'N of Few' - Clinical Trial Design for Small Cohorts

The vast majority of clinical trials are designed with a relatively large population in mind, but trials in the rare and orphan disease space lack the privilege of a broad participant selection. Designing a trial for 15 participants, as opposed to 1,500, presents unique challenges from start to finish – what strategies can be used in recruiting participants from a small population? How do researchers determine statistical significance and side effects with so few subjects? How can researchers ensure safety in a small cohort study?