Members of the Blood Products Advisory Committee, or BPAC, to the Food and Drug Administration convened for their 104th meeting in Rockville, MD on September 20-21 to advise the FDA on three issues relevant to the transfusion medicine community – HEV, Octapharma's solvent/detergent plasma, or octaplasLG, and considerations for strategies to further reduce the risk of bacterial contamination in platelets.
Hepatitis E Virus (HEV) and Blood Transfusion Safety
The FDA sought advice from the committee on whether the available scientific data indicate a need to determine the risk of HEV transmission by transfusion in the U.S. — and, if so, what studies would be the most useful to address this risk — and how best to characterize HEV assays for use in such studies.
HEV has been recognized since 2004 as a transfusion transmissible infectious agent and recent epidemiological data suggest that it may pose a safety threat to the US blood supply. Susan Zullo, Ph.D., Center for Biologics Evaluation and Research, FDA, stated that there is a period of asymptomatic viremia after initial infection with HEV when blood donors who appear healthy and feel well could be infected with HEV and donate blood. There is a high seroprevalence of anti-HEV reported in U.S. blood donors (13.7% - 31%) suggesting prior exposure to HEV. The variation in ranges reported is possibly due to the wide variation in the assays used for the studies.
Robert Purcell, MD, National Institutes of Health, or NIH, described the four major HEV genotypes. HEV is a small, noneveloped RNA virus belonging to the Hepevirus genus in the Hepeviridae family. There are four major genotypes representing one serotype causing infection in humans worldwide. Genotypes 1 and 2 only infect humans and are transmitted by contaminated water in developing countries. Genotypes 3 and 4 infect humans, domestic swine, wild boar and other animals and are responsible for sporadic cases of autochthonous HEV in both developing and developed countries — although genotype 3 is the only genotype currently identified as the cause of autochthonous infection in the U.S. HEV has a short period of viremia and a high proportion of subclinical cases. Purcell said that the U.S. is just beginning to recognize the disease and posed the question of whether it is a case of an emerging disease or an emerging awareness.
Harvey Alter, MD, NIH, stated that HEV was previously considered to be an acute, self-limited infection occurring only in endemic regions, however it now has been shown to occur in a surprisingly high frequency (20%) in non-endemic countries. Alter said that HEV evolves to chronic infection in immunosuppressed patients, to cirrhosis in those chronically infected, and also persists in asymptomatic chronic carriers who are otherwise eligible for blood donation. The NIH has found a comparable seroprevalence to other studies with 22.3% anti-HEV IgG positive and 0.3% anti-IgM positive after testing of more than 1000 blood donors. All antibody positive samples underwent nucleic acid testing and none were HEV RNA positive. Alter surmised that while it is too soon to begin testing all blood donors for evidence of HEV exposure, other actions are necessary. These include:
- Establish HEV standards and pedigreed panels for comparative antibody and molecular testing.
- Test 10,000 volunteer U.S. donors to determine true prevalence with reliable assays.
- Perform prospective follow-up of HEV RNA positive donors to determine duration of viremia and frequency of asymptomatic carrier state.
- Perform look-back studies of RNA positive donors and trace-back of donors to transfused hepatitis E cases.
- Test pre- and post-transfusion samples in existing repositories to establish incidence.
- Fund U.S. studies of immunesuppressed and liver disease cohorts to further assess disease outcomes.
Scott Holmberg, MD, MPH, Centers for Disease and Control and Prevention, described the NHANES III study which consisted of testing of over 18,000 samples from 1988-1994. The study determined HEV seroprevalence in the U.S. population to be approximately 21%. However, the CDC retested a subset of the samples using another anti-HEV IgG test and the serovalence number was adjusted to 16.8%. The CDC tested almost 8000 NHANES IV samples from 2009-2010 and found a seroprevalence of only 6.8%. Holmberg stated that the >2.5-fold lower seroprevalence is probably due to both a reduction in exposure (declining incidence) and natural loss of antibodies over time.
Other presenters discussed standardization of NAT assays using the WHO international standard for HEV RNA, validation of serological assays for HEV, and the makeup of the sample repositories suggested for use in further donor studies — TRIPS (Transfusion-Related Infections prospective Study) and RADAR (Retrovirus Epidemiology Donors Study (REDS) Allogeneic Donor and Recipient).
The FDA concluded the discussions by proposing to the committee a phased approach:
NAT assays could be characterized using the currently available WHO International Standard for HEV RNA and a panel of virologically confirmed clinical samples.
The well-characterized NAT assays could then be used to perform large-scale prospective studies on blood donors to determine the current prevalence of viremic (NAT-positive) blood donors.
Serologic assays will also need to be characterized using a pedigreed panel of virologically confirmed clinical samples from HEV-infected individuals.
Both validated NAT and serological assays could then be used to perform studies on donor-recipient linked sample from existing repositories — RADAR or TRIPS — to assess transfusion transmission of HEV infection. Prospective studies could also be considered.
Committee Discussion and Questions
Committee members expressed a concern about gaps in knowledge of the epidemiology of HEV in the U.S. Several speakers cast doubt on the early presumptions that consumption of pork is a primary route of transmission. Some members responded to the information presented that patient populations susceptible to transfusion transmission of HEV are the immunosuppressed and suggested that a selective testing model similar to CMV might be appropriate. Others thought it might be too early to plan policy in that direction.
Question 1 Do the available scientific data indicate a need to characterize the risk of HEV transmission by transfusions in the U.S.?
Vote – Unanimous Yes
Question 2 If so, please comment on FDA's proposed approach to:
- assay characterization for NAT assays
- assay characterization for serologic assays
- candidate study designs to establish HEV risk from transfusion
Several members agreed that there is not enough data about HEV testing in NAT pools. Committee members agreed assays for serologic testing should be developed even if not used for blood screening as they are needed for diagnostic screening and confirmation. Final committee comments were that a, b and c are needed.
Octapharma's Biologics License Application (BLA) for Pooled Plasma (Human), Solvent/Detergent (S/D) Treated (octaplasLG)
Octapharma submitted BLA (125416/0) for octaplasLG, a frozen, sterile, pyrogren-free, solvent/detergent (S/D) treated, ABO blood group specific, pooled human plasma intended for administration via transfusion. It is manufactured in Vienna, Austria or Stockholm, Sweden from 630-1,520 U.S.-sourced plasma units and is presented as a 200 mL dose filled in plasticized, polyvinyl chloride blood bags, overwrapped with polyamide/polyethylene film. OctaplasLG was developed as an alternative to single-donor fresh-frozen plasma, or FFP, to increase safety by minimizing the risk of viral transmission — preventing sepsis, increase prion safety, and to provide a standardized cell-free, coagulation-active plasma product to facilitate therapeutic predictability. Octapharma is seeking U.S. licensure for two of the six FFP indications, as detailed in the Circular of Information for the Use of Human Blood and Blood Components: 1) management of preoperative or bleeding patients who require replacement of multiple coagulation factors; and 2) substitution of intentionally removed plasma (e.g. plasma exchange in patients with thrombotic thrombocytopenic purpura, or TTP).
Nancy Kirschbaum, PhD, Chemist/BLA Chair, Office of Blood Research and Review, or OBRR, CBER, provided an overview of the Chemistry, Manufacturing, and Controls (CMC) information provided in the octaplasLG BLA including the product composition, manufacture, development rationale, and marketing history. Comparative product development summaries were also provided for two previous product generations which have been marketed outside of the U.S. since 1989. The first generation of octaplas (lyophilized, ABO blood group specific) is no longer marketed; generation 2a (liquid frozen, ABO blood group specific) has been marketed since 1992; and the proposed octaplasLG, subject of BLA 125416/0, has been marketed outside of the U.S. since 2009. The FDA's review of the CMC information submitted in the BLA was adequate to support the identity, quality, purity, potency, and safety. The FDA also noted the manufacturing process and biochemical properties of octapasLG are similar to other product generations.
Mitchell Frost, MD, Medical Officer, OBRR, CBER, summarized the FDA's review of the clinical data package submitted to the BLA. In total, 17 retrospective and prospective clinical studies were submitted to the BLA. However, only 9 studies were considered for clinical data review because the other 8 studies were too small or were literature reports and were therefore only evaluated from a safety perspective. Detailed summaries of the relevant clinical studies were also presented and included FFP as a comparator as well as bridging studies with former versions of the product. Although the submitted clinical data were limited, they were considered by the FDA to be supportive of safety and efficacy.
A summary of the postlicensure safety data was provided by Michael Nguyen, MD, Office of Biostatistics and Epidemiology, CBER. From 1989 to 2011, the period covering the first three generations of octaplas (generation 1, 2a, and 2b), Octapharma has collected postmarketing safety data from spontaneous reports, safety reports from the published literature, and clinical studies. During this period, approximately seven million bags of octaplas generation 1 and 2a were distributed and 122 serious adverse events were reported. Additionally, from June 2009 to August 2011 postmarketing data had been collected on approximately 125,000 octaplasLG (generation 2b) bags and eight serious adverse events had been reported. No cases were reported causally relating TRALI to octaplas administration. No transmissions of HIV, HBV, HCV, or HAV have been reported. Acute hypersensitivity reactions ranged from mild to serious and the majority of thromboembolism cases were derived from a single case series of TTP.
Bjarte Solheim, MD, PhD, professor emeritus, Institute of Immunology, Oslo, Norway, presented a comparative overview of the European and U.S. S/D treated plasma and reported on their extensive clinical use in several European countries. In Norway, octaplas began to be used in open heart surgery in 1992 and subsequently with liver transplantation. Solheim described its use in pediatric care, including neonates on ECMO treatment, and in adult treatments. Over 3000 plasma exchanges have been performed using octaplas —10-20 patients per year since 1993. He summarized the Norwegian experience by stating that hospital blood banks and clinicians are satisfied with the safety and clinical efficacy of a standardized product that has a predictable effect. He also noted that Finland began massive use of octaplas five years ago and that France has made extensive use of the product for several years. Solheim highlighted the cost-effectiveness of using European S/D plasma as it reduces the residual risk for viral infections.
Octapharma presented overviews of the regulatory history of octaplas and octaplasLG, quality and safety comparisons of single donor FFP versus octaplasLG, and summarized the clinical studies using octaplas and octaplasLG.
Committee Discussion and Vote
Committee members inquired whether octaplasLG would be regulated by the FDA as a derivative or a component and the FDA stated it would be regulated as a blood component. Members of the committee seemed especially concerned with the use of the product in trauma cases and when used to treat TTP. The need for Clinical Guidelines to be developed by the transfusion medicine community was noted. Several members noted the clinical trial data provided in the BLA was of poor quality, in that it primarily supported claims of safety not efficacy. Other members noted that the extensive and long-standing use of octaplas in the European Union cannot be ignored.
Committee members inquired why the usage rate of octaplas is so low in some European countries — namely in Germany, where octaplas and octaplasLG were first marketed in 1989 and 2009, respectively. Octapharma representatives noted that decision-making occurs at different levels (national, regional, local levels) for each Member State and therefore usage rates vary. Also noted is the fact that EU members have other options available — mainly pathogen reduction technology is available for use with whole blood products.
Question 1 Do the data show that octaplasLG is effective?
For the management of preoperative or bleeding patients who require replacement of multiple coagulation factors?
Vote 8-Yes, 4-No, 3-Abstain
As substitution of intentionally removed plasma (e.g. plasma exchange in patients with TTP?)
Vote – 10-Yes, 2-No, 3-Abstain
Question 2 Do the data show that octaplasLG has an acceptable safety profile for the indications stated in question 1?
Vote – 12-Yes, 3-No
Question 3 If the answer to question 1 or question 2 is no, what additional studies should be performed premarketing for the proposed indications?
Question 4 Please comment whether safety monitoring would be needed post-approval specifically to monitor:
- Thromboembolic events?
- Exceessive bleeding?
- Transmission of HEV?
The Committee elected to vote on this discussion item and a question was formed: Should active surveillance be required post approval versus passive?
Vote – Unanimous Yes
The chair went on record stating that he was not sure that the HEV topic was adequately addressed by the company. (See previous notes regarding concern over use with TTP and in trauma cases.)
Considerations for Options to Further Reduce the Risk of Bacterial Contamination in Platelets
The FDA sought the committee's advice on whether there is a need for additional measures to decrease the current risk of transfusion of bacterially-contaminated platelet products. Salim Haddad, M.D., OBRR, presented an overview and options for consideration of strategies to further reduce the risk of bacterial contamination in platelets. The FDA does not have regulations or guidance recommendations specific to testing of platelet components for evidence of bacterial contamination. Current strategies in the U.S. that include culture-based and rapid tests are based on requirements of the "Standards for Blood Banks and Transfusion Services" published by AABB. Haddad reviewed the results of several studies that demonstrate there is still a residual risk for contamination.
Strategies proposed for consideration by FDA to mitigate the residual risk of contamination include:
- Shortening platelet shelf-life to four days – early culture still required.
- Retesting with a rapid test after 4-day storage – early culture still required, and other caveats that could lead to relabel with a 7-day shelf life.
- Retesting with a culture test on Day 4 – early culture still required, would potentially permit relabel with a 7-day shelf-life.
- Culturing using a constant proportion sampling volume with the objective to increase the sensitivity of culture by decreasing sampling error.
Following the opening summary from the FDA, Michael Jacobs, MD, professor of pathology and director of clinical microbiology at University Hospitals Case Medical Center in Cleveland, Ohio, described his study of detection of bacterial contamination in prestorage culture-negative apheresis platelets on day of issue with the Verax Platelet PGD Test, or PGD. Eighteen hospitals studied the PGD test by performing the test on the day of issue on 27,620 apheresis platelets released by collection centers as culture-negative. The PGD test result was reported as reactive if two of three results were reactive. PGD results were reported reactive for 151 of the apheresis products. Nine were confirmed by culture, and 142 were culture-negative. Two units that were reported nonreactive by PGD testing were later cultured as part of the study and found to be positive. Another contaminated unit was found through reporting from a hospital following transfusion. Based on his study results, Jacobs concluded that application of PGD on day of issue can interdict contaminated units and prevent transfusion reactions.
The Irish Blood Transfusion Service, orIBTS, experience was explained by William Murphy, MD. In 2004 the IBTS began 100 percent testing on day 4 using one 8 mL sample and in 2005 changed to two 7.5 mL samples and use of an anaerobe bottle. In 2005 the shelf life was extended to day 7 if the day 4 retest was clear. Murphy explained that the advantage of a culture performed on day 4, besides having a 92 hour inoculum, is that it will have at least 36 hours before day 5 expiry and extended product storage begins. However, low sensitivity due to low numbers of bacteria and delayed or slow growth means that culture will never reach an acceptable level of detection no matter how large the sample or sensitive the test. The next step for the IBTS involves using hemovigilance data to study pathogen inactivation versus testing for bacterial contamination. In Ireland, active surveillance of transfused patients is performed by dedicated hospital staff who follow up with each patient post-transfusion. Murphy explained that expanding the bacterial testing program to community hospitals with fewer resources has brought the IBTS face-to-face with some of the logistical problems that the U.S. transfusion community is discussing.
The transfusion services perspective was represented by two presenters: Larry Dumont, MBA, PhD, from Dartmouth Hitchcock Medical Center; and Mark Yazer, MD, from the Institute for Transfusion Medicine, or ITxM, in Pittsburgh. Dumont's academic tertiary care medical center uses approximately 2,500 apheresis platelets yearly, including 6-day and 7-day platelets when medically necessary. Their experience with rapid testing of apheresis platelets on day 4 identified no true positive bacterial contamination. With use of the rapid test on day 4, 59% of apheresis platelets did not have secondary screening with a rapid test prior to release. There were no septic transfusion reactions identified in 8,159 platelet transfusions, including 6- and 7-day old platelets. Dumont concluded that routine use of a rapid test at time of apheresis platelet release would improve the test rate, but also increase the number of false positives. He emphasized that in a small, rural medical center like the one he represents, limiting shelf-life to four days would severely limit availability of platelets. Using rapid testing at the time of transfusion would not be sustainable for a small center. Dumont's facility included testing at time of issue in an earlier study and found it to be unsustainable.
Yazer presented the perspective of a centralized transfusion service that was described as a network of integrated hospital transfusion services that are supported by both on-site and central laboratory facilities. The ITxM experience using the Verax PGD rapid test has been published along with the Puget Sound Blood Center. The study was performed using whole blood-derived pools, prior to leukoreduction. Yazer described that in his labs the test is performed by lab aides and took only 40 minutes to complete, so it did not present too much strain from an operations viewpoint. The rate of true positives in whole blood platelet pools was approximately one in 10,000, and the false positive rate was high at about one in 300 pools. He emphasized that only 10 PGD positive platelet pools were issued prior to completion of testing. He talked about the auto sterilization effect of individual platelets that go into pools and explained in his opinion why a pool of five whole blood-derived platelets does not have five times the risk of an apheresis platelet. Also, the leukoreduction processing that occurs later may remove some residual bacteria.
During the open public hearing, AABB presented a statement that outlined the steps the association has taken to address the issue of bacterially contaminated platelets. AABB has developed a set of standards requiring its members to have processes in place to limit and detect or inactivate bacterial contamination in platelet components. The association would welcome guidance from FDA on ways to reduce the residual risk of contamination, but noted that further actions should be validated for efficacy and impact on availability to patients who depend on platelet transfusions. AABB representatives also reminded the FDA of the necessity to establish a policy for whole blood-derived platelet components as well as components that have early culture performed.
Other public comments were provided by representatives of blood centers, manufacturers of tests, physicians, and patient advocates who were personally affected by the safety of platelets.
Committee Discussion and Vote
The Committee discussion expressed concerns over the lingering issues of residual contamination due to bacteria. Other concerns noted and discussed included:
- Availability if the shelf life of platelets would be limited to four instead of five days.
- Making a decision that was too prescriptive and could potentially limit access to units during emergency situations.
- Dissatisfaction with the data available and belief that additional data should be acquired before regulatory action is taken.
At different times during the discussion questions were asked regarding current testing practices and speakers or members of the audience were asked to respond to questions such as:
- How soon after collection are platelets cultured?
- How long are the components held before release?
- What sample volumes are used to inoculate the cultures?
- Where are the platelets on day 3, day 4, day 5?
The FDA was asked to explain the agency's authority for testing that may occur in a transfusion service. Dr. Jay Epstein, director of OBRR, noted that transfusion services are under the oversight of the Centers for Medicare and Medicaid Services if they are not registered with the FDA. Use of a rapid test would otherwise bring them directly under FDA oversight only if there is a determination that use of such a test is a manufacturing step.
Question 1 Does the Committee find that additional measures are necessary to decrease the current risk of transfusion of bacterially-contaminated platelet products?
Vote - Unanimous Yes
Question 2 If yes to Question 1, please discuss whether,
Reduction in platelet product shelf-life from 5 to 4 days, and early culture would decrease the risk of transfusion-associated septic reactions sufficiently to obviate the need for additional testing.
The committee decided to vote on 2A. Vote – Unanimous No
(The Committee did not give feedback to specific parts B-D. In general they did not seem to think enough information had been presented for them to respond to.)
The available data are sufficient to support extension of platelet shelf-life up to 7 days if otherwise expired 4-day platelets (with negative day one cultures) are retested with an FDA-cleared rapid test and released within 4 hours of a negative test result.
The available data are sufficient to support extension of platelet shelf-life up to 7 days if otherwise expired platelets (with negative day one cultures) are retested on Day 4 with an FDA-cleared aerobic and anaerobic (10 mL/bottle) culture-based method
For options A, B, and/or C the bacterial culture should be conducted using a proportionate sampling volume
There are other test-based options that FDA should consider.
Committee members did note that they did not think that options should be mutually exclusive.
Question 3 During discussion of Question 3, the committee expressed concern that there were multiple questions contained in it and it would be difficult to vote on it in entirety. The question was separated into two parts. A clarification was received that the rapid test was not required to be performed within 4 hours of transfusion, but rather on the day of transfusion.
For platelets limited to 5 days of storage do the available data support a strategy to culture platelets after the first 24 hours of storage and then retest day 4 and day 5 platelets just once with a rapid test on day of transfusion?
Vote 16-Yes, 1-No, 1-Abstain.
Should the same strategy apply to retesting of day 3 platelets?
Vote 5 - Yes, 5-No, 7-Abstain.
Question 4 Please discuss the role of surveillance for any of the options listed above in determining the effectiveness of any new strategies implemented by blood collectors or transfusion services (e.g., culture testing of the platelet product at the time of transfusion or at product outdate to determine the residual contamination rate, and/or active monitoring of septic transfusion reactions).
No discussion was recorded.