CROs respond: FDA guidance on expansion cohort use in FIH trials a ‘welcome step’
The US Food and Drug Administration (FDA) recently published a draft guidance: “Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics.”
According to the agency, the purpose of the draft guidance is to provide advice to sponsors regarding the design and conduct of first-in-human (FIH) clinical trials. Specifically, it addresses using multiple expansion cohort study designs to expedite the clinical development of cancer drugs, including biological products.
As the guidance explains, such study designs employ “multiple, concurrently accruing, patient cohorts,” with individual cohorts assessing different aspects of a drug’s safety, pharmacokinetics, and anti-tumor activity.
Nicholas Kenny, PhD, executive vice president, oncology and hematology, Syneos Health, said the draft guidance is “a welcome step in support of innovation and efficiency in the development of cancer therapies.”
“As the guidance correctly advises, the multi-arm expansion cohort approach can offer many opportunities for faster data generation, better use of resources and time, and a more patient-centric approach to outcomes measurement,” he told us.
Lindsay McNair, MD, MPH, MSB, WIRB-Copernicus Group (WCG) chief medical officer explained that incorporating expansion cohorts into FIH trials “allows the assessment of a new compound to proceed more quickly, once a dose is identified that appears to be tolerated and potentially effective.”
“Instead of stopping the Phase I study, writing a new protocol, and going through the study approval and start-up process to begin Phase II, the investigation of efficacy can begin as part of the same study,” she told us. This enables faster data collection and the ability to more quickly reach a decision about a compound’s potential.
However, there are risks related to this type of trial design that investigators and the clinical research team must closely manage, Kenny said, adding that “novel trial designs such as this are not a panacea for time/cost savings and accelerated development.”
The studies require additional patient safeguards and consent and must have “clear and robust clinical rationales” as well as supportive biostatistical planning, Kenny added. This includes appropriate integration with biomarker development and validation.
Kenny said that stakeholders in such clinical trial designs need “clear and up-to-date optics on data that can be rapidly shared.”
“Sponsors should take advantage of the FDA’s interest and engage in early dialogue with the agency when considering this approach,” he added.
As the guidance describes and McNair noted, it is important to have a well thought out safety monitoring plan with an Independent Safety Assessment Committee (ISAC) “to be able to quickly and appropriately respond to new findings in this early stage of development.”
“A clear communication plan between the sponsor, investigators, ISAC and Institutional Review Boards is also important, both to ensure that new data is shared on a timely basis and protocol changes can be made as necessary, and also to ensure that the information provided to participants in the informed consent process is current and accurate,” McNair added.
A changing paradigm
According to Kenny, Syneos has seen a substantial increase in trial designs of this type in the past few years, and the CRO is currently managing multiple such trials across the US, Europe, and Asia.
“The increasing use of these designs is evidence that the traditional Phase I-Phase II-Phase III development paradigm is no longer the standard, especially in oncology drug development,” said McNair.
Outside of oncology – where FIH studies can be conducted with healthy participants – Dr. Graham Wood, chief R&D officer at Altasciences told us the company is designing “more and more studies that have expansion cohorts using patients and often examining biomarkers.”
“While these studies do not have the same ethical and safety concerns as oncology studies, many of the same consideration need to be taken into account,” he said, “such as working of the safety committee, how to structure the protocol or amendments to the protocol.”