Rapid Tests for Detection of Bacterial Contamination of Platelets for Transfusion BPAC March 8-9, 2006

1. Rapid Tests for Detection of Bacterial Contamination of Platelets for TransfusionBPAC March 8-9, 2006 Jaro Vostal, MD, PhD Division of Hematology, OBRR, CBER, FDA

2. FDA Clearance of Bacterial Detection Devices is Based on Their Intended Use • Quality control (QC) indication: sampling of small number of collected products to assure collection process is in control (as few as 4/month) • Transfuse product without waiting for results • Product release indication: screening of all products prior to release for transfusion • Decision to transfuse depends on results • Products can be labeled as “tested negative for bacteria by ……. method”

3. Criteria for Clearance of Bacterial Detection Devices for Quality Control • Clearance is based on in vitro testing • Device is tested on platelet products intentionally contaminated with variable levels of bacteria (spiking study) • In vitro testing identifies • Analytical sensitivity for particular bacterial species • Adequate sampling times, sample volumes and hold periods • Limitations • Clinical sensitivity, specificity and predictive value are unknown and need to be defined by a field trial

4. Criteria for Clearance of Bacterial Detection Devices for Release of Platelet Products • More stringent validation criteria are needed than for QC testing because the intended use is to assure, with defined confidence, that released products are not contaminated • Bacteria, if present, will be below a certain level • The frequency of contamination is predictably low (known frequency of false negatives) • Clinical (field) studies are needed to establish the false negative and the false positive rates for the device under actual use conditions

5. Regulatory History of Bacterial Detection Devices • 2001 Two culture based bacterial detection devices cleared for quality control (QC) testing of apheresis platelets (Pall, bioMerieux) • 2004 Non-culture detection system cleared for QC of apheresis platelets (Hemosystems) • 2001-2004 FDA outlines path for clearance of a bacterial release test (BPAC December 2003). Requests field trial to validate performance of bacterial detection devices on clinical products (50,000 products) Progress towards a release test stalls • 2004 AABB bacterial detection standard goes into effect, QC data collected across country

6. Regulatory History of Bacterial Detection Devices(continued) • 2004AABB, FDA, CDCwork together in Bacterial Contamination working group • 2004 FDA outlines new pathway to obtain a release test indication utilizing available quality control (QC) data • 2005 Gambro follows new pathway and obtains clearance for 7 day platelets when tested with culture-based bacterial detection device (bioMerieux) • 2005 Baxter follows same pathway and obtains clearance for 7 day platelets • 2005 clearance of pre storage pooling bag to pool and store platelets up to 5 days when tested with a culture-based bacterial detection device (QC indication) (Pall) • 2005 culture-based device cleared for QC of pooled platelets (bioMeriuex)

7. Current Approach to Validation of a Release Test Indication for Bacterial Detection Devices • Obtain data on performance of the FDA cleared devices when used to meet the AABB bacterial detection standard 5.1.5.1 since 3/04 • ~450,000 samples • Use data as a basis for approval of 7 day platelets provided there is a commitment to perform a post-marketing study • Post-marketing study will consist of additional cultures on outdated products (day 7) to confirm the day 1 negative culture readings • Goal is to demonstrate a point estimate of risk at day 7 to be 1/10,000 with a 95% upper confidence limit that the risk is <1/5,000 • Study size ~ 50,000 platelet units

8. Testing Scheme for Bacterial Detection Device Performance Validation (QC and Post Market Data) True Positive Repeat testing QC Data (400, 000 units) False Positive Bacterial detection result True Negative Post market Data 7 day storage Repeat testing Clinical use False Negative (50,000 units)

9. Culture-Based Bacterial Detection Devicesthat test for contaminated platelet units shortly after collection Advantages • High Sensitivity (1-10 CFU/mL) • Extensive data base on performance in QC application Disadvantages • 24 hour turn around after inoculated • Large volume samples 4-16 mL • High upfront cost due to hardware (incubators, detectors) • Only one major manufacturer

10. Rapid Bacterial Detection Devicesthat test for contaminated platelet units at time of issue Potential advantages • Rapid turn-around (minutes to hours) • Small sample volume <1-2 mL • Inexpensive Potential disadvantages • Lower sensitivity when compared to culture-based systems due to lower volume sampling and alternate technology • Single determination per sample vs continuous reading of culture bottle for length of product storage (BacT/Alert, bioMerieux)

11. Proposed Indications for Use for Rapid Bacterial Detection Devices • 510k application with currently marketed culture-based devices as predicates Proposed indications: • Quality control • Determines that the collection process does not introduce bacteria at greater than a predetermined rate • Adjunct to a bacterial release test • A test performed at point of issue in addition to a release test performed early in platelet storage • Current release test predicate is the Gambro or Baxter 7 day apheresis platelet collection system • Release test • Determines that a platelet product is not contaminated with bacteria

12. Determination of substantial equivalence to a marketed bacterial detection device Culture-based device sample Platelet bag sample Rapid detection device Day 0 Day 1 Day 2 Day 3

13. Sensitivity of rapid test device Sensitivity of culture- based device Detection Strategies for Fast and Slow Growing Bacteria Fast growing bacteria Slow growing bacteria BACTERIAL LOAD (log CFU/ML) 0 1 2 3 4 5 6 7 STORAGE DAYS

14. Potential Field Trial of Rapid Bacterial Detection Devices With rapid detection device to determine when test becomes positive Repeat testing Day 2 Day 3 Day 4…….Day 7 With culture-based device: true vs false positive culture-based device testing on Day 1 Clinical use of platelet products Repeat testing Day 2 Day 3 Day 4…….Day 7 Test at release of product with Rapid Detection Device: true negative vs false negative

15. Summary of Proposed Regulatory Pathways for Rapid Bacterial Detection Devices 510k application based on intended use of device • Quality Control (QC) • Define Analytical sensitivity by spiking studies • Same list of bacteria as used to validate the predicate devices • Establish substantial equivalence to marketed culture-based devices • Timed sampling study on spiked platelet units • Same list of bacterial species as used in the analytical sensitivity studies

16. Summary of Proposed Regulatory Pathways for Rapid Bacterial Detection Devices 510k application based on intended use of device • Adjunct to a release test • Obtain clearance for QC indication • Commitment to a post-market field trial with a timed sampling study • Repeat sampling of clinical units declared “positive” by a culture based-device to determine when the rapid detection device also identifies unit as positive • Testing of 60 units will provide 95% confidence that the device can detect 95% of contaminated units

17. Summary of Proposed Regulatory Pathways for Rapid Bacterial Detection Devices 510k application based on intended use of device • Release Test • Clearance for QC indication • Standard operating procedure (SOP) that defines appropriate sampling strategy which assures substantial equivalence to a marketed bacterial detection devices • Extensive data set on QC performance (100,000s + samples) • Commitment to a post market study on 50,000 units that will be retested at outdate

18. Questions to the committee: • Is the proposed 3 tiered regulatory scheme for clearance of rapid bacterial detection tests acceptable? The tiers, with increasing data requirements, include clearance for a Quality control indication, Adjunct release test indication, and a Release test indication. 2. What would be the minimum sensitivity in CFU/mL for detection of a contaminated platelet unit? 3. Is the kinetic comparison (timed sampling spiking study) an appropriate design of an equivalency demonstration between culture-based and rapid test devices?