1. Comments of International Society for Cellular Therapy (ISCT) to FDA Cellular, Tissue, & Gene Therapies Advisory Committee Elizabeth Read, MD March 30, 2007

2. ISCT Mission ISCT is the global forum and resource for developing and supporting innovative cellular therapies through communication, education, and training, thus furthering clinical based investigation for the benefit of patients

3. Cord blood draft guidance ISCT appreciates FDA’s thoughtful and flexible approach to licensure of allogeneic unrelated cord blood ISCT members and leadership have reviewed the document and participated in the AABB-ISCT-NMDP Work Group, which will submit written comments to the docket

4. Cord blood draft guidance Today’s comments are general concerns aimed at raising questions, promoting clarification, and stimulating further discussion We believe the most critical issues raised by this guidance relate to –Product potency –Product comparability –Impact on practice of medicine

5. Product Potency Recommended tests for Product Potency (p8, p35) include –Total nucleated cells (TNC) ≥ 5.0 x 10 8 / unit –Viability of NCs ≥ 85% (after volume reduction, before cryopreservation) –Viable CD34+ cells ≥ 1.25 x 10 6 / unit (after volume reduction, before cryopreservation) this value is achieved if minimum specified TNCs have at least 0.25% viable CD34+ cells

6. Product Potency Why is the selection of product potency assays challenging for cord blood? –Guidance is focused on banking for specified indications for which current data are available –Reality is that public cord blood units are and will be banked for a variety of current and future indications –With increasing use of nonmyeloablative transplants, we do not really know whether potency assays should be based on content of viable CD34 cells, immune cells, or something else, to be defined after further clinical trials –Use of double CB transplants is increasing and changes the way we view product dosing –We need to consider other potential uses of cord blood, such as cardiac or skeletal repair, which may not be dependent on hematopoietic progenitors

7. Product Potency Why is the number of viable CD34 cells not the ideal potency assay even for specified indications? –Published data show that TNC has been the best predictor of clinical outcome, and transplant physicians typically use TNC before CD34 cell dose in the unit selection process Many units never had CD34 measured CD34 quantitation in CB is not as well-standardized as for BM or PBSC, and thus is subject to greater inter- laboratory variability

8. Product Potency It is our understanding that FDA will require each bank to specify a potency assay or assays for its own use, but FDA is not defining exactly what that assay or assays must be We support this approach, but also encourage banks, transplant centers, FDA, and other parties to continue thinking broadly about this issue and to collaborate actively to identify the most appropriate potency assays for specified clinical uses of cord blood

9. Product Comparability Establishing comparability of units in pre-BLA inventory is perhaps the most critical and challenging issue Criteria for comparability encompass the entire manufacturing process, including –Donor eligibility –Ex vivo processing –Storage –Final product specifications –Labeling and expiration dating –CGMP practices and facility requirements

10. Product Comparability Concerns of cord blood banks and transplant physicians –Post-BLA units may be perceived as better than pre-BLA units –Valuable inventory would need to be discarded –The nature of the BLA process will likely result in proprietary communications between individual banks and FDA on this issue –Use of comparability standards will impact availability and use of CB units collected by non- US banks that are not FDA licensed

11. Product Comparability We strongly support collaborative efforts among banks, professional organizations, and FDA to establish industry standards for product comparability

12. Practice of Medicine Cord blood transplantation is often the last resort for patients with life- threatening illnesses Transplant physicians need latitude in electing to use CB units that may not meet BLA specifications, after weighing risks and benefits

13. Practice of Medicine We request that FDA consider and clarify its position, and provide additional comments on, options for –Continued storage of CB units that do not meet a licensed bank’s prospective or comparability specifications, for clinical use, and –Clinical use of CB units for indications other than transplantation of hematological malignancies

14. ISCT thanks you for considering these issues