Developing Targeted Therapies in Low-Frequency 

Molecular Subsets of a Disease 

Final Guidance for Industry 

What is recommended in this guidance? 

The final guidance, Developing Targeted Therapies in Low-Frequency Molecular 

Subsets of a Disease, provides important recommendations on the development of 

treatments that address molecular alterations that cause or contribute to diseases and !

the type and quantity of evidence that can demonstrate efficacy across patients with 

different molecular alterations, particularly those that are present in a small subset of 

patients. 

Drug Development and Regulatory Considerations 

Determining the Appropriateness of Pursuing a Molecular Subset for Inclusion in Clinical Trials 

Sponsors should justify why the strength of evidence supports the hypothesis that patients with the 

molecular alteration of interest will be more likely to respond to the targeted therapy. 

Generalizability of Findings 

It is acceptable to use an enrichment strategy based on molecular criteria, grouping patients with 

different molecular alterations, if it is reasonable to expect that the grouped patients will have similar 

pharmacological responses based on a strong scientific rationale supported by computational, 

experimental, and/or clinical evidence. In most circumstances, FDA will approve the drug for patients 

who meet inclusion criteria irrespective of the extent to which each subgroup or molecular 

alterations is represented. 

Labeling 

The indication as described in the INDICATIONS AND USAGE section of labeling should be sufficien tly 

broad to include treatment of patients with low-frequency molecular alterations who would have 

been eligible for the trial irrespective of the extent to which they were represented in clinical trials. 

The studies informing the basis for grouping patients (e.g., cell or animal models, PD data) should be 

clearly specified (e.g., in the CLINICAL PHARMACOLOGY or CLINICAL STUDIES section of labeling). 

Refining theTarget Population/Indication After Initial Approval 

Sponsors are encouraged to conduct additional studies in molecular subsets that may respond to the 

drug but were not eligible for inclusion in the original trials. The amount and nature of clinical efficac y 

data needed to expand a drug’s indication depends on the similarity of pharmacologic responses and the 

mechanistic rationale for the drug’s effect in the population for which efficac y was initially established 

and in the population to which the indication is being expanded. In addition, sponsors should collect 

data in the postmarket setting for the subsets of patients with limited or no enrollment in clinical trials to 

provide additional information regarding the risks and benefits of the drug. 

Guidance snapshots are communication tools and are not a substitute for a guidance document. To learn more about 

assessing targeted therapies in low-frequency molecular subsets of a disease, read the guidance: 

https://www.fda.gov/media/117173/download

www.fda.gov 
Before and during clinical development, sponsors should provide strong scientific rationale for how patients with 

different molecular alterations should be grouped for clinical trials. For example, patients with different molecular 

alterations should be expected to have similar response to the targeted therapy based on 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. In general, clinical studies are considered the strongest type of 

evidence to support grouping of molecular alterations for clinical trial enrollment. 

Guidance snapshots are communication tools and are not a substitute for a guidance document. To learn more 

about assessing targeted therapies in low-frequency molecular subsets of a disease, read the guidance:

https://www.fda.gov/media/117173/download

Background About the Guidance 

Targeted therapies are an eff ective treatment option for some 

patients. However, in a population of patients with the same 

clinical disease, the molecular causes may diff er and can

influence response to a particular treatment. In these situations,

it is challenging to demonstrate effi cacy in all possible molecular

subsets, some of which are extremely rare.

Why is this guidance important? 

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Many clinically defined diseases are caused by a range of different 

molecular alterations, some of which occur at low frequencies. Most 

medical treatments are designed for the “average patient” as a one-sizefits-all-approach. In contrast, targeted therapies may be designed to work 

in subsets of patients who have specific molecular alterations because they 

may be more effective or better tolerated in certain patient subsets. FDA 

issued this guidance to provide recommendations for evaluating the 

benefits and risks of targeted therapies in subsets of patients with specific 

molecular alterations within a clinically defined disease that do not occur 

frequently, making them difficult to evaluate. 

Drug Development Timeline – When to Apply 

the Guidance Recommendations? 

Basic 

Research 

Prototype 

Design or 

Discovery 

Preclinical 

Development 

Clinical Development 

Phase I Phase 2 Phase 3 

FDA Filing/ 

Approval 

Post-Market/ 

Post-Approval 

}

Studies 

Before and During Clinical Development 

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