Industry Proposes Changes to FDA’s FIH Expansion Cohort Guidance

Regulatory NewsRegulatory News | 16 October 2018 |  By 

Industry and oncology groups are calling for changes to the US Food and Drug Administration’s (FDA) recently released draft guidance on first-in-human clinical trials for oncology drugs that feature multiple expansion cohorts.
The 17-page draft guidance, released in August 2018, provides recommendations to sponsors on the design and conduct of such trials, which the agency says can “expedite development by seamlessly proceeding from initial determination of a potentially effective dose to individual cohorts that have trial objectives typical of Phase 2 trials.”
While the Biotechnology Innovation Organization (BIO) says it supports the framework detailed in the guidance, the industry group calls on FDA to make two main changes before finalizing the document.
According to BIO, the limits set on sample sizes in the guidance “may unnecessarily limit expansion of cohort trials that do not pose unexpected safety issues.” Instead, the group calls on FDA to make prescriptive recommendations on sample sizes to give sponsors greater flexibility in that regard.
BIO also says that FDA should spend more time discussing study design features for first-in-human cohorts and less on specific types of designs and statistical methods.
Specifically, BIO says FDA “should avoid mentioning specific statistical approaches,” such as Simon’s two-stage design, as the group believes there are other approaches “that potentially offer greater flexibility while still maintaining rigor.”
For its part, the American Society of Clinical Oncology (ASCO) says it supports FDA’s “initial thinking” with the guidance and says it believes expansion cohort trials “make trials easier for sites and patients due to having one protocol with multiple cohorts rather than multiple protocols.”
However, ASCO also calls for changes to the draft guidance, including expanding the guidance to cover trials with a single expansion cohort in addition to trials with multiple expansion cohorts and developing more specific requirements for transitioning from the dose escalation phase to the dose expansion phase.
The Drug Information Association’s Adaptive Designs Scientific Working Group also submitted comments suggesting the guidance could be further strengthened by including recommendations for adaptive dosing.
“While the draft guidance recognizes the desirability of adaptive, learn-as-you-go, seamless designs operating between trial participants, it ignores the real possibility of adaptively individualizing dose within participants on an N-of-1 basis,” the group writes.
In its comments, Pfizer suggests that FDA expand the scope of the guidance to other therapeutic areas outside of oncology, such as autoimmune diseases. “Most drugs approved for autoimmune disorders, Rituxan, Enbrel, Humira, Xeljanz, and Remicade for example, generally work across multiple diseases,” the company writes.
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