FDA Publishes Draft Biological Development Guidance on Serological Tests
FDA publishes guidance “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 (HCT/Ps)”
Introduction
The FDA, are notifying 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.
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).
Background
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. 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. 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.
Donor Screening Tests for Chagas Disease in the USA
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 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.
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.
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.
Risk of T.cruzi Infection to Recipients of Donated HCT/Ps
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.
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
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.
Availability of Appropriate Screening and/or Testing Measures
Appropriate screening measures have been developed for T. cruzi, such as the medical history interview. 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. 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)).
Recommendations for Donors of Whole Blood and Blood Components Intended for Use in Transfusion
Blood Donor Testing and Management
The FDA 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.
The FDA 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.
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.
The FDA 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.
Because the licensed test has demonstrated some reactivity in donors infected with pathogens other than T. cruzi, the FDA 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.
Product Management
We recommend that blood components from repeatedly reactive index donations be quarantined and destroyed or used for research.
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.
Recommendations for Donor of HCT/Ps
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.
Donor Testing
- 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)).
- Any HCT/P donor whose specimen tests negative (or non-reactive) for antibodies to T. cruzi may be considered to be negative (or non-reactive) for purposes of making a donor eligibility determination.
- 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)).
If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com
Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.
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