ABSTRACT
For rare disease drug development, one of the major challenges is that there are only limited subjects available for clinical trials. FDA (2019), however, indicated that the Agency does not have intention to create a statutory standard for rare diseases drug development. In this case, some out-of-the-box innovative thinking is necessary for obtaining substantial evidence for approval of rare disease drug product. The out-of-the-box innovative thinking includes (i) probability monitoring procedure for sample size requirement, (ii) the concept of demonstrating not-ineffectiveness rather than demonstrating effectiveness, (iii) borrowing Real-World Data (RWD) in support of regulatory approval of rare diseases drug products, and (iv) the use of complex innovative design to shorten the process of drug development. Along this line, Chow and Huang (2020) proposed an innovative approach for rare diseases drug development by first demonstrating not-ineffectiveness with limited subjects available and then utilizing (borrowing) RWD to rule out the probability of inconclusiveness for demonstration of effectiveness under a two-stage adaptive seamless trial design. In this chapter, an innovative approach proposed by Chow (2020) cannot only overcome the problem of small patient population for rare diseases but also achieve the same standard for evaluation of drug products with common conditions.
