Human radiolabeled mass balance studies are the most direct way of gathering quantitative data on a drug’s absorption, distribution, metabolism and excretion (ADME) in the human body, according to draft guidance the FDA issued in early May.

The FDA 11-page guidance says such studies should generally be carried out for all new molecular entities.

The guidance’s considerations for designing mass balance studies and reporting their results covers areas including study design, participants, radioactivity dose, investigational drug dose, route of administration and formulation of the drug, sample collection/handling and determination of absolute bioavailability for oral drugs, among others.

However, there are some situations in which they may not be advised “unless clinical concerns suggest otherwise,” including for:

• Drugs that have acceptable mass balance study results already available;
• Drugs that have known metabolism and elimination pathways based on basic pharmacology and nonclinical ADME information (such as monoclonal antibodies, endogenous substances and analogs);
• Drugs whose doses are nearly fully recovered as the unchanged parent drug in the urine; and
• Drugs with little to no systemic exposure.

Alternatives suggested by the guidance include animal mass balance studies, metabolic profiling using qualitative techniques, urine collection in phase 1 trials and in vitro assessments to characterize the drug’s ADME, but these should be discussed with the agency before being used.

Mass balance studies should be done early and prior to starting late-phase clinical trials at the latest so that data can be collected to inform the overall development program, the guidance says.

Comments on the draft guidance are due by Aug. 3.

Read the full guidance here: https://bit.ly/3L5Mx44.