Innovative design and analysis for rare disease drug development

One of the most challenges for rare diseases drug development is probably the availability of subjects with the diseases under a small patient population. It is then a great concern how to conduct clinical trials with the limited number of subjects available for obtaining substantial evidence regarding effectiveness and safety for approval of the drug product under investigation. For rare diseases drug development, FDA indicated that the Agency does not have the intention to create a statutory standard for approval of orphan drugs that is different from the standard for approval of drugs in common conditions. In this case, innovative thinking and approach for obtaining substantial evidence for approval of rare diseases drug products are necessarily applied. In this article, basic considerations for rare disease drug development are discussed. The innovative thinking of demonstrating not-ineffectiveness rather than effectiveness with a limited number of subjects available is outlined. In addition, an innovative approach utilizing a two-stage adaptive seamless trial design in conjunction with the concept of real-world data and real-world evidence is proposed not only to obtain substantial evidence for approval of rare diseases drug products, but also to meet the same standard as those drug products in common conditions. Under the two-stage adaptive seamless trial design, sample size calculation for rare diseases clinical trials based on the innovative probability monitoring procedure is also discussed.