June 15, 2009
Division of Dockets Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Room 1061
Rockville, MD 20852
Via electronic submission: http://www.regulations.gov/
RE: Docket No. FDA-2009-D-0137, 26 March 2009, “Draft Guidance for Industry: Use of Serological Tests to Reduce the Risk of Transmission of Trypanosoma cruzi Infection in Whole Blood and Blood Components for Transfusion and Human Cells, Tissues, and Cellular and Tissue-Based Products”
Dear FDA Dockets Manager:
AABB is an international association dedicated to advancing transfusion and cellular therapies worldwide. Our members include more than 1,800 hospital and community blood centers and transfusion and transplantation services as well as approximately 8,000 individuals involved in activities related to transfusion, cellular therapies and transplantation medicine. For over 50 years, AABB has established voluntary standards for, and accredited institutions involved in, these activities. AABB is focused on improving health through the advancement of science and the practice of transfusion medicine and related biological therapies, developing and delivering programs and services to optimize patient and donor care and safety.
AABB appreciates the opportunity to provide comments on this draft guidance document and has done so using expertise from its Transfusion Transmitted Diseases Committee and Cellular Therapies Committee. Comments to specific recommendations in the guidance document are arranged in the following format:
Section – language from draft guidance reprinted with page number and other identifying information.
Recommendation/Request for Clarification – recommendation or clarification request.
Background – rationale with information supporting the recommendation / clarification request.
An antibody test for Trypanosoma cruzi was FDA licensed in December 2006 following clinical trials showing yield of positive donors in the west and southwestern areas of the US (CDC; Morb Mortal Wkly Rep, 2007;51:210-211). In 2006, in the absence of FDA guidance, AABB Association Bulletin 06-08 was released to provide assistance for how to manage donors/components for those centers that chose to implement the test. Voluntary implementation of the licensed test occurred starting in January 2007. Through the end of 2008 (22-month experience) approximately 75-90% of blood centers have implemented the licensed test. Those who have implemented testing have done so using strategies that vary from universal testing (testing every donation from every donor) to various selective strategies ranging from using donor risk factors to select donors to test, testing only platelet components as those with the greatest risk, and also to qualifying donors based on a single nonreactive test result using the licensed test. The remaining 10-25% of blood facilities are skeptical as to whether any T. cruzi antibody testing is justified based on low clinical risk.
The algorithm being used by most collection facilities includes the Ortho T. cruzi ELISA test system followed by a more specific RIPA (an unlicensed radioimmunoprecipitation assay, commercially available through Quest Diagnostics). During the 22-month period from the implementation of testing in January 2007 through the end of November 2008 (for which US blood centers have reported data at a meeting of the Blood Products Advisory Committee (BPAC) on April 1st, 2009), there have been 2989 EIA-repeat reactive donors of which 735, from 41 states, have confirmed positive (AABB website).
The performance of the screening assay has been excellent, with a repeat reactive rate of 0.015% and a positive predictive value of 20-30% which is comparable to other screening/confirmatory tests. However, even with the use of a licensed screening test with excellent specificity and a research RIPA as a supplemental test for donor counseling, there still is the need for an FDA licensed supplemental test that may be used for reentry of donors with false-positive screening reactivity. We encourage the FDA to move quickly to license such tests once submitted, if they are suitable for donor counseling and reentry, and that such tests be made available for retesting of all repeat reactive donors independent of which manufacturer’s licensed screening test was used (assuming that multiple licensed screening tests will exist in the future).
To date only one test has been licensed and FDA issued draft guidance for use of the test in March 2009. Data reported at the April 1st meeting of BPAC are relevant to recommendations in the draft Guidance and form a basis for the following comments relating to testing for Whole Blood and Blood Components.
Whole Blood and Blood Components
Section II. Background A. Donor Screening Tests for Chagas Disease in the United States, page 3, paragraph 3. “Most donors that are repeatedly reactive by an ELISA test system for antibodies to T. cruzi have chronic, asymptomatic infections…..Therefore, prior donations from a donor who is repeatedly reactive on an ELISA test system were likely to harbor T. cruzi parasites.”
Recommendation –We recommend that the wording in the section be modified to be consistent with the industry experience using the licensed screening test. “Some donors that are repeatedly reactive by an ELISA test system for antibodies to T. cruzi have chronic, asymptomatic infections…..Therefore, prior donations from a donor who is repeatedly reactive on an ELISA test system may harbor T. cruzi parasites.”
Background – The data presented at the April 1st BPAC reported a positive predictive value of the screening test of 20-30%. (see General Comments). The majority of donors who test repeatedly reactive do not show evidence of actual infection.
Section II. Background B. Risk of T. cruzi Infection from Transfusion of Whole Blood and Blood Components, page 4, paragraph 3. FDA cites an overall frequency of transfusion transmission of 22.7% on the basis of pooled data from the US and Mexico.
“Studies also have looked at the rate of transfusion transmission from T. cruzi antibody-positive individuals. Published lookback studies in the U.S. and in Mexico of 22 transfusion recipients of seropositive donations, identified five of these recipients (22.7%) who later tested positive for antibodies suggesting transfusion transmission of T. cruzi.”
The background material should be updated based on studies conducted in the US. Transfusion transmission has been recognized in 4/260 recipients for a frequency of 1.5%.
We do not believe that the figure cited in the guidance document (22.7%) represents an accurate statement for the US. Based upon previous research studies (Leiby et al, Transfusion, 2002;42:549-555) and upon data from the use of the licensed test, there have been reports from a total of 260 recipients of prior donations from seropositive donors (242 for the 22-month experience of the American Red Cross, ARC combined with that of America’s Blood Centers, ABC, plus an additional 18 from previous ARC research studies). Only three recipients had clear evidence of transfusion-associated infection, based upon post-transfusion detection of antibodies to T. cruzi by EIA or IFA testing. One of these recipients had an additional risk factor for T. cruzi infection (prior residence in an endemic area). Additionally, a single case of transmission was noted from an index platelet product that was accidentally released after a donation tested positive (Leiby et al, N Engl J Med, 1999;341:1237-1239). This would represent a maximum of 4/260 recipients, or 1.5%. It should be noted that this figure may represent an underestimate of infectivity since most recipients of units from prior donations of T. cruzi confirmed-positive donors were not available for testing; i.e., survivor bias. For example, in the ARC studies, 78% of the total recipients transfused with cellular components from donors later found to be T. cruzi antibody positive were deceased and therefore, T. cruzi infection cannot be excluded as a contributor or cause of death.
Section III. Recommendations for Donors of Whole Blood and Blood Components Intended for Use in Transfusion A. Blood Donor Testing and Management 1. Donor Testing. “We recommend testing of all donations of allogeneic units of blood using a licensed test for antibodies to T. cruzi. You must follow the regulations under 21 CFR 610.40(d) for determining when autologous donations must be tested.”
We recommend that a donor be qualified for all future donations on the basis of a single nonreactive licensed screening test result for antibodies to T. cruzi. In addition, we recommend deletion of the recommendation to ask donors if they have had Chagas’ disease since we are now testing for antibodies for the agent using a specific test and due to the fact that this question, in the face of testing, is likely not to have any impact to recipient safety.
As reported to the BPAC, no overt seroconversion in a donor has been documented after approximately 2.6 million person-years of observation in the ARC and Blood Systems Inc (BSI) experiences. RIPA-positive donors have been identified with Ortho ELISA reactivity close to the assay cutoff, with ELISA results for prior donations that have been nonreactive. The ARC reported 16 such donors of which 11 had one prior nonreactive donation and 5 had multiple prior nonreactive donations; eight of the 16 had prior nonreactive reactivity within 20% of the cutoff. None of these donors represented incident infection since when 13 of the 16 were followed, no risk factors could be identified, all were nonreactive by parasitologic tests (PCR and hemoculture) and all had stable ELISA signals indicating either possible resolved infection or index false positivity. There is no evidence of an incident infection (i.e., an unequivocal seroconversion, or results from serial testing of index donation and follow-up specimens consistent with recent seroconversion) in any US blood donor in this, or any other dataset, past or present.
Section III. Recommendations for Donors of Whole Blood and Blood Components Intended for Use in Transfusion A. Blood Donor Testing and Management 5. Further Testing of Repeatedly Reactive Donors for Cross–Reacting Diseases. “Because the licensed test has demonstrated some reactivity in donors infected with pathogens other than T. cruzi, we recommend that medical follow up be considered for donors who are repeatedly reactive by the licensed test for antibodies to T. cruzi but who have no apparent basis for exposure to T. cruzi or who have negative results on more specific medical diagnostic tests. For example, testing for leishmaniasis may be appropriate in persons with geographic risk for exposure to Leishmania parasites and who appear to have a falsely reactive screening test for antibodies to T. cruzi.”
We do not believe that it is necessary or appropriate to provide recommendations to blood establishments regarding such testing; these decisions should be left to the discretion of the medical director, and as such suggest that this verbiage might be incorporated into the recommendations (4) for physician referral.
In the experience of the ARC, such testing has not been informative based on the nonspecificity of the diagnostic tests available for Leishmania; data supporting the absence of the utility of such testing on all RIPA-unconfirmed donors without apparent exposure to T. cruzi was presented to BPAC (April 2007 meeting). Based on feedback provided at the April 2007 BPAC meeting, ARC modified their algorithm to perform Leishmania testing only if the donor has traveled to an endemic area for Leishmania (such a question is asked of all reactive donors upon follow up). This is consistent with the verbiage in the recommendation (5). However, we do not believe that it is necessary or appropriate to provide recommendations to blood establishments regarding such testing.
Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)
Section IV. Recommendations for donors of HCT/Ps A. Donor Screening—Risk Factors or Conditions “…Ineligible potential donors include those who exhibit one or more of the following conditions or behaviors…Persons who have tested positive or reactive for T. cruzi antibodies using an FDA-licensed or investigational T. cruzi donor screening test” B. Donor Testing “…Any HCT/P donor whose specimen tests positive (or reactive) for antibodies to T. cruzi is ineligible to be a donor…”
Donors should be determined to be ineligible based on repeatedly reactive results, rather than reactive results.
The recommendation to determine that an HCT/P donor is not eligible based on a single reactive serological test result should be revised to included interpretation of repeat testing, as is common with other serological tests. Donors with repeat non-reactive results should be determined to be eligible.
Section II. Background C. Risk of T. cruzi Infection to Recipients of Donated HCT/Ps “Based on the risk of transmission, severity of effect, and availability of appropriate screening measures and/or tests, we have determined T. cruzi, the agent for Chagas disease, to be a relevant communicable disease agent or disease under 21 CFR 1271.3(r)(2).”
We question the designation of T. cruzi as a relevant communicable disease for the group of products (HCT/Ps) as a whole and we recommend further evaluation to determine the particular products for which the designation is appropriate.
HCT/P represents an extremely diverse range of products. It is reasonable to assume the same risk of transmission by hematopoietic progenitor cells as is assumed for whole blood, but the same risk does not seem reasonable when applied to ‘conventional’ tissues. In particular, some 99.4% of issued tissue products are highly processed in a way that is anticipated, or has been shown to inactivate or kill T. cruzi and the requirement for testing all donors is out of place.
AABB strongly supports initiatives that improve the safety of patients and donors, and the adequacy of the blood supply, and appreciates the opportunity to comment on this draft guidance. Should you have any questions regarding these comments or would like additional information, please contact me at 919-658-1689 or firstname.lastname@example.org.