FDA Perspective on the PASSPORT Study

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FDA Perspective on the PASSPORT Study

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

• FDA engagement in efforts to improve platelet
  storage
• ? BPAC Pre-storage pooling, seven-day
  platelets, bacterial contamination
• of platelets, rapid tests for detection
  of bacterial contamination
• ? Workshop on methods for reducing
  pathogens in cellular blood
• products
• 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

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PASSPORT Study

• 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
• 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

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PASSPORT Study Design
Days of storage

D7
D5
D4
D3
D2
D1
D6
Discard
Sample for culture using BacT/ALERT
2nd Sample for BacT/ALERT testing
-
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• Study sample size 50,000 outdated units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 lt 5 positive units at day
  7

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PASSPORT Interim Results
Days of storage

D7
D5
D4
D3
D2
D1
D6
Discard
Sample for culture using BacT/ALERT
2nd Sample for BacT/ALERT testing

Transfuse
January 2008 Sponsors raise safety concerns
? Day 1 193, 078 collections tested with 48
true positives ? True positive rate at
day 1 1/5,000 ? Day 7 2 true positives
out of 2, 571 platelet units tested ?
Platelet transfusion recipients Out of 5
reported reactions, 3 septic reactions
(STR) confirmed to be resulting from transfusion
of a contaminated platelet product ?
septic transfusion rate of 1/64,000
collections
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Comparison of Septic Transfusion Reactions

• 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 ABCs Platelet Conference, Nov
2007 and HHS Advisory Committee

on Blood Safety and
Availability, January 2008
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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
• 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 lt 5 positives out of 50,000)

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Assessment of the PASSPORT Study

• 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
• 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

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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

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Impact on Safety, Availability, and TRALI
Mitigation

• Impact
• ? Availability of platelets
• ? TRALI mitigation strategies
• Concern of blood establishments over meeting
  cGMPs
• Americas Blood Centers survey need for a 19
  increase in platelet production
• AABB risk assessment on overall platelet safety

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Extension of Phase-out Period

• 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

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Next Steps

• 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