The FDA issued a guidance document in March 2022 on the design and conduct of first-in-human (FIH) clinical trials for the efficient development of oncology drugs and biologics using expansion cohorts. The guidance provides recommendations on the characteristics of drugs suitable for this type of trial design, information to include in investigational new drug applications, when to interact with the FDA, and safety considerations for subjects enrolled in FIH expansion cohort trials. In this article, we will provide insights on how sponsors can implement this guidance in practice to expedite the development of oncology treatments.
A common issue in drug development is validating an appropriate disease setting for treatment. One potential advantage of conducting FIH multiple expansion cohort trials is the ability to gain early evidence on the effectiveness of a drug across a range of diseases and populations. However, these trials also pose several challenges and risks, including the need to disseminate new safety information as soon as possible, the potential for exposing subjects to suboptimal or toxic doses of the investigational drug, exposing more subjects to the risks of the investigational drug than necessary, and the possibility of misinterpretation of preliminary results
The molecular target for precision medicine is often seen at various expression levels across different cancer types. The level of expression of a target, and its role in cancer cell development and proliferation may vary by cancer type or stage of disease. While the target may have been validated in animal models, finding the appropriate human setting may be challenging. By having expansion cohorts, the chance of finding a sensitive patient population, or accelerating development for more than one indication is increased. This needs to be balanced with having an appropriate Phase 2 dose, not exposing too many subjects to a therapy that might be ineffective or toxic, and for the developer, the cost of running the study.
A well-defined statistical analysis plan with sample size justification and stopping rules for each expansion cohort is crucial to properly evaluate study endpoints and minimize the number of subjects exposed to an ineffective drug. In exceptional cases where the data from an expansion cohort in a FIH study will be used as primary support for a marketing application, the protocol should include provisions for ensuring data quality, independent review of tumor-based endpoints, justification of the selected dosage regimen, and a prespecified statistical analysis plan. Normally, a subsequent Phase II study would be conducted to fully assess antitumor activity and support a marketing authorization. This may involve a protocol amendment to the FiH study protocol, or a new protocol. If the cohort becomes larger than 40 subjects for solid tumors or 20 subjects for hematologic malignancies, it may be necessary to file a separate IND that cross-references the initial IND.
FDA’s Project Optimus initiative aims to assist in identifying the optimal dose and schedule for novel oncology therapeutics, with a focus on understanding dose response relationships for safety and efficacy. If further exploration is required to determine an optimal dose, using a randomized study design is recommended to ensure balance among patient characteristics and covariates. By incorporating a robust understanding of dose-response relationships into their programs, sponsors can optimize dosing and potentially improve the chances of success in clinical trials.
It is important to consider statistical implications when making protocol amendments and to carefully plan for bridging data between studies conducted with drug products produced at different scales or with different manufacturing processes. This is particularly relevant in first-in-human (FIH) investigations, where the drug may initially be manufactured at a different scale than what is required later in development. Sponsors should be aware of the need to ensure that data from studies using different manufacturing processes can be appropriately compared and combined, if necessary. This may require careful planning and the use of statistical methods to account for any potential differences between the studies. By properly considering these issues, sponsors can ensure that they have a robust and reliable dataset to support the development of their drug.
When evaluating the combination of more than one drug in clinical trials, it is important to carefully assess the safety profile of each drug, particularly with regard to the potential for overlapping adverse events. Both nonclinical toxicity data (each drug alone and their combination) and clinical experience with each drug should be taken into account in this evaluation. Depending on the standard of care for patients being treated, the safety profile of the novel therapeutic is usually assessed clinically prior to a cohort dosed in combination. The combination of the investigational drug with an existing standard of care may be pre-specified in the initial protocol or added via a protocol amendment.
The FDA Reauthorization Act (FDARA) of 2017 stipulated that molecularly targeted oncology drugs must include an initial Pediatric Study Plan for testing in pediatric subjects. The plan needs to be based on the molecular target, not the adult cancer indication being sought. When testing drugs in pediatric subjects, there are additional protections in the Code of Federal Regulations, including the provision of “the prospect of direct benefit”, which usually follows a demonstration of efficacy in an adult population.
The inclusion of pediatric expansion cohorts in first-in-human clinical trials can be a useful way to expedite the development of oncology drugs and biologics for use in pediatric populations. To ensure the safety and efficacy of these drugs in children, it is important for sponsors to consider the specific needs of this population, including age-appropriate formulations and toxicity monitoring plans. It is also important to assess whether satisfactory alternative therapies exist for the pediatric population before enrolling them in expansion cohorts.
In conclusion, the use of multiple expansion cohort trials can be an efficient way to expedite the clinical development of oncology drugs, including biological products. However, it is important to carefully consider the characteristics of the drug product, the objectives of the expansion cohorts, and the appropriate safeguards to protect subjects enrolled in the trial. Statistical considerations, such as sample size justification, stopping rules, and the use of adaptive designs, can help to minimize patient risk while still achieving the objectives of the trial. Sponsors should also be mindful of the need to disseminate new safety information and the potential challenges of evaluating drug products with changes to formulation, presentation, or manufacturing processes. Overall, it is crucial to carefully plan how to conduct multiple expansion cohort trials to ensure the safety and effectiveness of the investigational drug. At Precision for Medicine, we have the experience and expertise to help in the design and conduct of these studies.
Explore the full scope of Precision’s Oncology services and expertise >
Vann Parker is the Head of Regulatory Consultancy (North America) for Precision for Medicine. He received his PhD in Molecular Biology from The California Institute of Technology and spent the past 30 years supporting biopharmaceutical and drug development. He currently focuses on strategies for clinical development and interactions with FDA and other regulatory agencies. In addition to support of pre-IND activities, Vann has supported sponsors throughout the drug development process including applications for Fast Track, Breakthrough Therapy and Orphan Designations, formal meetings with FDA and full NDA/BLA submissions.
Precision for Medicine is part of the Precision Medicine Group, an integrated team of experts that extends Precision for Medicine’s therapeutic development capabilities beyond approval and into launch strategies, marketing communication, and payer insights. As one company, the Precision Medicine Group helps pharmaceutical and life-sciences clients conquer product development and commercialization challenges in a rapidly evolving environment.
