Draft Guidance for Industry: Use of Serological Tests to Reduce the Risk of Transmission of Trypanosoma cruzi Infection in Whole Blood and Blood Components for Transfusion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
This guidance document is for comment purposes only.
Document Issued on: [March 2009]
Submit comments on this draft guidance by the date provided in the Federal Register notice announcing the availability of the draft guidance. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Submit electronic comments to http://www.regulations.gov. You should identify all comments with the docket number listed in the notice of availability that publishes in the Federal Register.
Additional copies of this draft guidance are available from the Office of Communication, Outreach and Development (OCOD) (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448, or by calling 1-800-835-4709 or 301-827-1800, or from the Internet at http://www.fda.gov/cber/guidelines.htm.
For questions on the content of this guidance, contact OCOD at the phone numbers listed above.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
Contains Nonbinding Recommendations
A. Blood Donor Screening Tests for Chagas Disease in the United States
B. Risk of T. cruzi Infection from Transfusion of Whole Blood and Blood Components
C. Risk of T. cruzi Infection to Recipients of Donated HCT/Ps
III. RECOMMENDATIONS FOR DONORS OF WHOLE BLOOD AND BLOOD COMPONENTS INTENDED FOR USE IN TRANSFUSION
A. Blood Donor Testing and Management
B. Product Management
C. Reporting the Test Implementation
IV. RECOMMENDATIONS FOR DONORS OF HCT/Ps
A. Donor Screening—Risk Factors or Conditions
B. Donor Testing
We, FDA, are notifying you, establishments that manufacture Whole Blood and blood components intended for use in transfusion, and establishments that make eligibility determinations for donors of HCT/Ps, about FDA approval of a Biologics License Application (BLA) for an enzyme-linked immunosorbent assay (ELISA) test system for the detection of antibodies to Trypanosoma cruzi (T. cruzi). This test is intended for use as a donor screening test to reduce the risk of transmission of T. cruzi infection by detecting antibodies to T. cruzi in plasma and serum samples from individual human donors, including donors of Whole Blood and blood components intended for use in transfusion, and HCT/P donors (living and cadaveric (non-heart beating)). This guidance document does not apply to the collection of Source Plasma.
In addition, we are providing you with recommendations for unit and donor management, labeling of Whole Blood and blood components, and procedures for reporting implementation of a licensed T. cruzi test at your facility or at your contract testing laboratory, as required for blood establishments under Title 21 Code of Federal Regulations 601.12 (21 CFR 601.12). For establishments that make donor eligibility determinations for HCT/P donors, we are notifying you that we have determined T. cruzi to be a relevant communicable disease agent under 21 CFR 1271.3(r)(2), and are providing you with recommendations for testing and screening donors for antibodies to T. cruzi.
The recommendations made in this guidance with respect to HCT/Ps are in addition to recommendations made in the document entitled “Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps),” dated August 2007 (Ref. 1).
We recommend that you implement the recommendations provided in this guidance within one year after a final guidance is issued.
FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe FDA’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in FDA’s guidances means that something is suggested or recommended, but not required.
Chagas disease is caused by the protozoan parasite, T. cruzi. The disease is found primarily in Mexico and Central and South America; the pathogenic agent has rarely been reported to cause human infection in the United States (U.S.) by natural vector transmission (Ref. 2). Natural infections are transmitted mainly when the feces of certain blood sucking insects (triatomine bugs, commonly referred to as kissing or chinch bugs) that harbor the infection are rubbed into a bug bite, other wound, or directly into the eyes or mucous membranes. Other primary forms of transmission include congenital (mother to unborn infant), organ transplantation, and blood transfusion. Current estimates are that at least 11 million persons in Mexico and Central and South America carry the parasite chronically and could present a potential source of infection should they become donors. The presence of the pathogenic agent in U.S. and Canadian donors is increasing due to immigration of infected individuals from endemic areas. Some experts estimate that there may be as many as 100,000 persons unknowingly infected with T. cruzi, who reside in the U.S. and Canada.
Vector-borne infections are mostly mild in the acute phase and then persist throughout life, usually without symptoms. Acute infection in patients with compromised immune systems, for example, from cancer therapy or organ transplantation, can be very serious and sometimes fatal. Treatment options are limited, but are most effective early in the infection. The lifetime risk of severe cardiac complications (cardiomegaly, heart failure and arrhythmias) or intestinal disorders (megacolon, megaesophagus) in infected individuals averages about 30% (range of 10 to 40% depending on a variety of factors) and may occur many years after the initial infection. During the acute phase of vector-borne Chagas disease, parasites are found in skin lesions at the site of transmission. The parasites are then spread through the bloodstream to various tissues, particularly skeletal muscle (Ref. 3). During the chronic stage of Chagas disease, most persons who harbor the parasite are asymptomatic and unaware of their infection. During this phase, parasites have been demonstrated in muscle (especially cardiac muscle), nerves, and digestive tract, but there has been very little investigation of tissue distribution during that phase (Refs. 3 through 10).
A. Donor Screening Tests for Chagas Disease in the United States
At the September 1989 Blood Products Advisory Committee (BPAC) meeting, the committee recommended testing donors of Whole Blood and blood components for Chagas disease when a suitable test became available. In a 1995 BPAC meeting, the committee considered whether the performance characteristics of the two FDA-approved tests then available for diagnosis of Chagas disease would be suitable for blood donor screening. The committee concluded that the tests discussed were not suitable for blood donor screening. Furthermore, the committee sought clarification of the criteria that FDA would use to license a Chagas test for donor screening. At the September 2002 meeting of BPAC, FDA presented its current considerations on the regulatory pathway and standards for licensing a donor screening test for Chagas disease and encouraged manufacturers to develop tests based on those considerations (Ref. 11).
In December 2006, FDA granted a license to one manufacturer of an ELISA test system for the detection of antibodies to T. cruzi in individual living blood and HCT/P donors. Since the end of January 2007, a number of blood centers representing a large proportion of U.S. blood collections have been testing donors using this licensed assay. In February 2009, FDA licensed this ELISA test system for the detection of antibodies to T. cruzi in cadaveric (non-heart beating) HCT/P donors.
Blood donor testing by an ELISA test system identifies donors that are repeatedly reactive for antibodies to T. cruzi. The presence of antibodies to T. cruzi is strong evidence that a donor is infected with this parasite. Most donors that are repeatedly reactive by an ELISA test system for antibodies to T. cruzi have chronic, asymptomatic infections acquired years earlier during residence in areas endemic for T. cruzi. Therefore, prior donations from a donor who is repeatedly reactive on an ELISA test system were likely to harbor T. cruzi parasites.
At the April 2007 BPAC meeting, FDA requested comments on scientific issues related to the implementation of blood donor testing for infection with T. cruzi (Ref. 12). Issues discussed by the committee included the need for additional data on the incidence and risk of transmission of T. cruzi by transfusion, the severity of Chagas disease, the performance of the antibody test, and, the lack of a licensed supplemental test for confirmatory testing.
The committee also commented on the design of research studies to validate a strategy for selective testing of repeat blood donors. The committee noted that a period of universal testing of all blood donors would generate critical data on the prevalence of T. cruzi infections in donors and that donor questions for selective donor screening needed validation.
B. Risk of T. cruzi Infection from Transfusion of Whole Blood and Blood Components
Blood donations from individuals from endemic areas are the primary source of risk for T. cruzi infection from transfusion. Studies in the mid-1990s (Ref. 1) estimated that the rate of seropositive blood donors in the U.S. ranged from 1 in 5400 to 1 in 25,000, depending on where the studies were conducted. However, more recent studies suggest that these rates have increased in the areas where donor testing has been performed over a period of time. For example, a rate of 1 in 2000 was found recently in the Los Angeles metropolitan area (Ref. 14). Transfusion transmission in endemic areas has been a major public health concern, and many countries considered endemic for T. cruzi infection screen blood donors for the presence of antibody. Therefore, in response to changes in donor demographics, we are now recommending blood donor testing in the U.S.
In the U.S. and Canada, only seven cases of transfusion-transmitted T. cruzi infections (Refs. 15 through 19) and five cases of infection from organ transplantation (Refs. 20 and 21) have been documented. However, transmission in immunocompetent patients is not likely to be apparent, and in many cases, even if symptoms appear, infection may not be recognized (Ref. 22).
Studies in blood centers which question donors about birth and/or residence in a T. cruzi-endemic country have shown such questions to be incompletely effective at identifying the seropositive donors. 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 (Refs. 18, 23 and 24). This transmission rate of 22.7% is consistent with the literature from Latin America on rates of blood-borne transmission from seropositive donors in Mexico and Central and South America (Ref. 25). However, we are aware that lookback studies conducted using the licensed ELISA test indicate that the risk of T. cruzi by transfusion of a seropositive unit in the U.S. may be much lower risk than previously thought. We note that these studies have confirmed the demographic characteristics of the typical seropositive donor as described in the first two paragraphs of section II. However, the data also suggest that there are seropositive individuals who acquired their infections within the U.S. (Ref. 26). Despite this new data, the rate of transfusion transmission of T. cruzi in the U.S. continues to be uncertain because of the limited number of studies conducted to date and the rate of transfusion transmission remains under investigation.
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). This determination was based on the following information.
1. Risk of Transmission
There is a risk of transmission of T. cruzi by HCT/Ps and there has been sufficient incidence and/or prevalence to affect the potential donor population.
Recognizing the risk of transmission from donated HCT/Ps, countries endemic for T. cruzi infection have instituted various practices to minimize transmission through transfusion or transplantation including screening donors for the presence of T. cruzi antibodies. Further, when human leukocyte antigen-matched bone marrow is obtained from an infected individual, the donor receives anti-parasitic treatment before the bone marrow is taken for transplantation. The World Health Organization recommends that:
- a heart from an infected donor not be transplanted;
- a liver from an infected donor only be transplanted to recipients already positive for Chagas disease, except in emergency cases; and
- when other organs are transplanted from a Chagas-positive donor, the recipient should receive prophylactic treatment for Chagas disease (Ref. 3).
Published data regarding the transmissibility of T. cruzi indicate that vertical transmission (congenitally from mother to infant), oral transmission (through breast milk or contaminated food) and conjunctival transmission (from contact with contaminated hands) have occurred (Ref. 3). In animal studies, T. cruzi has been shown to infect multiple tissues, including skeletal muscle, heart, bladder, peripheral nerve, liver, spleen, adrenal gland, brain, adipose tissue, ocular tissue, osteoblasts, chondroblasts, macrophages, and fibroblasts (Refs. 27 through 30). Human placental cells also have been experimentally infected with T. cruzi (Ref. 31). As noted previously in this section, T. cruzi has been transmitted via blood transfusions and organ transplantation (Refs. 20 through 22, and 32).
At the BPAC meeting of April 26, 2007, the committee noted that, though some HCT/Ps are processed in a manner that might inactivate T. cruzi in HCT/Ps from seropositive donors, current data are insufficient to identify specific effective processing methods that consistently render HCT/Ps free of T. cruzi. The committee concluded that, absent such data, it would be prudent to test HCT/P donors to decrease the risk of transmitting infection with T. cruzi (Ref. 12).
Information about prevalence of T. cruzi in the U.S. is provided in section II.B. of this document.
2. Severity of Effect
T. cruzi infections can be fatal or life-threatening, result in permanent impairment of a body function or permanent damage to a body structure, and/or necessitate medical or surgical intervention to preclude permanent impairment of a body function or permanent damage to a body structure.
3. Availability of Appropriate Screening and/or Testing Measures
Appropriate screening measures have been developed for T. cruzi, such as the medical history interview. (Screening measures for T. cruzi are discussed in section IV.A. of this document.)
A donor screening test for T. cruzi has been licensed and labeled for use in testing blood specimens from living and cadaveric donors of HCT/Ps (see section IV.B. of this document). You must use a donor screening test for T. cruzi that is specifically labeled for cadaveric specimens instead of a more generally labeled donor screening test when applicable and when available (21 CFR 1271.80(c)). Current FDA-licensed, cleared or approved donor screening tests for use in testing HCT/P donors are listed at http://www.fda.gov/cber/tissue/prod.htm.
- Blood Donor Testing and Management
- 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.
- Donor Deferral
We recommend that all donors who are repeatedly reactive on a licensed test for T. cruzi antibody or who have a history of Chagas disease be indefinitely deferred and notified of their deferral.
- Confirmatory Testing and Donor Reentry
At this time, there is no FDA licensed supplemental test for antibodies to T. cruzi that can be used for confirmation of true positive screening test results. FDA is not recommending reentry criteria for blood donors deferred indefinitely on the basis of a repeatedly reactive screening test for antibodies to T. cruzi due to the absence of a licensed supplemental test for antibodies to T. cruzi.
- Donor Counseling and Physician Referral
We recommend that donors who are repeatedly reactive using a licensed test for antibodies to T. cruzi be informed about the likelihood and medical significance of infection with T. cruzi. Additional medical diagnostic testing may provide information useful in donor counseling.
All repeatedly reactive donors should be referred to a physician specialist. It also may be useful to refer them to their state and local health departments or to other appropriate community resources
- 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.
- Product Management
- Index Donations
We recommend that blood components from repeatedly reactive index donations be quarantined and destroyed or used for research. Components determined to be unsuitable for transfusion must be prominently labeled: “NOT FOR TRANSFUSION,” and the label must state the reason the unit is considered unsuitable (e.g., the component is positive for T. cruzi (21 CFR 606.121(f))
- Lookback (Product Retrieval and Recipient Notification)
Within 3 calendar days after a donor tests repeatedly reactive by a licensed test for T. cruzi antibody, you should:
- identify all in-date blood and blood components previously donated by such a donor, going back either 10 years (or indefinitely where electronic records are available), or else 12 months prior to the most recent time that this donor tested negative with a licensed test for T. cruzi antibody, whichever is the lesser period (the lookback period);
- quarantine all previously collected in-date blood and blood components held at your establishment; and
- notify consignees of all previously collected in-date blood and blood components to quarantine and return the blood components to you or to destroy them.
In addition, when you identify a donor who is repeatedly reactive by a licensed test for T. cruzi antibodies and for whom there is additional information indicating risk of T. cruzi infection, such as geographical risk for exposure in an endemic area, or medical diagnostic testing of the donor, we recommend that you:
- notify consignees of all previously distributed blood and blood components collected during the lookback period; and
- if blood or blood components were transfused, encourage consignees to notify the recipient’s physician of record of a possible increased risk of T. cruzi infection.
We recommend that when there is additional information indicating risk of T. cruzi infection you make such notifications within 12 weeks of obtaining the repeatedly reactive test result.
There currently is no licensed T. cruzi supplemental test. When such a test is available, a positive test result will provide additional information indicating risk of T.cruzi infection.
Retrospective Review of Records
If you are a blood establishment that implemented screening with a licensed test for antibodies to T. cruzi prior to the effective date of this guidance, you may wish to perform a retrospective review of records to identify donors:
- with repeatedly reactive test results by a licensed test for T. cruzi antibodies; and
- for whom there is additional information indicating risk of T. cruzi infection, such as geographical risk for exposure in an endemic area, or medical diagnostic testing of the donor. There currently is no licensed T. cruzi supplemental test. When such a test is available, a positive test result will provide additional information indicating risk of T.cruzi infection.
If a donor is identified at risk of infection during the retrospective review, you may want to consider performing all the lookback actions described above.
- Autologous Donations
Although autologous use of blood does not increase a patient’s/donor’s risk of illness from a pre-existing infection, FDA regulations under 21 CFR 610.40(d) and (e) require testing of autologous blood donors under certain circumstances to prevent inadvertent allogeneic exposures to unsuitable units.
- We recommend that blood components from autologous donors that are repeatedly reactive by a licensed test for T. cruzi antibody be released for autologous use only with approval of the autologous donor’s referring physician. Establishments should provide the results of additional testing for antibodies to T. cruzi, as available to the autologous donor’s referring physician.
- Each autologous donation must be labeled as required under 21 CFR 610.40(d)(4), as appropriate. Given the seriousness of T. cruzi infections, autologous donations that are repeatedly reactive by a licensed test for T. cruzi antibody must bear a biohazard label as required under 21 CFR 610.40(d)(4).
- Circular of Information
Consistent with other donor screening tests, the instruction circular, also known as the “Circular of Information” must be updated to state that a licensed test for antibodies to T. cruzi was used to screen donors and that the results of testing were negative (21 CFR 606.122(h)).
- Biological Product Deviation Report and Fatality Report
Under 21 CFR 606.171, licensed manufacturers, unlicensed registered blood establishments, and transfusion services must report any event and information associated with the manufacturing, if the event either represents a deviation from current good manufacturing practice, applicable regulations, applicable standards, or established specifications that may affect the safety, purity, or potency of the product; or represents an unexpected or unforeseeable event that may affect the safety, purity, or potency of the product, and it occurs in your facility or another facility under contract with you and involves distributed blood or blood components. For additional information regarding reporting, you may refer to FDA guidance, “Guidance for Industry: Biological Product Deviation Reporting for Blood and Plasma Establishments,” dated October 2006 (Ref. 33). Also, when a complication of blood collection or transfusion (e.g., involving T. cruzi) is confirmed to be fatal, you must notify FDA in accordance with 21 CFR 606.170(b).
- Reporting the Test Implementation
1. If you are a licensed blood establishment and you begin using a licensed serological test for the detection of antibodies to T. cruzi according to the manufacturer’s product insert at your facility, then you must notify us of the testing change in your Annual Report (AR), in accordance with 21 CFR 601.12(d). If you already have an approved supplement to your BLA to use a contract laboratory to perform infectious disease testing of blood products, and the contract laboratory will now perform a serological test for antibodies to T. cruzi, you must report this change in your AR (21 CFR 601.12(d)).
2. If you are a licensed blood establishment and you use a new contract laboratory to perform a serological test for antibodies to T. cruzi (and the laboratory already performs infectious disease testing for blood products), then you must report this change by submission of a “Changes Being Effected” supplement, in accordance with 21 CFR 601.12(c)(1) and (c)(5). If your contract laboratory has not previously performed infectious disease testing for blood products, then you must report this change as a major change in a prior approval supplement, in accordance with 21 CFR 601.12(b).
Donor Screening—Risk Factors or Conditions
Under 21 CFR 1271.75(d), you must determine to be ineligible any potential donor who is identified as having a risk factor for or clinical evidence of relevant communicable disease agents or diseases. Ineligible potential donors include those who exhibit one or more of the following conditions or behaviors.
- Persons who have had a medical diagnosis of T. cruzi infection based on symptoms and/or laboratory results.
- Persons who have tested positive or reactive for T. cruzi antibodies using an FDA-licensed or investigational T. cruzi donor screening test (Ref. 1).
- Donor Testing
1. You must test blood specimens from all HCT/P donors for antibodies to T.cruzi using an FDA-licensed donor screening test (21 CFR 1271.80(c)).
2. Any HCT/P donor whose specimen tests negative (or non-reactive) for antibodies to T. cruzimay be considered to be negative (or non-reactive) for purposes of making a donor eligibility determination.
3. Any HCT/P donor whose specimen tests positive (or reactive) for antibodies to T. cruzi is ineligible to be a donor (21 CFR 1271.80(d)(1)).
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33. Guidance for Industry: Biological Product Deviation Reporting for Blood and Plasma Establishments, October 2006, http://www.fda.gov/cber/gdlns/devbld.htm.