Insights into the molecular basis of disease have led to the development of targeted therapies. Often, the pharmacological effect of a targeted therapy is related to a particular molecular alteration. Many clinically defined diseases are caused by a range of different molecular alterations, some of which may occur at low frequencies, that impact common proteins or pathways involved in the pathogenesis of diseases. In a population of patients with the same clinical disease, the heterogeneity in the molecular etiology may result in different responses to a particular targeted therapy. However, certain targeted therapies may be effective in multiple groups of patients who have different underlying molecular alterations. Therefore, FDA is providing guidance on the type and quantity of evidence that can demonstrate efficacy across molecular subsets within a disease, particularly when one or more molecular subsets occur at a low frequency.
The purpose of this guidance is to describe: (1) the FDA’s current recommendations on how to group patients with different molecular alterations for eligibility in clinical trials; and (2) general approaches to evaluating the benefits and risks of targeted therapies within a clinically defined disease where some molecular alterations may occur at low frequencies.