FocusRegulatory Science

Balancing Tissue and Tumor Formation in Regenerative Medicine

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Science Translational Medicine  15 Aug 2012:
Vol. 4, Issue 147, pp. 147fs28
DOI: 10.1126/scitranslmed.3003685


  • Fig. 1. FDA/CBER experience.

    Original submissions (~115) to initiate clinical investigations for cell-based RM products were submitted to FDA/CBER from 2007-2011. The cellular components of these products spanned a wide spectrum of (A) cell types and (B) tissue sources; ~70% of submissions were for new products and 30% were for new indications for previously evaluated (cross-referenced) products. Assessment of tumorigenicity risk was performed by direct testing of the product (in vitro or in vivo studies) (43%) or through consideration of product attributes, the scientific literature, and/or previous clinical experience (57%).



  • Table 1. Assessing tumorigenic potential.

    Although there currently is no check-the-box standard preclinical animal study design to evaluate a cell-based RM product’s ability to form tumors in vivo, an appreciation of the limitations and challenges associated with animal testing can aid in the design of product-specific science-based preclinical testing strategies.

    Considerations for cell-based RM productsAssociated challenges for preclinical animal studies
    The cellular component may form tumors after in vivo administration.Comprehensive preclinical testing may be necessary to identify and minimize the risk of tumor formation.
    The identical clinical product should be tested.Achieving durable cell engraftment in animals may be difficult.
    If the cells are expected to persist in humans, durable engraftment of the cellular product is necessary for a preclinical study to be informative.An immune response to human donor cells may prevent durable engraftment in an animal model (xenorejection). To address this caveat:

    • Use of immuno-compromised (IC) rodents or immuno-suppression (IS) regimens may facilitate engraftment, but IC animals may have shorter life spans, and IS regimens may cause toxicity in the host animal or to the administered cells.

    • The use of analogous animal cells may facilitate engraftment, but these cells may also have different bioactivity.
    Tumor formation is often a slowly occurring and rare event.Preclinical testing that is not conducted over a sufficient portion of the expected life span of an animal may yield a false-negative result. A large number of animals may be needed to detect rare tumor formation events.
    Some animals spontaneously develop tumors that are unrelated to administration of the product.Identification of tumor origin (donor- or host-cell) is necessary. A large number of animals may be needed to distinguish spontaneous tumor formation from those due to the product.
    The microenvironment may influence a product’s tumorigenic potential.Cell delivery to an anatomical location other than the intended clinical location may not adequately inform clinical risk.

    Scaffolding or other product components may provide environmental cues that influence bioactivity.Xenogeneic environments may not provide clinically relevant cues, which may influence interpretability of results.
    Tumor formation may be dose dependent.It may not be possible to administer the absolute clinical dose in an animal model.

    The sensitivity of testing methods may need to be confirmed with appropriate positive controls.
    A product may induce tumor formation from existing subclinical host malignant cells.Established animal models relevant to the target patient population may not exist.
    Product characteristics may introduce new risk factors for tumor formation.There are no standard preclinical methods of evaluation; new products may require new testing paradigms.

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