Regulatory strategies for ADCs

This is the third in a four-part series about challenges and best practices in developing antibody-drug conjugates (ADCs).

How can we succeed in developing ADC drugs? 

Favorable clinical benefits/risk profiles of ADCs should be demonstrated to the FDA for approval. To enable success, the early stage of drug development is critically important, as it builds preliminary knowledge systems for three core deliverables: target validation, disease selection, and dose optimization. These three deliverables are entangled together with enormous uncertainties given the limited clinical data and information gaps at the early stage of drug development. 

To make critical decisions on the three core deliverables, all available nonclinical and clinical data should be pooled for integrated dose-exposure-response analyses. Knowledge about the target, disease, and dose is built by organizing useful information derived from from all sources. The judicious application of synthesized knowledge in decision-making yields a higher probability of success compared to decisions based on fragmented information or isolated data elements.

Project Optimus: A paradigm shift in anticancer drug development

Project Optimus is an FDA initiative to reform the dose optimization and dose selection paradigm in oncology drug development. In 2021, the Oncology Center of Excellence (OCE) started to enforce “Project Optimus” to require dose optimization of anticancer drugs, after metanalyses suggested that the traditional Maximum Tolerated Dose (MTD) approach might be responsible for the detrimental effect on the overall survival of some PI3K and PARP inhibitors. 

Per Project Optimus, the FDA expects sponsors to optimize the dose at the early development stage before initiating the registrational trial. The FDA defines an optimal dose as one that maximizes the benefit-risk profile of a drug, providing the desired therapeutic effect while minimizing toxicity. When the FDA reviewer team assesses whether a proposed dose is optimal, two simple questions will be asked: Could the dose be higher? Could the dose be lower? If the answers are not a “NO” to each of the two questions with confidence, then further dose optimization will be needed. Failure to comply with Project Optimus may lead to a “Clinical Hold” that may significantly delay the drug development for years.

Special challenges of dose optimization for ADCs

In comparison to the small molecules or monoclonal antibodies, the dose optimization of ADCs is more challenging. The steep dose/exposure-response relationships make it difficult to select doses for randomized dose-finding studies, because the increment may be too small to distinguish the clinical outcomes with a small sample size of subjects. Moreover, the structural complexity of ADCs leads to the liabilities of both antibody and small molecules in drug-drug interaction, immunogenicity, and bioanalytical assays (for ADC, antibody, and free payload). Therefore, more thoughtful considerations and proactive planning are needed for ADC development to facilitate drug development.

Seamless design for ADC drug development

Seamless design aims to develop ADC drugs in the shortest time with limited resources, which is critically important for sponsors. The most important step from the regulatory perspective is the randomized dose-finding study, which should be designed as randomized (preferably blinded) with at least two dose levels, 20-40 per dose cohort in a clearly defined patient population. The sponsor should reach agreements with the FDA on 1) the design (dose selection sample size, disease definition, and clinical efficacy endpoints) before the study initiation; and 2) the determination of RP2D based on the results of the randomized dose-finding study. 

For the selection of at least two dose levels for randomized dose-finding, an efficacious dose range should be identified in patients at the dose escalation stage. Commonly identifiable MTD of ADC drugs or incidences of AEs after multiple treatment cycles could be used to determine a dose as the upper bound of the efficacious dose range. On the other hand, it is more challenging to determine the lower bound of the efficacious range. Nonclinical pharmacological and toxicological data (binding kinetics, cell killing kinetics, xenograft mice model, allometric scaling, etc.) could be used to predict the target concentration/dose range in humans. Then backfilling of patients can be initiated to the dose level that reaches the target concentration. The lower bound of the efficacious dose range could be confirmed with prespecified criteria of antitumor activity (e.g. 30% ORR in no less than 10 subjects at a specific dose level). 

It is noteworthy that backfilling multiple tumor types to multiple dose levels may also help rank the clinical outcomes to identify the most promising disease setting, which will be further tested in the randomized dose-finding study. 

As long as the FDA agrees with the proposed optimal dose as the RP2D based on the randomized dose-finding study, other disease settings may be tested with the same optimal dose in a basket design, if no evidence suggests a significant difference in PK, PD, target expression, etc.  Otherwise, additional randomized dose-finding studies may be needed for different tumor types or combination therapy.

Tips for success of ADC drug development

To develop an ADC drug efficiently and successfully, the following tips will be helpful: 

• Tell a compelling story to convince FDA on the dose selection and optimization, disease selection, and target validation. Conduct integrated dose-exposure-response analyses by pooling all the available clinical and nonclinical data to build a knowledge system as the storyline.
• Demonstrate to the FDA your endless efforts in dose optimization. At the early stage of drug development, there is limited data so information gaps are  expected. It is critical to closely communicate with the FDA to reach agreements for green lights.
• Understand the FDA’s “Three birds one stone” expectations on the randomized dose-finding study (one stone) to remove uncertainties of target validation, disease selection, and dose optimization (three birds).

How we can help

Our strong team of commercial strategists, clinicians, former regulators, and market access experts can partner with you to de-risk your drug development and illuminate the path to commercial success. It is an exciting time for the industry, and we look forward to joining you in the journey to bring important innovations to patients. 

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