/>iAntibody Drug Conjugates (ADCs) are a class of small molecule drugs (also known as a payload) and an antibody conjugated together by a chemical linker. ADCs are designed to target specific cells, such as cancer cells, while minimizing the impact on non-targeted, healthy cells. The goal of ADCs is to maximize efficacy and minimize systemic toxicity.
The U.S. Food and Drug Administration (FDA) has already approved several ADCs and more are currently under development, with clinical trials being conducted in relation to same. As discussed in our prior article on the FDA Perspective of ADCs, ADCs are subject to relevant laws and regulations for biological products, including those governing product development under Investigation New Drug exemptions (INDs), testing, and FDA review and approval prior to commercialization and marketing. The FDA approval process includes and necessitates the conduct of clinical trials, which trials need to be designed and conduced so as to be capable of producing clinical data supportive of FDA approval.
In May 2024, FDA issued guidance on the Clinical Pharmacology Considerations for Antibody-Drug Conjugates to address a range of considerations necessary for ADCs under development. While ADCs are subject to the typical laws and regulations for biological products, in the issued guidance FDA emphasized that ADCs are distinct from both biologics and small molecule drugs, requiring special considerations throughout the development process due to their unique structure and mechanism of action.
Accordingly, careful consideration should be given to the design and conduct of clinical trials involving ADCs due to the importance of generating comprehensive clinical data necessary to obtain the investigational drug’s approval.
Drug Development Timeline
FDA’s recommendations in the guidance are applicable during the development phase, commencing with preclinical development through clinical development and Phase 1, 2, and 3 trials.
In its guidance, FDA indicates that information and data collected in preclinical assessment and early studies will inform the ADC’s development strategy and the overall design of later stage studies. For example, FDA provides that an in vitro Drug-Drug Interactions (DDI) risk assessment should inform the need for, and design of, in vivo DDI studies. The absorption, distribution, metabolism, and excretion information from the preclinical and early clinical studies will inform whether intrinsic factors, such as organ impairment, should be evaluated in pivotal studies or in dedicated studies.
ADC Development Considerations
The guidance covers a wide range of considerations when designing ADC studies including:
- Dosing Strategies
- Bioanalytical Approach
- Dose- and Exposure-Response
- Intrinsic Factors
- QTc Assessment
- Immunogenicity
- Drug-Drug Interactions
Many of these considerations impact early stages of development and FDA may recommend conducting additional risk assessments or validations that exceed what is typically required for other drugs early on in the drug development process to ensure a thorough evaluation of the investigational drug and its constituent parts. For example, FDA recommends conducting a multi-tiered immunogenicity assessment to evaluate immunogenicity to ADCs and the potential impact on pharmacokinetics (PK), safety, and efficacy because ADCs tend to have a relatively narrow therapeutic range. FDA may also require multiple assays to evaluate where the anti-drug antibodies bind to.
Clinical Trial Considerations
Because of the increased requirements that commence and are applicable to the early stages of development, it is critical that developers of ADCs carefully structure their drug development programs to ensure that all preclinical studies, along with Phase 1, 2, and 3, studies are appropriately capturing the level of detail and thoroughness which FDA will require when reviewing an IND, and ultimately, an NDA. It is imperative that developers of ADC maintain a strong working relationship with FDA throughout this process and stay informed regarding any new guidance that may impact ADC development.
In addition, ADC developers should establish strong compliance programs, such as conducting frequent internal auditing and maintaining robust standard operating procedures, beginning as early as prototype design and discovery to ensure that the developer, as a clinical trial sponsor, meets all quality system and other FDA requirements.
ADC developers should also pay careful attention when negotiating clinical trial agreements to ensure all early stage preclinical and clinical data, information, and results are protected, confidential, and owned by the sponsor.
