Considerations for Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease

Abstract

Advances in our understanding of the molecular underpinnings of disease have spurred the development of targeted therapies and the use of precision medicine approaches in patient care. While targeted therapies have improved our capability to provide effective treatments to patients, they also present additional challenges to drug development and benefit-risk assessment such as identifying the subset(s) of patients likely to respond to the drug, assessing heterogeneity in response across molecular subsets of a disease, and developing diagnostic tests to identify patients for treatment. These challenges are particularly difficult to address when targeted therapies are developed to treat diseases with multiple molecular subtypes that occur at low frequencies. To help address these challenges, the US Food and Drug Administration recently published a draft guidance entitled "Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease." Here we provide additional information on specific aspects of targeted therapy development in diseases with low-frequency molecular subsets.

Figure 1.

Types of molecular heterogeneity. A clinically-defined disease may have varying degrees of diversity in the molecular etiology underlying the clinical phenotype including A) uncharacterized molecular etiology, B) known molecular etiology in most patients with a single pathological variant, C) known molecular etiology in most patients with multiple variants, some of which occur at low frequencies, and which in some cases can be grouped into categories based on functional effect or likelihood that they are amenable to treatment with a targeted therapy that has a specific mechanism of action (categories are denoted by shading) and D) known molecular etiology in most patients with multiple variants, all of which occur at low frequencies but may be amenable to grouping.