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Legislative Issues
In the United States, the Stem Cell Therapeutic and Research Act of 2005 mandates that through the C.W. Bill Young Cell Transplantation Program umbilical cord blood is not only collected, tested, cryopreserved and stored and made available, but that the “scientific factors necessary to define a cord blood unit as a high-quality unit” must be defined. Furthermore, the Act stipulates that the Secretary of Health and Human Services shall provide contracts to “qualified cord blood banks to assist in the collection and maintenance of 150,000 new units of high-quality cord blood to be made available for transplantation through the C. W. Bill Young Transplantation Program. Through the Secretary of Health and Human Services, the Administrator of the Health Resources and Services Administration (HRSA) contracted the successor to the National Bone Marrow Donor Registry to provide the means to increase the number of transplants to meet these requirements. The National Marrow Donor Program (NMDP) in Minneapolis, MN received a contract that provided the primary searchable database for these so-called high-quality cord blood units.
Standards
There are several organizations that are associated with standards for stem cell transplantation. These organizations include the American Association of Blood Banks (AABB), the International Society of Cellular Therapy (ISCT) and the American Society for Blood and Marrow Transplantation (ASBMT), which together with ISCT merged their standards and established the Foundation for the Accreditation of Cellular Therapy (FACT). FACT, in turn, collaborated with the Joint Accreditation Committees of ISCT and the European Group for the Blood and Marrow Transplantation (EBMT) to establish JACIE. FACT therefore accredits facilities under two sets of international standards developed in cooperation with JACIE and NetCord, the first being standards for bone marrow and peripheral blood collection, processing and administration, while the latter is specific for Cord Blood Collection, Processing, Testing, Banking, Selection and Release of cord blood units. Accreditation is through an inspection process that follows the FDA’s rules for current Good Tissue Practices (cGTP).
Regulations for Umbilical Cord Blood
The potency of an assay is interpreted in the United States Code of Federal Regulations (21 CFR 600.3) to “mean the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result”. From the previous section, it follows that the CFC assay, as it was original designed and as it has remained, is certainly not an appropriate laboratory test, although it has been the only test available. The "controlled clinical data" is, in this particular case, the transplantation itself. According to 21 CFR 610.10, “tests for potency shall consist of either an in vitro or in vivo test, or both, which have been specifically designed for each product so as to indicate its potency”. As stated at the beginning, the CFC was never specifically designed as a potency assay.
The latest edition of the FACT-JACIE International Standards for Cellular Therapy Product Collection, Processing, and Administration states, in Section D6.13.1.3, that “For products undergoing manipulation that alters the final cell population, a relevant and validated assay, where available, should be employed for evaluation of the target cell population before and after the processing procedures". The CFCassay may be relevant, but it has never been validated as a potency assay, and in its present form, it is doubtful whether it ever will be validated.
Yet in a recent “Guidance for Industry” from the United States Food and Drug Administration (FDA) in which stem cell processing systems and storage are considered (Docket 2007D-0025), the performance characteristics of the cord blood product prior to and after cryopreservation include nucleated cell count, viability, several phenotypic markers such as CD34 and so-called “total colony forming unit granulocyte macrophage (GM-CFC), total burst-forming unit-erythroid (BFU-E), if application, total colony for unit-granulocyte erythrocyte monocyte macrophage (CFU-GEMM), if applicable”. Although this guidance document actually defines the assays to determine performance characteristics, it actually appears to contradict both the Code of Federal Regulations (CFR) and the FACT-JACIE Standards. First it contradicts the latter for the requirement for a validated potency assay. Second it contradicts other FDA Guidances for Industry by the FDA since one of the issues such an FDA-released Guidance entitled, “Release Testing of Cell Therapy Products”, is not only that an assay should be a “rapid, sensitive and reliable test method”, but that the “product potency for living cell products may be compromised by extensive assay times”. One of the criticisms of the CFC assay, as it has been used in the stem cell processing laboratory is that it takes 14 days to complete the assay. This is approximately the same time as it takes a patient to engraft after transplantation. Therefore, the CFC assay is retrospective in nature and cannot be used for engraftment or reconstitution prediction purposes.
In addition, the term “validated potency assay” is key. Assay validation identifies sources of potential variability and addresses the quantification of these errors in the assay method. The assay validation procedure assigns acceptable values for the assay parameters (accuracy, precision, detection limits, quantitation limits, specificity, linearity, reproducibility and suitability) all of which will ultimately address the reliability and robustness of the assay procedure.
In a recent Forum on Bioassays, the Center for Biologics Evaluation and Research of the FDA, discussed potency assays for complex biological products. In the absence of a direct measurement for biological activity, one of the potency measurements used for in vitro cell and tissue culture is considered to be proliferation. Proliferation, as a surrogate measure of potency, is substantiated by a direct correlation with the results, i.e. biological activity, since without proliferation, the stem cell product will not be able to differentiate into the lympho-hematopoietic lineages needed for reconstitution. The use of a proliferation assay, rather than a CFC differentiation assay, provides all of the characteristics required to measure stem cell potency and can include proficiency testing under the auspices of independent agencies, a fact that has sadly been averted.