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.

中文翻译：

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罕见病药物开发的创新设计和分析。

罕见病药物开发的最大挑战之一可能是患者人数少的疾病患者的可用性。因此，非常关注如何在数量有限的受试者中进行临床试验，以获取有关批准所研究药物的有效性和安全性的大量证据。对于罕见病药物开发，FDA表示，FDA无意制定与一般情况下的药物批准标准不同的法定孤儿药物批准标准。在这种情况下，必须采用创新的思想和方法来获得批准罕见病药品的大量证据。本文讨论了罕见病药物开发的基本注意事项。概述了创新的思想，即在有限的可用科目下展示非无效而不是有效性。此外，提出了一种创新的方法，该方法采用了两阶段自适应无缝试验设计，并结合了真实数据和真实证据的概念，不仅获得了批准罕见病药品的大量证据，而且还满足了与通常情况下的药品相同的标准。在两阶段自适应无缝试验设计中，还讨论了基于创新概率监测程序的罕见病临床试验的样本量计算。提出了一种利用两阶段自适应无缝试验设计并结合实际数据和真实证据的概念的创新方法，不仅可以获取批准罕见病药品的大量证据，而且还可以达到相同的标准作为一般条件下的药品。在两阶段自适应无缝试验设计中，还讨论了基于创新概率监测程序的罕见病临床试验的样本量计算。提出了一种采用两阶段自适应无缝试验设计并结合实际数据和真实证据的概念的创新方法，不仅可以获取批准罕见病药品的大量证据，而且还可以达到相同的标准作为一般条件下的药品。在两阶段自适应无缝试验设计中，还讨论了基于创新概率监测程序的罕见病临床试验的样本量计算。