Small Clinical Trials: Issues and Challenges

Clinical trials have a long history of well established, documented, and validated methods for design, conduct, and analysis. Appropriate study design includes sufficient sample size (n) and statistical power, and control of bias to allow for a meaningful interpretation of the results. The number of participants in a clinical trial should always be large enough to provide a sufficiently precise answer to the research question posed, but should also be the minimum necessary to achieve this aim. Adequately powered randomized clinical trials and double-blinded, randomized clinical trials are generally regarded as the most authoritative research methods for establishing the efficacy of new therapeutic interventions. By allocating sufficient numbers of individuals to groups, for example, experimental or control, investigators can estimate or determine with some degree of certainty the effect of a given intervention. However, when the clinical context does not provide a sufficient number of research subjects for an adequately powered and controlled trial—for example, because treatments are unavailable for a rare disorder or a unique patient population uch as astronauts, or because studies require the participation of patients with terminal or severely debilitating or incapacitating disorders— researchers are often faced with insufficient design and analysis tools that would allow them to move forward. In response to the need for such tools, an Institute of Medicine committee was asked to assess the current methodologies and appropriate situations for conducting clinical trials with small sample sizes. The committee’s report, Small Clinical Trials: Issues and Challenges, contains recommendations that describe approaches that can be taken in the design and analysis of trials involving a small sample of individuals to obtain reliable and valid results.