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J Biopharm Stat. 2019 Aug 27:1-13. doi: 10.1080/10543406.2019.1657441. [Epub ahead of print]

Statistical considerations for rare diseases drug development.

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Department of Biostatistics and Bioinformatics, Duke University School of Medicine , Durham , North Carolina , USA.
Department of Biostatistics, BeiGene, Ltd ., San Mateo , California , USA.


One of the most challenges for rare disease clinical trials is probably the availability of a small patient population. It is then a great concern on how to conduct clinical trials with a small number of subjects available for obtaining substantial evidence regarding safety and effectiveness for approval of the rare disease drug product under investigation. FDA, however, does not have the intention to create a statutory standard for approval of orphan drugs that are different from the standard for approval of drugs in common conditions. Thus, it is suggested that innovative trial designs such as a complete n-of-1 trial design or an adaptive design should be used for an accurate and reliable assessment of rare disease drug products under investigation. In this article, basic considerations, innovative trial designs, and statistical methods for data analysis are discussed. In addition, some innovative thinking for the evaluation of rare disease drug products is proposed.


N-of-1 trial design; Substantial evidence; adaptive design; historical control; probability monitoring approach; reproducibility

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