FDA calls for collaboration on CAR T-cell therapies database

by Alexey Bersenev on March 16, 2016 · 1 comment

in regulation

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 – announced a pilot project for CAR T-cell database. You can watch FDA’s presentation on the project here (starts on 2h 38 min).

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.

{ 1 comment… read it below or add one }

basleewis March 21, 2016 at 12:16 pm

I like the idea, but I am also skeptical that this will be an acceptable approach by the industry.
Lets say that from the database it becomes clear that T-cell products with certain depleted or enriched cell (sub)populations have a higher success rate. I would imagine that this would need to be reported in some form if not for ethical reasons alone. This in turn would enable groups in development to adjust their manufacturing process based on anonymized third party data to have a more competitive product with less development time. We need to consider the reality that the current costs of product development needs to be covered to allow more products to be developed later on. As this is at least partly covered by product sales, enabling a direct competing product may not be interesting to most companies

I do believe that there are many positives to this initiative:
– Increase understanding and characterization of cellular products.
– Potentially increase the products efficacy for specific patient groups
– Decrease development costs which in turn would decrease the required product cost which would help with reimbursement

I believe that if the database would be started with something less manufacturing specific the willingness to share would better. I would therefore love to see just the APH collection data from different sites as a pilot project. It may be to ambitious to request all the information the FDA is currently proposing, even if the FDA indicated that sponsor feedback has been very positive.


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