August 07, 2024

On July 18, 2024, the FDA finalized its guidance on human radiolabeled mass balance studies for investigational drugs, providing crucial recommendations for sponsors navigating the drug development process. This guidance is pivotal, emphasizing the inclusion of clinical pharmacology data in premarket applications to ensure new drugs' safety and efficacy.

Key Aspects of the Finalized Guidance

Recommendations for Human Radiolabeled Mass Balance Studies

The FDA underscores that mass balance studies are generally recommended for all new molecular entities (NMEs) to aid in drug development. However, there are specific scenarios where these studies may not be required:

Existing Data: If comprehensive data can be obtained from existing literature or FDA-approved labels, a new study may be unnecessary.

Well-Understood Metabolism: For drugs with well-characterized metabolism and excretion profiles, such as monoclonal antibodies and peptides, a mass balance study might be waived unless significant structural changes are anticipated.

Minimal Systemic Exposure: Drugs excreted unchanged in urine or with minimal systemic exposure may not need a mass balance study.

For drugs where radiolabeled mass balance studies are impractical due to safety concerns or extensive distribution in vital organs, alternatives like animal studies, non-radiolabeled clinical sample analysis, or in vitro methods are recommended.

Timing of Mass Balance Studies

The FDA advises conducting mass balance studies early in the drug development timeline, ideally before late-phase clinical trials. This early timing is crucial for:

Understanding Metabolism and Excretion: Provides essential insights into the drug’s metabolic pathways and excretion routes.

Designing DDI Studies: Informs the design of drug-drug interaction studies.

Identifying Metabolites: Aids in nonclinical safety assessments.

Guiding Impairment Studies: Helps tailor studies for renal and hepatic impairments.

Study Design Considerations

The guidance details specific elements for designing mass balance studies:

Study Type: Generally non-randomized and open-label.

Participants: Should involve healthy adults, with a recommended minimum of six evaluable subjects for reliable results.

Radioactivity Dose: Adhere to safety guidelines and perform dosimetry calculations to estimate absorbed doses.

Investigational Drug Dose: Use the final or anticipated therapeutic dose, with a single-dose study typically sufficient.

Bioavailability: If only an oral formulation is available, combine the mass balance study with an absolute bioavailability study.

Sample Collection: Collect plasma, urine, and feces to assess total radioactivity, parent drug, and metabolites, aiming for over 90% recovery of radioactivity.

Reporting of Study Results

The final report should encompass:

Concentration-time Profiles: For total radioactivity, parent drug, and key metabolites.

Pharmacokinetic Parameters: Descriptive statistics including AUC, Cmax, Tmax, and terminal half-life.

Cumulative Recovery Percentages: Of administered radioactivity in urine, feces, and total excreta.

Biotransformation Scheme: Showing identified metabolites.

Impact on Drug Development

The finalized guidance is set to streamline the drug development process by offering clear, actionable recommendations for conducting mass balance studies. Adhering to these guidelines in regulatory submissions will enhance the quality and reliability of applications, leading to the development of safer and more effective drugs.

Conclusion

The FDA's finalized guidance on radiolabeled mass balance studies represents a significant advancement in the regulatory framework for investigational drugs. By clarifying the importance of these studies and providing detailed instructions on their execution, the FDA aims to improve the drug development process. This guidance not only supports better decision-making but also contributes to the safety and efficacy of new therapeutics, ultimately benefiting both the pharmaceutical industry and patients. Embracing these recommendations can position your organization as a leader in compliance and innovation, making it an attractive partner for clients seeking reliable and effective drug development solutions.