Toward Patient-Centered Drug Approval for Treatment of Rare Diseases.

Objectives: This commentary seeks to improve the design and analysis of trials undertaken to obtain approval of drugs for treatment of rare diseases.

Methods: Methodological analysis reveals that use of hypothesis testing in the Food and Drug Administration drug approval process is harmful. Conventional asymmetric error probabilities bias the approval process against approval of new drugs. Hypothesis testing is inattentive to the relative magnitudes of losses to patient welfare when types 1 and 2 errors occur. Requiring the sample size to be large enough to guarantee the specified statistical power particularly inhibits the development of new drugs for treating rare diseases. Rarity of a disease makes it difficult to enroll the number of trial subjects needed to meet the statistical power standards for drug approval.

Results: Use of statistical decision theory in drug approval would overcome these serious deficiencies of hypothesis testing. Sample size would remain relevant to drug approval, but the criterion used to evaluate sample size would change. Rather than judging sample size by statistical power, the Food and Drug Administration could require a sample to be large enough to provide a specified nearness to optimality of the approval decision.

Conclusions: Using nearness to optimality to set sample size and making approval decisions to minimize distance from optimality would particularly benefit the evaluation of drugs for treatment of rare diseases. It would enable a dramatic reduction in sample size relative to current norms, without compromising the clinical informativeness of trials.