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May 18, 2022 Regulatory Affairs

FDA Releases Draft Guidance for Industry on Clinical Pharmacology Considerations for Human Radiolabeled Mass Balance Studies


The FDA’s Office of Clinical Pharmacology within the Office of Translational Sciences released a new draft guidance document that, for the first time, clearly addresses the FDA’s recommendations and expectations for human mass balance studies of investigational drugs. As stated in the guidance, these studies are “… the single most direct method to obtain quantitative and comprehensive information on the absorption, distribution, metabolism, and excretion (ADME) of the drug in the human body.”

A human mass balance study is generally recommended for all new molecular entities and helps elucidate a drug’s ADME including metabolic pathways and identification and quantification of metabolites, the elimination routes and extent for each route, and describes time course for these processes. This information is extremely valuable for understanding and predicting the potential for drug-drug interactions, determining whether renal or hepatic impairment studies are recommended, assessing the absolute bioavailability and evaluating pharmacological and/or toxicological effects of the investigational drug and its metabolites. The guidance also addresses situations where such a study may not be appropriate or necessary.

A human mass balance study should be conducted early in the development program because it provides helpful guidance in the design of pivotal clinical trials and guidance on the overall development strategy for the investigational drug. This guidance provides further clarifications on various aspects of a human mass balance study such as the selection of the most appropriate radiolabel position, dose of the radiolabeled drug, various considerations in the proper design of the study, dose administration and collection, analysis and reporting of data from the study.

This guidance documents categorizes the relevant clinical pharmacology considerations in ten categories. These are study design, study participants, administered radioactivity dose and radiolabel position, investigational drug dose, route of administration and formulation of the investigational drug, determination of absolute bioavailability for orally administered investigational drugs in a mass balance study, recovery, sample collection and handling, parent and metabolites and bioanalysis. Finally, the guidance provides details on how to report the results of the human mass balance study and what information is generally expected by FDA in the New Drug Application (NDA). The FDA has also clarified that information from this study is generally included in Section “12.3 Pharmacokinetics” of the approved prescribing information.

It should be noted that while most of the information was known from several related guidance documents and incorporated as industry best practices, there was no formal guidance from the FDA on this topic. The release of this draft guidance places all the considerations in a single easy to follow document. It also clearly describes FDA expectations for human mass balance studies.

FDA has published this draft guidance and public comments may be submitted to the docket (FDA-2022-D-0113) available at https://www.regulations.gov up to 90 days following publication (Aug 3, 2022).

If you are considering a human mass balance study as part of your new drug development program, you will benefit from discussions and guidance from ProPharma Group’s clinical pharmacology experts. ProPharma Group can help you develop a comprehensive clinical pharmacology strategy to ensure the best possible outcome to help you reach your company objectives.

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