# Blood Products Advisory Committee

March 13, 2003

Gaithersburg MD

# Summary for Topic II: Discussion on Extension of the storage period for pooled platelets. 

# 

[Issue: What approach should FDA take to scientific validation of a
possible extension of the storage period for pooled
platelets?]{.underline}

[Background:]{.underline}

The dual objectives of improving bacteriological safety and making more
efficient use of platelet inventories would be better served if random
donor platelets could be pooled prior to storage and tested only once
for bacterial contamination, combined with an extension of dating from 5
to 7 days. However, the FDA's current regulations state that a platelet
pool must be transfused within 4 hours of pooling. The storage period
for pooled platelets has been only 4 hours mainly because of the
concerns about accelerated bacterial growth. The growth of the bacteria
may be increased when the contaminated unit of random donor platelets is
combined with a pool of 5-6 other random donor platelets that would
provide a larger volume of media for growth (1). In addition, there have
been theoretical concerns about interactions of leukocytes from
different donors with each other (mixed lymphocyte reaction) that could
increase the rate of adverse reactions to platelet transfusions, and
damage the platelets as well (2,3). The efficacy of the platelets stored
under these conditions has not been investigated thoroughly in the US.

In Europe, platelet pooling and storage up to 5 days has been
incorporated into routine clinical practice (4-8). There is a difference
between European and US platelet processing and that is the use of buffy
coat platelets. In Europe platelets are prepared by immediate cooling of
whole blood with butane-1,4 diol cooling plates to 22 C and stored for
4-22 hours. The whole blood is then subjected to a hard spin and
separated into plasma, buffy coat and red cells. The buffy coats are
allowed to rest for 2 hours and then 5 ABO-compatible buffy coats are
pooled into a single container via a sterile connecting device with 1
unit of plasma from one for the donors. The pool is subjected to a light
spin and the platelet rich plasma is filtered through a leukocyte
reduction filter into a final platelet pool storage bag. Several
European countries allow storage of the platelet pools for up to 7 days
while some countries have a 5 day storage limit. Screening for bacterial
contamination is required.

In US the whole blood collected and stored at room temperature for up to
8 hours. Platelet rich plasma is prepared by a light spin and separated
into a separate storage bag. Platelet concentrate is prepared by a hard
spin of the platelet rich plasma. Platelet-poor plasma is then removed
but enough plasma is left behind to resuspend the platelet concentrate
for storage of up to 5 days. Platelet pools can be made up to 5 days
later by combining 4-6 units but must be transfused within 4 hours.
Leukoreduction can be done on individual units or pooled products up to
72 hours after collection.

The FDA historical concerns for pre-storage pooling of random donor
platelets focused on the issues of a) potential adverse events and
decreased platelet clinical performance associated with the pooling
process and b) increased bacterial proliferation in contaminated pools.
The European experience with pre-storage pooled platelets may be
sufficient to demonstrate that the concept of long term storage of
pooled platelets is viable. However, differences in the way platelets
are prepared in Europe and in the US may be significant enough not to
allow the extrapolation of the European experience with buffy coat
platelets to platelets prepared by the PRP method. For example, the PRP
platelets may have more severe collection damage due to the hard spin
and resuspension and thus may not store as well as buffy coat platelets.
There are several options that could be recommended to evaluate the
clinical performance of buffy coat pooled platelets and PRP pooled
platelets. One would be to incorporate the buffy coat method for all
pre-storage pooling as is done in Europe. The identical storage
conditions and storage bags used in Europe could then be approved in the
US based on data obtained in Europe. Another option would be to compare
the clinical performance of platelets collected by the buffy coat and
PRP method in a clinical study. The storage conditions and storage bags
for the PRP platelets could then be approved in the US based on this
study. A yet another option, which the FDA currently favors, would be to
evaluate clinical performance of PRP platelets in a clinical trial to
compare pre-storage pooled platelets against platelets pooled within 4
hours of transfusion.

The issue of detecting bacterial contamination in PRP pooled platelets
and buffy coat pooled platelets is similar. The European experience with
bacterial detection devices may be sufficient for the US market if the
platelet collection and storage conditions are reproduced in the US. On
the other hand application of these devices to PRP platelets may need a
field trial similar in design to what the BPAC concurred with in
December 2002 for apheresis platelets.

[Proposed plan for validation of extended storage of pooled
platelets:]{.underline}

Clinical performance of platelets

Because of the possible concerns, FDA believes that the safety and
efficacy of the platelets stored under pooled conditions in a particular
storage bag needs to demonstrated. In vitro studies can be done to
evaluate the pre-storage pooled platelets and the extent of the mixed
lymphocyte reaction in the pooled product. The critical study will be a
transfusion of the pooled platelets into thrombocytopenic patients to
assess the clinical performance of the platelets. A comparison of
platelets pooled at the time of transfusion with platelets pooled
pre-storage can be done. Each manufacturer will need to validate their
storage bag for its ability to store pooled PRP platelet products. The
general approach to validation of the storage containers and bacterial
detection is outlined below:

> Storage containers need to be validated for storing platelet pools for
> 5 or 7 days with supporting in vitro tests and by clinical studies
> that evaluate platelet performance. The clinical study would involve a
> comparison between transfusions of platelet pools formed pre-storage
> or formed 4 hours prior to transfusion. The primary endpoint would be
> corrected count index (CCI) in a thrombocytopenic patient population.
> A less than 20 % difference between results in the two arms would be
> considered as equivalent.

Bacterial detection

The extension of the storage of pooled platelets will require a
bacterial detection device that has been validated to detect bacterially
contaminated platelet pools in clinical practice. The current detection
devices (Pall BDS and BioMerieux Bact T Alert) have been cleared by the
FDA for quality control of platelet products (leukoreduced apheresis and
single random donor units) (9,10). It is our current thinking that to
obtain FDA clearance for a screening device for release of products for
transfusion, a field trial will need to be performed that demonstrates
that the device can predict if a unit, sampled early in the storage
period and declared negative, will remain "culture negative" to the end
of storage. This approach was presented to the BPAC on December 2002 and
the committee agreed with the general concept although details of these
studies were left up to the interested sponsors. The general approach to
validation of the bacterial detection devices is outlined below:

> Bacterial contamination screening methods and devices need to be
> validated with in vitro tests and with a "field trial" that evaluates
> their ability detect contaminated platelet pools in actual clinical
> practice. A field trial would sample actual platelet pools at two time
> points to confirm the initial sample results. The study would need to
> be large enough to assure with 95% confidence that both cultures agree
> 95% of the time. Such trial may require a large number of units
> screened due to the low rate of contamination (\~1/2000 units).

Questions to the committee:

1\) Please comment on the FDA proposed plan for validating an extension
of the storage time for pooled platelets?

a)  In vitro validation of the storage containers

b)  Controls and clinical end-points for demonstration of clinical
    efficacy

c)  Validation of the bacterial detection system

2\) Please comment on the applicability of the European experience with
pre-storage platelet pooling of buffy coat platelets to the FDA proposed
criteria for approval of pre-storage pooled PRP platelets.

3\) Please comment on the following bacterial detection validation
isssues:

a)  How useful is the bacterial detection data on buffy coat platelets
    collected in Europe to validation of bacterial detection devices for
    PRP platelet pools?

b)  If bacterial detection devices are validated for single PRP-prepared
    random donor platelet units do they need to be to be re-validated in
    PRP platelet pools?

c)  If bacterial detection devices are validated for leukoreduced
    platelet products do they need to be re-validated for
    non-leukoreduced platelet products?

References:

1\) Wagner et al. Comparison of bacteria growth in single and pooled
platelet concentrates after deliberate inoculation and storage.
Transfusion 35;298-302, 1995

2\) Snyder et al. Storage of pooled platelet concentrates: In vitro and
in vivo analysis. Transfusion 29;390-395, 1989

3\) Moroff et al. Storage of pools of six and eight platelet
concentrates. Transfusion 33; 374-378, 1993

4\) Boomgaard et al. In vitro evaluation of platelet concentrates,
prepared from pooled buffy coats, stored for 8 days after filtration.
Transfusion 34;311-316, 1994

5\) Wildt-Eggen et al. Evaluation of storage conditions of platelet
concentrates prepared from pooled buffy coats. Vox Sang. 70;11-15, 1996

6\) Van der Meer et al. WBC-reduced platelet concentrates from pooled
buffy coats in additive solution; an evaluation of in vitro and in vivo
measures. Transfusion 41;917-922,2001

7\) Van der Meer et al. Leucoreduced platelet concentrates in additive
solution: an evaluation of filters and additives solutions. Vox Sang.
81;102-107

8\) Krailadsiri et al. Platelet storage lesion of WBC-reduced, pooled,
buffy coat-derived platelet concentrates prepared in three in-process
filter/storage bag combinations. Transfusion 41;243-250, 2001

9\) Brecher et al. Evaluation of an automated culture system for
detecting bacterial contamination of platelets: an analysis with 15
contaminating organisms. Transfusion 41;477-482, 2001

10\) McDonald et al. Evaluation of the BacT/Alert automated blood
culture system for detecting bacteria and measuring their growth
kinetics in leucodepleted and non-leukodepleted platelet concentrates.
Vox Sang. 81;154-160, 2001