1. Safety Review

2. Sources of Safety Information • BLA 125397 (Applicant’s data) • 1993-2007: Voluntary questionnaires • 2008-present: SCTOD • FDA Dockets • Literature Search • The COBLT Study • Prospective clinical study of safety and efficacy of unrelated donor cord blood transplantation • Sponsored by the NHLBI

3. Review Strategy • Characterize the safety profile of the applicant’s product • Units manufactured using the method intended for licensure • TNC dose >2.5 x 107/kg • Summarize the safety information from the additional public sources • Emphasis on product-related outcomes • Infusion reactions, delayed neutrophil recovery, graft failure, early mortality

4. Agenda • Describe the datasets used • Summarize safety outcomes • Summarize infusion reactions

5. Datasets Used In FDA Analyses • BLA 125397 (Applicant) • Datafile for 3619 patients transplanted with 3946 cord blood units • Limited to 409 patients transplanted 2007 to 2011 with 432 cord blood units manufactured using the method intended for licensure • Pooled Dataset (Public Information) • NYBC: 550 patients transplanted 1993-1998 • COBLT: 356 patients transplanted 1999-2004 • NMDP: 577 patients transplanted 2000-2006

6. Patient Demographics

7. Transplant Characteristics

8. Agenda • Describe the datasets used • Summarize safety outcomes • Summarize infusion reactions

9. Hematopoietic RecoveryTNC Dose >2.5 x 107/kg * Includes death, 2nd transplantation or autologous recovery for patients surviving at least 14 days without neutrophil recovery For all patients in the pooled dataset: • Primary graft failure was associated with TNC dose, degree of HLA mismatch and diagnosis • Time to ANC>500 was associated with TNC dose and degree of HLA mismatch

10. Hematopoietic Recovery by Diagnosis(Pooled Dataset -TNC Dose >2.5 x 107/kg)

11. Day 100 MortalityTNC Dose >2.5 x 107/kg For all patients in the pooled dataset: • Day-100 Mortality was associated with TNC dose, degree of HLA mismatch, diagnosis and gender.

12. Additional Outcomes of Interest ∙ GVHD in patients who received a TNC dose >2.5 x 107/kg. For all other outcomes, patients receiving any TNC dose are considered. +From The COBLT Study dataset only.

13. Safety Outcomes Overview • Applicant’s Data (TNC Dose >2.5 x 107/kg) • Primary graft failure in 14% • Median time to neutrophil recovery is 20 days • Day-100 mortality is 25% • Mortality due to graft failure is 3.9% • Transmission of a genetic disorder is rare • Additional Information • Donor cell leukemia and transmission of infections are additional rare events. • Engraftment syndrome is an additional common event.

14. Agenda • Describe the datasets used • Summarize safety outcomes • Summarize infusion reactions

15. Infusion Reaction Characterization • Applicant’s Data (n=244 infusions) • Data questionnaire: Requested information on any SAE or any event that required intervention • SCTOD: Requested information on 17 specific adverse events and SAEs • No grading • The COBLT Study (n=523 infusions) • Prospectively requested information on 13 specific adverse events with grading by NCI CTC criteria • Any SAE also graded and reported.

16. Infusion Reactions

17. Infusion Reactions

18. Infusion Reactions - Cardiopulmonary

19. Cardiopulmonary SAEs • Spectrum of signs and symptoms includes hypertension, cardiomyopathy, pulmonary edema, acute respiratory distress and acute renal failure. • Applicant reports 4 infusion-related SAEs (0.1%) • None of the reports involved units manufactured with the method intended for licensure • Four (0.8%) such SAEs were also reported in The COBLT Study dataset. • Five additional published cases

20. Composition of Prepared Unit ∙ Prepared according to applicant’s instructions. The instructions do not include an infusion rate. Dextran 40 • Side effects include pulmonary edema, congestive heart failure, acute renal failure, bleeding disorders and anaphylactoid reactions • Recommended dose is 5-10 mL/kg over 12-24 hours (available as a 10% solution)

21. Infusion Reactions Overview • Applicant’s Data (TNC Dose >2.5 x 107/kg) • Reported infusion reaction rate is 18% • Serious cardiopulmonary events in 0.1% • The most common infusion reactions are hypertension (14%), nausea (5%), vomiting (4%), and hypoxemia (3%) • Additional Information • Reported infusion reaction rate is 65% • Serious cardiopulmonary events in 0.8% • Severe allergic reactions occurred in 0.2%.