The Value of the Information That Can Be Generated: Optimizing Study Design to Enable the Study of Treatments Addressing an Unmet Need for Rare Pathogens

In traditional phase 3 trials confirming safety and efficacy of new treatments relative to a comparator, a 1-sided type I error rate of 2.5% is traditionally used and typically leads to minimum sizes of 300–600 subjects per study. However, for rare pathogens, it may be necessary to work with data from as few as 50–100 subjects. For areas with a high unmet need, there is a balance between traditional type I error and power and enabling feasible studies. In such cases, an alternative 1-sided alpha level of 5% or 10% should be considered, and we review herein the implications of such approaches. Resolving this question requires engagement of patients, the medical community, regulatory agencies, and trial sponsors.