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Abstract:
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Clinical development in rare diseases entails unique and important challenges, e.g., choice of control and endpoints and statistical tools, especially in the absence of randomization and blinding and with small sample sizes. The regulatory statutory standard for approval requires substantial evidence. Although regulatory agencies have been flexible within the limits imposed by law, the general consensus is not to lower the bar for rare diseases. This results in increased demand for innovative designs and statistical tools. In this paper, we will examine examples of such innovative designs, e.g., historical-controlled trials, as well as some novel statistical tools, e.g., meta-analysis, matching, simulation, modeling, and Bayesian approaches. In addition, we will discuss how statistics can play a leading role throughout the process of design, analysis, and regulatory submission, review, and approval in rare disease drug development. These considerations lead to opportunities for statisticians to exhibit leadership, not only in proposing statistical tools that can impact business success, but extending to guiding teams toward sophisticated scientific and quantitative thinking.
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