94th Meeting, April 1, 2009

Rockville, MD


Issue Summary


Topic I.B.:  Testing donors of human cells, tissues, and cellular and tissue-based products (HCT/Ps) for hepatitis B virus infection by nucleic acid testing

Issue: FDA seeks advice and input from the Committee on issues related to testing donors of human cells, tissues, and cellular and tissue-based products (HCT/Ps) for hepatitis B virus (HBV) DNA by nucleic acid testing (NAT).



The Office of Cellular, Tissue and Gene Therapies (OCTGT) within CBER regulates human cells, tissues, and cellular and 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.  Donors of HCT/Ps may be either living or deceased (i.e., cadaveric).  Examples of HCT/Ps include, bone, ligament, skin, dura mater, heart valve, and cornea from deceased donors; hematopoietic stem cells derived from peripheral and cord blood, manipulated autologous chondrocytes, epithelial cells on a synthetic matrix, and semen or other reproductive tissue from living donors.    


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 21 CFR § 607 and 207, 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 21 CFR §809.3(a).


Relevant Communicable Disease Agents or Diseases and Donor Screening


In order for there to be a requirement 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 regulation 21 CFR §1271.3(r)(1), while others must meet certain criteria, listed in 21 CFR §1271.3(r)(2) to be considered a RCDAD.  The provisions in 1271.3(r)(2) were established to allow FDA to address emerging infectious diseases.  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).


The term “donor screening” has a specific meaning in the context of HCT/Ps.  In some circumstances, the term donor screening may also encompass 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 issue summary focuses on issues related to the testing of HCT/P donors for hepatitis B virus.


HCT/P Donor Testing


HCT/P donors must be tested using an appropriate FDA-licensed, approved, or cleared donor screening test in accordance with the manufacturer’s instructions to adequately and appropriately reduce the risk of transmission of the relevant communicable disease agent or disease (21 CFR § 1271.80(c)).  We list tests that we currently consider to meet the requirements in §1271.80(c) to adequately and appropriately reduce the risk of communicable disease transmission in section VI of our August 2007 Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products ( 


The following tests adequately and appropriately reduce the risk of communicable disease transmission under §1271.80(c):  

1.      HIV, type 1 (FDA-licensed screening test either for anti-HIV-1 or combination test for anti-HIV-1 and anti-HIV-2; and FDA-licensed screening NAT test for HIV-1, or combination NAT that includes HIV-1) (establishments not utilizing an FDA-licensed screening test that tests for group O antibodies must evaluate donors for risk associated with HIV group O infection);

2.      HIV, type 2 (FDA-licensed screening test either for anti-HIV-2 or combination test for anti-HIV-1 and anti-HIV-2);

3.      HBV (FDA-licensed screening test for Hepatitis B surface antigen (HBsAg) and for total antibody to Hepatitis B core antigen (anti-HBc)(IgG and IgM);

4.      HCV (FDA-licensed screening test for anti-HCV; and FDA-licensed screening NAT test for HCV, or combination NAT that includes HCV); and

5.      Treponema pallidum (FDA-cleared screening test for syphilis or FDA-cleared diagnostic serologic test for syphilis).


As described in the guidance and reflected in the above list, in some instances establishments need to conduct more than one test to adequately and appropriately test for a single communicable disease agent or disease.  There is currently no recommendation regarding HBV NAT testing in the Donor Eligibility guidance.




As described in the issue summary on blood donor testing, the three major issues currently being considered include the availability of tests with triplex testing capabilities, the improved availability of efficient HBV NAT testing that could potentially increase the detection of HBV DNA positive/HBsAg and anti-HBc negative donors in the donor pool, and concerns regarding the potential for “breakthrough” hepatitis B infection in donors previously vaccinated for hepatitis B.  


HCT/P donor testing has some unique aspects that should be considered, including:

·         format of donor testing (Individual Donor (ID) NAT vs. minipool (MP) NAT);

·         lack of yield data in living donor populations (other than the blood donor population); and

·         difficulty in assessing yield data in cadaveric donors.


Testing Format


HCT/P donor specimens are required to be tested in accordance with the manufacturer’s instructions for use.  Currently, donors of hematopoietic stem/progenitor cells (HPCs) and donor lymphocytes for infusion (DLI) are the only HCT/P donors where there are manufacturer’s instructions that would allow for pooled donor specimen testing.  Specimens from all other living donors of HCT/Ps, as well as from cadaveric donors, must be tested in ID format.  Thus, the potential yield for testing most HCT/P donors for HBV NAT would be maximized to the extent possible utilizing current technology.


Lack of Yield Data


When tests are either licensed or under consideration for licensure as a blood donor screening test, manufacturers are not required to submit additional clinical data specific to living donor populations (other than donors of blood and blood products) in order to allow ID testing in those other living donor populations.  These “other living donors” can be donors of organs or tissues such as reproductive HCT/Ps, HPCs, or DLI, or can be heart-beating organ donors.  The rationale is that since the blood specimens tested in the “other living donors” is the same specimen type as that extensively evaluated for blood donors (i.e., peripheral blood from a heart-beating individual), the analytical performance of the assay should be the same as is established for blood donors—even though there is no clinical data reviewed for those specific donor populations. 


On the other hand, FDA would evaluate additional clinical data specific to any particular donor population where there is consideration for pooled testing, given that pooling inherently reduces the sensitivity of a test because any positive specimens are diluted when pooled.  To date, donors of hematopoietic stem/progenitor cells (HPCs) and donor lymphocytes for infusion (DLI) are the only HCT/P donors where there are manufacturer’s instructions that would allow for pooled donor specimen testing for HBV NAT.


In today’s meeting, information will be provided to the Committee comparing the prevalence of infectious diseases among donors of HPC/DLI as compared to blood donors.  This information could be useful when considering the potential generalizability of blood donor data to that particular donor population. 


The Committee will also hear information about the difference in window period closure between ID NAT and MP NAT, as determined by data collected on blood donors.  Because the yield data used to obtain licensure for a particular NAT test is demonstrated in clinical trials utilizing blood donors, there is a lack of similar specific clinical trial data demonstrating the yield of a particular test in living HCT/P donors.  It is anticipated that the window period closure would be similar between living HCT/P donors and blood donors and that the yield for ID testing would also be similar to that in blood donors.  However, this is an area where further research would be useful.


Difficulty Assessing Yield in Cadaveric Donors


Cadaveric donor specimens are different than peripheral blood specimens from living (heart-beating) donors.  After death, there is decomposition and varying degrees of hemolysis of the blood, and this process may form “inhibitors” in the blood that interfere with test results.  The specific inhibitors that may be present have not been well studied and characterized, but this phenomenon is known to occur.  Manufacturers therefore are required to perform additional validation studies specific to cadaveric blood specimens in order to obtain an indication for cadaveric donor specimen testing in addition to an indication for blood donor testing.  To date, the validation studies performed in order to receive the cadaveric donor testing claim are comprised of spiking studies, as described in our November 2004 Guidance for Industry: Recommendations for Obtaining a Labeling Claim for Communicable Disease Donor Screening Tests Using Cadaveric Blood Specimens from Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (


During clinical trials for NAT tests on blood donors, any positive NAT result that may be determined to be a yield case (HBV NAT positive/HBsAg and anti-HBc negative) must be confirmed by follow-up testing of the donor by alternate NAT methodologies and by demonstrating seroconversion in the donor.  For obvious reasons, this type of confirmation of a yield case is not feasible in a cadaveric donor.  Confirmation of true positive screening test results in the absence of follow-up testing is another area where further research would be useful. 


It should be noted, however, that while the prevalence rate of HBV is lower among tissue donors than among the general population, the relative incidence of undetected viremia with HBV in cadaveric tissue donors is estimated to be higher than that found among first-time blood donors.1  The reasons for the increased likelihood of incident infection within the window period for detection in cadaveric donors is not fully known and is likely to have several explanations, including: 

·         donor screening must be performed by asking questions of someone other than the donor;

·         questioning a relative or significant other while bereaved may affect the accuracy of their answers; and 

·         blood donors who are provided educational materials prior to donation may self-defer while cadaveric donors cannot do so.


While the probability of collecting products from an HBV viremic cadaveric donor using current HBV donor testing methodologies is likely to be low, though not negligible, donor testing should be as sensitive as possible in the cadaveric donor population, to detect what would otherwise be unknown infections and protect public health.



Questions to the Committee:


1.         Please comment on the potential benefit of HBV NAT testing in the ID NAT format and in the small minipool format for living donors of hematopoietic stem/progenitor cells (HPCs) and DLI.


2.         Please comment on the potential benefit of HBV NAT testing in the ID NAT format for:

a) other living donors; and


b) cadaveric donors



Reference :


1.  Zou, S, et. al.  Probability of Viremia with HBV, HCV, HIV, and HTLV among Tissue Donors in the United States.  New England Journal of Medicine 2004; 351: 751-9.