# Presentation: 711777

## Gambro/Fenwal PASSPORT Post Marketing Study – 7 Day Platelets Blood Products Advisory CommitteeRockville, MDMay 1, 2008

- Larry J. Dumont, MBA, PhD
- Dartmouth-Hitchcock Medical Center
- Lebanon, New Hampshire

**Notes:**
update

## 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:**_
**True contamination rate: **
**178/M (1/5618) to 349/M (1/2865), [based on one bottle testing]**
**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:**_
**True contamination rate: **
**178/M (1/5618) to 349/M (1/2865), [based on one bottle testing]**
**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.**

## SEPT 2003: 7-day platelet function OK

**SEPT 2003:**** 7-day platelet function OK**

## Slide 7

## 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

_**Release Test**_** – 2 bottle**

**Incubate**

**Data Analysis**

**D1**

_**Surveillance Test**_** – 2 bottle**
**N ~ 50,000**

**Incubate 7d**

_**7-Day Apheresis Platelets**_

- 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 US**

**March**

**2008**

- Implemented 7DP

- (5)

**33 organizations (51 centers) Participating Nationwide**

## Slide 13

**Notes:**
Update for 4Q

## Surveillance through 11 Feb 2008

**Notes:**
Updated

## Slide 15

| Event | Not Transfused | Transfused |
| --- | --- | --- |
| True Positive | Positive confirmatory test | Positive confirmatory test, OR
Post-transfusion sepsis confirmed by blood culture |
|  |  |  |
| False Positive | Negative confirmatory test | Negative confirmatory test, AND
No clinical or microbiological evidence of post-transfusion sepsis |
|  |  |  |
| Indeterminate | No confirmatory test, OR
Couldn’t be interpreted | Post transfusion sepsis with no confirmatory test, OR
Other 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, AND
Organism match between product and patient, AND
Positive confirmatory test on product |

## Release Test

|  | Cumulative
Sept 2005 – Dec 2007 | Events
per million
 (95% CI) |
| --- | --- | --- |
| SDP Collections | 320 983 |  |
| 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) |

- **Double product – day 6 transfusions; one patient with fever; CNS blood and unit
- **Double product – day 4 transfusions; STR 6-8h post both pts; staph aureus

- AABB Bulletin #04-07, Oct 2004

**Notes:**
4Q numbers are in – update second false negative

## Surveillance Test

**4369 tested after day 7**
**3 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**

## Slide 18

**Notes:**
updated

## 3 / 4369

**3 / 4369**

**7 / 8282**

**6 / 6438**

**Notes:**
updated

## 2-Bottle Results

| 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**

**Notes:**
updated

## 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 strep | pos
 | 2 | 15 , 16 | 17.3 , 13.7 |
| Group G beta hemolytic strep | pos
 | 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 | Txn
Day | 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 | Txn
Day | 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 |

**Notes:**
4Q adds

## Clinical Outcomes - 3

| Classification | Release Test | Recipient | Txn
Day | 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 |  |  |  |  |

**Notes:**
4Q adds

## 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)**

**Notes:**
updated

## Thank you!