Not Lost in Translation: Preclinical cell product development – analysis of FDA’s IND submissions

by Alexey Bersenev on November 7, 2014 · 0 comments

in cell product, educational

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Earlier this year FDA published the first analysis of trends in IND (Investigational New Drug application) submissions to Center for Biologics Evaluation and Research (CBER)/ Office of Cellular, Tissue and Gene Therapies (OCTGT). Recently, the second trends analysis paper was released. This analysis is dedicated to preclinical cell product development. This is again a great job by FDA’s fellows and recognition of significance of cell therapy/ regenerative medicine field.

Before I go through the paper, I’d like to share a general 10-years trend of all IND submissions to CBER OCTGT, presented by Director – Celia Witten at Stem Cell Meeting on the Mesa a month ago:
FDA_INDs (This is a screenshot of Celia Witten presentation. Please refer it to the video.)

As we can see in the last 3-4 years the trend line is going up.

Bailey’s analysis captures 163 IND submissions between 2006 and 2013 with most applications (69%) for Phase 1 trials. Interestingly, the authors limited their analysis to cell-based regenerative medicine (RM) products only:

We define regenerative medicine products as those that incorporate a viable cellular component and are intended to repair, replace or restore diseased, damaged or missing tissues (for the analyses presented here, we exclude genetically modified and oncology products).

I’d highly recommend you to read full text of the analysis. Below I’ve picked some interesting points that I wanted to bring to your attention and discuss:

  1. FDA perspective on cell-based RM is outlined in 2013 Guidance for Industry on preclinical assessment of cell products. The guidance is providing recommendations to developers (not enforcement) and reflects expectations of the agency.
  2. The most important message from the analysis – case-by-case approach is commonly used for assessing preclinical testing programs. There are no universal requirements to preclinical testing, which could be applied to all cell-based RM products. The complexity of such products make them unique.
  3. Relevant animal models should be used. For example, disease or injury models instead of healthy animals. It seems to me, the agency is in favor of large animal models, which are more fully resemble human in terms of size of organs and physiology. The other important advantage of using large animal models is testing of different routes of administration, which could be quite problematic in small animals. Only 26% of INDs used large animal models. FDA may ask you to test product in more than one animal species. Importantly, FDA recognizes that due to complexity of RM cell products, animal models sometimes cannot predict the results of first-in-human or Phase 1 trials.
  4. Immune rejection is a specific issue of cellular RM products. Majority of INDs (65%) implemented genetically defined immunodeficient mice for investigational product (IP). Testing of original IP in animals is always preferred. In some cases, when IP cannot be used (or doesn’t make sense), analogous (animal-derived) product could be tested. 25% of INDs included testing of analogous product.
  5. Tumorigenicity testing is very important for cellular RM products. It cannot be done with analogous products. Cellular component of the IP “must persist in animals long enough to allow potential tumor formation” (quote). I wonder, how requirement for tumorigenicity testing would be different for products with transient (short-term) persistence (typical case for MSCs). The most frequent animal model for tumorigenicity was immunodeficient animals (92%). Since NOD-SCID mice were mentioned as an example, I wonder, why developers do not implement more sensitive modern models, such as NOG/NSG or humanized mice? Won’t FDA ask them to be up to date? Yet another point for discussion – immunocompetent animals instead of immunosuppressed/ /immunodeficient – it will more closely resemble regenerative medicine applications. Interestingly, the median duration of tumorigenicity assay was 4 months. Shouldn’t it be for lifelong or at least 1-2 years? I think, FDA has the same expectation. I also wonder how requirements (if any) for tumorigenicity testing will be different for “non-stem cell products” (ex: T-cells, skin fibroblasts…).
  6. Finally, a big emphasis on toxicology! Multiple cell doses, multiple time points and appropriate controls should be implemented in toxicology studies. Many considerations for toxicology outlined in the Guidance.

I hope it was not the last FDA’s analysis from CBER OCTGT! It provides great value for cell product developers! Finally, consider Guidance for Preclinical Assessment as your Bible before pre-IND meeting with FDA.

This post is a part of Not Lost in Translation online community project. In this series we will try to bridge the translational gaps between scientific discovery in research labs and clinical cell applications for therapies. We will look at challenges in translation of cell product development and manufacturing in academic and industry settings. If you would like to contribute to this community project, please contact us!

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