1. FDA Perspective on the PASSPORT Study FDA Perspective on the PASSPORT Study Salim A. Haddad, M.D. Laboratory of Cellular Hematology Division of Hematology Office of Blood Research and Review Office of Blood Research and Review Center for Biologics Evaluation and Research Food and Drug Administration Blood Products Advisory Committee May 1, 2008

2. Background FDA engagement in efforts to improve platelet storage: FDA engagement in efforts to improve platelet storage: BPAC: Pre-storage pooling, seven-day platelets, bacterial contamination ► BPAC: Pre-storage pooling, seven-day platelets, bacterial contamination of platelets, rapid tests for detection of bacterial contamination of platelets, rapid tests for detection of bacterial contamination Workshop on methods for reducing pathogens in cellular blood ► Workshop on methods for reducing pathogens in cellular blood products products The purpose of the PASSPORT study was to address the issue of bacterial contamination of platelets stored for 7 days The purpose of the PASSPORT study was to address the issue of bacterial contamination of platelets stored for 7 days Prior to the initiation of the PASSPORT study, FDA conducted extensive dialogue with the blood community Discussions included FDA participation on the AABB Task Force on Bacterial Contamination

3. PASSPORT Study March 2005: Gambro clearance for 7-day platelets when the platelets were tested with BacT/ALERT early in storage March 2005: Gambro clearance for 7-day platelets when the platelets were tested with BacT/ALERT early in storage Phase IV PASSPORT post marketing study Phase IV PASSPORT post marketing study Objective of PASSPORT: to confirm that 7-day platelets, when tested early in storage with BacT/ALERT, presented no greater risk for bacterial contamination than untested 5-day platelets Objective of PASSPORT: to confirm that 7-day platelets, when tested early in storage with BacT/ALERT, presented no greater risk for bacterial contamination than untested 5-day platelets Fenwal: co-sponsor in Nov 2005 Fenwal: co-sponsor in Nov 2005

4. Sample for culture usingBacT/ALERT PASSPORT Study Design D7D5D4D3 D2D1 2nd Sample for BacT/ALERT testing Days of storage Days of storage + : Discard - : D6 Transfuse  Primary hypothesis: UCL residual bacterial contamination rate of 7-day platelets was no greater than 1/5,000 with 95% confidence  Study sample size: 50,000 outdated units  Success: detection of < 5 positive units at day 7

5. Sample for culture using BacT/ALERT PASSPORT Interim Results D7D5D4D3 D2D1 2nd Sample for BacT/ALERT testing Days of storage Days of storage + : Discard – : D6 Transfuse January 2008: Sponsors raise safety concerns: Day 1193, 078collections tested with 48 true positives ▪ Day 1: 193, 078 collections tested with 48 true positives → True positive rate at day 1 ~ 1/5,000 → True positive rate at day 1 ~ 1/5,000 ▪ Day 7: 2 true positives2, 571 platelet units tested ▪ Day 7: 2 true positives out of 2, 571 platelet units tested ▪ Platelet transfusion recipients: Out of 5 reported reactions, 3 septic ▪ Platelet transfusion recipients: Out of 5 reported reactions, 3 septic reactions (STR) confirmed to be resulting from transfusion of a reactions (STR) confirmed to be resulting from transfusion of a contaminated platelet product → septic transfusion rate of 1/64,000 contaminated platelet product → septic transfusion rate of 1/64,000 collections collections

6. PASSPORT study septic reaction rate: 1/64,000 compared to American Red Cross septic reaction rate: 1/120,000*  PASSPORT study septic reaction rate: 1/64,000 compared to American Red Cross septic reaction rate: 1/120,000*  No statistically significant difference (Fisher Exact Test) * Transfusion July 2007; vol 47: 1134-1142 * Updates at ABC’s Platelet Conference, Nov 2007 and HHS Advisory Committee on Blood Safety and Availability, January 2008 Comparison of Septic Transfusion Reactions

7. Conclusions from the PASSPORT Interim Analysis STR comparison, while showing no conclusive evidence that PASSPORT rates were higher than those of ARC study, did raise safety concerns STR comparison, while showing no conclusive evidence that PASSPORT rates were higher than those of ARC study, did raise safety concerns Results of testing after day 7 (2 positive results out of 2,571 units tested) suggested that the likelihood of a successful outcome was low (success: < 5 positives out of 50,000) Results of testing after day 7 (2 positive results out of 2,571 units tested) suggested that the likelihood of a successful outcome was low (success: < 5 positives out of 50,000)

8. Assessment of the PASSPORT Study Divergence of opinion among the sponsors: immediate suspension vs. introduction of additional safeguards Divergence of opinion among the sponsors: immediate suspension vs. introduction of additional safeguards No stopping rules were established in the protocol, the high contamination and septic transfusion rates were not foreseen No stopping rules were established in the protocol, the high contamination and septic transfusion rates were not foreseen Transfusion sepsis risk at days 6 and 7 not fully assessed, the study did not include reporting of the proportion of platelets transfused after day 5 Transfusion sepsis risk at days 6 and 7 not fully assessed, the study did not include reporting of the proportion of platelets transfused after day 5 Cessation of the PASSPORT study: return to 5-day storage with potential for platelet shortage Cessation of the PASSPORT study: return to 5-day storage with potential for platelet shortage

9. Phase-out of the PASSPORT Study Balancing concerns for platelet safety and availability, FDA opted for a phase-out period to allow the participating centers to adjust to a reversion to 5 day platelets Balancing concerns for platelet safety and availability, FDA opted for a phase-out period to allow the participating centers to adjust to a reversion to 5 day platelets

10. Impact on Safety, Availability, and TRALI Mitigation Impact Impact ▪ Availability of platelets ▪ Availability of platelets ▪ TRALI mitigation strategies ▪ TRALI mitigation strategies Concern of blood establishments over meeting cGMPs Concern of blood establishments over meeting cGMPs America’s Blood Centers survey: need for a 19% increase in platelet production America’s Blood Centers survey: need for a 19% increase in platelet production AABB risk assessment on overall platelet safety AABB risk assessment on overall platelet safety

11. Extension of Phase-out Period Request for an extension of the phase out period from 28 to 90 days Request for an extension of the phase out period from 28 to 90 days FDA did not object to the extension as a prudent measure to enable users of the Gambro and Fenwal apheresis devices to revert back to 5 days in an effort to avert platelet shortages and minimize other potential risks of this transition FDA did not object to the extension as a prudent measure to enable users of the Gambro and Fenwal apheresis devices to revert back to 5 days in an effort to avert platelet shortages and minimize other potential risks of this transition

12. Next Steps FDA will continue to monitor and evaluate the data generated as PASSPORT is phased out FDA will continue to monitor and evaluate the data generated as PASSPORT is phased out FDA will work with sponsors and the AABB to redesign the study with additional safeguards to reduce the septic and contamination rates of 7 day platelets FDA will work with sponsors and the AABB to redesign the study with additional safeguards to reduce the septic and contamination rates of 7 day platelets