ABSTRACT
Rare diseases present numerous challenges for drug development in two broad areas: (1) difficulties in study design due to lack of experience and knowledge concerning the disease, possible therapies, and end points; and (2) accrual difficulties due to the small populations from which to draw clinical trial participants. The informational design is a pivotal study in which a subset of the patients are randomly enrolled into an informational cohort to provide randomized controlled information to inform an adaptation at the end of the study, essentially a phase II substudy within a pivotal study. In this section, we briefly review the challenges of development in the rare disease space and describe the informational design and its potential applications, including a proposed new application of choosing the pivotal study end point based on informational cohort data according to prospective rules, possibly circumventing the need for a separate natural history study in the rare disease space.
