Gambro/Fenwal PASSPORT Post Marketing Study –

7 Day Platelets

Blood Products Advisory Committee

Rockville, MDMay 1, 2008

Larry J. Dumont, MBA, PhDDartmouth-Hitchcock Medical CenterLebanon, 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 2004AABB OCT 2004

AUG 2004AUG 2004

MARCH 2005MARCH 2005

OK!

PASSPORT..SEPT 2005SEPT 2005

7-Day

SEPT 2003:SEPT 2003: 7-day platelet function OK

May 2006GAMBRO

&Fenwal

…

7-Day Platelet Release Test

• Sampling 24 - 36 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 bottleN ~ 50,000

Incubate 7d

Storage Days

D7D5D4D3D2 D6 D8

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 24-36 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 USMarch 2008

Implemented 7DP

(5)

33 organizations (51 centers) Participating Nationwide

PASSPORT Enrollment - Participating Regional Sites

51

4743

3833

18

12

119

0

10

20

30

40

50

60

Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

2005 2006 2007

Surveillance through 11 Feb 2008

PASSPORT ACCRUALS

5,883

320,983

193,078

84,380

27,221

4,369

2,571

1,234

367

0

50,000

100,000

150,000

200,000

250,000

300,000

350,000

Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

2005 2006 2007

Cu

mu

lati

ve R

ele

ase

Te

st

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

4,500

5,000

Cu

mu

lati

ve S

urv

eil

lan

ce

Tes

t

Event Not Transfused Transfused

True PositivePositive confirmatory test

Positive confirmatory test, ORPost-transfusion sepsis confirmed by blood culture

False PositiveNegative confirmatory test

Negative confirmatory test, ANDNo clinical or microbiological evidence of post-transfusion sepsis

IndeterminateNo confirmatory test, ORCouldn’t be interpreted

Post transfusion sepsis with no confirmatory test, OROther combinations of component and recipient results in situations where the component has been transfused

True Negative Not Applicable Post transfusion sepsis with negative confirmatory test

False Negative

Not Applicable

Post transfusion sepsis with blood culture confirmation, ANDOrganism match between product and patient, ANDPositive confirmatory test on product

Release Test

CumulativeSept 2005 – Dec 2007

Eventsper million (95% CI)

SDP Collections320 983

Interdicted

True Positive 62 193 (148-247)

False Positive 528 1645 (1508-1790)

Indeterminate 45 140 (102-187)

Transfused

True Positive 13 41 (22-69)

False Positive 41 128 (92-173)

Indeterminate 202 629 (546-722)

False Negative** 2 6 (1-22)

1)**Double product – day 6 transfusions; one patient with fever; CNS blood and unit2)**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 73 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

Release Test - Confirmed Positive

185118

234312 329

445

865

10

100

1000

10000

1,004,206 320,983 320,983 12,823 30,407 8,995 26,579

ARC PASSPORT PASSPORT Irish Aph Irish BC Welsh Aph Welsh BC

1-Bottle Test 2-Bottle Test

Po

siti

ve p

er m

illio

n

Release and Surveillance Confirmed Positive

185

118

234312 329

445

686845

865932

10

100

1000

10000

1,004,206 320,983 320,983 PASSPORT 12,823 Irish 30,407 8,995 Welsh 26,579

ARC PASSPORT PASSPORT Surv. Irish Aph Surv. Irish BC Welsh Aph Surv. Welsh BC

1-Bottle Test 2-Bottle Test

Po

siti

ve p

er m

illi

on

3 / 4369 7 / 8282 6 / 6438

Interdicted Transfused Total

True Positive 62 True Positive 13 75

Aerobic Only 10 Aerobic Only 0 10

Anaerobic Only 24 Anaerobic Only 13 37

Both 28 Both 0 28

False Positive 528 False Positive 41 569

Aerobic Only 211 Aerobic Only 14 225

Anaerobic Only 298 Anaerobic Only 27 325

Both 19 Both 0 19

Indeterminate 45 Indeterminate 202 247

Aerobic Only 12 Aerobic Only 34 46

Anaerobic Only 31 Anaerobic Only 160 191

Both 2 Both 2 4

Neither** 6 6

2-Bottle Results

** based on clinical reports

True Positive – Both Bottles

Organism Gram Staining n TTD (h) BPA TTD (h) BPN

Citrobacter NEG 2 4.2 , 8.8 4.4 , 8.4

E. coli NEG 4 9.8 (7.9 – 13) 9.2 (7.7 – 10.8)

K. pneumoniae NEG 1 10 10

Serratia Marcescens NEG 1 6.1 7

Group C streppos

2 15 , 16 17.3 , 13.7

Group G beta hemolytic streppos

2 8.7 , 8.9 8.4 , 8.6

Enterococcus faecalis pos 1 8.1 8.5

Staph Aureus pos 7 10.6 (8.2 -23) 12.7 (8.5 – 27.2)

Staph Epidermidis (CNS) pos 3 19.8 (16.2 -23.3) 33.5 (15 – 69.3)

Strep viridans pos 1 20.9 18

Strep Gallolyticus / bovis pos 5 11.8 (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. 1 11.28

Corynebacterium species 1 29.1

Staph Aureus 2 10.2, 13.3

Staph Epidermidis 1 29

Strep - Alpha hemolytic 1 17.5

Strep - Beta Group C 1 16.2

Strep salivaris 1 12.4

Anaerobic Bottle Only (BPN)

Coag Neg Staph 3 36.8 (21-32)

Strep spp. 3 11.4 (10.6 - 12.2)

Corynebacterium species 2 74.4, 77.8

diptheroid 6 103 (84 – 137)

***Propionibacterium sp. 21 103 (53 -127)

Aspergilus 1 72.8

E. coli 1 11.5

Lactobacillus 1 105.6

***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

Classification Release Test Recipient TxnDay

Clinical Blood culture

Confirmatory Test

False Negative Negative A 6 No rxn neg nd

B 6 Febrile CNS CNS

False Negative Negative A 4 Fever, resp distress, pulmonary edema, hypotension, leukopenia

Staph aureus

Staph aureus

B 4 Fever, hypotension

neg Staph aureus

True Positive BPN (105.6h)P. acnes

A 5 Febrile CNS nd

B-not transfused

N/A N/A N/A P.acnes

True Positive BPN (77.8h) Corynebacterium species

A 3 No rxn nd nd

B 3 SOB, hypotension nd diphtheroids

Clinical Outcomes - 2

Classification Release Test Recipient TxnDay

Clinical Blood culture

Confirmatory Test

Indeterminate BPA (185h) Bacillus sp

A 3 No rxn nd nd

B 5 Nonhemolytic, hypotension

CNS nd

Indeterminate Negative A 4 No rxn nd nd

B 4 Febrile Negative nd

Indeterminate Negative Single 4 Hypotension, febrile

Staph epi nd

Indeterminate Negative A 5 No rxn nd nd

B 6 Chills, hives Enterococcus

nd

Indeterminate Negative A 4 No rxn nd nd

B 4 Febrile CNS bacillus

Indeterminate Negative Single 7 Periorbital edema, hives legs

Neg Strep nonhemolytic

Clinical Outcomes - 3

Classification Release Test Recipient TxnDay

Clinical Blood culture

Confirmatory Test

Indeterminate BPA (41.5h)diphtheroids

Single 5 Hives Nd neg

Indeterminate Negative A 5 No rxn Nd nd

B 5 Citrus nausea and back pain

Nd nd

Indeterminate Negative A 4 Immediate rxn Nd nd

B 7 No rxn Nd nd

Platelet Age Number of Reactions

Day 3 1

Day 4 6

Day 5 4

Day 6 2

Day 7 1

Summary

• 2-bottle Release Test:– True Positive 234/M (184-293)– True Pos + Indeterminate 1003/M (897-1118)– 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!