The Food and Drug Administration convened a meeting of the Blood Products Advisory Committee Dec. 14-15 in Gaithersburg, Md. The main agenda items for the meeting were the risk of dengue virus infection in blood donors and issues related to murine leukemia virus-related retroviruses and blood safety. Updates also were provided to the committee regarding the 1) Nov. 4-5, 2010, meeting of the Health and Human Services Advisory Committee on Blood Safety and Availability; 2) Dec. 9-10, 2010, FDA workshop titled "Product Development Program for Interventions in Patients With Severe Bleeding Due to Trauma and Other Causes"; 3) FDA Guidance for Industry: Use of Serological Tests to Reduce the Risk of Transmission of Trypanosoma cruzi Infection in Whole Blood and Blood Components Intended for Transfusion; and 4) a study to further define the incidence of T. cruzi infection in the U.S. blood donor population.
This summary provides an overview of the presentations given on the main agenda items addressed by the committee, along with votes taken by the panel to provide guidance to the FDA that could help shape future regulatory policy decisions. Complete briefing materials are available.
Risk of Dengue Virus Infection in Blood Donors
Dengue is the most important mosquito-borne viral disease in the world, and in the last 50 years, dengue incidence has increased 30-fold worldwide. It is highly endemic in most tropical and subtropical areas of Asia and the Americas and is the most frequently diagnosed cause of fever in travelers returning from those areas. In the U.S., dengue is endemic in Puerto Rico (all four serotypes), Virgin Islands and most U.S.-affiliated Pacific Islands. Outbreaks exist in Texas along the U.S.-Mexico border and have occurred in Hawaii. More recently (2009-10), a locally transmitted dengue outbreak was identified in Key West, Fla., and one case in Broward County, Fla. The 2010 dengue season in Puerto Rico has been the heaviest in more than a decade, with more than 30 deaths as of mid-November. The committee heard the following:
- Transfusion-transmitted dengue (Hong Kong, Singapore, Puerto Rico) has been reported involving all blood components (fresh frozen plasma, red blood cells, and platelets) with five reported transmissions from three donations. There are no reported transfusion-transmitted cases of dengue in the U.S.
- Currently, there are no FDA-approved or -licensed tests for diagnosing or screening for dengue. Dengue can be detected by nucleic acid tests, antigen (NS1) tests and antibody tests.
- FDA labs are proactively involved in the production of RNA standard reagent for dengue to facilitate development and evaluation of performance of new assays, and determine future need for lot release. Dengue antigen panels will be developed if needed.
- Donor testing under IND by ARC in Puerto Rico has produced rates of donor RNA of 1:1,376 (2005 RNA by TMA), 1:529 (2007 RNA by TMA), 1:1,467 (2007 NS 1 Ag confirmed by RNA). NS1 Ag is not as sensitive as RNA for blood donor screening, but does detect high RNA titers. Duration of RNA by TMA is more than 29 days.
- The CDC dengue transfusion risk model prediction (using approx six days as the period of viremia following incubation) equaled the actual NAT yield from ARC testing in Puerto Rico, July-December 2007.
- A REDS II study in Brazil will attempt to:
- Establish background dengue seroprevalence rates in donors and recipients according to their transfusion history
- Launch a dengue transmission and disease penetrance study.
AABB, the American Red Cross and America's Blood Centers presented a joint statement in response to the questions posed to the committee and noted that if a travel deferral were to be considered to mitigate dengue risk from U.S. travelers to areas that are not also malaria endemic, it should be confined to the interval of known asymptomatic viremia. The position of the blood organizations was that 28 days would appear to be sufficient to avoid viremic, infectious donors with a substantial margin of safety and be consistent with evolving approaches in the European Union and Asia-Pacific regions.
Questions for the Committee:
Are safety interventions warranted to address the risk of transfusion transmission of dengue viruses
in non-endemic areas of the U.S.?
3 Yes; 8 No - plus the non-voting industry representative; 0 Abstentions
in endemic areas of the U.S.? (The committee understood this question to include U.S. territories.)
10 Yes - plus the non-voting industry representative; 1 No; 0 Abstentions
Do the available scientific data support a temporary deferral for donors living in U.S. non-endemic/non-outbreak areas who have traveled to an outbreak and/or endemic area?
3 Yes; 7 No - plus the non-voting industry representative; 1 Abstention
If so, what deferral period should FDA consider?
Several members suggested a month would seem reasonable. One member indicated that it would be important to keep a close eye on the potential impact on blood availability since many of the large urban areas that are endemic for dengue are favorite traveler destinations.
Please discuss what interventions, if any, would be appropriate for donors who are residents of endemic or outbreak regions within the U.S. and its territories.
The committee mentioned several alternatives that have been used in various endemic areas throughout the world, including outbreaks of other agents such as chikungunya, with varying degrees of success — stopping collection in the affected area, performing selective component collection and processing, and performing selective testing of the traveler. In an area such as Puerto Rico, testing is warranted in peak times, and industry and FDA should work together to have a licensed test available. It was noted that defining the beginning and end of an outbreak/epidemic becomes critical.
Please comment on the potential utility of dengue virus tests (nucleic acid, antibody and antigen tests) in donor screening.
The RNA test appears to be preferable to the NS1 antigen test. The NS1 antigen test appeared to detect high titer units.
Murine Leukemia Virus Related Retroviruses and Blood Safety
FDA sought the advice of the committee on the deferral of donors based on a diagnosis of chronic fatigue syndrome or prostate cancer and testing for the newly identified murine leukemia virus related retroviruses (that include xenotropic murine leukemia virus-related virus, or XMRV) associated with CFS and prostate cancer that may pose a concern for blood safety. MLVs are gamma retroviruses that are widespread in vertebrates and in animals and cause a wide range of diseases including cancers, immunodeficiency, and neurological disorders. XMRV, the first gamma retrovirus known to infect humans, was originally identified in 2006 in prostatic tissue from patients with familial prostate cancer. XMRV is a simple xenotropic MLV-related human retrovirus unrelated to HIV and unlike the human immunodeficiency virus or the human T-lymphotropic virus, accessory or regulatory genes have not been identified to date. XMRV is highly similar to mouse retroviruses. Although early sequence data indicated that the genetic sequence of XMRV is highly conserved, recent studies have reported genetic variation in XMRV sequences. Sequences of a new polytropic MLV-related virus, which are clearly different from the XMRV strains previously reported, were found in CFS samples, suggesting that there may be several MLV-related viruses in addition to XMRV. Therefore, the term MLV-related retroviruses is used to include both xenotropic and polytropic viruses.
The science of MLV-related viruses in humans is still evolving. While many laboratories have detected MLV-related sequences in prostate cancer samples, others have not. The frequency of positive samples varies widely among laboratories. There is controversy about the detection of MLV-related sequences in CFS, with the majority of laboratories failing to detect MLV sequences. There are ongoing studies to determine whether technical issues, such as extraction methods or primers and/or subject selection, including clinical criteria and geographic issues, might influence the detection of MLV sequences. Potential transmission through blood has not been demonstrated. There is no known causative relationship between MLV infection in humans and disease. The committee heard updates of current research on epidemiology, disease association, animal transmission studies, ongoing validation studies of assays and panels for MLV-related retroviruses, and other relevant studies on the association of MLV-related viruses with CFS, prostate cancer and blood donors.
During the open public hearing, a statement was presented on behalf of the AABB Interorganizational Task Force on XMRV that provided AABB's perspective on the questions that FDA prepared for the committee's discussion. AABB issued Association Bulletin #10-03 in June 2010 recommending that blood collectors, through the use of donor information materials available at the donation site, actively discourage potential donors who have received a diagnosis of CFS from a physician from donating blood. AABB standards already require that prospective donors be in good health and be free of cancer. In general, donors who present with a history of prostate cancer are deferred until they are disease-free and no longer receiving therapy. These donor eligibility criteria for prostate cancer are supported by several epidemiologic studies that have shown no association between prostate cancer and a history of transfusion. Therefore, the Association Bulletin recommendations did not include a change in the deferral criteria for potential blood donors with a history of prostate cancer.
Several other presentations were made during the open public hearing, including one from the Chronic Fatigue Immune and Dysfunction Syndrome Association of America requesting that the FDA institute a policy of deferral for patients with CFS.
Questions for the Committee:
Do the scientific data support asking donors about a medical history and/or diagnosis of CFS as a basis for indefinite deferral?
The committee voted with an understanding that a "no" vote affirmed the use of donor educational materials instructing patients with CFS not to donate as the appropriate measure to take at this point in time.
9 Yes; 4 No - plus the non-voting industry representative; 0 Abstentions
Please discuss whether the scientific data support asking donors about a medical history and/or diagnosis of prostate cancer as a basis for indefinite deferral.
Committee members noted that blood centers currently ask about a history of cancer due to an AABB standards requirement, and until further data are available they believe this is sufficient.
Please comment on the scientific evidence that would be needed to justify a policy of donor testing for infection with MLV-related retroviruses. In particular, should donor testing be considered in the absence of confirmed disease causation?
No. Committee members noted several issues that would be helpful — consistent evidence of association with disease; transmission by transfusion; and improvement/consistency in assays used.
Assuming that testing is warranted, please comment on the potential utility of NAT and/or serologic testing of blood donations to ensure safety of the blood supply from transmission of MLV-related retroviruses.
Committee members noted that information is needed on the biology of the virus before the question can be answered.
The committee received updates from the December meeting of the HHS Advisory Committee on Blood Safety and Availability and a Dec. 9-10 workshop on product development for interventions in severe bleeding due to trauma or other causes. Despite major advances in therapies and medical practice, mortality due to severe trauma pre- and in-hospital remains high. Severe bleeding associated with trauma contributes significantly to this high mortality. The workshop was structured to do the following:
- Gather information on the evaluation of products intended to be used in patients with severe bleeding from trauma or other causes.
- Obtain practical information for the FDA that could be used by sponsors to support market applications.
- Develop a uniform approach to facilitate research and development and ultimately lead to FDA approval of products for severe bleeding.
It is hoped that outcomes from the workshop will contribute to a resolution of this major health issue that civilian and military trauma physicians and surgeons are faced with on a daily basis.
Highlights of the December 2010 FDA Guidance for Industry: Use of Serological Tests to Reduce the Risk of Transmission of Trypanosoma cruzi Infection in Whole Blood and Blood Components Intended for Transfusion were presented to the committee. Recommendations contained in the guidance include continuation of the question "Have you ever had Chagas' disease" at every donation and testing each donor one time for antibodies to T. cruzi. Nonreactive donors may return to donate without further testing; establishments must review records to determine the testing history of each prospective donor. Donors with repeatedly reactive test results should be deferred indefinitely and counseled to seek a physician's advice. Re-entry recommendations are not available at this time since there is no licensed supplemental test. Donations corresponding to repeat reactive results should be removed from inventory and destroyed, and prior collections should be retrieved and destroyed. A lookback algorithm is provided.
Data from an ongoing study (universal testing in blood regions having the highest prevalence in the southern portion of the U.S.) to further define the incidence of T. cruzi infection in the U.S. blood donor population continue to show that being born in endemic countries, living in endemic countries for more than a year, or being Hispanic are the most common factors among blood donors with repeat reactive T. cruzi results. To date, there have been no incident cases observed, and lookback has revealed two apheresis platelet recipients from two different donations from an Argentine donor. The results of the study so far (less than one case per million person years) are well within the criterion established for the study: Upper limit of acceptable risk +2.4 cases per million person years to be comparable with other infectious disease risks or one to two cases per year. The conclusion, at 43 months, is that a selective testing strategy based on qualifying a donor by a single negative donation has a high sensitivity and has significantly reduced the amount of testing required without compromising recipient safety.