FDA Proposes New Databases to Monitor CAR T-Cell Safety Across INDs

March 16, 2016 – NEW HAVEN. CAR T-cell therapy is disruptive technology on many levels. One of such levels is regulation. On the one hand regulators have not seen such impressive efficacy data for long time and it is very inspiring (FDA keeps awarding CAR T-cell developers with “Breakthrough Therapy” designation). On the other hand, high efficacy “comes with a high price” of toxicity. At this point, regulators are not sure how to deal with CAR T-cell therapy-related toxicities (FDA used to suspend every trial after every death case). As a response to uncertainties, brought by “fast and furious CAR T-cell explosion”, FDA recently made a smart (and unusual) move to monitor CAR T-Cell safety across INDs.

The main goal of the project is to (1) collect CAR T-cell trials data across all submitted INDs and (2) analyze and utilize data for benefit of sponsors and the agency. Cytokine release syndrome (CRS), as the most frequent toxic side effect of CAR T-cell therapies, was a driving reason behind creation of database. It was FDA’s response to uncertainty about toxicities, associates with new therapeutic agent. This uncertainty is totally understandable, because until now CART field did not come up with common grading system for CRS (so there is no consensus on what to do if… happen). It is purely practical project, based on integration of huge amount of safety data, accumulated by the agency.

Two big chunks of data will be collected: (1) all about toxicities and (2) all about manufacturing (information, provided by sponsors as CMC part of IND). FDA’s benefit here is to know (i) how to deal with toxicities and (ii) critical quality attributes of CAR T-cell products. It could potentially improve FDA’s review of CAR T-cell INDs, making it more rigorous and efficient. Sponsors will benefit by receiving advice/ suggestion from the agency on mitigation/ response to toxicities and on technical improvements in product development. Basically, FDA can leverage collective wisdom for approval of better CAR T-cell therapies.

The most important part of this project is information sharing. As authors of the project have claimed, participation of sponsors in the database will be totally voluntary. All sponsors with CAR T-cell therapy INDs will be asked to collaborate, and may decline. FDA highly emphasized that they will ensure data confidentiality and there will be no sharing of proprietary information. What is not very clear to me is whether sponsor, who did not wish to participate in this collaboration, would benefit from it anyway (I’d guess – yes). Here is one interesting Q&A piece about data sharing:

However, Mildred Cho, associate director of the Stanford Center for Biomedical Ethics, asked whether FDA would share or present their analyses or aggregate data from the pilot. O’Leary responded that the agency hasn’t gotten that far in their planning yet, but said that sharing of high-level data would not be “unrealistic.” Keith Wonnacott, director of regulatory affairs at Novartis, responded by asking how FDA would protect confidential information if the agency plans to share data from the pilot. In response, Shultz said she imagines the data would represent trends or ranges of information rather than individual data points that could be tied back to the companies that provided them, thus protecting individual sponsors’ commercial interests.

It will be great to see some pieces of data on public domain to get some “inspiring ideas” about your future product, but sponsors will be afraid of any sort of public sharing. The sharing with FDA should be based on trust, first of all. With wild commercialization of CAR T-cell field, information sharing between developers became impossible, but this database could potentially provide an opportunity to individual developer to learn from experience of 100 other developers through the messenger – FDA. Isn’t it great?

The manufacturing part of database at this point is much less clear than safety part. FDA got a lot of questions from RAC members about how agency will ensure the quality and comparability of such data. Let’s say if they will collect data on T-cell phenotype from incoming apheresis collection, how these data will be comparable across INDs if different antibodies, flow cytometers and parameters were used? How much data will be enough for statistical rigor (to draw the trend and find commonalities)? Will it be even possible? The same questions could be applied to whole manufacturing process – all developers use different cell culture media, processing devices, analytical methods and so on.

At this point, it is unclear whether pilot FDA”s CAR T-cell project will succeed. But, I think, idea is great! It looks to me like regulatory disruption, which could be applied (if successful) to other cell therapies in the future. Finally, I’d give a couple of advises to commercial CAR T-cell developers – (1) collaborate and (2) hire Kimberly Schultz after she will be done with her fellowship at FDA.

Source: Alexey Bersenev MD, PhD. Director of Cell Therapy Processing and Advanced Cell Therapy Laboratories at Yale-New Haven Hospital, Yale University. This work is licensed under a Creative Commons Attribution-NoDerivs 3.0 Unported License.