A Statement Presented Before the Food and Drug Administration's Blood Products Advisory Committee
01 November 2013
MP Biomedicals' Biologic License Application for the MP Diagnostics HTLV Blot 2.4, a Western Blot Intended for Use as a Confirmatory Test for Blood Donors
Louis M, Katz, MD, chair, AABB Transfusion Transmitted Diseases Committee
Blood donation screening for antibodies to human T-lymphotropic viruses (HTLV) has been in place in the United States since the end of 1988, first focused on HTLV-I and then on HTLV-I and HTLV-II. HTLV-II is likely less pathogenic than HTLV-I but all data indicate that HTLV-II is more common in the US than HTLV-I and, like HTLV-I, is transmitted in the US primarily via illegal injection drug use and sexually (mostly male to female, explaining higher prevalence rates in females). The HTLV donation prevalence rate in the US is comparable to that of HIV (approximately 3 per 100,000 donations) according to data generated by the American Red Cross (ARC); very low rates of incident infections have also been documented (again, mostly in females). Low prevalence in the US and Canada is also associated with the absence of documented transfusion transmission since screening was initiated.
The issue before the BPAC today is that since screening began in 1988, multiple FDA-licensed screening tests with varying specificities have been used; however, no licensed confirmatory/supplemental test has ever been available. This is primarily due to the very small market for HTLV testing in the US (and worldwide) and the costs associated with bringing donor testing products to market in the US. In the absence of a licensed confirmatory assay, donor counselling messages have been based on research assays, or just a repeat reactive screening result. Although research supplemental assays exist, they do not require the strict cGMP manufacturing and quality assurance requirements needed for FDA licensure. In the absence of a licensed confirmatory test, blood centers are left with the option of using research assays and associated complex algorithms that may involve long turn-around times, or referring donors to clinicians far less familiar with HTLV epidemiology, the probabilities of adverse clinical outcomes, and follow-up testing. The most commonly used supplemental system has been the algorithm performed by the State of CA Department of Public Health Viral and Rickettsial Diseases Laboratory that involves up to six assays (an enzyme immunoassay, 2 indirect immunofluorescence assays, 1 western blot and 2 radioimmunoprecipitation assays), which is considered by many to be the system with the highest performance standards.
Since 1988, we conservatively estimate that >200,000 donors testing falsely positive on licensed HTLV screens, in the absence of other evidence of infection, have been deferred.1 Some of these donors have had additional testing performed for counselling purposes, but many have not. Thus, these donors enter the health care system with incomplete data leaving primary care physicians confused as to the meaning of a reactive screening test (and the meaning of additional research supplemental tests). Additionally, since 1988 no donor deferred for HTLV false reactivity has been eligible for reentry. That is, many healthy donors with HTLV false positivity remain unable to donate.
During this time period, the MP Biomedicals' HTLV-I/II Western Blot (WB), version 2.4 has been the only assay submitted to the FDA for consideration for test licensure. This WB has a long history since it was first developed by GeneLabs and later manufactured and marketed internationally by Diagnostic Biotechnologies Ltd in Singapore, first as version 2.3 and then version 2.4. The latter is the assay now manufactured and marketed by MP Biomedicals. The challenge for WB confirmatory tests has been to detect the presence of the viral envelope (env) protein bands (the native, glycosylated viral env protein is denatured during gel electrophoresis and visible only on very high-titer antibody-positive samples). Thus, recombinant proteins and peptides have been developed to enhance the sensitivity for env bands. The first env recombinant protein added to WBs (i.e., p21e) has been associated with high rates of false positivity; thus, current versions of recombinant env proteins used in commercial WBs have been truncated to eliminate regions associated with nonspecific reactivity. The MP Biomedicals WB, version 2.4 uses a combination of three recombinant envelope proteins (truncated p21e, referred to as GD21; and two peptides, one associated with HTLV-I and the other with HTLV-II). This product has been in widespread use since the 1990s internationally and its performance is extensively published.
In addition to envelope banding, an HTLV antibody-confirmed positive test result is required to have reactivity to epitopes from a second viral gene, referred to as core or gag. The MP Biomedicals WB, version 2.4 relies on viral lysate for gag reactivity, and as such many donor samples exhibit nonspecific reactivity to gag precursors and/or gag intermediates unrelated to HTLV infection. This has been shown in numerous studies, described by the FDA in their briefing materials, and in discussion today. The appearance of isolated or multiple gag bands (in the absence of the primary gag protein, p24) has been referred to as HTLV-gag indeterminate patterns (HGIP). Such patterns, when evaluated by a variety of techniques including PCR, culture, and donor follow-up have never indicated any risk of HTLV infection or other viral infection. Accordingly, MP Biomedicals chooses to grade these patterns as "negative." In terms of donor safety and counselling, and further messaging for physicians, interpreting HGIPs as negative is appropriate and should be encouraged. In addition, the presence of an additional 10-20% of indeterminate results, with no biological meaning, ill serves both our donors and the health care system. In fact, such donors, if nonreactive subsequently on two licensed screening assays, should be considered for donor reentry. Studies have shown that the rate of positivity of the MP Biomedicals WB is comparable to the State of CA's algorithm and this is being further validated in studies by the ARC, including donor follow-up to determine if HGIP donor patterns evolve; although no literature published in over 20 years would indicate such evolution in the absence of risk.
The three organizations encourage FDA licensure of the MP Biomedicals, version 2.4 WB as an HTLV confirmatory test to be used for donor counselling and from which to develop a donor reentry algorithm. Licensure allows better oversight of production, less reliance on complex algorithms, more assurance of a continued supply chain, improved turn-around times, and gives manufacturers the message that developing a confirmatory test for the US market is a worthwhile endeavor. With licensure, we need to ensure appropriate messaging to donors that avoids unnecessary donor anxiety from clinically irrelevant indeterminate interpretations of nonspecific gag (non-env) banding. The scientific data argue persuasively that such test results should be interpreted as negative. As part of confirmatory testing algorithms, we strongly encourage the FDA to allow the industry to continue to use the dual screening test algorithm that has served us well for nearly 20 years and to retain the ability for donors to remain eligible for donation until reactive by two licensed screening tests on the same donation or a single screening test on two donations. The use of a dual test algorithm with orthogonal screening assays minimizes the number of WBs that need to be performed, and most importantly, provides a necessary opportunity to reduce the number of donors with biological false reactivity that is associated with triggering confirmatory testing from a single manufacturer's reactive screening test. Screening tests validated extensively for sensitivity allow false positives (i.e., those discordant on the two screening tests) to avoid further testing, and will serve in data collection for the validation of a donor reentry algorithm.
AABB is an international, not-for-profit association representing individuals and institutions involved in the field of transfusion medicine and cellular therapies. The association is committed to improving health by developing and delivering standards, accreditation and educational programs that focus on optimizing patient and donor care and safety. AABB membership consists of nearly 2,000 institutions and 8,000 individuals, including physicians, nurses, scientists, researchers, administrators, medical technologists and other health care providers. AABB members are located in more than 80 countries.
Founded in 1962, America's Blood Centers is North America's largest network of community-based, independent blood programs. The network operates more than 600 blood donor centers providing over half of the U.S., and a quarter of the Canadian blood supply. These blood centers serve more than 150 million people and provide blood products and services to more than 3,500 hospitals and healthcare facilities across North America. America's Blood Centers' U.S. members are licensed and regulated by the U.S. Food and Drug Administration. Canadian members are regulated by Health Canada.
The American Red Cross shelters, feeds and provides emotional support to victims of disasters; supplies about 40 percent of the nation's blood; teaches skills that save lives; provides international humanitarian aid; and supports military members and their families. The Red Cross is a not-for-profit organization that depends on volunteers and the generosity of the American public to perform its mission. About 5.6 million units of whole blood are collected from roughly 3.3 million Red Cross volunteer donors, separated into 8 million transfusable blood products and supplied to approximately 2,700 hospitals and transfusion centers across the country for patients in need.
- In the ARC system, 70,557 donors deferred with no other testing deferrals from 1995-2009 (Stramer et al, TRANSFUSION, 2011) were extrapolated to >100,000 from 1989-2013 for the ARC and doubled to estimate the number in the US.