DRAFT ISSUE SUMMARIES

**TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES**

**ADVISORY COMMITTEE MEETING**

**18-19 JANUARY, 2001**

**ISSUE 2.**

**Suitability Determination for Donors of Human Cells, Tissues, and
Cellular and Tissue-Based Products: CJD and vCJD**

# ISSUE

Classic CJD has been transmitted through the transplantation of certain
tissues, i.e., dura mater and cornea. Based on known and theoretical
risks, FDA currently recommends that blood donors and donors of human
tissue intended for transplantation should be screened for classic CJD
and CJD risk factors. Additionally, blood donors are screened for
history of travel or residence in the United Kingdom as a precautionary
measure to reduce the theoretical risk for transmission of variant CJD
(vCJD) based on possible exposure to the BSE agent. The committee is
asked to consider the scientific basis for development of policies to
address the risk of transmission of vCJD by donations of human cells,
tissues and cellular and tissue-based products other than blood. \[Note:
While FDA regulates these entities, HRSA and HCFA oversee organ
transplantation.\]

[BACKGROUND AND DISCUSSION]{.underline}

Current FDA guidances contain recommendations to exclude donors of
tissue (musculoskeletal, ocular, integumental) who are diagnosed or have
risk factors for TSEs, specifically classic CJD, although current FDA
regulations for human tissue do not address TSEs (1). In an FDA guidance
to industry on screening and testing donors of human tissue intended for
transplantation (2), the agency recommends that the donor medical
history screening interview should include questions to defer potential
donors with a diagnosis of CJD, a known family history (blood relative),
or who have received human pituitary growth hormone or dura mater
transplants. In another FDA guidance to industry specifically about
human dura mater (3), donor evaluation includes all of the above, and in
addition recommends exclusion of donors diagnosed with any degenerative
or demyelinating disease of the CNS, or who died in a
neurological/psychiatric hospital. Other recommendations include gross
and histological examination of the brain (full autopsy), archiving
samples of brain and dura mater tissue for at least 10 years, performing
a validated test for PrP-RES, when available, CJD disinfection by a
method validated to reduce CJD infectivity, record keeping and tissue
tracking, consistent with medical device requirements, and prohibition
of batch processing.

Recently, the Centers for Disease Control and Prevention (CDC), together
with the Infectious Disease Society of America and the American Society
of Blood and Marrow Transplantation, published guidelines for preventing
opportunistic infections among hematopoietic stem cell transplant
recipients (4). They recommend that the medical history of the
prospective donor should include history of risk factors for classic
CJD, including any blood relative with CJD, receipt of a human
pituitary-derived growth hormone or receipt of a corneal or dura mater
graft, in addition to vCJD risk factors, including a history of
cumulative travel or residence in the UK for 6 months or more during
1980-1996 or receipt of injectable bovine insulin since 1980, unless the
product was not manufactured since 1980 from cattle in the UK. The
guidelines state that although no classic or vCJD has ever been reported
among hematopoietic stem cell transplant recipients, donors with a
history of these risk factors should be excluded from allogeneic
donation if a choice exists between two otherwise equally suitable
donors.

Voluntary industry standards contain recommendations to prevent
transmission of prion-associated diseases through transplantation of
tissues. The American Association of Tissue Banks (AATB) Standards
excludes persons with a history of dementia or degenerative neurologic
disorders of viral or unknown etiology. The Eye Bank Association of
America (EBAA) Medical Standards consider death with neurologic disease
of unestablished diagnosis as a contraindication to corneal donation.
However, none of these guidances or standards address donor deferral for
risk of vCJD, i.e., residence/travel to BSE countries.

There have been no reports of transmission of vCJD by transplantation of
human tissues. Iatrogenic transmission of classic CJD has been reported
through dura mater and cornea. The majority of dura mater transmissions
occurred from the use of one particular brand of cadaveric dura mater
graft, Lyodura, which prior to May 1987 was batch-processed, resulting
in cross-contamination (5). Transmissions of CJD by ocular tissue have
included one definitive case in the U. S. (1974), one possible case in
Japan (1994) and in Germany (1997), and the transplantation, and
subsequent explantation of two corneas and sclera from a Scottish woman
who was later determined to have CJD (6).

FDA is implementing a new proposed approach to the regulation of
cellular and tissue-based products. This tiered, risk-based approach
attempts to regulate all cells, tissues, and products containing cells
and tissues under one umbrella. These would include musculoskeletal
tissue (bone, cartilage, ligament, tendon, fascia, pericardium), ocular
tissue (cornea, sclera), skin, somatic cell and gene therapy products,
reproductive cells and tissue (semen, oocytes, embryos), hematopoietic
stem cells from peripheral blood and from placental/umbilical cord
blood, and combination products consisting of tissue and a device-like
component. These cells and tissues are obtained from living or cadaveric
donors.

The donor suitability regulations being proposed for [all]{.underline}
of these donors (7) would require

screening the donor for risk factors and clinical evidence of relevant
communicable diseases, including HIV, HBV, HCV, and TSEs (e.g., CJD).
All donors would be tested for relevant communicable disease agents,
including HIV-1, HIV-2, HBV, HCV, and syphilis. In addition, donors of
certain types of cells and tissue would be tested for HTLV-I and II,
CMV, Chlamydia and Neisseria. The proposed regulation does not mention
specific risk factors or clinical evidence---these details would be
contained in a guidance document currently under development.

Therefore, at this time, FDA is asking the TSEAC to advise them on
whether or not to recommend deferral of cell and tissue donors based
upon risk factors for vCJD, i.e., residence in or travel to BSE
countries and potential exposure to the BSE agent. Should such deferral
occur for donors of all types of cells and tissue, or, based upon
differential risks of transmission, should deferral be limited to donors
of certain types (e.g., dura mater and cornea, which have historically
transmitted classic CJD)? Since the protease-resistant prion protein in
vCJD appears to have a predilection for lymphoid tissue, should deferral
of donors of leukocyte rich cells and tissues (e.g., hematopoietic stem
cells, semen) be considered?

In November 1999, FDA published revised precautionary measures to reduce
the possible risk of transmission of vCJD by blood and blood products
(8), following the recommendations of the TSEAC, by implementing a
policy that would defer persons who have spent six months or more
cumulatively in the United Kingdom from 1980-1996 from blood donation.
(The guidance also addresses risk factors for classic CJD.) This
deferral policy for blood donors was a conservative approach, since
blood and blood products have never been reported to transmit vCJD in
humans. With this in mind, and knowing that certain tissues have indeed
transmitted classic CJD to human recipients, we ask for your
recommendations concerning cell and tissue donors and their exclusion
based upon travel/residence history.

To FDA's knowledge, states that license tissue banks (NY, FL, CA) have
not adopted any policy concerning vCJD. Although foreign governments
have taken a position regarding blood donation, they have not made
similar decisions regarding tissue donation. The one known exception is
Canada. The preamble to its proposed donor screening questionnaire for
tissue donors, developed by an Expert Working Group, discusses the
rationale, based upon risk management, for not applying a UK residence
exclusion to organ and tissue donation. Part of this decision was the
possibility of making up for the loss of blood donors by increased
recruitment methods. Such a strategy would not be feasible for organs
and tissues where there is a limited supply. It was noted that the risks
and benefits of all transplants were significantly different from blood
and blood products.

There is very little data on the effect of a UK deferral on the supply
of particular cells and tissues. A survey, similar to the one conducted
of blood donors, may provide additional information, if it were to be
conducted. The Eye Bank Association of America (EBAA) commissioned a
committee to provide an independent report on the occurrence and
transmissibility of CJD as it relates to cornea transplantation and the
impact of screening on donor supply (9).

It is unlikely that travel/residence history, or some information about
risk factors for classic CJD, for that matter, could be obtained from a
review of medical records. This type of information is more likely to be
obtained by direct questioning of the living donor, or for the cadaveric
donor, a person knowledgeable about the donor, such as the next of kin,
a relative, a household member, another individual with an affinity
relationship, or the primary treating physician. Certain states (FL, TX,
MD) have active legislative consent laws, which permit cornea retrieval
without the consent of the next of kin. In these states, approximately
50% of all corneas recovered are procured in this manner, whereas
nationwide, the number is 5-10% of all corneas recovered. These states
might experience local shortages of corneal grafts if FDA were to
require a donor medical history interview in order to obtain information
about risk factors for CJD and vCJD. According to the 1999 EBAA
Statistical Report, the total number of corneal grafts has increased by
1% and the number of grafts exported internationally has increased by
31% since 1998.

[REFERENCES]{.underline}

1.  [Human Tissue Intended for Transplantation. FDA Final rule. 62
    Federal Register 40429, July 29, 1997](../3681b1_02_01.htm).
    [txt](../3681b1_02_01.htm)

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2.  [FDA Guidance for Industry: Screening and Testing of Donors of Human
    Tissue Intended for Transplantation. July
    1997](http://www.fda.gov/cber/gdlns/tissue2.pdf)
    [txt](http://www.fda.gov/cber/gdlns/tissue2.txt)

3.  [FDA Guidance for Industry and/or for FDA Reviewers/Staff and/or
    Compliance: Guidance for the Preparation of a Premarket Notification
    Application for Processed Human Dura Mater. July 31,
    1999](http://www.fda.gov/cdrh/ode/054.html).

4.  MMWR 2000; 49(No. RR-10): 1-128. Guidelines for Preventing
    Opportunistic Infections Among Hematopoietic Stem Cell Transplant
    Recipients.

5.  MMWR 1997; 46(No. 45): 1066-1069. Creutzfeldt-Jakob Disease
    Associated with Cadaveric Dura Mater Grafts---Japan, January
    1979-May 1996.

6.  Hogan NR, Brown P, Heck E, Cavanaugh HD. Risk of Prion Disease
    Transmission from Ocular Donor Tissue Transplantation. Cornea. 1999.
    18(1): 2-11.

7.  [Suitability Determination for Donors of Human Cellular and
    Tissue-Based Products. FDA Proposed rule. 65 Federal Register 52696.
    Sept. 30, 1999](http://www.fda.gov/OHRMS/DOCKETS/98fr/093099a.pdf).
    [txt](http://www.fda.gov/OHRMS/DOCKETS/98fr/093099a.txt)

8.  [FDA Guidance for Industry: Revised Precautionary Measures to Reduce
    the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD)
    and New Variant Creutzfeldt-Jakob Disease (nvCJD) by Blood and Blood
    Products. November
    1999.](http://www.fda.gov/OHRMS/DOCKETS/98fr/970318g3.pdf)

9.  Kennedy RH, et al. Summary Report by Committee on Prion Disease,
    commissioned by EBAA, January 27, 2000.

[CHARGE]{.underline}

FDA asks the TSEAC to evaluate the risk of transmission of vCJD through
the transplantation, implantation, infusion, or transfer of human cells,
tissues, and cellular and tissue-based products, and compare this risk
to that of the transfusion of blood and blood products, for which
precautionary measures have already been adopted. Based upon this
evaluation, and considering the potential effect on supply, the
committee is asked to recommend whether FDA should defer donors of these
cells and tissues who have possibly been exposed to the BSE agent
through residence in or travel to BSE countries.

In addition, the TSEAC is asked to consider how information about
residence/travel history can best be obtained. This is particularly
relevant to the situation, in which corneas are procured under
legislative consent. This term relates to state laws that allow the
medical examiner or coroner to procure corneal tissue in the absence of
consent of the donor's next of kin, and hence, in the absence of a donor
medical history interview with the next of kin.

[QUESTIONS]{.underline}

1.  Compared to the risk of transmission of variant CJD by blood
    transfusion, is there a significant risk of transmission of vCJD
    from human cells, tissues, and cellular and tissue-based products
    that are transplanted, implanted, infused, or transferred?

> \--What are the relative risks for different cells and tissues?

2.  The committee has previously assessed the risk of transmission of
    vCJD by blood, and has made recommendations accordingly. Based upon
    the committee's assessment of the risk of transmission of vCJD by
    human cells and tissue, and considering the potential impact on
    supply, should FDA recommend donor deferral criteria for possible
    exposure to the BSE agent?

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A.  If no, are there additional data that should be gathered that might
    alter this decision?

B.  If yes, what deferral criteria should FDA recommend:

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i.  Exclusion only for certain types of cells and tissues (which ones?)

ii. UK only? UK and France? Other BSE countries (which ones?)

iii. Time period of exposure---limit to 1980-1996

iv. Duration of exposure---limit to 6 months cumulative exposure?

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3.  If a deferral policy were to be put into place, how can information
    about the donor's risk factors for CJD and vCJD be obtained---is a
    donor medical history interview required?

> \--Currently, several states permit the recovery of corneas under
> legislative consent, whereby an interview with the next of kin may not
> take place. Should FDA require an interview for [all]{.underline}
> cornea donors?