Small Clinical Trials: Issues and Challenges

he design and conduct of any type of clinical trial requires three considerations: first, the study should examine valuable and important biomedical research questions; second, it must be based on a rigorous methodology that can answer a specific research question being asked; and third, it must be based on a set of ethical considerations, adherence to which minimizes risks to individuals. Whenever possible standard trial designs should be used in clinical trials. Moreover, investigators should strive to design clinical trials that contain adequate statistical power. However, there are times when the number of experimental subjects is unavoidably small. For example, the rapid progress that is occurring in a variety of areas of science (e.g. biotechnology, organ transplantation, gene therapy, cellular therapies, bioartificial organs, and designer genes tailored to an individual) has resulted in the need for clinical trials with small numbers of participants and new approaches to optimization of the design and analysis of clinical trials when the number of experimental participants (the sample size) in unavoidably small. Clinical trials with small numbers of participants, however, must address broad sets of issues different from those that must be addressed in trials with large numbers of participants. It is in those circumstances of trials with small sample sizes that approaches to optimization of the study design and data interpretation pose greater challenges. Copyright © National Academy of Sciences. All rights reserved. Small Clinical Trials: Issues and Challenges http://www.nap.edu/catalog/10078.html x PREFACE Clinical trials involving astronauts share characteristics with clinical trials of the new technologies mentioned above, as astronauts comprise a population with small numbers of subjects, and many variables that affect this group during space travel cannot be controlled on Earth. However, interventions that prevent potentially life-threatening conditions such as accelerated bone mineral density loss on long space missions must be explored if long missions in space are to be successful. Therefore, the National Aeronautics and Space Administration (NASA) asked the Institute of Medicine (IOM) to convene a panel of experts to recommend optimal approaches to the design, implementation, and evaluation of outcomes in clinical trials with small numbers of participants. NASA commissioned this fast-track study because the opportunity to plan for the next clinical trial during a space mission was rapidly approaching and important questions needed to be answered. A group of experts in statistics, clinical research study design, epidemiology, and pharmacology made a major effort to prepare what I believe will be a widely useful report. Robert Gibbons, a biostatistician and liaison from the IOM Board on Health Sciences Policy, participated throughout the study as a full committee member. A centerpiece of the committee’s activity was an invitational workshop. Experts from the United States and Canada spent a full day providing additional information and expertise to the committee during the invitational workshop discussing future directions for small clinical trials with small numbers of participants. Their efforts were particularly important in helping the committee prepare this report. After careful consideration the committee developed recommendations for approaching the issues and challenges inherent in clinical trials with small sample sizes. Moreover, the design and implementation of future research in this newly developing area of clinical investigation will improve the ability of investigators to evaluate outcomes efficiently and in a cost-effective manner to allow advances in medicine to be available to patients with life-threatening diseases in an efficient manner. Finally, the IOM staff, led by Charles Evans, contributed significantly to the final outcome. We owe a tremendous gratitude to Kathi Hanna, a highly skilled science writer, and to Veronica Schreiber, the research assistant on the project, for their untiring efforts and assistance to the committee throughout all phases of the study.

 Suzanne T. Ildstad
Committee Chai