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

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Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease 1

Guidance for Industry This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page. I. INTRODUCTION AND BACKGROUND 2

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 3

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 influence responsiveness to a particular targeted therapy. However, certain targeted therapies may be effective in multiple groups of patients who have different underlying molecular alterations because the functional effect of the molecular alterations may be similar. Therefore, the 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 1

This guidance has been prepared by the Office of Translational Sciences in the Center for Drug Evaluation and Research in cooperation with the Center for Biologics Evaluation and Research at the Food and Drug Administration. 2

For the purpose of this guidance, a targeted therapy is defined as a drug intended for populations that are subsets of clinically-defined diseases and that are identified by using diagnostic testing. For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological products unless otherwise specified. 3

For the purpose of this guidance, molecular alteration refers to a broad array of molecular changes in DNA, RNA, or proteins, including point mutations, gene fusions, mutational load, epigenetic changes, and over- or under-

expression. Molecular subset refers to a subgroup of the clinically defined disease caused by a specific molecular alteration or group of molecular alterations that are observed in the clinical disease. 1 Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease

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