The U.S. Food and Drug Administration (FDA) has finalized its guidance on Clinical Pharmacology Considerations for Antibody-Drug Conjugates (ADCs), offering a structured framework for oncology drug developers. Originally issued in draft form in February 2022, the guidance was finalized in March 2024 and focuses on the clinical pharmacology strategies essential for the successful development of these targeted therapies, which deliver cytotoxic small-molecule drug payloads to cancer cells via monoclonal antibodies.
Key Areas of Focus in the FDA Guidance
The guidance provides comprehensive insights into various aspects of ADC development, including bioanalytical methods, dosing strategies, dose- and exposure-response analysis, intrinsic patient factors, QTc assessments of proarrhythmic potential, immunogenicity, and drug-drug interactions (DDIs). It emphasizes the importance of understanding the behavior of specific ADC analytic moieties, such as free and total antibody, free small molecule, linker, and pharmacologically active small molecule metabolites.
Bioanalysis Considerations
The guidance specifies which analytes sponsors should measure at different stages of drug development. For instance, in first-in-human (FIH) studies, it is recommended to measure the ADC, its constituents, and its pharmacologically active metabolites. Later in development, the focus shifts to measuring the ADC, its constituent, and its pharmacologically active metabolites that are quantifiable in systemic circulation to inform exposure-response analyses. The guidance also addresses scenarios where measuring certain ADC constituents or metabolites may be excluded later in development. Of note, if the target is significantly shed, bioanalytical assays need to distinguish the target-unbound from target-bound ADC.
Exposure/Response Analysis
To support dose selection, the FDA recommends conducting exposure-response analyses of clinical trials for safety and efficacy, considering the ADC, its constituents, and any pharmacologically active metabolites. Justification may be provided for not conducting these analyses with an ADC constituent or pharmacologically active metabolites in later development. For ADCs where the antibody target is significantly shed into systemic circulation, exposure-response analyses should focus on the ADC and/or total antibody unbound to the circulating shed target.
Intrinsic Patient Factors
The guidance highlights the importance of evaluating intrinsic factors such as renal or liver impairment, pharmacogenomics, body weight, age, gender, and race, which can influence the exposure of the ADC, its constituent parts, and pharmacologically active metabolites. These factors should be assessed through clinical studies or population pharmacokinetic (PK) analysis. A population PK approach can be used to assess the effects of organ impairment on the unconjugated payload and pharmacologically active metabolites if patients with organ impairment are enrolled in pivotal studies and relevant data are available.
QTc Assessment for Cardiac Safety
The unconjugated payload is identified as the component with potential risk for QT prolongation. The guidance recommends that any ADC QT assessment plan should consider all factors relevant to a small-molecule drug QT assessment. While the ADC is unlikely to interact with the hERG channel due to low circulating payload concentrations, the FDA may request clinical assessment of QT prolongation risk. Studies evaluating QTc prolongation risk have been conducted for brentuximab vedotin in patients with CD30-positive hematologic malignancies and for trastuzumab emtansine in HER2-positive metastatic breast cancer patients.
Drug-Drug Interaction Risk Assessment
ADC development programs should include in vitro DDI risk assessment for the unconjugated payload and pharmacologically active metabolites, evaluating both CYP enzyme- and transporter-related interactions. The FDA may recommend in vivo DDI evaluation of the unconjugated payload and consider physiologically-based pharmacokinetic (PBPK) modeling. The agency may also recommend assessing the DDI potential for the antibody component. Extensive in vitro DDI risk assessment can help rationalize clinical DDI study waivers, and the FDA supports using PBPK modeling to strengthen the evidence. The agency may also borrow drug interaction information from other approved ADCs under certain conditions.
Dosing to Maximize Therapeutic Index
The FDA's Project Optimus and the new guidance emphasize dose optimization principles for ADCs. This is particularly complex due to the dual nature of ADCs, which have both biologic and small molecule components. For example, AbbVie adjusted the dose of telisotuzumab vedotin from 2.7 mg/kg Q3W to 1.9 mg/kg Q2W based on exposure/response relationships to determine the optimal dose.
Implications for ADC Development
This finalized guidance underscores the FDA's focus on a comprehensive understanding of the clinical pharmacology of ADCs. Sponsors should pay close attention to in vitro and in vivo ADME characterization, bioanalytical method strategy, translational PK/PD strategy, dose and regimen selection using exposure/response, concentration/QT assessment, and modeling and simulation strategies.
