This is Part 2 of a 3-Part series on recent pressing topics affecting Phase I trials. Click here to read Part 1: "How Good Is the Data on ClinicalTrials.gov?". Click here to read Part 3: "The 100 Largest Clinical Trials on ClinicalTrials.gov"

William (Bill) Slichenmyer MD (Partner at Alacrita) brought to my attention a recent communication from the FDA about the growing size of Phase 1 studies: an issue brief titled "Conference on Clinical Cancer Research". This was the result of a meeting in Bethesda that was organized by a nonprofit group called the Friends of Cancer Research.  The FDA was represented at the meeting, as were industry and academia and the group discussed concerns around the rising trend of "Expansion Cohorts" in clinical studies. I'd like to dive into why these clinical operations teams are using expansion cohorts, and why this raises concerns, but first some context about the meeting in Bethesda.

The meeting in Bethesda was specifically on the growing size of Phase I studies in oncology. Merck’s Keytruda for the treatment of metastatic melanoma was the drug highlighted in the document as breaking the ground in this area. The use of “Expansion Cohorts” has been the key element here and the study by Merck has now enrolled around 1200 subjects with one cohort being 173 subjects! The FDA have gone on to say that they note there are “over 3 dozen” such studies registered at the FDA within this framework.

One of the conclusions in this document is the recommendation by the FDA that trial oversight committees are initiated to oversee the trial. Also the FDA has given guidance as to how and when expansion cohorts should be considered, how to consider the statistics and how to manage the process including on-going dialogue with the agency.

There is a follow-up article in CCRFocus on exactly this discussion with an expanded evaluation of the overarching concept of the change in clinical trials: Expansion Cohorts in First-in-Human Solid Tumor Oncology Trials.

There are many concepts and discussions that are introduced into these publications, and too much to put out in a single blog post. I would recommend the interested reader to take a few minutes and read these two articles which nicely articulate the issues, concerns and yet how to manage this process. We are obviously moving into a new era in clinical trial development with the further graying of the edges of the different phases. I have previously worked on Phase II studies morphing to Phase III, or adaptive design trials, but this type of Phase I with growing cohorts has been a new paradigm, and apparently a successful one with Keytruda making it to the market as the first PD1 inhibitor.

Does the growing need for expansion cohorts make you think we need to redefine the clinical trial phases? Should we now have Phase I and Phase Ib or should this be called a Phase IE (Phase I Expansion cohort study)? Leave a comment below to join the discussion.

Topics: Clinical Trials

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