Description
This guidance provides recommendations to assist industry and other parties involved in the development of antibody-drug conjugates (ADCs) with a cytotoxic small-molecule drug or payload. Specifically, this guidance addresses the FDA’s current thinking regarding clinical pharmacology considerations and recommendations for bioanalytical methods, dosing strategies, dose- and exposure-response analysis, intrinsic factors, QTc assessments, immunogenicity, and drug-drug interactions (DDIs). The principles discussed in this guidance might not be applicable to the development of other types of ADCs (e.g., ADCs with payloads other than cytotoxic small molecule drugs and/or for indications other than oncology).
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
2Specific type of therapeutic protein discussed for DDIs; Focus of biologics DDI evaluation.; ADCs consist of a small molecule drug component conjugated to an antibody.
Products combining drug, device, or biological constituents; Generally recommended for Enhanced Documentation; Requires 14971-based framework incorporating ICH Q9; A drug-device combination where the device constituent part detects ingestion.
Regulatory Context
Regulatory Activities
2BLA application type eligible for reduced fees.
Drug-drug interaction studies to measure unconjugated payload.
Attributes
2DAR of at least one for an ADC
ADC average DAR can be used as one constituent part in the analysis.
Technical Details
Substances
7ADC payload component
Medications that may affect ADC PK via immunogenicity.
Constituent part of the ADC that impacts the efficacy and safety profile.; The small molecule component of the ADC.
Metabolite from the metabolism of the unconjugated payload.
Metabolic enzyme (CYP2D6) impacting clearance.
Transporter (BCRP) impacting pharmacokinetic clearance.
Receptors affecting antibody-dependent cellular cytotoxicity.
Testing Methods
7Recommendations for clinical pharmacology considerations
appropriate to demonstrate BA or BE for complex products
All bioanalytical methods should be validated and reported.
Measuring the unconjugated payload and pharmacologically active metabolites is usually sufficient.
Analyses conducted for safety and efficacy with the ADC and its constituent parts.
Used to assess the effects of organ impairment on the unconjugated payload.
Confirmatory assessment for detecting ADAs.
Processes
2Assessment for the unconjugated payload as inhibitor or inducer.
Absorption, distribution, metabolism, and excretion properties evaluated for extrapolation.
Clinical Concepts
5Evaluation of cardiac safety in ADC development
Assessment of the immune response to the biological product
Evaluation of DDIs for ADCs
Specific subsets of patients in pivotal studies.; Subsets of patients requiring dedicated dosing studies.
Potential safety concern/adverse effect of some antiemetic drugs.
ICH References (3)
Drug concentrations in study samples should be measured in accordance with ICH M10, Bioanalytical Method Validation and Study Sample Analysis.; Bioanalytical method validation and study sample analysis
Clinical Evaluation of QT/QTc Interval Prolongation.
Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization
Related CFR Sections (1)
- 21CFR3.2§ 3.2 Definitions.
For the purpose of this part:Read full regulation →
Related MFDS Guidelines
Korean regulatory guidelines covering similar topics
See Also (6)
- Submissions for Postapproval Modifications to a Combination Product Approved Under a BLA, NDA, or PMA: Draft Guidance for Industry and FDA Staff (Status: Draft)
- Glass Syringes for Delivering Drug and Biological Products: Technical Information to Supplement International Organization for Standardization (ISO) Standard 11040-4: Draft Guidance for Industry and FDA Staff (Status: Draft)
- Current Good Manufacturing Practice Requirements for Combination Products: Guidance for Industry and FDA Staff (Status: Final)
- Comparative Analyses and Related Comparative Use Human Factors Studies for a Drug-Device Combination Product Submitted in an ANDA: Draft Guidance for Industry (Status: Draft)
- Technical Considerations for Demonstrating Reliability of Emergency-Use Injectors Submitted under a BLA, NDA or ANDA: Draft Guidance for Industry and Food and Drug Administration Staff (Status: Draft)
- Questions and Answers on Biosimilar Development and the BPCI Act Guidance for Industry: Guidance for Industry (Status: Final)