# Presentation: 433615

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

- Jaro Vostal, MD, PhD
- Division of Hematology, OBRR, CBER, FDA

## 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”

## 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

## 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

## 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

## Regulatory History of Bacterial Detection Devices (continued)

**2004**** **AABB, FDA, CDC** **work 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)

## 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

## Testing Scheme for Bacterial Detection Device 

- Bacterial
- detection
- result

- Repeat
- testing

- True Positive

- False Positive

- 7 day storage

- Clinical use

- Repeat
- testing

- True Negative

- False Negative

- Testing Scheme for Bacterial Detection Device
- Performance Validation (QC and Post Market Data)

**QC**** **
**Data ****(400, 000 units)**

**Post **
**market **
**Data**

**(50,000 units)**

## Culture-Based Bacterial Detection Devices that 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

## Rapid Bacterial Detection Devicesthat 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)

## 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

## Determination of substantial equivalence to a marketed bacterial detection device

**Day 0****	****           Day 1****	****       Day 2              Day 3**

- Culture-based
- device

- Platelet bag

- Rapid detection
- device

- sample

- sample

## Detection Strategies for Fast and Slow 

** ****0             1             2              3             4             5             6             7**
**	****	****	****STORAGE DAYS**

**BACTERIAL LOAD (log CFU/ML)**

- Fast growing
- bacteria

- Slow growing
- bacteria

- Detection Strategies for Fast and Slow
- Growing Bacteria

##  Potential Field Trial of Rapid Bacterial Detection Devices

- culture-based device
- testing on Day 1

- Repeat
- testing

- With culture-based device:   true vs false positive

**Day 2  Day 3****	****Day 4.......Day 7**

- With rapid detection device to determine when
- test becomes positive

-  Potential Field Trial of Rapid Bacterial Detection Devices

- _Clinical use  of platelet products_

**Day 2  Day 3****	****Day 4.......Day 7**

- Test at release of product with
- Rapid Detection Device: true negative vs false negative

- Repeat
- testing

## 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

## 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

## 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

## 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?