Blood Products Advisory Committee

89th Meeting, April 26-27, 2007

Gaithersburg, Maryland


Issue Summary



Topic I.A:    Advice Sought on Issues Related to Implementation of Blood Donor Screening for Infection with Trypanosoma cruzi.


FDA seeks the advice of the Committee on issues related to blood donor screening and product management based on use of a licensed test for antibodies to T. cruzi.  In addition FDA seeks advice on design of research studies to (a) validate a strategy for selective screening of repeat donors and (b) evaluate cross reactivity of the licensed test for antibodies to T. cruzi with other pathogens.


I.  Background


Chagas’ disease is caused by the protozoan parasite, Trypanosoma cruzi.   Natural infections are transmitted mainly when the feces of 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.  Natural transmission is found almost exclusively in Mexico, Central and South America; the agent has rarely been reported to cause human infection in the United States by natural vector transmission.  The prevalence of the infection in the US and Canada, however, is increasing due to immigration of infected individuals from endemic areas.  Acute, vector-borne infections are mostly mild, but then persist throughout life, usually without symptoms.  The life-time risk of severe heart or intestinal problems (megacolon, megaesophagus) in infected individuals averages about 30% (range of 10-40% depending on a variety of factors) and may occur years to decades after the initial infection.  During the chronic stage, most persons who harbor the parasite are asymptomatic and unaware of their infection.  In contrast, 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. 


It is estimated that there are at least 11 million persons who carry the parasite chronically in Mexico and in Central and South America.  Of those infected, up to 45,000 fatalities may occur annually.  Transfusion transmission in endemic areas has been a major public health concern and many countries that are considered endemic for T. cruzi infection screen blood donors for the presence of antibody.  Some experts estimate that there may be as many as 100,000 persons unknowingly infected with T. cruzi who have legally immigrated to the US and Canada.  Blood donations from immigrants from endemic areas are the primary source of risk for T. cruzi infection from transfusion.  Prior studies estimated that the rate of seropositive blood donors in the US ranges from 1 in 5400 to 1 in 25,000 dependent on where the studies were conducted.  However, ongoing investigational studies suggest that these rates have increased and are as high as 1 in 2000 in the Los Angeles metropolitan area.


In the US and Canada, only eight cases of transfusion-transmitted T. cruzi and five cases of infection from organ transplantation have been documented; however, it is well accepted that many other transmissions are likely to have occurred and gone unrecognized.  Transmission in an immunocompetent patient is likely to be inapparent, and in many cases, even if symptoms appear, infection will likely not be recognized.


Studies in blood centers on questioning of donors for birth and/or residence in an endemic country have shown such questions to be incompletely effective at capturing all seropositive donors.  Studies have also looked at the efficiency of transmission from T. cruzi antibody-positive individuals.  Published lookback studies in the US and in Mexico have identified five positive recipients of the 13 (38.5%) who received transfusions from seropositive donors; this figure is consistent with the literature from Latin America on rates of blood-borne transmission from seropositive donors.



II. Discussion


Blood Donor Screening for Chagas disease in the USA


At the September 1989 Blood Products Advisory Committee (BPAC) meeting the committee recommended donor screening for Chagas provided there is a suitable test available.  At the 1995 BPAC meeting, the question was posed to the committee whether the two FDA-approved tests available for diagnosis of Chagas were suitable for blood donor screening. The committee concluded that the tests discussed were not suitable for blood donor screening. Further, the committee was not clear about the FDA standards required for the approval of a Chagas test for donor screening.  At the September, 2002 BPAC meeting, the FDA presented its current considerations on the regulatory pathway and standards for a blood donor screening Chagas test and encouraged manufacturers to develop tests based on those considerations.


In December, 2006, the FDA granted a license to one manufacturer of a test for antibodies to T. cruzi (Ortho® T. cruzi ELISA Test System).  The Ortho T. cruzi antibody test is based on the capture of T. cruzi antibody in a sample of the donor’s serum or plasma by purified T. cruzi epimastigote lysate on a solid phase. This product is intended for use as a donor screening test to detect antibodies to T. cruzi in plasma and serum samples from individual human donors, including donors of whole blood, blood components or source plasma, and other living donors. It is also intended for use to screen organ and tissue donors when specimens are obtained while the donor’s heart is still beating. At this time, the test is not approved for use on specimens from cadaveric donors (non-heart-beating) and is not intended for use as an aid in diagnosis.  The test is not intended for use on samples of cord blood.


Beginning Jan. 29, 2007 the American Red Cross and Blood Systems Inc. initiated screening with the Ortho test and reactive donors have been identified at the rate expected from studies conducted pre-approval.  A presentation will be made reporting the results of blood donor screening to date.


Blood donor screening will identify donors who are repeatedly reactive on the ELISA.  The presence of antibodies to T. cruzi is strong evidence that the donor is infected with this parasite.  Most likely the donor has a chronic, asymptomatic infection acquired years before when he or she lived in an area endemic for T. cruzi.  Therefore, any prior donations are likely to harbor T. cruzi parasites.  For this reason, notification of recipients of prior donations (lookback) is appropriate.  However, despite the apparent high specificity of the licensed screening test, many of the repeatedly reactive results are expected to be false positives and it is desirable to contact prior donation recipients following confirmation of the T. cruzi antibody status of the donor.  Ideally, this confirmation should be done with a supplemental test for T. cruzi that is licensed by the FDA for this intended use.  However, at the present time, there is no licensed supplemental test for infection with T. cruzi.


Needs for Further Research


1.  Possibility for targeted screening of repeat donors


Concern has been expressed that universal testing, particularly of repeat donors is burdensome and may not be necessary.  At this time, the FDA is considering recommending universal screening of blood donors for antibodies to T. cruzi as well as appropriate research studies performed concurrently to validate approaches to selective screening of repeat donors.  Questions could be designed to trigger retesting of repeat donors based on a history of travel to endemic areas or other risk factors for exposure.  Dr. Brian Custer’s presentation will address a possible approach to this issue.


2.  Possibility of cross-reactive antibodies of medical significance 


The results of Ortho Clinical Diagnostic’s performance evaluation studies show that the ELISA assay is cross reactive with antibodies to the protozoan parasite Leishmania (74/100 Leishmania positive specimens collected in a region non endemic for T. cruzi reacted with the Ortho T. cruzi ELISA).  To a lesser extent, there was cross reaction with specimens from malaria positive individuals (1/100).  There was also reactivity with specimens positive for antibodies to Paracoccidiodes braziliensis (2/5), though co-infection with T. cruzi could not be ruled out.  However, in the US random donor study, specimens that were repeat reactive with the Ortho T. cruzi ELISA and negative with the radioimmune precipitation assay (RIPA) were further tested by Leishmania IFA and malaria IFA, but none were positive for these other agents.  These findings raise the question whether testing for antibodies to Leishmania, Plasmodium and Paracoccidioides braziliensis or other agents should be considered in donors repeatedly reactive in the licensed ELISA for antibodies to T. cruzi when more specific tests are negative for such antibodies.   CDC will provide a discussion of proposed studies to address this issue.


Issues for Implementation of Blood Donor Screening for antibodies to T. cruzi


FDA is considering recommending universal screening of blood donors for antibodies to T. cruzi.  Similar to FDA recommendations for other infectious diseases, such recommendations might address the following topics:


1.  Management of Donors


·         Donor testing of donations of allogeneic and autologous blood for antibodies to T. cruzi to prevent transfusion transmission of acute and chronic Chagas’ disease.  Recommendations might include strategies for selective screening of donors based on validation of such strategies in further studies.  


·         Donor deferral (indefinite) of donors who test repeatedly reactive by the licensed test for T. cruzi antibody and notification of donors of their deferral.


·         Donor counseling: informing donors who test repeatedly reactive by the licensed test for antibodies to T. cruzi about the likelihood and medical significance of infection with T. cruzi.   Additional medical diagnostic testing may provide information useful in such donor counseling.


·         Further testing for cross reacting disease states: Medical follow up may be important for donors who are found to be repeatedly reactive by the licensed test for antibodies to T. cruzi, but have no apparent basis for exposure to T. cruzi  or have negative results on more specific medical diagnostic tests.



2. Product Management


·         Index donations: As a preventive measure against transfusion transmission of acute and chronic Chagas ’ disease, recommendations might address whether components from repeat reactive index donations should be quarantined and destroyed, or else used for research following appropriate labeling.


·         Retrieval of Products from Prior Collections:  recommendations might address whether in-date components from prior collections from the same donor should be promptly quarantined and release of such units if further information establishes that the screening test result is falsely positive. No licensed test is presently available to make that determination. 


·         Lookback (recipient tracing and testing):  Again, scientific data support the likelihood that prior blood collections from test reactive donors were contaminated with T. cruzi.  Recommendations might address whether Medical Directors should consider notifying consignees of blood units previously collected from a donor who is repeat reactive by a licensed test for T. cruzi antibodies to permit possible notification of the treating physician of recipients of such units. 


·         Autologous donations:  Although autologous use of blood does not increase a patient/donor’s risk for a pre-existing infection, FDA regulations under 21 CFR 610.40 (d) require testing of autologous blood donors under certain circumstances to prevent inadvertent allogeneic exposures to unsuitable units and test reactive units can be released for autologous use, but must bear a biohazard label.  Recommendations might address labeling of autologous donations.


·         Source Plasma: Current methods for manufacture of plasma derivatives are considered highly effective for removal and inactivation of parasites.  FDA would take this information into account for Source Plasma donations which are intended solely for further manufacturing use, in considering whether there is a need for Source Plasma to be screened for antibodies to T. cruzi. 


·         Inventory testing: When blood centers initiative prospective donor screening for antibodies to T. cruzi, a question will arise whether extant inventories additionally should be screened.  FDA’s recommendations might address whether each blood establishment should assess this need based on the local risk.


·         Label and Circular of Information:  FDA recommendations might address the need for Component labels and the Circular of Information to be updated stating the use of the licensed test for antibodies to T. cruzi to screen donors, and that the results of testing were negative.  


·         Biological Product Deviation Report (BPDR) and Fatality Report:  FDA’s recommendations might address BPDR submissions if subsequent to the availability of the reactive test result, a blood component was released from a current or prior donation from a donor testing repeat reactive by the licensed test.  Additionally, the recommendations might address fatality reports to FDA related to suspect blood components (i.e.., components from donors who tested repeatedly reactive by the licensed test).



Topic I.B.:    Advice Sought on Issues Related to the Potential Transmission of  Trypanosoma cruzi by Human Cells, Tissue and Cellular and Tissue-Based Products (HCT/P)


FDA seeks discussion by the Committee on the current scientific data as it relates to testing of all allogeneic HCT/P donors for antibodies to T. cruzi to prevent the potential transmission of Chagas' disease by HCT/Ps.


I.  Background


The Office of Cellular, Tissue and Gene Therapies (OCTGT) within CBER regulates human cells, tissues, and cellular or tissue-based products (HCT/Ps), which cover a broad range of individual products.  The regulations define HCT/Ps (21 CFR 1217.3(d)) as articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.  Examples of HCT/Ps include, but are not limited to, bone, ligament, skin, dura mater, heart valve, cornea, hematopoietic stem cells derived from peripheral and cord blood, manipulated autologous chondrocytes, epithelial cells on a synthetic matrix, and semen or other reproductive tissue.  The following articles are not considered HCT/Ps:


(i)         Vascularized human organs for transplantation;

(ii)        Whole blood or blood components or blood derivative products subject to listing under parts 607 and 207 of this chapter, respectively;

(iii)       Secreted or extracted human products, such as milk, collagen, and cell factors; except that semen is considered an HCT/P;

(iv)       Minimally manipulated bone marrow for homologous use and not combined with a drug or a device (except for a sterilizing, preserving, or storage agent, if the addition of the agent does not raise new clinical safety concerns with respect to the bone marrow);

(v)        Ancillary products used in the manufacture of HCT/P;

(vi)       Cells, tissues, and organs derived from animals other than humans; and

(vii)      In vitro diagnostic products as defined in Sec. 809.3(a) of this chapter.


In order to screen or test HCT/P donors for an infectious agent, that agent must be considered by FDA to be a relevant communicable disease agent or disease (RCDAD).  RCDADs are designated two ways in the regulations—some diseases are specifically listed in the rule, and others must meet certain criteria to be considered “new” RCDADs.  This allows FDA to address emerging infectious diseases, if they meet the criteria.  Disease agents specifically listed in 21 CFR 1271.3(r)(1) include the following for all HCT/Ps:


     Human immunodeficiency virus (HIV), types 1 and 2;

     Hepatitis B virus (HBV);

     Hepatitis C virus (HCV);

     Human transmissible spongiform encephalopathy (TSE), including Creutzfeldt-Jakob disease (CJD); and

     Treponema pallidum (syphilis).


Additionally, a communicable disease agent or disease meeting the following criteria (Sec. 1271.3(r) (2)), but not specifically listed, is relevant if it is one:


a.   For which there may be a risk of transmission by an HCT/P, either to the recipient of the HCT/P or to those people who may handle or otherwise come in contact with the HCT/P, such as medical personnel, because the disease agent or disease:


i.       is potentially transmissible by an HCT/P; and


ii.      either (1) has sufficient incidence and/or prevalence to affect the potential donor population (Sec. 1271.3(r)(2)(i)(B)(1)), or (2) may have been released accidentally or intentionally in a manner that could place potential donors at risk of infection (Sec. 1271.3(r)(2)(i)(B)(2));


b.   That could be fatal or life-threatening, could result in permanent impairment of a body function or permanent damage to body structure, or could necessitate medical or surgical intervention to preclude permanent impairment of body function or permanent damage to a body structure (Sec. 1271.3(r)(2)(ii)); and


c.       For which appropriate screening measures have been developed and/or an appropriate screening test for donor specimens has been licensed, approved, or cleared for such use by FDA and is available (Sec. 1271.3(r)(2)(iii)).


If FDA determines that an infectious disease agent or disease meets the definition of a RCDAD under Sec. 1271.3(r) (2), we would notify the public of our intention through a guidance document (usually as a draft document for comment, unless immediate implementation was warranted).  The draft guidance would explain how FDA concluded that the disease meets the criteria and would contain recommendations for donor screening and testing (if an FDA-licensed, approved, or cleared test were available).  We would also provide public notification through a guidance if we conclude that a disease identified as “relevant” under Sec. 1271.3(r)(2) no longer meets the criteria as a “relevant” disease for purposes of the donor eligibility regulations.  We have also stated that in suitable situations, we will hold public meetings or consult with advisory committees to help us identify communicable disease agents or diseases for which donor screening and testing is warranted.


To date, FDA has issued guidance describing West Nile Virus, Sepsis, and Vaccinia (the virus used in smallpox vaccine) to be RCDADs for tissues.  We have recommended screening measures for these agents and have not yet made testing recommendations.


We would also like to clarify the use of the term “donor screening.”  In some circumstances, the term donor screening includes donor testing.  However, the HCT/P regulations distinguish between donor screening (medical history interview, physical assessment and medical record review) and donor testing.  HCT/P donors are tested using donor screening tests.  This discussion focuses on issues related to the testing of HCT/P donors for Chagas’ disease.


To date, FDA has not had a public discussion of Chagas’ disease as it relates to HCT/P donors.  Although we are not aware of a case of tissue transmission, we need to consider scientific information that relates to the potential for transmission via HCT/Ps.  We bring this issue to the Committee so that we can obtain the committee’s expert scientific input on this topic. 


 II. Discussion


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 entrance via the conjunctiva through hand contamination have occurred.  T. cruzi has been transmitted via blood transfusion and organ transplantation, but to date there have been no reports of transmission though cell or tissue transplantation. 


There may be several reasons for the absence of reports.  The association between the tissue transplant and the development of symptoms may not be recognized because there is a long time between exposure to development of symptoms in immunocompetent individuals, and the acute and chronic phases are usually asymptomatic.  In addition, it may be difficult to recognize a transplant-transmitted infection in an endemic area, where the exposure is probably environmental.  Also, in general, tissue allografts undergo various degrees of processing and it is possible that some methods may remove or inactivate T. cruzi.  Some cellular products are cryopreserved and some tissues are frozen.  The parasite may survive two to three weeks at refrigerator or freezing temperatures, but its survival beyond that time period is unknown.


Information about the distribution of the parasite in various tissues is scant.  During the acute phase, 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.  During the chronic, asymptomatic phase, parasites have been demonstrated in muscle (especially cardiac muscle), nerves, and digestive tracts, but there has been very little investigation of tissue distribution during that phase.  For individuals who die with cardiomyopathy, megaesophagus, or megacolon, the parasites have been demonstrated in these tissues.


Infectious disease transmission by HCT/Ps is complex.  In cases of known transmission of other infectious disease agents (e.g., HIV, HBV, and HCV), it has been difficult to determine whether transmission occurs because the agent is in the tissue, or because the agent is in blood that is in the tissue.


In endemic countries, various practices are in place to minimize transmission through transfusion or transplantation.  Many countries that are considered endemic for T. cruzi infection screen blood donors for the presence of antibody.  When HLA-matched bone marrow is obtained from an infected individual, the donor receives anti-parasitic treatment before the bone marrow is taken for transplantation.  Pancreas, lung, cornea, vascular grafts and other types of tissue transplants from known infected donors are not transplanted, except in extreme cases.  The World Health Organization recommends that a heart from an infected donor not be transplanted, that a liver from an infected donor only be transplanted to recipients positive for Chagas except in emergency cases, and that when other organs are transplanted from a Chagas positive donor, the recipient receive prophylactic treatment for Chagas. 


Similar to the other issues pertaining to blood donors that will be discussed today; we are also interested in the suggestions from the Committee on the design of research studies to validate a strategy for selective screening of repeat donors because some HCT/P donors, such as semen donors, donate repeatedly.  In addition, some HCT/P donors are living donors (e.g., donors of hematopoietic stem/progenitor cells; donors of reproductive cells and tissues).  Therefore, medical follow up for cross-reacting diseases may be important for those donors who are found to be repeatedly reactive by a licensed test for antibodies to T. cruzi, but have no apparent basis for exposure to T. cruzi or have negative results on more specific medical diagnostic tests.


III. Questions for the Advisory Committee


Question #1


Please comment on any scientific issues that FDA should further consider in developing its recommendations on implementation of blood donor screening for antibodies to T. cruzi.


Question #2


What suggestions does the committee have on the design of research studies to validate a strategy for selective screening of repeat donors?


Question #3


Please comment on the need for and design of studies to determine whether repeatedly reactive test results for antibodies to T. cruzi should be further investigated for cross-reactivity to Leishmania, Plasmodium, Paracoccidioides braziliensis or other agents when the donor lacks risk factors for T. cruzi infection or a test sample is found negative by other, more specific tests.


Question #4


Please comment on the implications of the current scientific data as it relates to the potential for transmission of Chagas Disease by HCT/Ps.