Guidance Snapshot

Clinical Pharmacology Considerations for

Antibody-Drug Conjugates
Final Guidance for Industry

What is Recommended in
This Guidance?
This guidance discusses clinical
pharmacology considerations for
the development of antibody-drug conjugates
(ADCs) with small molecule drugs that are
cytotoxic.

Why Is This Guidance

Important?
ADCs are distinct from both
biologics and small molecule drugs.
There are special considerations for
ADCs due to their unique structure and mechanism
of action. This guidance provides comprehensive
clinical pharmacology recommendations specific What is an ADC?
for ADCs to support the growing number of
ADCs under development. Topics covered in An ADC is generally composed of a small
the guidance include dosing strategies, the molecule drug, also known as a payload,
bioanalytical approach, intrinsic factors, drug- and an antibody or antibody fragment,
drug interactions (DDIs), and more. conjugated together by a chemical linker. As
such, an ADC has multiple constituent parts.
ADCs are designed to target specific cells,
such as cancer cells, while minimizing effects
on non-targeted cells. When the antibody
binds to its target antigen on the cell surface,
the ADC is internalized and the cytotoxic
payload is released to kill the tumor cells.

Guidance Snapshots are a communication tool and are not a substitute for the guidance document.
[Link] To learn more about clinical pharmacology considerations for antibody-drug conjugates,
read the guidance. To see additional Guidance Snapshots, check out the pilot program.
Clinical Pharmacology Considerations During ADC Development
Dosing Strategies dedicated studies. Although dosage adjustment is
challenging for ADCs, the assessment of intrinsic
The payload and antibody parts of an ADC can
factors (e.g., organ impairment) is essential to
independently contribute to safety and/or efficacy.
inform labeling strategy, such as, to avoid dosing
Therefore, selection of optimal dosing strategies
in a specific population.
for ADCs requires careful consideration for the
pharmacokinetics (PK) and pharmacodynamics
of the ADC, the antibody, and the payload. This QTc Assessment
guidance recommends assessing a broad dose QTc assessment is recommended for all ADC
range early during drug development to inform development programs. In general, the antibody
dose selection of the ADC. part of ADC has a low likelihood of direct
ion channel interactions; therefore, the QTc
Bioanalytical Approach assessment should focus on the unconjugated
payload, linker, and any pharmacologically
The bioanalytical assay should be validated. The
relevant metabolites. The principles for
guidance provides recommendations regarding
characterization of QT prolongation risk are similar
which analytes should be measured in different
to those for small-molecule drugs.
dedicated clinical pharmacology studies. If
the antibody’s target is shed into the systemic
circulation, the assay should distinguish the Immunogenicity
target-bound vs. target-unbound ADC. It is important to evaluate immunogenicity to
ADCs and the potential impact on PK, safety,
Dose- and Exposure-Response and efficacy given that ADCs generally have a
relatively narrow therapeutic range. A multi-tiered
Exposure-response analyses support dosage
immunogenicity assessment is recommended.
selection and dosage adjustments. Evaluation
In addition, multiple assays may be needed to
of the ADC and its constituent parts early in
evaluate where the anti-drug antibodies bind to.
drug development is recommended to fully
characterize the exposure-response relationship.
If the target is known to shed into circulation, Drug-Drug Interactions
exposure-response analyses should be An in vitro assessment of DDI risk associated with
conducted with the ADC and/or total antibody drug metabolizing enzymes and/or transporters
that is not bound to the shed target in circulation should be conducted for the unconjugated
as well as those bound to the shed target in payload and relevant ADC constituent parts,
circulation. both as a precipitant and as a substrate. In vivo
studies may be recommended by the FDA based
Intrinsic Factors on the outcomes of the in vitro characterization.
Assessment of the unconjugated payload as a
Any intrinsic factor that has the potential to affect
substrate can be recommended even if systemic
exposure of ADC or its constituent parts should
exposure is low, as a relatively small increase in
be evaluated. These intrinsic factors can be
systemic exposure of the cytotoxic payload could
evaluated through population PK analysis or in
have an impact on safety.

Guidance Snapshots are a communication tool and are not a substitute for the guidance document.
[Link] To learn more about clinical pharmacology considerations for antibody-drug conjugates,
read the guidance. To see additional Guidance Snapshots, check out the pilot program.
 Background of This Guidance
This is FDA’s first guidance document providing clinical pharmacology recommendations
specifically for ADCs. FDA has accumulated decades of experience evaluating a large
variety of ADC applications and has approved 11 ADCs for oncology as of January
2024. This guidance provides FDA’s current thinking regarding the clinical pharmacology
considerations to facilitate the development and approval of ADCs. ADCs are subject to all pertinent laws
and regulations for biological products. Given that ADCs also include a small-molecule drug component,
there are recommendations that are applicable to ADCs that would not necessarily apply to other
biological products.

Drug Development Timeline

* When to Apply the Guidance Recommendations FDA
Filing &
Clinical Approval
Prototype development*
design or Preclinical Postmarket or
Basic
discovery development* Phase 1* Phase 2* Phase 3* Postapproval
Research
Studies

Recommendations in the guidance are applicable from preclinical development through clinical development:
Information and data collected in preclinical assessment and early clinical studies will inform the development strategy
and design of studies in the later stages of ADC development programs. For example, in vitro DDI risk assessement for the
unconjugated payload uisng both drug metabolizing enzyme- and transporter-related assays will inform the need for and
design of in vivo DDI studies. Absorption, distribution, metabolism, and excretion information of the unconjugated payload
from preclinical and early clinical studies will inform whether organ impairment should be evaluated in pivotal studies or in
dedicated studies.

Guidance Recap Podcast

Hear highlights from FDA staff
Speakers:
Qin Sun, PhD, Biologics Lead, and Sarah Ridge, PhD, Policy Analyst, in the Center for Drug Evaluation
and Research (CDER),Office of Clinical Pharmacology.

Click here to
Click here to listen read transcript

Guidance Snapshots are a communication tool and are not a substitute for the guidance document.
To learn more about clinical pharmacology considerations for antibody-drug conjugates,
[Link] read the guidance. To see additional Guidance Snapshots, check out the pilot program.