Small Clinical Trials Issues and Challenges (2001) / Chapter Skim
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Executive Summary
Executive Summary
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, individually tailored therapies, in environments that are isolated, in emergency situations, and in instances of public health urgency. Properly designed trials with small sample sizes may provide substantial evidence of efficacy and are especially appropriate in partic?
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In general, certain types of analyses are more amenable to studies with small numbers of participants, including sequential analysis, hierarchical analysis, Bayesian analysis, decision analysis, statistical prediction, meta-analysis, and risk-1based allocation. Because of the constraints of conducting research with small sample sizes, the committee makes recommendations in several areas: defining the research question, tailoring the study design by giving careful consideration to alternative methods, clarifying sample characteristics and methods for the reporting of results of clinical trials with small sample sizes, performing corroborative analyses to evaluate the consistency and robustness of the results of clinical trials with small sample sizes, and exercising caution in the interpretation of the results before attempting to extrapolate or generalize the findings of clinical trials with small sample sizes.
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This is in contrast to the sample sizes of some large clinical trials, where the number of participants is in the thousands. This report focuses on the issues and challenges presented by clinical trials with very small sample sizes.
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A committee of nine members comprising experts with knowledge in biostatistics, clinical pharmacology, clinical research, ethics, and research design methods reviewed the scientific literature relevant to clinical trials with small sample sizes and held three meetings, including an invitational conference on future directions in clinical trials with small sample sizes. Conference participants consisted of individuals from federal research and regulatory agencies, industry, academia, and other areas of clinical research and practice.
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· Properly designed trials with small sample sizes can contribute to substantial evidence of efficacy and are especially appropriate in particular situations (Box 21. However, the conclusions derived from such studies may require careful consideration of the assumptions and inferences, given the
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A number of trial designs especially lend themselves to use in studies with small sample sizes, including e-of-1 designs, sequential designs, decision analysis-based designs, ranking and selection designs, adaptive designs, and risk-based allocation designs (Box 31. A necessary companion to a well-designed clinical trial is an appropriate statistical analysis of the data from that trial.
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RECOMMENDATIONS Because of the constraints of trials with small sample sizes, for example, trials with participants with unique or rare diseases or health conditions, it is
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Because of the limitations of small clinical trials, it is especially important that the results be reported with accompanying details about the sample size, sample characteristics, and study design. The details necessary to combine evidence from several related studies, for example, measurement methods, main outcomes, and predictors for individual participants should be published.
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In small clinical trials, more so than in large clinical trials, one must be particularly cautious about recognizing individual variability among participants in terms of their biology and health care preferences and administrative variability in terms of what can be done from one setting to another. The diminished power of studies with small sample sizes might mean that the generalizability of the findings might not be a possibility in the short term, if at all.
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Appropriate federal agencies should increase support for expanded theoretical and empirical research on the performances of alternative study designs and analysis methods that can be applied to small studies. Areas worthy of more study may include theory development, simulated and actual testing including comparison of existing and newly developed or modified alternative designs and methods of analysis, simulation models, study of limitations of trials with different sample sizes, and modification of a trial during its conduct.
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Thus, for some trials it might be impossible to definitively answer a research question with a high degree of confidence. In those cases, perhaps the best that one can do is assess the next set of questions to be asked.
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