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Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)
Martha A. Wells, MPH, RAC
Division of Human Tissues
Office of Cellular, Tissue and Gene Therapies

martha.wells@fda.hhs.gov
American Association of Bioanalysts Annual Meeting
College of Reproductive Biology Symposium
May 17, 2007, Orlando, FL

Donor Eligibility (DE) Guidance

  • Finalization
  • Significant Changes
  • Items that have been changed
  • Donor screening criteria
  • Donor tests
  • Reproductive donor specific information
  • Ineligible donor utilization

Abbreviations

  • HIV = Human Immunodeficiency Virus
  • HBV = Hepatitis B Virus
  • HCV = Hepatitis C Virus
  • HTLV = Human T-lymphotrophic virus
  • CMV = Cytomegalovirus
  • §= Section (of the rule) ex. §1271.3
  • TSE=Transmissible Spongiform Encephalopathy
  • CJD = Creutzfeldt-Jakob disease (vCJD=variant)
  • NAT = Nucleic Acid Amplification Technology or “Nucleic Acid Test”—Polymerase Chain Reaction (PCR) and Transcription-Mediated Amplification (TMA)


DE Guidance

  • Published February 27, 2007
  • Implementation not later than 6 months after issuance
  • Finalizes both
    • Draft DE guidance dated May 2004
    • Draft CJD/vCJD guidance dated June 2002
  • FDA received comments to both draft guidances and considered those comments when finalizing the combined guidance document
  • Guidance is considered FDA’s current thinking
  • You may use an alternative approach if it adequately and appropriately reduces risk
    • Approach should be as stringent as FDA’s recommendation

Significant Changes

  • Finalizes new Relevant Communicable Disease Agent or Diseases (RCDADs) added in draft guidance
    • Vaccinia (smallpox vaccine), West Nile Virus (WNV), Sepsis
    • SARS removed from list of RCDADs
  • Clarifies requirements for testing labs
    • Registration
  • Clarifies relevant medical records
  • Updates many donor screening criteria

Significant Changes

  • Clarifies what screening criteria in the clinical evidence or physical evidence may be reviewed in light of other information obtained about the donor
  • Finalizes current list of specific donor tests that FDA believes are adequate and appropriate to reduce the risk of transmission of relevant communicable diseases under 1271.80(a) and 1271.85(a)
  • Recommend reviewing the guidance in detail

Who Makes the DE Determination?

  • A responsible person must determine and document the donor’s eligibility (§ 1271.50(a))
  • Responsible person is a person who is authorized to perform designated functions for which he or she is trained or qualified (§ 1271.3(t))
  • Responsible person should have appropriate medical training and adequate knowledge of relevant Federal regulations and guidance

New Relevant Communicable Disease Agent or Diseases (RCDADs)

  • West Nile Virus (WNV)
  • Sepsis
  • Vaccinia
  • SARS was not included
  • Guidance provides information about how each new RCDAD meets § 1271.3(r)(2) definition of RCDAD and how you should screen for these
  • Appendix provides further information

Departure from Procedures

  • Departure – intended change from established procedures that occurs prior to HCT/P distribution and is consistent with applicable regulations and standards
  • Departures must be recorded and justified at the time a departure occurs; before distributing HCT/Ps under the departure, a responsible person must determine that the departure did not increase the risk of communicable disease transmission (§ 1271.47(d))
  • Example of departure: use of a different manufacturer’s reagents because usual reagents are not available at a recovery site

Summary of Records Includes

  1. Statement that communicable disease testing was performed by lab that is either CLIA certified or meets equivalent requirements as determined by CMS
  2. Listing & interpretation of results of all tests performed for RCDADS, and, if applicable, for CMV
  3. Name and address of establishment making DE determination
  4. Statement noting reason for determination of donor ineligibility based on screening, when HCT/P released under § 1271.65 (for allogeneic use in a first- or second-degree blood relative, directed repro, urgent medical need)
  • Note that for donors with multiple CMV results who have seroconverted, you may either indicate a positive test result or provide information about all test results

Summary of Records

  • Accompanies HCT/P when placed into distribution, including when the distribution occurs within one facility
  • Once the consignee receives the summary of records, it is not necessary for the records to physically accompany the HCT/P to the bedside as long as the records are available for review by medical personnel needing to access those records in order to provide patient care
  • Summary of Records may be made electronically accessible as long as they are in compliance with § 1271.55(c) (specifically, deletion of donor’s personal information)

Shipping HCT/Ps in Quarantine

  • Identify the donor (e.g., by a distinct identification code if it is an anonymous donor affixed to the HCT/P container);
  • State that the donor-eligibility determination is not complete; and
  • State that the HCT/P must not be implanted, transplanted, infused, or transferred until the donor-eligibility determination is complete, except in cases of urgent medical need under § 1271.60(d)

Relevant Medical Records

Under § 1271.75(a) donor screening includes review of relevant medical records:

  • Current donor medical history interview
  • Current report of physical examination for living donors
  • Other available records

Relevant Medical Records

Donor Medical History Interview

  • Documented dialogue (§ 1271.3(n)) concerning donor’s medical history and relevant social behavior
  • May take place in person or over the phone
  • If questionnaire is self-administered, in order to be a documented dialogue, the interviewer should review and verify the answers with the individual who filled out the form

Relevant Medical Records

  • Physical assessment – non-living donor
  • Physical examination – living donor
    • May examine only those parts of the body that are necessary to evaluate for RCDADs based on relevant donor history obtained during the interview and review of available records
    • You may rely on records of recent report of a physical examination by a health care professional

Relevant Medical Records

Other records (if available)

  • Lab test results (other than results required for DE determination)
  • Medical records
  • Available means that record or information exists or is pending, can be obtained through due diligence, within a reasonable amount of time

Risk Factors or Conditions

Except as noted, you should determine to be ineligible any potential donor who exhibits one or more of the following conditions or behaviors:

  • Men who have had sex with another man in the preceding 5 years
  • Persons who injected drugs for a non-medical reason in the preceding years, including IV, IM or subcutaneous injections
  • Persons with hemophilia who received human-derived clotting factor concentrates in the previous 5 years

Risk Factors or Conditions

  • Persons who engaged in sex in exchange for money or drugs in preceding 5 years
  • Persons who have had sex in preceding 12 months with any person previously described or with a person who has HIV infection, HBV infection, or clinically active HCV infection
  • Persons exposed in previous 12 months to known or suspected HIV, HBV, and/or HCV-infected blood through percutaneous inoculation (needle-stick) or contact with open wound, non-intact skin, or mucous membrane

Risk Factors or Conditions

  • Children born to mothers with or at risk for HIV infection
    • If 18 months of age or younger; or
    • If breast-fed within previous 12 mos.
  • Persons who have been in juvenile detention, lock up, jail or prison > 72 consecutive hours in preceding 12 months
  • Persons who lived with (resided in same dwelling) another person who has HBV or clinically active HCV in preceding 12 mos.

Risk Factors or Conditions

Persons who have

  • Undergone tattooing, ear piercing or body piercing in preceding 12 mos, in which sterile procedures were not used
  • Had past diagnosis of clinical, symptomatic viral hepatitis after their 11th birthday, unless evidence from the time of illness documents that the hepatitis was identified as being caused by hepatitis A virus, EBV, or CMV

Risk Factors or Conditions

  • Persons who are deceased and have a documented medical diagnosis of sepsis or have documented clinical evidence consistent with sepsis that is not explained by other clinical conditions at the time of death
    • N/A for reproductive donors
  • Vaccinia deferrals described in detail in guidance - based on time of vaccination or exposure to vaccinee and development of lesions

Risk Factors or Conditions

Persons who have

  • Medical diagnosis or suspicion of WNV infection (based on symptoms and/or lab results, or confirmed WNV viremia) should be deferred 120 days following diagnosis or onset of illness, whichever is later
  • Tested positive/reactive for WNV using FDA-licensed or investigational WNV NAT donor screening test in preceding 120 days

Risk Factors or Conditions

  • Reproductive HCT/P donors who have been treated for or had chlamydia or gonorrhea in preceding 12 months.
  • Note: persons who have been treated for chlamydia or gonorrhea infection may be eligible if evidence is presented that the treatment occurred more than 12 months ago and was successful
  • Donors treated for or had syphilis within the preceding 12 months – can be determined eligible as above

Risk Factors or Conditions

  • CJD/vCJD screening questions – if person interviewed is not familiar with the term Creutzfeldt-Jakob Disease or variant CJD you may try to describe in layman’s terms.
  • If the person being interviewed is still not familiar with those terms, you may consider the lack of familiarity with those terms as a negative response to questions using those terms

Risk Factors or Conditions

  • Persons who have been diagnosed with vCJD or any other form of CJD
  • Persons diagnosed with dementia or any degenerative or demyelinating disease of the central nervous system or other neurological disease of unknown etiology

Risk Factors or Conditions

Further evaluation of delirium and dementia:

  • Delirium, for example caused by toxic/metabolic disease or recent head trauma, would not necessarily be considered dementia and should be evaluated by the medical director
  • Donors with dementia who are confirmed by gross and microscopic evaluation of the brain to be caused by a cerebral-vascular accident or brain tumor and confirmed not to have evidence of TSE on micro exam of the brain may be acceptable based on evaluation by the medical director
    • N/A for reproductive donors

Risk Factors or Conditions

  • Persons who are at increased risk for CJD
    • Received non-synthetic dura mater
    • Received human pituitary derived growth hormone
  • >/= 1 blood relative diagnosed with CJD
    • Persons with a history of CJD in blood relative unless:
    • Diagnosis subsequently found incorrect
    • CJD was iatrogenic –transmitted surgically
    • Lab testing (gene sequencing) shows donor does not have mutation associated with familial CJD

Risk Factors or Conditions

  • Persons who spent 3 months or more cumulatively in the UK between 1980 through the end of 1996
  • Military or related personnel who resided at US military bases in Northern Europe for 6 months or more cumulatively from 1980-1990; or elsewhere in Europe for 6 months or more cumulatively between 1980-1996
  • Persons who spent 5 years or more cumulatively in Europe from 1980 until the present (including time spent in the UK between 1980-1996)

Risk Factors or Conditions

  • List of BSE-affected European countries applicable to donor deferral
    • Albania, Austria, Belgium, Bosnia-Herzegovina, Bulgaria, Croatia, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Liechtenstein, Luxembourg, Macedonia, Netherlands, Norway, Poland, Portugal, Romania, Slovak Republic, Slovenia, Spain, Sweden, Switzerland, United Kingdom1, and Yugoslavia.
    • For purposes of this guidance, the United Kingdom should include all of the following: England, Northern Ireland, Scotland, Wales, the Isle of Man, the Channel Islands, Gibraltar, and the Falkland Islands
  • Persons who received any transfusion of blood or blood components in the UK or France between 1980 and the present

Risk Factors or Conditions

  • Persons or their sexual partners who were born or lived in certain countries in Africa after 1977 (HIV group O)
    • Cameroon, Central African Republic, Chad, Congo, Equatorial Guinea, Gabon, Niger, or Nigeria
  • Persons who have received a blood transfusion or any medical treatment involving blood after 1977 in those same African countries (HIV group O)
  • Establishments utilizing an HIV antibody test that has been approved or licensed by FDA for detection of HIV group O viruses may delete the screening questions for HIV group O from their screening procedures

Risk Factors or Conditions

  • Xenotransplantation product recipients or intimate contacts of a xenotransplantation product recipient
    • Xenotransplantation products include live cells, tissue, or organs from a nonhuman animal source or human body fluids, cells, tissue, or those (including human body fluids that have had ex-vivo non-human contact (co-culture of embryos)
    • Persons who share housing or are casual contacts (hugging or kissing without the exchange of saliva) are not considered intimate contacts

Clinical Evidence

  • Except as noted in the guidance, you should determine to be ineligible any potential donor who exhibits one or more of examples of clinical evidence of RCDADs
    • Example: do not defer a donor where elevated ALT/AST tests are determined to have a cause other than viral hepatitis
  • Determined by review of relevant medical records- including a physical examination of a living donor
  • You may rely on records of a recent report of a physical examination by other health professionals
  • Review records for signs that may indicate high-risk behavior for or infection with a RCDAD

Clinical Evidence

  • For a living donor, the physical examination may include only those parts of the body that are necessary to evaluate for RCDADs based upon relevant donor history that has been obtained during the interview and review of available records
  • Some examples of physical evidence discussed in the guidance are not specific for HIV, Hepatitis, syphilis or vaccinia but are indications of high-risk behavior associated with these diseases and would increase the donor’s relevant communicable disease risk

Evaluate Records for Clinical Evidence for

  • HIV infection
  • Viral hepatitis infection
  • Syphilis, Chlamydia trachomatis, or Neisseria gonorrhea infection
  • Other sexually transmitted diseases – genital ulcerative disease, herpes simplex, chancroid
  • Vaccinia infection
  • WNV infection
  • Sepsis
  • HTLV infection

Examples of Physical Evidence

  • Nonmedical percutaneous drug use such as needle tracks; examination should specifically include examination of tattoos, which might be covering needle tracks
  • Recent tattooing, ear piercing, or body piercing in the preceding 12 months, in which sterile procedures were not used or instruments that have not been sterilized between uses were used (consistent with risk factors)

Requirements Applicable to Laboratories Performing Donor Testing for RCDADs

  • Establishment registration and HCT/P listing with FDA (under § 1271.1) using Form 3356
  • Under § 1271.55(d), maintain documentation of results and interpretation of all testing for at least 10 years after performing the test
  • Other applicable sections of current good tissues practices requirements may apply such as:
    • HCT/P deviation reporting, complaint files
    • Quality program
    • Facilities, equipment, supplies

Donor Testing Labs Continued

  • Use appropriate FDA licensed, approved or cleared donor screening tests, if such tests are available, according to manufacturer’s instructions
  • Use donor screening tests specifically labeled for use with cadaveric specimens instead of one more generally labeled if applicable and available
    • N/A for reproductive donors
  • Clinical Laboratory Improvement Act certified or meet Centers for Medicare and Medicaid Services equivalent requirements

General Testing Issues

  • Use appropriate FDA-licensed, approved, or cleared donor screening tests
  • Test according to the manufacturer’s instructions in the test kit’s package insert
  • Use tests to adequately and appropriately reduce the risk of transmission of RCDADs
  • Tests that FDA considers to meet the requirements of § 1271.80(c) are listed in the guidance and will be covered in this talk

General Testing Issues

General Testing Issues

  • Specimen collection - § 1271.80(b) requirement for specimens to be collected within 7 days before or after recovery of HCT/Ps (with some exceptions)
  • Peripheral blood stem/progenitor cell and bone marrow donors – specimen collection up to 30 days prior to HCT/P collection because of myeloablation of recipient
  • Oocyte donor – specimen collection up to 30 days prior because of hormonal stimulation of donor

General Testing Issues

  • Interpreting test results
    • Too many different testing algorithms to provide guidance; follow the package insert instructions
  • When should testing be performed once the specimen is collected
    • Should follow package insert instructions (some have time limits on how long after collection specimens can be tested) and
    • If no time limits are mentioned, we recommend testing as soon as possible after collection

Testing

Tests that we currently consider to meet the requirements in §1271.80(c) to adequately and appropriately reduce the risk of transmission of RCDADs

  • 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;
    • Establishments not utilizing an FDA-licensed screening test that tests for group O must defer donors at risk for HIV group O infection (as described in section IV.E.30. and 31. of the guidance)

Testing

  • HIV, type 2
    • FDA-licensed screening test either for anti-HIV-2 or
    • Combination test for anti-HIV-1 and anti-HIV-2
  • 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)
  • HCV
    • FDA-licensed screening test for anti-HCV; and
    • FDA-licensed screening NAT test for HCV, or combination NAT)

Syphilis Testing

Treponema pallidum (FDA-cleared screening test)

  • Under §1271.80(d)(1), you may determine to be eligible a donor whose specimen tests reactive (or positive) on a screening test for syphilis and
  • Negative or nonreactive on a confirmatory test (e.g., fluorescent treponemal antibody with absorption test (FTA-ABS),
    • So long as all other required testing and screening are negative or nonreactive.

Syphilis Testing

  • A donor whose specimen tests positive or reactive on a confirmatory test is not eligible
  • Guidance gives additional information about syphilis testing helpful for interpreting results
  • Pre-amendment devices (tests) marketed for use in donor screening for syphilis, that have not been FDA-cleared, are acceptable

Testing Viable, Leukocyte-rich HCT/Ps

  • Human T-lymphotropic virus, types I and II
    • FDA-licensed screening test for anti-HTLV I/II
  • Cytomegalovirus
    • FDA-cleared screening test for anti-CMV (total IgG and IgM)
    • CMV is not a RCDAD (must test but donors who test positive or reactive are not necessarily ineligible to donate
    • Must establish and maintain an SOP regarding distribution of HCT/Ps where test is positive
    • Include SOP on how test result is communicated to the physician responsible for accepting the HCT/P (in summary of records)

Testing Viable, Leukocyte-rich HCT/Ps

  • Examples of viable, leukocyte-rich cells or tissue include, but are not limited to:
    • Hematopoietic stem/progenitor cells
    • Semen
  • Though an embryo is not considered leukocyte-rich
    • When embryo is intended for use in an individual who is not a sexually intimate partner,
    • The semen donor should be tested for HTLV types I and II and for CMV

Additional Testing for Donors of Reproductive HCT/Ps

  • You must test donors of reproductive HCT/Ps (who are not sexually intimate partners) for evidence of infection due to relevant genitourinary disease agents (§ 1271.85(c)). These include:
  • Chlamydia trachomatis; and
  • Neisseria gonorrhea.

Testing Donors of Reproductive HCT/Ps

  • Currently, there are no FDA-licensed, cleared or approved donor screening tests for chlamydia or gonorrhea
  • FDA recommends Chlamydia trachomatis and Neisseria gonorrhea diagnostic tests utilizing NAT technology to adequately and appropriately reduce the risk of infectious disease transmission

Testing Donors of Reproductive HCT/Ps

  • If the reproductive cells or tissue are recovered by a method that ensures freedom from contamination of the cells or tissue by infectious disease organisms that may be present in the genitourinary tract, then tests for Chlamydia trachomatis and Neisseria gonorrhea are not required (§ 1271.85(c)).
  • However, if these tests are performed and one or both results are reactive, the donor must be determined ineligible, regardless of the recovery method used (§ 1271.80(d)(1)).

Other Reproductive Donor Specific Information

  • Anonymous semen donors
    • 6 month quarantine and rescreen/retest required
    • Repeat testing if CMV positive not necessary, though information should be in summary of records
    • If discontinues donation, should wait at least 6 months and retest/screen except can use results of Chlamydia and Neisseria tests obtained at the final donation as the test of record
  • Directed semen donors
    • No quarantine and retest required
    • My elect to do so if specimens frozen for later use and performing testing within 7 days is not an option.

Other Reproductive Donor Specific Information

  • Gestational carrier/Surrogate
    • Not considered donors – are recipients
    • No required testing or screening
    • Guidance provide several specific scenarios for testing and screening donors utilized for a procedure involving a gestational carrier or surrogate
    • Will discuss more in next talk

Exceptions from DE Determination

  • There are five situations in which you are not required to make a determination of donor eligibility or to perform donor screening and testing (§ 1271.90(a) and §1271.15(a))
  • You must apply special labels if you do not screen and test (§ 1271.90(b))
    • If it is not physically possible (too small or frozen) to affix labels to the HCT/P container then labels may accompany the HCT/P
  • Will discuss reproductive HCT/P exceptions/labeling in more detail in next talk

Ineligible Donors

Under §1271.65(b), an HCT/P from an ineligible donor, based on required testing and/or screening results, is not prohibited from use for implantation, transplantation, or transfer in the following three circumstances:

  1. The HCT/P is for allogeneic use in a first-degree or second-degree blood relative
  2. The HCT/P consists of reproductive cells or tissue from a directed reproductive donor
  3. There is an urgent medical need for the HCT/P based upon a physician’s request and documented by the establishment
    • DE determination must be performed
    • Labeling requirements apply
    • Manufacturer must document that the physician using the HCT/P was notified of results of screening & testing

Ineligible Donors

The nonclinical use of HCT/Ps from a donor determined to be ineligible is not prohibited, so long as the HCT/Ps are labeled “For Nonclinical Use Only” and with a biohazard legend (§ 1271.65(c))

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Updated: August 9, 2007