Gambro/Fenwal PASSPORT Post Marketing Study – 7 Day Platelets Blood Products Advisory Committee...
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Transcript of Gambro/Fenwal PASSPORT Post Marketing Study – 7 Day Platelets Blood Products Advisory Committee...
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!