Limitations of Randomized Clinical Trials

Abstract

Randomized clinical trials are essential for determining the efficacy of interventions, but have limitations. The types of limitations discussed in this review may be grouped in 11 categories including incorrect statistical inference, low internal or external validity, misinterpretation of the difference between frequentist and Bayesian statistical approaches, publication bias, that healthy persons with a given condition participate in clinical trials although they are not representative of the population as a whole, the rather short duration (3 to 5 years) that does not give correct estimates of the lifetime effects of the interventions or the legacy effect when participants who receive active therapy derive residual benefit after the end of the study when all participants receive active medication and the tension between the generalizability of the evidence versus the reliability of the findings of different types of clinical trials and the difficulty in applying the findings of randomized clinical trials to individual patients. These limitations are described and illustrated by examples and figures from the literature. In conclusion, this review will be useful to clinical trialists, clinical trial participants and regulatory agents.