# Presentation: 554052

## Verax Biomedical

**Platelet PGD****®**** Test**

## Verax Biomedical Platelet PGD® Test

**Verax Biomedical Platelet PGD****®**** ****Test**

**  ****Results in approximately 30 minutes**

**  ****Designed for use with LR or non-LR:  RDPs, Pooled RDPs & SDPs**

**  ****2 to 3 minutes attended labor per test**

**  ****Analytical sensitivity ~ 10****3**** – 10****4**** CFU/mL **

**  ****510(k) lots produced, prepared to enter clinical trials**

## Medical Advisory Board

**Medical Advisory Board**

***James AuBuchon, M.D.***

**Dartmouth-Hitchcock Medical Center **

***Leslie Silberstein, M.D.***

**Harvard School of Medicine**

***Ira Shulman, M.D.***

**University of Southern California**

***Roslyn Yomtovian, M.D.***

**Case Western Reserve University**

***Mark Brecher, M.D.***

**University of North Carolina**

## Patented PGD® technology

**Patented PGD****®**** technology**

- Detects conserved antigens on bacteria

- Expressed on surface of bacteria

- >  200,000 copies per cell

- Therapeutic antibody targets

- Antigen detection via immunoassay

-   LPS on all Gram-negative

-   LTA on all Gram-positive

***Pan Genera Detection ***

## PGD Immunoassay Format – two tests run simultaneously

**antibodies**

- Gram positive
- Sandwich Immunoassay

**LTA capture**
**antibodies**

**GP bacterial capture**

**Labeling by LPS**
**conjugate**
**antibodies**

- Gram negative
- Sandwich Immunoassay

**LPS capture**
**antibodies**

**GN bacterial capture**

**PGD Immunoassay Format – two tests run simultaneously**

## A.

**1**

-  Add **8 drops** of
**Reagent **
**to 500uL Platelet Sample**
**-**
**Solution Turns**
**Green**

**A.**

- Spin for 5 Minutes
- & Decant

**Verax Biomedical Platelet PGD****®**** Test procedure**

- Add **8 drops**** **of
**Reagent**

**2**

**B.**

**C.**

- Add **4 drops** of
**Reagent**
**Solution Turns yellow**

**3**

**GP**

**GN**

**C**

**C**

**GP**

**GN**

**C**

**C**

- Transfer to
-  well and
- Wait for results

**Negative**

**Positive**

**Invalid**

- Interpret results

***Centrifugation***

***Resuspension***

***Reading***

- and Resuspend Pellet
- Solution Turns
- BLUE

## Unused test cartridge 

**Unused test cartridge **

**Test Results and Interpretation**

## Valid non-reactive result 

**Valid non-reactive result **

**Test Results and Interpretation**

## Valid reactive result

**Valid reactive result**

**Test Results and Interpretation**

## Invalid result

**Invalid result**

**Test Results and Interpretation**

## Pre-Storage Testing

**May be too few bacteria to sample**

**Results in False Negatives**

**Clinical sensitivity**

**Sampling early in life limits**

***Pre-Storage Testing***

**Not all units “bloom” within 24 hours**

***Culture sample @ 24 hours***

***High Titer***
***False Negatives***

**Current early sampling techniques risk false negatives **

## Breakthrough cases – False Negatives associated with current testing

**Reported by CDC at January 2005 DHHS Blood Safety & Availability Meeting:**

**  ****FATALITY - Culture false negative**

**  ****FATALITY - Culture false negative**

**  ****FATALITY - pH false negative **

- 74 year old patient with leukemia receiving a routine platelet transfusion.  Received a 5 unit
- irradiated platelet pool tested normal by pH (>6.4). Pool contaminated with Staph aureus.
- Patient died after a 21 day hospital stay.

- 79 year old coronary-artery bypass patient transfused apheresis unit that tested negative
- for bacteria by BacT Alert on a 24 hour sample. Unit contaminated with Staphylococcus lugdunensis.  Patient died 27 hours later. Original BacT culture still negative after 10 days.

- Premature newborn received two doses from an apheresis platelet unit. Unit tested negative
- by 24 hour sample plate culture and normal pH (7.3).  Unit contaminated with Serratia marcescens.  Child died 27 hours later.  Second culture on original sample also negative.

## Testing near time of transfusion offers a potential benefit

**maximizes clinical sensitivity**

**Testing close to transfusion**

***Testing at Release***

**Simple pre-transfusion test**

**Avoid call-backs**

**Reduce false negatives**

***Run our test at time of issue***

***Minimizes***
***False Negatives***
***& Their Titer***

## This approach is the one most likely to demonstrate equivalence for 

- QC purposes:

**Considerations for the establishment**
**  ****of a regulatory pathway for rapid**
**  ****tests for bacterial contamination....**

-  Allows for the differing analytical sensitivities of the two methods

**Kinetic studies for QC claim equivalence**

-  Allows for the widely differing time of sampling for culture methods and
-   rapid tests intended to be used near the time of release

## We must be careful in establishing a priori analytical sensitivity targets now for tests intended for use near the time of transfusion: 

**Considerations for the establishment**
**  ****of a regulatory pathway for rapid**
**  ****tests for bacterial contamination....**

* *_*Time of testing*_ is likely to be a more significant driver of clinical performance
- 	than _*analytical sensitivity*_

-  The more important question is: how many contaminated units
-    do we avoid transfusing? – best answered with populations studies

**Analytical sensitivity targets**

## +

**Residual Risk of Testing**
** ****With a Rapid Test With a **
**Sensitivity of:**

- =

**Assuming:  1:2,000 Underlying Incidence Rate & Testing Within 4 Hours of Transfusion**

**Calculated Impact of Analytical Sensitivity Testing Close to Transfusion **

## Calculated Impact of Analytical Sensitivity Testing Close to Transfusion 

**Calculated Impact of Analytical Sensitivity Testing Close to Transfusion **

- Approximates
- 1:10,000
- FDA Hurdle for
- Culture Release
- Indication

- Typical
- Platelet PGD®
- Analytical Sensitivity

## Given the need for tests with release indications, we are concerned that    

- FDA’s proposal may not be the least burdensome route to a release test:

**Considerations for the establishment**
**  ****of a regulatory pathway for rapid**
**  ****tests for bacterial contamination....**

* *a 450,000 unit post market surveillance data set, plus

-  an additional 100,000 unit post market study comparing with culture @ outdate
-   (how is this possible when units have been transfused?)

**Three tiers of data required for**
**a release test indication**

* *a post market study of unknown size testing culture positives, plus

* *the requirement for* *a QC equivalence claim, plus

## For example: 

**Considerations for the establishment**
**  ****of a regulatory pathway for rapid**
**  ****tests for bacterial contamination....**

* *this pathway would likely delay a release indication by 3 to 4 years

**Three tiers of data required for**
**a release test indication**

* *this pathway would take longer to answer the question of the actual clinical
-   sensitivity of the method than simply performing a classic virus screening trial

* *the 3 post market data sets would appear to gather overlapping data
-  some data (culture confirmation at outdate for rapid test-negatives)         	could not be obtained as the platelets would have been transfused

## We recommend that FDA consider a streamlined, two-step regulatory strategy for a release claim: 

- -  Step 1:  510(k) for Quality Control

-   Step 2:  Screening for release (well-controlled, structured trial comparing
- 	to culture at time of transfusion on 50,000 to 100,000 units)

**Three tiers of data required for**
**a release test indication**

**Considerations for the establishment**
**  ****of a regulatory pathway for rapid**
**  ****tests for bacterial contamination....**

-   Supplemented by ongoing post market surveillance of observed
-     incidence data from end-users