How Should Efficacy Be Evaluated in Randomized Clinical Trials of Treatments for Depression?

The present system of conducting studies of promising antidepressant therapies has evolved through the collaborative efforts of government, industry, and academicians and is costly and inefficient. At least one third of the published clinical trials of approved antidepressants are negative for efficacy, which can be partly explained by the clinical and neurobiological heterogeneity of the depressive disorder and partly because of methodological inadequacies. Unfortunately, too little attention is given to ensuring the reliability of diagnoses and dependent measures, sample sizes are seldom large enough to detect modest yet honestly significant differences, and too many trials are pursued before dose-response characteristics are fully understood. At present, the only data beyond 1 year of treatment—and the only evidence about protection against recurrent depression—come during postmarketing or phase 4 of the drug development process. Moreover, efficacy data for depressed children and adolescents, bipolar depression, psychotic depression, dysthymia, and frail or medically ill elderly patients are rarely available at the time a drug is introduced. Thus, it is remarkable how little clinicians know about a new antidepressant at the time it is first approved for general use. Within a research strategy, tactics that ensure reliability, encourage attention to adherence, and lessen attrition at the outset of a study will increase the power and design sensitivity of a particular trial. Additionally, the issues of research funding—including division of the research pie—and the relationship of the Food and Drug Administration and investigators to the pharmaceutical industry and the National Institute of Mental Health need to be revisited. Finally, extension of a compound’s patent life might be considered to expand the necessary postmarketing research. This article describes the process of conducting the clinical trials that support a New Drug Application, discusses issues in evaluating efficacy, and offers suggestions for modifying and improving the drug development process so that clinicians can better judge new drugs.