BLOOD PRODUCTS
ADVISORY COMMITTEE
92nd
Meeting, September 10-11, 2008
Issue Summary
Topic I. Strategies
to Enhance Bacterial Safety of 7 day Platelets for Transfusion
Issue: FDA seeks the advice of the Committee on the development of new testing paradigms that will reduce the rates of bacterial contamination and septic transfusion associated with platelet products
Background:
Platelets are currently stored
at room temperature up to 5 days. They can
be a medium for bacterial growth if the platelet product is contaminated during
collection. Bacteria introduced in small
numbers into a platelet bag can proliferate to bacterial concentrations of 1012
CFU/mL and greater. While some contaminated
units may display visible changes, often they do not appear much different from
uncontaminated units. When transfused,
contaminated units can have grave results.
FDA extended platelet
shelf life to 7 days in the mid 1980’s.
However, after approximately 1.5 years, FDA, on advice from BPAC, reduced
the shelf life back to 5 days because of increased septic transfusion reaction
rates from the 7 day platelets. Since
then several advancements made it possible to re-introduce 7 day platelets on
the market. Devices to detect bacterial
contamination of platelets were developed and cleared by the FDA for quality
control of platelet products. The device
manufacturers did not seek a claim for a release test and thus no clinical study
was done to validate such a claim.
However, the use of culture based devices has become routine for quality
control screening of 5 day platelets and a large body of data became available
on detection of contaminated products when these were sampled 24 hours after
collection. The contamination rate was
found to be about 1/5,000, which was generally thought to be the contamination rate
based on several small studies that screened collected platelet products. It was also thought that the use of these
devices early in the storage period would be sufficient to reduce the contamination
rate of 7 day platelets.
Several companies validated
their collection containers for platelet storage up to 7 days. One company, Gambro, collected performance
data on the use of BacT Alert for quality control testing of platelets and
prepared a study proposal for establishing uniform use of the bacterial
detection device to screen platelets. Gambro
received clearance from the FDA for marketing 7 day apheresis platelets with
labeling that specified the use of the BacT Alert culture system on a platelet
sample obtained 24 hours after the collection.
Additionally, FDA required that the users participate in a post market
study to validate the performance of the BacT Alert device for reducing the
contamination rate of 7 day platelets.
This study became known as the PASSPORT (Post Approval Surveillance
Study of Platelet Outcomes, Release Testing) study and was eventually joined by
a second sponsor, Fenwal Corporation.
PASSPORT
Study Design
The objective of the study
was to demonstrate that the point estimate for the contamination rate of 7 day apheresis
platelets is 1/10,000 or less, with the upper 95% confidence limit not greater
than 1/5,000. The 1/5,000 rate was
chosen because this was thought to be the contamination rate of untested 5 day
products. The study had a standardized
testing protocol that used two culture bottles (aerobic and anaerobic), each
inoculated with 4-5 ml of sample collected 24 to 36 hours after venipuncture. There was no requirement for diversion of
initially collected blood although many collection centers used this practice
anyway. The products were held for 24
hours after testing and, if negative at that time, were released for
transfusion. The inoculated culture bottles
were monitored in the incubator for 7 days.
The products were transfused for up to 7 days. Outdated products were sent back to the
collection center for retesting (surveillance).
The study was planned for testing of 50,000 outdated units and allowed less
than 5 true positives in the outdated units (5/50,000 = 1/10,000).
Over the course of
approximately 2.5 years the study tested 320,983 products at 24 hours and 4,369
products at outdate. The detected contamination
rate was approximately 1/5,000 at 24 hours and 1/1,400 at outdate (3/4,369). These results showed that testing of 24 hour
platelets had a high false negative (FN) rate (approx. 74%)
Day 1 Day 7
Contamination rate 1/4,273 1/1,456
N= 320,983 4,369
Approximately two years
into the study after the first interim analysis the sponsors became aware of
the unexpectedly high contamination rate of outdated products. They became concerned over the safety of 7
day platelets and decided to stop production of 7 day platelets even though the
study tested only a fraction of the planned 50,000 outdated units. Two
main conclusions emerged from the first interim analysis of the data: 1) The
number of bacterially contaminated units identified at outdate (2 out of 2,571
tested) made it very unlikely that the study would meet its objective, based on
previously set statistical considerations; and 2) The transfusion recipient
septic transfusion reaction rate was close to double that of a parallel
surveillance study on 5 day dated platelets conducted by the American Red Cross
(yet with no statistically significant difference) raising safety concerns of
the 7-day product. Subsequently seven day platelets were phased out over a 90 day period
to minimize shortages and the blood banking system reverted back to storing
platelets to 5 days.
Concurrent
Studies
American Red Cross
The American Red Cross (ARC)
supplies a large number of platelet products.
ARC did not participate in the PASSPORT study, but used the BacT Alert
device for screening platelet products stored for 5 days. The ARC uses a single aerobic bottle for
sampling at 24 hours, does not re-culture outdated products and relies on
following the septic transfusion rates from their platelets as a signal for
product contamination rates. Before
initiating the culture screening, the septic transfusion rate was
1/40,000. After initiating culturing of
products, this rate decreased to 1/75,000. When diversion of the initial blood collection
and doubling the culture volume from 4 to 8 mL were later instituted, the rate
decreased to 1/140,000.
Septic
reaction rate before culture after culture after culture+ diversion
+ 8mL
(STR) 1/40,000 1/75,000 1/140,000
N= ~500,000 1,496,134 697,637
The ARC study also tracked
the age of the platelets in relation to the septic transfusion rate. Day 4 platelets had a small increase compared
to days 1-3 while day 5 had a substantial increase in the septic transfusion
rate compared to earlier days. In
addition, 3 mortalities were reported as associated with bacterially
contaminated platelets and all occurred with day 5 platelets
Irish Blood Transfusion Service
In 2005 the Irish Blood Transfusion
Service started culture testing of apheresis and pooled whole blood derived
platelets with the BacT Alert device. Their
protocol was to sample at 12 hours for apheresis and 36 hours for whole
blood-derived platelets, inoculate 7.5 ml each into aerobic and anaerobic
bottles. Platelets to be stored out to 7
days were re-sampled at day 4 with 7.5 ml samples inoculated into each an aerobic
and anaerobic bottle and those that remained at outdate (day 7) were tested
again. The confirmed positive results
were as follows:
Day
1 Day
4 Day 7
Contamination
rate 1/3,300 (apheresis) 1/3,310 (all) 1/1,183 (all)
N= 43,230 3,310 8,282
Based on these results, the
detection rate by the initial 24 hour culture was estimated to be 29% (False Negatives
= 71%).
Lessons Learned from the Original
PASSPORT Study
The sensitivity of the
BacT Alert device in identifying contaminated products through a sample taken
after the first 24 hours is poor (False Negatives approximately 74%). Slow-growing organisms do not proliferate to
substantial levels until day 5 and possibly continue to proliferate over days 6
through 7. The PASSPORT study design did
not track septic transfusion reactions by product shelf life day and thus it
was not possible to determine risk based on storage age of the cells. Day 5 platelets were associated with a higher
septic transfusion rate than day 3-4 platelets in the ARC study but this could
not be correlated with the results of the PASSPORT study. The PASSPORT study did not have prospective stopping
rules or a Data Safety Monitoring Board which would have made the decision to
continue or halt the study much easier.
Discussion:
Platelet storage out to
day 7 post collection remains desirable as a strategy to reduce platelet
outdating and to provide greater flexibility for management of platelet
donations and platelet inventories. For
this reason there is a goal to reestablish conditions for use of 7 day
platelets with added safeguards that would decrease the risk of septic
transfusion reactions that is associated with longer storage. FDA seeks input from the Committee on
conditions that would be adequate to address this risk.
Sponsor
Proposal (Gambro/Fenwal/ AABB Task Force) on Bacterial Contamination
The sponsor has proposed
to add new labeling to the platelet bags to warn the user of the results of the
original PASSPORT study and to inform the user there are rapid bacterial
detection tests that could be used to decrease the risk. Product labeling will specify use of standardized
skin preparation and blood diversion methods and will direct users to sample the
products at 24-36 hours, by inoculating 8 ml each into aerobic and anaerobic
bottles.
The proposed revised
PASSPORT study will consist of passive reporting of transfusion reactions. There
will not be any cultures taken later in storage either prior to product issue or
as surveillance cultures performed at outdate.
The primary outcome of the study will be rate of sepsis which will also
be tracked as a function of product age.
There will be a Data Safety Monitoring Board to adjudicate and monitor
the septic transfusion reaction rates, and predetermined stopping rules for the
study will be defined.
FDA
Proposal for Conditions of Use of 7 Day Platelets
FDA favors the addition of
a second bacterial detection step during the course of platelet storage to
reduce the risk of contaminated platelets on days 5 through 7. In brief, standardized collection methodology
would be applied that includes a diversion pouch and standard skin prep. The products would be sampled on Day 1, by
inoculation of 8 ml each into aerobic and anaerobic bottles. Products could be released after 24 hours (12
hours if there is a robust notification system for notifying transfusion
centers with any positive results).
Products remaining on the shelf on the morning of Day 5 would be re-sampled,
again placing 8 ml each into aerobic and anaerobic bottles and could be released
after 12 hours of culture if not positive.
These products could be used for transfusion out to day 7. Outdated products would be sent back to the
collection center and re-sampled placing 8 ml each into aerobic and anaerobic
bottles to obtain the surveillance cultures.
In addition, use of a rapid bacterial detection device would be required
prior to release of products transfused at day 6 and 7. The septic transfusion rate will be tracked
for each day of platelet storage including monitoring of the number of
platelets of that storage age that are released. A Data Safety Monitoring Board
will monitor the product contamination rates and septic reaction rates. There will be predetermined stopping rules
for the study.
This approach would
achieve several objectives:
a) Reduce the septic
reaction rates associated with day 5 platelets (as reported in the ARC study)
and reduce the risk of day 5 through 7 platelets which was the basis of ending
the original PASSPORT study.
As demonstrated in the Irish
study, testing at day 4 is not sensitive enough to identify contaminated products
at day 7. Testing one day later is
likely to increase this sensitivity.
b) Validate performance of
rapid bacterial detection devices.
Rapid bacterial detection
devices have not been validated in a clinical setting and thus use of this
device during the clinical trial would validate its clinical sensitivity and
possibly justify its use as a stand-alone quality control or release test.
Questions to the Committee:
1. Does the Committee agree that to optimize culture sensitivity the initial sample taken at 24 hours of platelet storage should be tested with both an aerobic bottle and an anaerobic bottle using 8 ml volumes for each bottle?
2. Does the Committee concur with an industry proposal that the following collective measures are sufficient to allow use of 7 day platelets in the absence of a study to retest platelets for bacterial contamination on or after day 5 of storage?
If so, what would the committee consider as an acceptable septic transfusion rate for 7-day stored platelets?
3. If not,
a. Should an additional culture be performed on day 5? If so,
i) Would a single anaerobic culture on day 5 be sufficient?
ii) Should testing with a rapid bacterial test be additionally required on or after day 5?
b. Would rapid bacterial detection device on the day of issue on or after day 5 be sufficient, i.e. as a substitute for a day 5 culture?
c. Should the performance of the bacterial detection during the course of platelet storage (e.g. day 1 and day 5) be confirmed by a surveillance culture on outdated platelets (in addition to monitoring the rate of sepsis)?