FDA’s position on assessment of tumorigenic potential of cell products for regenerative medicine

by Alexey Bersenev on October 25, 2012 · 1 comment

in cancer, cell product

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Recently I was reading very interesting article about assessment of tumor formation in cellular regenerative medicine products. This article was written by FDA’s expert Alex Bailey. I think, it nicely reflects the current position of FDA. Because article is important, but not freely available, I’ll try to summarize the major points here.

Some FDA statistics
115 submissions were received by agency for cell-based regenerative medicine products in the period of 2007-2011. Cell-based products for oncology and gene-modified products were excluded from analysis. The major cell type was mesenchymal stem cells and major tissue source – bone marrow. Interestingly, only in 43% of submissions tumorigenicity assays were performed by testing a product directly. In 57% of submissions, tumorigenic potential was assumed, based on “consideration of product attributes, literature and/or previous clinical experience”. It was something very new from me to learn. I thought direct testing of product is always required.

Some general considerations

  • FDA considers potential risk of tumor formation for “all cell-based regenerative medicine (RM) products”;
  • Evaluation of tumorigenic potential of cell-based RM products is very challenging for both sides – agency and developers;
  • FDA employs “data-driven, case-by-case” approach to assess tumorigenic risks of cell-based RM products. It means, that each product is assessed individually and universal scheme could not be applied to similar group of cell products;

This approach to preclinical tumorigenicity testing, in which the panel of tests is tailored for each specific product, is in contrast to the established rodent bioassays used for carcinogenicity testing of small-molecule pharmaceuticals.

  • For some type of products in vivo testing is not necessary.
  • New products “may require new testing paradigms“. It means that if FDA reviews absolutely new type of product (never had experience before), new tumorigenicity assays could be developed/ discussed.
  • Because “there currently is no check-the-box standard preclinical animal study design” for evaluation of tumorigenicity of cell products, agency provides some considerations and highlights challenges (see a table in the article) for developers.


… there is presumably less risk of tumor formation after administration of low–passage number, differentiated fibroblasts compared with either of the hypothetical cell-based RM products discussed above. For the former, animal studies to evaluate tumorigenicity may not be necessary; rather, in vitro characterization of the cellular product and assessment of its biological stability may be sufficient.

For embryonic stem (ES) cell-based products:

…there is also a greater risk that a suspension of ES cell–derived cardiomyocytes contains residual undifferentiated cells that could form teratomas after administration. To help ensure that the tumorigenicity testing of such a product is interpretable, the study design should include groups of animals that receive undifferentiated ES cells, serial dilutions of a population of undifferentiated ES cells combined with ES cell–derived cardiomyocytes, and the final intended clinical product.

Choice of in vivo model:

… administration of human cells to an immunocompetent rodent will result in their rapid elimination. If these cells are expected to persist in the clinical setting, it would be difficult to gauge the level of risk of tumor formation from these results alone.

This article is recommended to all cell therapy products developers!

{ 1 comment… read it below or add one }

Mindy L April 17, 2013 at 7:16 pm

Hi Alexey,

First, thank for this informative article. Second, can you provide a follow-up article discussing other assays beside the mouse study that can be used to test tumorigenicity?




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