PWI-004 - EVIDENCE SUPPORTING EFFICACY EXTRAPOLATIONS FOR TARGETED THERAPIES ACROSS MOLECULARLY DEFINED SUBSETS OF DISEASES IN THE ABSENCE OF SUBSET-SPECIFIC CLINICAL DATA.

L. Akinola, S. Ridge, M. Pacanowski, I. Zineh, A. Ramamoorthy; U.S. Food and Drug Administration.

Background: Genetic heterogeneity poses significant challenges to the development of targeted therapies. The rarity of some molecular alterations makes it challenging to enroll enough patients in clinical trials and robustly confirm efficacy based on clinically meaningful endpoints. Sometimes, rare molecular alterations cannot be studied in clinical trials, and efficacy findings are extrapolated based on other evidence. The FDA’s guidance, “Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease,” provides a framework for extrapolating efficacy across molecular subsets in such cases. Here, we characterized evidence supporting efficacy extrapolations for drugs approved in molecular subsets for which clinical efficacy data were lacking.

Methods: We reviewed new molecular entities (NMEs) approved by the FDA between 2018 and 2022 to identify targeted therapies approved in at least one molecular subset of patients for which there were no direct clinical efficacy data, by cross referencing information on molecular alterations studied in pivotal clinical trials and nonclinical studies, with the approved treatment population (Fig. 1). For these, we then determined what evidence supported their approvals in the absence of clinical efficacy data for those patient subsets.

Results: Of the 247 NMEs approved between 2018 and 2022, 33 drugs were targeted therapies. Of these, 5 drugs were approved for specific variants within a gene (i.e., single nucleotide variants), 12 for variants in a gene region (i.e., exon/intron/codon), and 16 for genetic structural variants (i.e., gene fusions and rearrangements) (Fig. 1). Among these, 24 drugs were broadly approved in at least one molecular subset of patients with no direct clinical efficacy data based on scientific principles in the guidance, including: mechanistic rationale, evidence from nonclinical assays, evidence from other drugs in the same pharmacological class, and molecular grouping in clinical trials, and were supported by clinical evidence of efficacy in other studied subsets.

Conclusion: This highlights that the guidance framework can be utilized to support the approval of targeted therapies across molecular subsets in the absence of subset-specific clinical data, allowing patients with rare genetic alterations access to treatments.