FDA sheds light on conducting human radiolabeled mass balance studies
The US Food and Drug Administration (FDA) has issued draft guidance outlining the clinical pharmacology considerations for human radiolabeled mass balance studies for investigational drugs, including when to conduct the study, the study design, and what elements to include in the study report.The draft guidance, issued on 5 May, does not cover animal mass balance studies, safety testing of drug metabolites or recommendations for selecting the radioactive dose. (RELATED: CDER unveils 30 planned guidance documents in 2022 agenda, Regulatory Focus 07 February 2022)
FDA said mass balance studies are generally needed for all new molecular entities but if a study is not conducted, the sponsor should provide the agency with an “adequate justification.” The agency noted that a mass balance study might not be recommended in cases in which mass balance study results can obtained from the literature for existing product labeling. Additionally, some drugs, such as monoclonal antibodies, have known metabolism and elimination pathways. Mass balance studies also may not be needed for drugs where 90% or more of the dose is received in the urine as the unchanged parent drug with minimum metabolism or for drugs with no or negligible systemic exposures.
FDA advised that the mass balance studies should be conducted before initiating a late-phase clinical trial so that the findings can be incorporated into the overall development program.
Mass balance studies are generally non-randomized and open label and are conducted in healthy adult subjects. These studies should include at least six evaluable subjects, according to FDA.
The draft guidance calls for the absorbed dose of radioactivity to be estimated via dosimetry calculations based on animal data unless the administered radioactivity dose is less than 1,000 nCi.
“The position of the radioisotope should be chemically and metabolically stable such that the radionuclide is not lost during metabolism, and both the parent drug and metabolites can be detected and quantified,” FDA wrote in the draft guidance. “Two separate labeling positions can be used if needed.”
Obtaining information on the absolute bioavailability of the investigational drug can help interpret the mass balance data and provide better understanding of the overall drug elimination process, according to the draft guidance. In cases where only an oral formulation of a drug is being developed, the absolute bioavailability study and the mass balance study can be combined in a single protocol of a two-part study, provided the two parts of the study have an adequate washout period. FDA suggested a parallel study design for drugs with long elimination half-lives.
FDA also recommends that sponsors perform metabolite profiling to provide information on whether metabolites should be considered for addition drug-drug interaction evaluation.
Draft guidance
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