December 15, 2017
Authored and Edited by Jorge F. Gonzalez; Shana K. Cyr, Ph.D.
On December 15, 2017, FDA released draft guidance on “Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease.” Molecular subsets occur when a disease is caused by a range of molecular alterations in patients’ DNA, RNA, or protein. Some subsets of a disease are more prevalent than others, and targeted therapies may or may not work for multiple subsets. In the draft guidance, FDA discusses (1) how to identify and group patients from different subsets of a disease for clinical trials, (2) whether clinical trial results with one subset may be extrapolated to other subsets, (3) what should be included in the drug label in such instances, and (4) circumstances where the approved population may be expanded or narrowed.
First, FDA will allow sponsors to group patients with different molecular alterations for clinical enrichment strategies if the patients are reasonably expected to have similar pharmacological responses based on a strong scientific rationale. Sponsors can support their grouping strategies with the following exemplary evidence, listed in order of decreasing strength: clinical studies, nonclinical studies, in silico or mechanism-based evidence, evidence from other drugs in the same pharmacological class, and phenotypic characterization of molecular alterations.
Second, sponsors may be able to extrapolate their clinical trial results to multiple subsets. Depending on the strength of the evidence supporting the sponsor’s grouping strategy, FDA may approve the drug for all patients who meet the inclusion criteria, even if the trials did not involve patients from all subsets.
Third, when FDA approves a drug for multiple subsets, the label should reflect the approval: the INDICATIONS AND USAGE statements should be sufficiently broad to include all approved subsets; the CLINICAL PHARMACOLOGY or CLINICAL STUDIES section should specify the basis for the grouping; and the CLINICAL STUDIES section should provide evidence supporting the drug’s efficacy for each subset. When accurate testing for molecular alterations is essential for the safe and effective use of the drug, an assay for identifying patients in the clinical setting should be commercially available.
Fourth, after approval, FDA may expand or narrow a patient grouping based on, for example, observational studies, randomized trials, registry data, or other post-marketing data. The amount and nature of clinical efficacy data needed to expand the grouping depends on the similarity of pharmacologic responses and the mechanistic rationale for the drug’s effect in the initial population and the expanded population. Conversely, if emerging data indicates lack of efficacy in a subset, FDA will consider narrowing the intended population to remove that subset.
Readers are encouraged to read the draft guidance, available on FDA’s website. Comments on the draft guidance should be submitted by February 13, 2018, to ensure that FDA considers them before beginning work on the final version of the draft guidance.
drugs, Food and Drug Administration (FDA), FDA Guidance, 505(b)(2) application, Investigational New Drug Application (INDA), new drug application (NDA)
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