that a meaningful therapeutic difference would be detected. When 36 topics with conflicting results that included over 200 randomized clinical trials in cardiology and gastroenterology were reviewed, it was discovered that results of randomized clinical trials often disagree because the complexity of the randomized clinical trial design and the clinical setting creates inconsistencies and variation in the therapeutic evaluation. Nine methodologic sources of this variation were identified, including six items concerned with the design of the trials, and three items concerned with interpretation. The design issues include eligibility criteria and the selection of study groups, baseline differences in the available population, variability in indications for the principal and concomitant therapies, protocol requirements of the randomized clinical trial, and management of intermediate outcomes. The issues in interpreting the trials include the regulatory effects of treatments, the frailty of double-blinding, and the occurrence of unexpected trial outcomes. The results of this review suggest that pooled analyses of conflicting results of randomized clinical trials (meta-analyses) may be misleading by obscuring important distinctions among trials, and that enhanced flexibility in strategies for data analysis will be needed to ensure the clinical applicability of randomized clinical trial results.