Gambro/Fenwal PASSPORT Post Marketing Study – 7 Day Platelets Blood Products Advisory Committee Rockville, MD May 1, 2008 Larry J. Dumont, MBA, PhD Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire

Conflicts of Interest Consultant –Gambro BCT –bioMérieux –BCSI –Verax Biomedical Research support DHMC –Cerus –Fenwal –Gambro BCT –Haemonetics –Immunetics –Navigant Biotechnologies –Verax Biomedical Travel Support –FDA

Important Facts! 7-day platelets are 510(k) cleared by FDA –Gambro BCT, Inc. –Fenwal, Inc. PASSPORT = The post-marketing surveillance of 7- day platelets (a.k.a., Phase IV trial) –Not IND or IDE study as a prerequisite for clearance PASSPORT has: –An explicitly stated primary hypothesis with a written analysis plan which was reviewed and accepted by FDA –The planned analysis has not been conducted and the primary hypothesis has not been tested

Important Facts! Assumptions: 1.True contamination rate: 178/M (1/5618) to 349/M (1/2865), [based on one bottle testing] 2.The Release Test would detect at least 50% Therefore, residual risk ~100/M (1/10,000) This lead to the SAMPLE size calculation:  4 positive out of 50K surveillance tests Upper 95% CL of no more than 1/5K (200/M) residual risk NB: These risks are NOT weighted for the clinical risk that may be presented by organism or day the organism may be detectable.

Important Facts! Assumptions: 1.True contamination rate: 178/M (1/5618) to 349/M (1/2865), [based on one bottle testing] 2.The Release Test would detect at least 50% Therefore, residual risk ~100/M (1/10,000) This lead to the SAMPLE size calculations:  4 positive out of 50K surveillance tests Upper 95% CL of no more than 1/5K (200/M) residual risk NB: These risks are NOT weighted for the clinical risk that may be presented by organism or day the organism may be detectable. These assumptions were incorrect

1986: 1986: Last 7-day PLT STOP! AABB OCT 2004 AUG 2004 MARCH 2005 OK! PASSPORT.. SEPT Day SEPT 2003: SEPT 2003: 7-day platelet function OK May 2006 GAMBRO & Fenwal …

7-Day Platelet Release Test Sampling h post apheresis collection 4-5 mL aliquots of SDP in both one aerobic and one anaerobic culture bottles Release if no growth indicated after 24 h on test Culture bottles remain on test until positive or SDP expiry Standard practices indicated for microbiology and clinical follow-up for any positive cultures.

Release Test – 2 bottle Incubate Data Analysis D1 Surveillance Test – 2 bottle N ~ 50,000 Incubate 7d Storage Days D7D5D4D3D2D6D8 7-Day Apheresis Platelets Tier 1 Tier 2 PASSPORT - Post Marketing Surveillance

PRIMARY HYPOTHESIS 7 Day SDP when tested using the BTA Device and Methods as described (i.e., at hours post collection, aerobic and anaerobic bottles) will not present a greater risk of a detectable bacterially contaminated platelet unit than 5 Day SDP untested for bacterial contamination. “New endpoint [for a modified study design]: estimate residual bacterial risk for a 7 day old platelet unit tested for bacteria on day 1. Approve 7 day platelet storage if the bacterial risk at day 7 is lower than the current bacterial risk of untested platelet products.” FDA’s Current Thinking on Bacterial Detection in Platelets. ACBSA. August 27, 2004

SPECIFIC AIMS Determine the Specificity, Sensitivity, Negative Predictive Value, and Positive Predictive Value of the 2-bottle Release Test. Determine prevalence of bacterial contamination for untested and for 2 bottle BTA tested SDP. Determine performance contribution of the anaerobic bottle to the BTA and assess the need for anaerobic culturing in this application.

7 Day Platelet Adoption in the US March 2008 Implemented 7DP (5) 33 organizations (51 centers) Participating Nationwide

Surveillance through 11 Feb 2008

EventNot TransfusedTransfused True Positive Positive confirmatory test Positive confirmatory test, OR Post-transfusion sepsis confirmed by blood culture False Positive Negative confirmatory test Negative confirmatory test, AND No clinical or microbiological evidence of post-transfusion sepsis Indeterminate No confirmatory test, OR Couldn’t be interpreted Post transfusion sepsis with no confirmatory test, OR Other combinations of component and recipient results in situations where the component has been transfused True NegativeNot ApplicablePost transfusion sepsis with negative confirmatory test False Negative Not Applicable Post transfusion sepsis with blood culture confirmation, AND Organism match between product and patient, AND Positive confirmatory test on product

Release Test Cumulative Sept 2005 – Dec 2007 Events per million (95% CI) SDP Collections Interdicted True Positive ( ) False Positive ( ) Indeterminate ( ) Transfused True Positive 1341 (22-69) False Positive (92-173) Indeterminate ( ) False Negative** 26 (1-22) 1)**Double product – day 6 transfusions; one patient with fever; CNS blood and unit 2)**Double product – day 4 transfusions; STR 6-8h post both pts; staph aureus AABB Bulletin #04-07, Oct 2004

Surveillance Test 4369 tested after day 7 3 True Positives 686/M (95%CI 142 – 2005) Unit 1: Staph Aureus, BPA 3.7h BPN 7.2h, confirmed Unit 2: Split donation; Staph epi BPA 7.2h BPN 4.3h; Second bag transfused on day 4 with no adverse reaction reported Unit 3: Strep veridans; BPA 30.8h BPN 9.6h – confirmatory test diphtheroid like gram positive rods

3 / / / 6438

InterdictedTransfusedTotal True Positive62True Positive1375 Aerobic Only10 Aerobic Only010 Anaerobic Only24 Anaerobic Only1337 Both28 Both028 False Positive528False Positive41569 Aerobic Only211 Aerobic Only14225 Anaerobic Only298 Anaerobic Only27325 Both19 Both019 Indeterminate45Indeterminate Aerobic Only12 Aerobic Only3446 Anaerobic Only31 Anaerobic Only Both2 24 Neither**66 2-Bottle Results ** based on clinical reports

True Positive – Both Bottles OrganismGram StainingnTTD (h) BPATTD (h) BPN CitrobacterNEG24.2, , 8.4 E. coliNEG49.8 (7.9 – 13)9.2 (7.7 – 10.8) K. pneumoniaeNEG110 Serratia MarcescensNEG16.17 Group C strep pos 215, , 13.7 Group G beta hemolytic strep pos 28.7, , 8.6 Enterococcus faecalispos Staph Aureuspos710.6 ( )12.7 (8.5 – 27.2) Staph Epidermidis (CNS)pos319.8 ( )33.5 (15 – 69.3) Strep viridanspos Strep Gallolyticus / bovispos511.8 (9.3 – 14.5)10.7 (8.6 – 11.7)

True Positive – One Bottle Only Organism n TTD (h) Aerobic Bottle Only (BPA) Bacillus Sp Corynebacterium species Staph Aureus , 13.3 Staph Epidermidis 1 29 Strep - Alpha hemolytic Strep - Beta Group C Strep salivaris Anaerobic Bottle Only (BPN) Coag Neg Staph (21-32) Strep spp ( ) Corynebacterium species , 77.8 diptheroid (84 – 137) ***Propionibacterium sp ( ) Aspergilus E. coli Lactobacillus ***typically obligate anaerobe

Clinical Outcomes 13 true positive, 202 indeterminate transfused No deaths Reported 14 transfusion reactions related to bacterial contamination 44/M (24-73)

Clinical Outcomes - 1 ClassificationRelease TestRecipientTxn Day ClinicalBlood culture Confirmatory Test False NegativeNegativeA6No rxnnegnd B6FebrileCNS False NegativeNegativeA4Fever, resp distress, pulmonary edema, hypotension, leukopenia Staph aureus B4Fever, hypotension negStaph aureus True PositiveBPN (105.6h) P. acnes A5FebrileCNSnd B-not transfused N/A P.acnes True PositiveBPN (77.8h) Corynebacterium species A3No rxnnd B3SOB, hypotensionnddiphtheroids

Clinical Outcomes - 2 ClassificationRelease TestRecipientTxn Day ClinicalBlood culture Confirmatory Test IndeterminateBPA (185h) Bacillus sp A3No rxnnd B5Nonhemolytic, hypotension CNSnd IndeterminateNegativeA4No rxnnd B4FebrileNegativend IndeterminateNegativeSingle4Hypotension, febrile Staph epind IndeterminateNegativeA5No rxnnd B6Chills, hivesEnterococ cus nd IndeterminateNegativeA4No rxnnd B4FebrileCNSbacillus IndeterminateNegativeSingle7Periorbital edema, hives legs NegStrep nonhemolytic

Clinical Outcomes - 3 ClassificationRelease TestRecipientTxn Day ClinicalBlood culture Confirmatory Test IndeterminateBPA (41.5h) diphtheroids Single5HivesNdneg IndeterminateNegativeA5No rxnNdnd B5Citrus nausea and back pain Ndnd IndeterminateNegativeA4Immediate rxnNdnd B7No rxnNdnd Platelet AgeNumber of Reactions Day 31 Day 46 Day 54 Day 62 Day 71

Summary 2-bottle Release Test: –True Positive 234/M ( ) –True Pos + Indeterminate 1003/M ( ) –Generally consistent with other reports 256 collections not interdicted prior to transfusion Surveillance: –686/M (95%CI 142 – 2005) –Generally consistent with other reports No deaths reported –Ness et al. 15/M 14 transfusion reactions –44/M (24-73) –Ness et al. 70/M donations (49-105)

Thank you!