The Food and Drug Administration’s Blood Products Advisory Committee met April 1-2 to advise the agency on blood donor screening and testing donors of human cells, tissues, and cellular- and tissue-based products for hepatitis B virus infection by nucleic acid testing; potential testing strategies for
Trypanosoma cruzi infection in blood donors; and current considerations on plasma obtained from whole blood donors for further manufacturing use.
Hepatitis B Virus Infection Blood Donor Screening Through Routine Nucleic Acid Testing
FDA and members of the transfusion medicine community provided informational presentations on screening of blood and HCT/P donors for hepatitis B virus by NAT. Donors are currently required by FDA to be tested for HBV surface antigen, or HBsAg, and the antibody to HBV core antigen, anti-HBc. As of December 2008, there were three NAT tests available: COBAS AmpliScreen HBV Test and COBAS TaqScreen MPX Test, a multiplex assay for HBV, HCV and HIV — both of which are manufactured by Roche Molecular Systems Inc. — and Procleix Ultrio Assay, a multiplex assay for HBV, HCV and HIV, which is manufactured by Gen-Probe Inc. Although these assays have approved indications for donor screening and some U.S. blood establishments are using them, HBV NAT has not been recommended by the FDA for routine donor screening based on a previous assessment that determined this provided limited added value to the public health.
A presentation from Blood Systems Research Institute/University of California, San Francisco on HBV viral dynamics, infectivity and incidence window-period risk modeling was followed by
an American Red Cross review of current incidence and residual risk of hepatitis B infection among blood donors in the U.S. The American Red Cross then presented data from an “evaluation of the yield of HBV DNA-positive, seronegative donors using an automated HIV-1/HCV/HBV triplex assay.” Data was collected on donations that were HBsAg and anti-HBc nonreactive using a combination of ID NAT and MP NAT of 16 donations. The study also focused on determining the rate and characteristics of HBV yield donors and the HBV screening claim approved by FDA for using MP NAT with a pool size of up to 16 donations.
According to the data presented, the ARC study detected nine HBV DNA-positive, HBsAg- and anti-HBc-negative donations using HBV NAT, and it produced comparable yields to other HBV yield studies performed in the U.S. Six of the nine donations were from immunized individuals (vaccine breakthrough cases) that had anti-HBs at index or shortly thereafter, and three of the nine were considered window-period donations. In addition, it was noted that eight of the nine cases were detected using MP NAT with a pool size of 16. ARC stated that the data does not suggest a benefit of using a pool size smaller than 16, and the high yield of an MP of 16 has a value that compares to ultrasensitive HBsAg assays. The ninth case was only detected by ID NAT and not detected when using a smaller pool size of four or eight. Although ID NAT has additional value, at the present time it is not logistically feasible and is not supported by a yield perspective from the study, where ID NAT only identified one donor with a breakthrough infection.
Breakthrough infections often are characterized by low viral load and are asymptomatic. The rate of breakthrough infections among HBV-vaccinated individuals is unknown and may be detected with NAT window period modeling. One question discussed at length is whether the units from donors with apparent vaccine breakthrough are infectious. FDA noted that estimated residual risk by modeling does not include vaccinated donors, breakthrough infections are unlikely to be detected without NAT and risk of transfusion-transmitted infections due to units from donors with breakthrough infections cannot be dismissed.
In a joint statement with the American Red Cross, AABB stated that adopting HBV NAT will provide an “incremental improvement in HBV transfusion safety… from donors with acute infection whether previously vaccinated or naïve.” The organizations also explained that it is reasonable for FDA-licensed blood establishments to implement HBV MP NAT on a voluntary basis until the FDA mandates testing and that MP NAT with pool sizes of six or 16 should be used because there is no benefit to smaller MP sizes from either modeling studies or clinical studies. The organizations stated that they oppose a mandate for ID NAT at this time due to the relatively small increased yield observed in the Red Cross study, increased donor deferral and donation loss due to false positively, and logistics of a six- to 16-fold increase in test volume and cost. “As a final comment, the absence of effective reimbursement mechanisms by which hospitals can recover the increased costs of blood safety initiatives, implemented voluntarily or after an FDA recommendation, remains a serious flaw in the regulatory process. HBV NAT is an example of such an initiative that will come as an unfunded mandate if FDA recommends its use.”
An ABC statement expressed concern about manufacturers bundling tests that then result in an FDA recommendation for their use in the absence of a recognized need for higher sensitivity or specificity of existing assays. “ABC members suggest that the implementation of NAT for HBV be a decision made between blood centers and their local medical community.”
The committee was asked to reconsider routine blood donor screening by HBV NAT based on the FDA-approved assays, new data on utility and yield, and recognition of hepatitis breakthrough infections by vaccinated donors.
FDA posed several questions to the committee:
Does the committee agree with FDA that units from donors with apparent vaccine breakthrough HBV infections (HBV NAT-positive and anti-HBs-positive) should be presumed infectious pending further studies?
Please comment on the value and design of candidate studies using animal models to assess the infectious potential of units from hepatitis B-vaccinated donors with breakthrough hepatitis B infections.
Considering the estimated yield of HBV-infected window period donations and the answer to question one, please comment on the benefit of routine screening of blood donors by HBV NAT if testing were performed using available licensed tests on minipools, assuming a sensitivity of at least 100 IU/mL for individual samples.
The committee had a majority vote that breakthrough HBV infections should be presumed infectious pending further studies. It was expressed that it is important to take preventive measures but that more studies are required for future discussions. The committee discussed the value of animal models for the purpose suggested but made no concrete suggestions. With regard to question three, several committee members noted that the data presented indicated that NAT minipools of 16 detected the breakthrough cases, and the sensitivity of that pool size is 166 IU/mL for individual samples, rather than the 100 IU/mL FDA asked them to consider.
Nucleic Acid Testing for Human Cells, Tissues, and Cellular- and Tissue-Based Products for Hepatitis B Virus Infection
Currently, all HBV NAT tests are approved for individual donation NAT or minipool NAT of hematopoietic progenitor cells and donor lymphocytes for infusion, while all other living and cadaveric HCT/P donors must be tested using ID NAT.
When reviewing testing of HCT/P donors, FDA explained that there are unique aspects to consider: the testing format (either ID NAT or MP NAT), the lack of yield data in living donor populations and the difficulty in obtaining yield data in cadaveric donors. Yield data for living HCT/P donors are not readily available because screening tests that have an indication for use in blood donors can obtain an indication for use in “other living donors” using blood donor ID testing data without submitting additional data. These tests use the same type of blood specimen as that used for blood donors, which has been evaluated extensively. In addition, yield data is difficult to obtain because it is only required to be collected in the blood donor population when nucleic acid tests are reviewed for licensure. The number of HCT/P donors is smaller than blood donors, and it would take much longer to collect yield cases. FDA noted that it believes HBV NAT performance in living HCT/P donors is comparable to performance in blood donors, and the window period closure and yield will be similar between living HCT/P donors and blood donors.
The American Red Cross presented two analyses on the subject — “Validation of Minipool NAT as Opposed to Individual Donation NAT for Donors of Hematopoietic Stem/Progenitor Cells” and “Assessment of Residual Risk Among Tissue Donors” — on behalf of several organizations. The data analyzed were submitted from 10 organizations (Blood System Laboratories, American Red Cross, Puget Sound Blood Center, Bonfils Blood Center, National Marrow Donor Program, StemCyte, Florida Blood Services and Central Indiana Regional Blood Center), with many representing multiple organizations. It was concluded from both studies that HIV, HCV and HBV rates from HPC donors are equivalent to blood donation types already included in the intended use statements for licensed NAT assays. The risks associated with MP NAT as compared to ID NAT for HPC donations are no greater than the difference between MP NAT and ID NAT for donations of whole blood. For tissue donors, however, undetected viremia at the time of donation is reduced with the use of ID NAT.
FDA posed several questions to the committee:
Please comment on the potential benefit of HBV NAT testing in the ID NAT format and in the small minipool format for living donors of hematopoietic stem/progenitor cells and DLI.
Please comment on the potential benefit of HBV NAT testing in the ID NAT format for:
a) other living donors
b) cadaveric donors
The committee discussed these questions in relation to the information presented and indicated that based on the data it is appropriate to use HBV MP NAT for HCT/P living donors if the package insert includes this clearance, but minipool testing may not be suitable for nonheart-beating donor specimens.
Potential Testing Strategies for Trypanosoma Cruzi Infection in Blood Donors
Since FDA licensed the Ortho Trypanosoma cruzi ELISA Test System for the detection of antibodies to T. cruzi in December 2006, facilities representing a large proportion of U.S. blood collections have been voluntarily testing all their donors using this assay.
During the BPAC meeting, the committee reviewed and discussed
the scientific merit and public health benefit of implementing selective testing of donors for antibodies to T. cruzi as an alternative to universal testing of all blood and tissue donations, which was recommended in a draft guidance issued by FDA in March 2009.
FDA’s opening presentation provided background to the committee on universal and selective testing strategies. According to the agency, when evaluating selective testing, there are several key factors that must be considered:
prevalence of T. cruzi infection in blood donors; rate of transmission from a presumed seropositive unit in the U.S.; ability of risk questions to identify the confirmed positive donors or newly acquired infections; evidence of endemic vector-borne transmission in the U.S. (autochthonous cases); frequency of incident T. cruzi infections in blood donors; the prevalence of confirmed positive donors with prior negative test results that arise not from incident infections but from low signal-to-cutoff values (test sensitivity).
In an effort to assess potential strategies, FDA built a probabilistic, mathematical model of the major factors affecting transfusion-transmitted T. cruzi in the U.S., and the uncertain inputs, such as the probability of transmission, were represented by statistical distributions. This model allows for “what if” scenarios to compare risk management strategies. The agency explained that there also are at least two additional sources of increased risk with selective testing compared to universal testing: 1) an uninfected donor who was screened once or twice becomes infected after the tests; and 2) a repeat donor who was infected has a false-negative ELISA result on one or two screenings. FDA noted, however, that it is not aware of data on the probability that a donor may become infected with T. cruzi after one or two negative results, but it assumes it must be greater than zero. In addition, although the FDA-approved test has a high sensitivity, the agency thinks that multiple tests will reduce the risk of a false-negative result from a single test.
Several scenarios with hypothetical options were reviewed for the committee. The FDA concluded that compared to universal testing, selective testing would slightly increase the estimated risk of transfusion-transmitted infections, but there is substantial overlap of the confidence intervals between some of the strategies.
The Centers for Disease Control and Prevention provided BPAC with an overview of Chagas’ disease in the U.S. According to the presentation, Chagas’ disease has been observed in the country since 1855, and there are approximately 11 potential vector species. It is estimated that approximately 300,000 immigrants to the U.S. are infected with T. cruzi. People at risk of infection in the U.S. include those exposed to infected vectors and reservoirs; children of infected mothers; transplant recipients; transfusion recipients; and laboratory staff working with vectors, reservoir species or the parasite.
U.S.-acquired infections have been reported in patients of all age ranges. In addition, there are ongoing investigations of potential cases from 2007 involving two blood donors in Mississippi. There are no confirmed cases of congenital transmission in the U.S., and there have been five published cases of transplant transmission. There have been seven transfusion-transmission cases reported in the U.S. and Canada, but it is believed that this is likely underrecognized and underreported. The CDC presentation also emphasized that in the U.S. most physicians are not familiar with the disease, nor is it a nationally notifiable event. While it was pointed out that there is no systematic public health surveillance, the
AABB Chagas’ Biovigilance Network does gather data from ongoing, voluntary testing.
The Red Cross presented its study findings (in collaboration with Blood Systems Inc.) on the effectiveness of a selective testing strategy compared to universal testing. The findings were based on the number of positive donors/donations identified by universal testing during a 22-month period. Also evaluated were the results of additional tests to determine evidence of circulating parasites in the positive donors, donor questioning and identification of risk factors in positive donors, test performance characteristics, and lookback data and its significance. The results supported a selective testing strategy, as evidenced by:
The prevalence of T. cruzi antibody positive donations in the U.S. is approximately 1:30,000.
“Born in endemic country” is the only significant risk factor identified from multivariate analysis; these risks are remote and do not represent incident infection.
Autochthonous cases occur and limit a selective testing strategy based on questioning; risks when identified are remote and do not represent incident infection.
RIPA-positive donors may have reactivity at the assay cutoff; no incident cases were identified in 2.6 million person-years of observation.
Lookback experience to date is limited but suggests infrequent transmissions.
Selective testing strategies could be pursued based on a prior donation test-negative model.
A selective testing strategy within current good manufacturing practices can be accomplished with some modification of software to create a donor “assertion” for donors that test negative. This would be communicated to the laboratory testing information system to facilitate electronic sample sorters for placement into automated testing equipment. Results also would be prevented from being released for donors that lack an “assertion” if the required nonreactive test result is missing.
Blood Systems Research Institute provided details of its experiences with questioning and screening donors for Trypanosoma cruzi. BSI began universal testing for antibodies to T. cruzi in January 2007 and added questions to the routine donor registration questionnaire to determine if they would be useful in a selective testing strategy. BSI questionnaires already gathered information on the donor’s race, ethnicity and country of birth. The additional questions asked if they spent time that adds up to three months or more in areas endemic for T. cruzi, if the donor’s mother had spent time that adds up to three months or more in endemic areas, and if the donor had traveled to endemic areas since his/her previous donation. BSI also followed up with repeat-reactive donors, if they consented, to determine donor symptoms and risk factors, and perform a clinical evaluation study, including a physical, EKG and echocardiogram. Additional sample collection and testing by T. cruzi ELISA, RIPA and PCR also was performed.
The BSI study found an unexpected rate of discordant responses to the additional T. cruzi questions in sero-reactive and sero-negative donors. Following evaluation of the results, BSI determined that the country of birth question in particular is highly predictive of infection; 30 percent of RIPA-positive and 3 to 5 percent of negative donors gave discordant responses; the combination of all questions had a sensitivity of approx 75 percent.
During the period of the study, BSI collection centers had zero incidence of T. cruzi seroconversions in allogeneic repeat donors. There were 305,190 donors with two or more donations, and the study encompassed 267,333 person-years of observation.
AABB and the American Red Cross submitted a joint statement before the committee calling for a selective screening approach. “Based on the above, continued universal testing (i.e., testing every donor at every donation) is not medically appropriate and we know that blood collectors who did voluntarily initiate universal testing in 2007 are now looking at various other options. We should focus on selective testing strategies that adequately protect recipient safety and have been used successfully for multiple agents, including T. cruzi, outside of the U.S. A precedent for selective testing is particularly important as we consider other emerging infectious diseases for which it may be impractical or unnecessary to perform universal testing. Examples include babesiosis and dengue.” The organizations stated a preference for one-time screening, and noting that “this strategy is based on the excellent performance characteristics of the current licensed screening test, the lack of observed incident donor infections and the rarity of transfusion transmission demonstrated by lookback.”
A statement presented on behalf of ABC facilities suggested a variety of strategies that could be utilized, including performance of regular surveillance studies to assess changes in prevalence of antibodies over time, and “if T. cruzi testing is recommended, blood centers be allowed to determine the optimal screening strategy for their community.”
FDA posed several questions to the committee:
Does the committee agree with FDA that the scientific data on effectiveness of risk questions in general do not support a selective testing strategy in which donors who previously tested negative for antibodies to
T. cruzi are tested again only if their answers to risk questions indicate they have risk of a newly acquired infection?
Do the combined scientific data on risk of transfusion transmission of
T. cruzi support a selective testing strategy in which:
One negative test would qualify a donor for all future donations without further testing or questions regarding risk of a newly acquired infection
subject to continuation studies to define the incidence of new infections in previously screened negative donors?
If the answer to 2A is “no,” would negative tests on two independent donations qualify a donor for all future donations without further testing or questions regarding risk of a newly acquired infection?
Please provide any additional comments on considerations for selective testing for antibodies to
T. cruzi in repeat donors.
A majority of the committee voted in favor of a selective strategy to test blood donors and agreed that one negative test should allow future donations without further testing or risk-based questions to assess the potential for newly acquired infection, but it also determined that studies should continue to define the incidence of new infections in donors who previously screened negative.
A majority of the committee also agreed with FDA’s position that scientific data on the effectiveness of risk questions do not support a selective testing strategy in which donors who previously tested negative for T. cruzi antibodies are tested again only if their answers to these questions indicate the potential for new infection.
Current Considerations on Plasma Obtained from Whole Blood Donors for Further Manufacturing Use
The final topic of discussion at the BPAC meeting — FDA’s current considerations for plasma for further manufacturing use obtained from a whole blood donor — was of particular interest to the AABB Interorganizational Plasma Task Force. There currently are two plasma products commonly used for further manufacturing, but only one is FDA-licensed. Source plasma — the FDA-licensed product — is collected by plasmapheresis, and 80 percent of what is collected is used for manufacture of plasma derivatives. Recovered Plasma, derived from whole blood collections or expired fresh frozen plasma, is shipped through short-supply agreement provisions of 21 CFR 601.22; contracts between the blood collection facility and plasma manufacturer define the product standards required by the manufacturer since it is not an FDA-licensed product. Since 2002 the AABB task force has petitioned FDA for a pathway to licensure for Recovered Plasma.
FDA provided an overview of these issues and explained that it has considered establishing standards for two new licensed plasma products — Component Plasma and Concurrent Plasma — that would replace Recovered Plasma for Further Manufacturing Use. This effort would bring all of these plasma products under the regulatory umbrella of FDA licensure and would meet the goals of the AABB task force to allow plasma collected from whole blood donors (by manual or automated methods) to be sent for further manufacture when not needed for transfusion. Recovered Plasma, however, would remain an option for further manufacture of noninjectable products.
According to FDA, Component Plasma could be plasma collected under whole blood donor standards by plasmaphereis as a stand-alone product, or by one-time relabeling of plasma for transfusion (prior to expiration). Infrequent plasmapheresis guidelines would apply to the collection of this product.
Concurrent Plasma could be defined as a product collected concurrently with a licensed cellular product, either by whole blood collection or by apheresis. It may be labeled immediately at the time of collection or by one-time relabeling of plasma for transfusion (prior to expiration) that was collected concurrently with a cellular product.
FDA discussed a 10-year shelf life for both products, but after listening to concerns from blood and plasma industry participants reconsidered a shorter period of time.
FDA currently is considering standardized labeling categories for key conditions of collection, freezing and storage that may impact the final product so that domestic and international purchasers would know the salient characteristics of each product. The agency also stated that the labeling changes under consideration would establish conditions of manufacturing that are substantially consistent with current manufacturing practices, but these categories and potential changes should be designed to preserve the flexibility as new scientific information becomes available. These changes include:
Replacing -20 C for -18 C for all conditions of freezing, shipping and storage.
Shipping temperature ≤ -20 C rather than ≤ -5 C or ≤ -18 C.
Allow a shipping and storage temperature deviation that can exceed -20 C for ≤ 72 hours total, never > -5 C (never refrozen) in contrast to none for FFP.
Storage up to 10 years (same as Source Plasma) rather than one year for FFP.
Plasma in contact with cells not to exceed 120 hours (in contrast to up to 40 days for Liquid Plasma).
Not using plasma that has been thawed and refrozen.
The AABB Interorganizational Plasma Task Force gave the committee a historical perspective of its efforts in pursuing licensure for the product currently manufactured as Recovered Plasma. It
expressed its support for licensure of plasma for further manufacture — by whatever name(s) is selected — and stated that this will help blood centers regain flexibility in inventory management of plasma products because many voluntary blood donations now are collected on automated platforms. According to the presentation, the task force has proposed in comments to the Federal Register docket that CFR 21 640.30 and 640.34 could be amended to provide a rational pathway to include a product collected by apheresis methods for use in further manufacturing for injectable, lifesaving plasma products. Plasma manufacturing companies that make the final end product for patient use define specifications for the plasma. This occurs via contracts that will still be viable following licensure. As such, CFR requirements should be minimal. “The task force strongly believes the proposed new product(s) will have no impact on maintaining the voluntary donor pool. The core mission of blood centers to provide lifesaving components for transfusion will not change. Automation has changed the dynamics of how blood collections occur. We do not want to discard plasma, or deliberately not collect it, solely based on the use of automated platforms for voluntary blood donor collections.”
Representatives from the Plasma Protein Therapeutics Association addressed the committee and noted their agreement with FDA’s “overall concept to recognize a plasma component for manufacturing use manufactured by apheresis under regulatory criteria for whole blood donors. PPTA has worked with the blood organizations as a member of AABB’s Plasma Task Force for the past several years with this as the task force’s goal.” PPTA stressed the need to keep the concepts simple — one product label would suffice; minimal regulatory requirements for freezing, storage and shipping; suggested regulatory language for 21 CFR 640.60, 64030(a)(2), 640.34; and noted an exception provision in 610.53(d) that could be used pending regulatory change. PPTA further noted that the short supply agreement provisions in 21 CFR 601.22 can be removed as the regulations are updated.
Representatives from several patient advocacy groups addressed the committee and stressed the importance of remembering how all decisions affect the safety of the recipient, many of whom are immunocompromised.
FDA requested the committee consider the framework proposal and respond to several questions:
Does the committee agree that the “framework” for standards proposed by FDA for collection, freezing, storage and labeling for Concurrent Plasma and Component Plasma is reasonable and appropriate to ensure the quality necessary for manufacture into injectable plasma products?
Please comment on the impact that the proposed new products would have on maintaining the voluntary donor pool that is critical to community-based voluntary blood donation.
After reviewing the data and discussing the issue with the speakers, the committee was in unanimous agreement with the proposed framework for the plasma products under consideration by FDA. In response to the second question, the committee was in general agreement that most donors are interested in knowing that all of their donation is used and that it is equally important that donors understand when a portion of their donation is directed into a commercial stream.
It is expected that FDA, after taking time to evaluate the committee’s input, will issue a draft guidance document with recommendations for plasma for further manufacture.