FDA Announces Availability of a Draft Guidance Entitled Clinical Pharmacology Considerations for Antibody-Drug Conjugates
On February 8th, 2022, the FDA announced the availability of a draft guidance for industry entitled Clinical Pharmacology Considerations for Antibody-Drug Conjugates. This draft guidance provides recommendations to assist industry and other parties involved in the development of an antibody-drug conjugate (ADC) consisting of a cytotoxic small molecule drug or payload conjugated by a chemical linker to an antibody moiety.
The antibody or antibody fragment of an ADC is selected or engineered against a specific antigen of interest present on the target cell surface, which is ideally unique to the disease state being treated (e.g., a tumor-specific antigen). In general, when the antibody binds to its target antigen, the ADC is internalized through physiological mechanisms (e.g., endocytosis), and the payload is subsequently released to exert its effect in the targeted cell (e.g., the cells expressing the specific antigen of interest) while minimizing effects on non-targeted cells (e.g., the cells that do not express the specific antigen of interest).
ADCs combine the selectivity of an antibody for a specific target with the potency of a small-molecule drug. Selection of optimal dosing strategies for ADCs requires careful consideration of the pharmacokinetic and pharmacodynamic characteristics of the antibody and the payload. Given that payloads are cytotoxic, a relatively small increase in the systemic exposure of the payload can cause significant adverse reactions and is dose limiting from a safety perspective. In addition, the antibody fragment of an ADC could be affected by intrinsic or extrinsic factors that impact efficacy. As a result, having a thorough understanding of the pharmacokinetics and pharmacodynamics of the ADC and its constituent parts early in development and their relationships to safety and efficacy outcomes is crucial to optimize the dose of the ADC. In addition, the impact of the intrinsic and extrinsic factors on the pharmacokinetics, safety, and efficacy of the ADC should always be evaluated in development programs to inform labeling instructions for use in specific patient subsets.
This draft guidance addresses the FDA’s current thinking regarding clinical pharmacology considerations and recommendations for ADC development programs, including bioanalytical methods, dosing strategies, dose- and exposure-response analysis, intrinsic factors, QTc assessments, immunogenicity, and drug-drug interactions.
The “Clinical Pharmacology Considerations for Antibody-Drug Conjugates” guidance is available at https://go.usa.gov/xtf8M. Please refer to the draft guidance for more details. The FDA is publishing this draft guidance to collect additional public comments. You may submit your comments regarding the draft guidance to the docket (Docket No. FDA-2021-D-1051) available at https://www.regulations.gov up to 90 days following publication in the FEDERAL REGISTER. This draft guidance, when finalized, will represent the current thinking of the FDA on this topic. It does not establish any rights for any person and is not binding on FDA or the public. Your comments do make a difference and can impact the outcomes of FDA regulatory policy. Share your knowledge and experience and make your voice count.
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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.