Highlights on Q&A from two workshops given by FDA at CAR-TCR Boston Summit
One hour presentation followed by one hour Q&A was given by FDA CBER experts to reviewing clinical regulatory considerations and CMC considerations for commercial development today at Boston.
Among intensive questions and discussions, major points are focused on 5 topics: FDA's perspectives on 1) CRS and trial hold due to safety findings; 2) CMC changes and comparability management across the product development; 3)required RCR/RCL testing and 15 years safety follow up; 4) regulatory pathway for regenerative therapy; 5) experience gained from FDA database and industrial submission reviews.
For CRS and trial hold due to safety findings, comparing to 10 years ago when fatal event will cause an immediate hold of the IND, with more experience acquired from past 10 years, FDA anticipates that Sponsor conducts an immediate and thorough investigation to find out the root causes of fatal event (i.e. disease burden, underlying concurrent conditions, insufficient safety management, etc) and mitigation plans (i.e. protocol amendment to adjust patient eligibility, modify safety management plan/algorithm, sites training plan etc). For CRS grading criteria in CAR-T therapy setting, CTCAE grading is not applicable. Current multiple academic grading criteria are published and applied across CAR-T clinical trials. They all look reasonable, while FDA would encourage the medical community, especially KOLs take the lead to open the discussion and come up with a consensus on an uniform CRS criteria to be used in all future clinical trials.
For CMC changes and comparability management across the product development, experts admitted that CMC changes during development is unavoidable, but emphasized that a rather stabilized manufacture process should be reached before starting Phase III trial. When asked whether changes on scFv or stimulator of CAR with the same target will cause the requirement of a new IND, experts suggested to reach FDA on case by case basis. Evaluation of changes will be focusing on CMC and clinical outcomes. CMC reviewers will first evaluate and advise clinical reviewers whether or not the changes should be considered as critical changes. If from CMC perspective the changes are non-critical, clinical will further review the safety and efficacy profile. When necessary, FDA may request a bridging clinical trial with single digits patients enrolled and treated to prove the clinical comparability.
For required RCR/RCL testing and 15 years safety follow up, question was raised on the rationale for RCR/RCL Test is not required if cell culture for expansion is less than 4 days. It was also clarified that 15 years follow up was only required for integrated retrovirual vector such as lentiviral vector, when 3 years follow up is required for non-integrated virtual vectors. When asked for the possibility of the removal of 15 years follow up requirement due to the limited data observed from Novartis and other CAR-T trial, FDA experts made it clear that hard to see this potential in the near to middle term future.
For regulatory pathway for regenerative therapy, Regenerative Medicine Advanced Therapy (RMAT) launched in 2016 by FDA was highlighted. RMAT holds similarities as of breakthrough designation, but with more specific resource alignments inside FDA to support regenerative therapy development. Apply for both RMAT and BTD is not recommended. Clarification was also given regarding Fast Track granted based on preclinical data that the designation maybe withdrawn if later emerging clinical data cannot support the preclinical findings. About the timing of pre-IND meeting, even though the interval between pre-IND meeting and IND submission varied per FDA experts' observation, they do suggest to reach FDA for pre-IND meeting at least when CMC process passed the pilot batch manufacturing.
For experience gained from FDA databases and industrial submission reviews for CAR-T therapies, multiple questions raised on the observations so far, any potential conclusions or impact on future development and trial design, the answer remains as both data and experience are limited so far to reach any conclusive points, more observations are needed.
联系客服
