FDA issues clinical pharmacology draft guidance for antibody-drug conjugates

The US Food and Drug Administration (FDA) on Monday issued a draft guidance on clinical pharmacology considerations for sponsors interested in developing antibody-drug conjugates (ADC). There is currently no guidance addressing these drugs, said the agency.
 
The guidance provides recommendations for ADCs, which are defined as an antibody or antibody fragment conjugated to at least one payload molecule via a chemical linker for treating cancer. They are regulated as biologic-drug combination products. The agency directs sponsors to consult existing guidance in many areas of ADC clinical development.
 
The agency has approved 12 ADCs, including Kadcycla (ado-trastuzumab emtansine) for metastatic breast cancer; Polivy (polatuzumab vedotin) for relapsed or refractory diffuse large B-cell lymphoma; and Adcetris (brentuximab vedotin) for treating relapsed or refractory Hodgkin lymphoma. The latest approval was for Tivdak (tisotumab vedotin-tftv) in September 2021 for treating metastatic cervical cancer. (RELATED: FDA Approvals Roundup: Exkivity, Tivdak, Opzelura, Regulatory Focus, 22 September 2021)
 
The guidance covers bioanalytical methods, dosing strategies, dose and exposure response analyses, QTc assessments, immunogenicity and drug-drug interactions (DDIs).
 
FDA explains that ADCs “combine the selectivity of antibody for a specific target with the potency of a small-molecule drug. Therefore, development pf ADCs requires careful consideration of the differences between the clinical pharmacology of the antibody or antibody fragment and the small molecule.”
 
Agency supports broad dose range studies
 
In terms of dose selection, FDA “strongly encourages broad dose-ranging in first-in-human studies” as well as multiple-dose levels for evaluating these drugs in early phase I or phase II development. In addition, “overall tolerability studies” should be considered in choosing dosing.
 
While it may be challenging to adjust dosages because of intrinsic or extrinsic factors, such as renal or hepatic impairment affecting the drug’s pharmacokinetics, safety and efficacy, the impact of these factors “should always be evaluated in ADC development programs to inform labeling instructions for use in specific patient subsets.”
 
In terms of the bioanalytical considerations, FDA advises sponsors to consult its guidance on bioanalytical method validation issued in May 2018.
 
Sponsors should also conduct exposure-response analyses to help support dose escalation and to adjust dosing, and this analysis should be conducted as per the FDA’s guidance issued in 2003 on exposure-response relationships.
 
An assessment of QT prolongation risk should also be submitted, which should adhere to the principles outlined in FDA’s 2012 guidance for industry on clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs.
 
FDA said that it is important to evaluate the drug’s immunogenic impact on PK, safety and efficacy as “immune responses to an ADC can be generated to any constituent part of the ADC, including the antibody, the payload, or epitopes created by the conjugation’s linker.” The agency directs sponsors to consult the 2014  guidance on immunogenicity assessments for therapeutic protein products. Sponsors should also consult FDA’s 2019 guidance on validating  assays for ADCs,
 
The comment period on the draft guidance is open for 90 days.
 
FDA draft guidance on ADC development