Frontier Insights | FDA Clinical Pharmacology Considerations for ADC Drug Development (Part II)

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 Clinical Pharmacology Considerations

Given that antibody-drug conjugates (ADCs) consist of an antibody, a chemical linker, and a payload, evaluating the clinical pharmacology of ADCs may be more complex than that of standalone small or large molecules.
A. Bioanalytical Methods
All bioanalytical methods should be validated and reported in accordance with the FDA guidance Bioanalytical Method Validation (May 2018). Generally, starting from first-in-human (FIH) trials, the ADC, its components, and pharmacologically active metabolites (if applicable) should be quantified. In subsequent development stages, systemic levels of the ADC, its components, and quantifiable pharmacologically active metabolites should be measured as outlined in Section III.B to support dose- and exposure-response analyses. If, during later development, a decision is made to discontinue testing for ADC components or pharmacologically active metabolites, the following should be considered: pharmacokinetic (PK) characteristics from early clinical trials (e.g., total antibody concentration, ADC concentration, and correlations between unconjugated payload and pharmacologically active metabolites); relevant nonclinical pharmacology, PK, or safety data (e.g., nonclinical data); mechanism of action (MOA) data for the ADC; pharmacological activity of the unconjugated antibody; and pharmacological activity of metabolites. Additionally, the impact of exposure-response data for ADC components on safety and/or efficacy should be evaluated.
For example:




  • If sufficiently sensitive assays cannot detect unconjugated payload, the FDA may not recommend its measurement.
  • If the antibody component serves solely as a selective delivery vehicle for the payload (i.e., a carrier) and total antibody concentration is highly correlated with ADC concentration, the FDA may not recommend measuring unconjugated antibody.
Notably, bioanalytical assays for unconjugated payload should be sufficiently sensitive to detect clinically meaningful changes in systemic exposure, even at low levels. Furthermore, if the antibody target sheds into systemic circulation at significant levels, bioanalytical methods should distinguish between unconjugated and conjugated ADC. Refer to Section III.B for additional details on dose- and exposure-response analyses.
The following specialized clinical pharmacology studies describe the quantification of ADCs, their components, and pharmacologically active metabolites (if applicable) using validated bioanalytical methods:
  • Organ Impairment Studies: Measure ADC, unconjugated payload, and pharmacologically active metabolites. If total antibody is relevant to the MOA, its concentration should also be assessed. See Section III.C.1 for organ impairment details.
  • QTc Assessment: Measuring unconjugated payload and pharmacologically active metabolites is typically sufficient. If unconjugated payload exposure is low and unquantifiable, a time-based analysis (e.g., measuring ADC to confirm drug exposure) may be conducted. See Section III.D for QTc assessment details.
  • Drug-Drug Interaction (DDI) Studies: If bioanalytical sensitivity can detect low systemic exposure of unconjugated payload, measuring unconjugated payload and pharmacologically active metabolites is sufficient. If the antibody is predicted to contribute to DDIs via its MOA, measuring ADC or total antibody is recommended in relevant studies. See Section III.F for DDI details.
  • PK Comparability Studies (e.g., manufacturing process changes or formulation modifications): Measure ADC and its components.
B. Dose- and Exposure-Response
To characterize the safety and efficacy of the ADC, its components, and pharmacologically active metabolites (if applicable), exposure-response analyses should complement dose-response assessments. These analyses inform dose selection and adjustment, as described in the FDA guidance Exposure-Response Relationships – Study Design, Data Analysis, and Regulatory Applications (April 2003). In later development, justification should be provided if exposure-response analyses for ADC components or pharmacologically active metabolites are not conducted (e.g., low exposure to payload or metabolites, lack of pharmacological activity of the antibody, or high correlation between total antibody and ADC concentrations). Refer to Sections II.B.1 (Dose Selection During Clinical Development) and II.B.2 (Dosing Strategies Considering Intrinsic and Extrinsic Factors).
Additionally, if the antibody target sheds into systemic circulation to a notable extent, exposure-response analyses for ADC and/or total antibody are needed only when ADC and/or total antibody do not bind to the shed antigen. Considerations for such analyses include:
  • Relative concentrations of antigen-bound ADC versus unbound (free) ADC in circulation.
  • Concentration correlations between antigen-bound and unbound (free) ADC.
  • Potential retention of pharmacological activity by antigen-bound ADC.
C. Intrinsic Factors
Intrinsic factors (e.g., renal or hepatic impairment, pharmacogenomics, body weight, age, gender, race) that may affect exposure to the ADC, its components, or pharmacologically active metabolites (if applicable) should be evaluated through either:
  1. Clinical studies using population PK analysis, or
  2. Dedicated studies.
Specific considerations for organ impairment and pharmacogenomics include:
  1. Organ Impairment Unconjugated payload and pharmacologically active metabolites (if applicable) may be cleared via renal or hepatic routes. Renal or hepatic impairment could alter unconjugated payload exposure, potentially impacting ADC safety and/or efficacy. Thus, per the FDA guidance Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling (May 2003), the effects of renal and hepatic impairment on unconjugated payload PK should be evaluated throughout clinical development. Assessing the impact of organ impairment on ADC or total antibody exposure may also be valuable. For instance, if antibody fragments are present or the ADC molecular weight is <69 kDa, renal elimination may occur. Changes in ADC exposure have also been observed in patients with hepatic impairment. Sponsors should justify the inclusion or exclusion of organ impairment assessments for ADC, its components, and pharmacologically active metabolites (if applicable), considering PK, safety, and efficacy data in the target population. Dose adjustments for organ-impaired subjects are recommended. See Sections II.B.1 and II.B.2 for details.
If organ-impaired patients are included in pivotal trials, PK data, safety, and efficacy informa

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