January 31, 2008
Ron K. Labrum, Chief Executive Officer
Fenwal Blood Technologies
David Perez, President
The abrupt discontinuation of the Passport Study by Gambro BCT and Fenwal, requiring rapid reversion to 5-day plateletpheresis dating, is a major disappointment to those in the blood community who are dependent on 7-day apheresis platelets. We are concerned the disruption engendered will precipitate acute platelet shortages. We believe this action, based on the data cited, is premature and fails to balance the overall risks and benefits of a seven day platelet inventory. Valid concerns about the bacterial safety of 7-day platelets would make this precipitous action both understandable and imperative; however, the existing data suggest that the incremental risk from 7-day platelets is small when evaluated in the overall context of platelet transfusion therapy. For example, a cultured apheresis platelet stored for five to seven days is a safer product than five day old whole blood derived platelets which have not undergone bacterial culturing but can still be transfused according to FDA regulations. It is predictable that shortfall in the availability of apheresis platelets will cause some migration to the use of uncultured whole blood derived platelets. Some collection facilities may revert to less robust culture protocols for apheresis platelets, in use before Passport, in an effort to get platelets to hospitals with maximum remaining shelf life. Based on these anticipated changes, we should be asking what will be the net impact on bacterial sepsis?
Our understanding is that the Passport study is being halted due to an initial assessment of the release and surveillance culture data accumulated to date. We are aware that 2 of approximately 5000 Tier 2 Passport surveillance cultures (re-cultures of outdating plateletpheresis units that had negative early cultures) have been positive. However, the lower bound of the 95% confidence interval of this proportion is within the pre-established bound that the FDA has indicated they would accept at the end of the study to support the continued acceptance of 7-day platelets. Furthermore, there have been no severe adverse recipient outcomes or deaths reported from the study. We do not understand the urgency of suspending the study based on these data, and communication so far from the sponsors has not explained it.
Two additional sources of data have been cited in the communication to Passport participants and on the Passport website. We believe these data have important limitations if they are used to estimate the current risk from 7 day platelets in the US. The Foley AABB Annual meeting abstract reported data from Ireland with cultures inoculated a minimum of 12 hours after collection as opposed to the minimum of 24 hours in Passport; in addition, most of these data were from buffy coat derived rather than apheresis platelets. These two factors may account for higher rates of contaminated units missed with the initial culture than would be true with the Passport protocol. The published data of Eder et al included an interval during which the diversion pouch was on the return line of the apheresis circuit, where it would not be effective in removal of the skin plug believed responsible for a significant proportion of bacterial contamination. A more recent American Red Cross estimate of the continuing rate of platelet-associated bacterial sepsis after remediation of this oversight is 1 in 175,000 (Benjamin R, ABC Platelet Conference, Nov. 2007. Unpublished). Preliminary data from Tier 1 Passport suggest the residual risk of signs or symptoms temporally associated with infusion of a unit missed by early culture is about 1/40000 (with very wide confidence intervals). It is not clear that all of these cases were associated with storage of more than 5 days, and therefore would be prevented by discontinuing the study.
The extension of platelet storage to 7 days has been associated with increased platelet availability and decreased outdating of this critical product. In some locales, the impact on availability has been extremely pronounced, with falls in outdate rates reported to be from 6-10% to <1% in some systems. This clearly must be an important consideration in a decision to suspend the study and the sponsors’ communication was silent on this point. It is difficult to envision how affected blood centers can compensate for this kind of shortfall over the next 28 days.
In addition to ensuring adequate platelet inventory, critical cGMP issues must be addressed if the study is, in fact, suspended. These include developing appropriate change control where archived SOPs will need to be reinstituted, staff will need to be retrained, computer systems will need to be rolled back and revalidated, and discontinued labels reordered and validated. The 28 day interval recommended by Gambro and Fenwal is too short a phase out period for an orderly transition in platelet supply.
An increased appreciation of the importance of TRALI complicating the transfusion of high plasma volume components is leading to changes that will decrease the eligible pool of platelet donors. Investigators at the Mayo Clinic have published an estimate that in transfused ICU patients the incidence of TRALI may be as high as 8%. TRALI mitigation efforts being considered and adopted all over the country, including at centers not currently using 7-day platelets, include preferential recruitment of male donors, exclusion of multiparous female donors and screening platelet apheresis donors for anti-leukocyte antibodies pathogenically implicated in many cases. Constraining the platelet supply by the premature reversion to 5-day platelets may paradoxically delay the mitigation of TRALI risk, which is orders of magnitude more common than clinical sepsis from platelets.
Our recommendation is that the Passport study be continued while adjustments to the protocol addressing safety concerns can be considered and implemented. This will require close cooperation among interested investigators and the sponsors. If suspension is inevitable, a longer time line for discontinuation may be needed by participating centers, and we will ask FDA to use enforcement discretion if 7-day collection facilities are unable to meet the arbitrary 28 day timeline suggested by the study sponsors. Critically, we believe that a precipitous suspension of the study carries a risk of disrupting the platelet supply in those systems that are using 7-day outdating and hence will affect the care of patients. The level of communication from the sponsors to the involved centers prior to the announcement of the study’s suspension was grossly inadequate, and has magnified the difficulty of arriving at a satisfactory consensus about maximizing blood safety. The study sponsors must respond to these issues with study participants, and the FDA must be involved in these discussions.
Louis M. Katz, Chair
AABB Bacterial Contamination Standard Task Force
CC Jesse Goodman, Director
Center for Biologics Evaluation and Research
Jay Epstein, Director
Office of Blood Research and Review, CBER
Jaroslav Vostal, Laboratory Chief
Division of Hematology, OBRR, CBER