ISSUE SUMMARY---TOPIC 1.

**TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES**

**ADVISORY COMMITTEE MEETING**

**June 26, 2002**

Validation of Procedures to Prevent Contamination and
Cross-Contamination with TSE Agents of Human Tissue Intended for
Transplantation

# ISSUE

FDA requests advice from TSEAC on measures for donor screening and
tissue processing that are appropriate to prevent contamination and
cross-contamination of Human Cells, Tissues, and Cellular and
Tissue-Based Products (HCT/Ps) by TSE agents, and on the design of
scientific studies to validate clearance of TSE agents in processing.

# BACKGROUND AND DISCUSSION

Classic CJD has been transmitted through the transplantation of certain
human tissues, i.e., dura mater and cornea, as well as by human
cadaveric pituitary-derived hormones. FDA is concerned about the actual
and theoretical transmission of TSE agents by transplantation of these
and other human cells, tissues, and cellular and tissue-based products
(HCT/Ps). There are at least three approaches to reduce the risk of TSE
transmission by such products. One is by careful screening of the
potential HCT/P donor for risk factors for TSEs, and for TSE disease
(including testing of the donor, if and when validated screening tests
become available) and deferral of these donors. A recently published
draft guidance for industry, focusing on donor screening
recommendations, addresses this approach. A second approach is to
control the recovery and processing of HCT/Ps so as to prevent
contamination and cross-contamination by TSE agents. A third approach
would be to introduce into the manufacture of HCT/Ps a step or steps to
remove or inactivate TSE agents. FDA is asking the TSEAC to consider
which of these approaches---donor eligibility, tissue recovery and
processing measures and controls, and/or validated TSE clearance
processes---might be appropriate to reduce the risk of contaminating or
cross contaminating HCT/Ps with TSE agents.

Iatrogenic transmission of CJD through transplantation of dura mater
allograft (currently regulated by FDA as a device) and cornea (regulated
by FDA as a "361" tissue) has been reported. There have been more than
100 cases of transmission of CJD by dura mater allografts worldwide,
including three cases in the U.S. The mean interval between receipt of
dura mater and onset of disease was 8.6 years, with the longest latent
period being 18.2 years (1). The first case was reported in 1987, in a
28-year-old woman who had received a lyophilized, irradiated human
cadaveric dura mater graft (a product never cleared by FDA), imported
into the U.S. from Germany through Canada (2). This patient died 22
months after receiving the graft. A case in New Zealand and four cases
in Spain, all involving the same brand of dura mater grafts, were
subsequently reported. A second U.S. case associated with a dura mater
graft in a 28-year-old woman was reported in 1994 (3). Before 1987, the
involved product had been prepared using a method that commingled dura
mater from many cadavers in the same container during processing. In
1998, a third U.S. case occurred in a 39-year-old woman who had received
dura mater made by a different manufacturer; that dura mater had not
been intentionally commingled (4). The donor had been inadequately
screened, and the dura had been soaked for one hour in a solution of
sodium hydroxide, but at 0.1N rather than 1.0 N as recommended by FDA.
The majority of CJD transmissions from dura mater have occurred in Japan
since 1985. Japan has recognized at least 67 cases -- almost all in
patients believed to have received dura mater made in a commingled
process (5).

Transmissions of CJD by ocular tissue have included one definite case in
the United States (6), one possible case in Japan (7), and one possible
case in Germany (8). There was concern about the potential for
transmission of CJD after the transplantation, and subsequent
explantation, of two corneas and sclera donated by a Scottish woman who
was later determined to have CJD (9). The first case, described in the
U. S. in 1974, was that of a 55-year-old woman who received a cornea
from a donor who had died of a neurological illness characterized by
ataxia, memory deficit, myoclonus, and other involuntary movements.
After the cornea was transplanted, the donor's autopsy revealed
spongiform changes consistent with CJD. The recipient became ill 18
months after transplantation, and died 8 months later; her autopsy
revealed spongiform encephalopathy consistent with CJD. The Japanese
report in 1994 was that of a 63-year-old woman who developed
neurological symptoms 15 months after receiving a cornea. She died 40
months later and had histological changes typical of CJD at autopsy;
full details about the donor were not published, but a link between her
disease and a previous corneal transplant was asserted. The German case,
published in 1997, was that of a 45-year-old woman who developed
neurological symptoms and EEG signs of CJD. She had no family history of
CJD, no genetic markers of familial CJD, and was homozygous for
methionine at codon 129 of the PRNP gene on chromosome 20. She had
received a corneal transplant thirty years earlier. Although the
pathology slides from the donor were no longer available for review, the
original medical records and necropsy reports indicated the donor had
died of CJD. No autopsy was performed on the recipient.

There is no reason to believe that there would be any less risk of
transmitting variant CJD by transplantation of dura mater and cornea. In
addition, there is some risk of transmitting both CJD and vCJD by other
tissues (10).

Under the legal authority of section 361 of the Public Health Service
Act, FDA has promulgated regulations and recommendations to prevent the
introduction, transmission and spread of communicable disease through
cell and tissue transplantation. Some of these are currently in effect,
and others have been proposed and are being finalized.

FDA regulations currently in effect address preventing transmission of
HIV, HBV, and HCV through the transplantation of human tissue by
screening and testing the potential tissue donor. Current regulations
also require that written procedures be prepared, validated, and
followed to prevent infectious disease contamination or
cross-contamination by tissue during processing (11).

Current FDA guidance recommends excluding potential donors of tissue
(musculoskeletal, ocular, integumental) who are diagnosed with sporadic
CJD or who have risk factors for iatrogenic or familial CJD. In an FDA
guidance for industry on screening and testing tissue donors (12), the
agency recommends that the donor medical history interview include
questions to defer potential donors with a diagnosis of CJD, with a
known family history of CJD, or who have received human pituitary growth
hormone or dura mater transplants. In another FDA guidance for industry
specifically about human dura mater (13), donor evaluation includes all
of the above recommendations, and in addition, FDA recommends exclusion
of donors with any degenerative or demyelinating disease of the CNS and
donors who died in a neurological/psychiatric hospital. This last
guidance also recommends performing gross and histological examination
of the brain (full autopsy) of each dura mater donor, use of processing
controls such as disinfection by a method validated to reduce CJD
infectivity, and the prohibition of batch processing.

In March 2002, FDA published a final guidance entitled "Validation of
Procedures for Processing of Human Tissues Intended for Transplantation"
(14). This guidance reminds all tissue establishments of the requirement
to prepare, validate, and follow written procedures to prevent
contamination or cross-contamination with infectious disease agents
during tissue processing, and explains that contamination may be caused
by a variety of infectious disease agents, including viruses, bacteria,
fungi, and TSE agents (TSE-associated prions). The document defines
validation and gives examples of methods to obtain validation data. FDA
now expects validation of methods used to prevent contamination and
cross-contamination of HCT/Ps with viruses, bacteria, and fungi.
Validation of methods to prevent contamination or cross-contamination by
TSE agents would be required routinely if and when such methods are
agreed upon by scientific experts and become available.

Proposed FDA regulations (15) would require screening, to include
obtaining a medical history for all potential donors regarding risk
factors and clinical evidence of relevant communicable diseases,
including HIV, HBV, HCV, and TSEs (e.g., CJD), and screening some donors
of particular cells and tissues for other relevant diseases. The
proposed regulations would also require testing the blood of all donors
for relevant communicable diseases, including HIV, HBV, HCV, and
syphilis, and testing some donors of particular cells and tissues for
other relevant diseases. Other proposed regulations (16) would define
current good tissue practices (cGTPs) and require that cGTPs be followed
during all aspects of manufacture of the cells or tissues. These
practices would include establishing and maintaining effective controls
over facilities, personnel, equipment, environment, incoming materials,
labeling, and storage, as well as process controls and validation,
record keeping, reporting of adverse reactions and product deviations,
and tracking of HCT/Ps from the donor to the recipient and vice versa.
More specifically, the proposed GTP rule states that human cells or
tissue from two or more donors shall not be pooled (placed in physical
contact or mixed in a single receptacle) during manufacture of the
HCT/P. However, the proposed rule would allow a cell or tissue
establishment to request an exemption or alternative from any GTP
requirement, provided that, after reviewing valid scientific data
submitted in the request, FDA finds that the exemption or alternative is
consistent with the goals of preventing the introduction, transmission,
and spread of communicable disease. If a request for an exemption from
the pooling prohibition were to be submitted, FDA would weigh the
potential increased risk of contamination and cross-contamination with
emerging infectious disease agents (e.g., TSE agents) against the
potential benefit of improved elimination of conventional infectious
disease agents (e.g., viruses, bacteria, or fungi) in determining
whether or not to grant the request. The donor eligibility and the GTP
proposed rules are being finalized.

In the process of developing guidance on TSE issues, FDA requests advice
on any additional measures for donor screening and tissue processing
that TSEAC considers to be appropriate. The committee might consider,
among other matters, risk assessment, including models for estimating
the risk of transmitting TSE by human tissue, the possibility of
requiring autopsy for each donor or the potential value of post-mortem
transorbital needle biopsy in situations where full brain autopsy may
not be feasible, lessons learned from batch processing of human
pituitary growth hormone, effects on risk from limiting batch size, the
value of requiring single-donor aseptic recovery and processing
techniques, specified methods of decontamination of facilities and
equipment, process validation data that are currently required by FDA
for processes used to clear conventional infectious agents, validation
data from several large tissue processors, and TSE clearance studies in
experimental models.

In deliberating these issues, the TSEAC may consider, in the context of
risk and benefit analysis, the potential effects that various FDA
policies might have not only on safety but also on supply of HCT/Ps.

## References

1.  Brown P. et al. Iatrogenic Creutzfeldt-Jakob Disease at the
    Millennium. Neurology 2000; 55:1075-81. (\***enclosed**)

2.  CDC. Rapidly progressive dementia in a patient who received a
    cadaveric dura mater graft. MMWR.1987; 36:49-50, 55.
    <http://www.cdc.gov/mmwr/preview/mmwrhtml/00000861.htm>.

3.  Lane KL, et al. Creutzfeldt-Jakob disease in a pregnant woman with
    an implanted dura mater graft. Neurosurgery 1994; 34:737-40.

4.  Hannah EL, et al. Creutzfeldt-Jakob disease after receipt of a
    previously unimplicated brand of dura mater graft. Neurology 2001;
    56:1080-3. (**\*enclosed**)

5.  Nakamura Y. Epidemiologic features of 65 Creutzfeldt-Jakob Disease
    patients with a history of cadaveric dura mater transplantation in
    Japan. Epidemiology and Infection 2000; 125:201-5.

6.  Duffy P., Wolf J., et al. Possible person-to-person transmission of
    Creutzfeldt-Jakob disease. *New England Journal of Medicine.* 1974;
    290:692-3.

7.  Uchiyama K, Ishida C, et al. An autopsy case of Creutzfeldt-Jakob
    disease associated with corneal transplantation. *Dementia*. 1994;
    8:466-73.

8.  Heckmann JG, Lang CJG, Petruch F, et al. Transmission of
    Creutzfeldt-Jakob disease via a corneal transplant. *Journal of
    Neurology, Neurosurgery & Psychiatry*. 1997; 63: 388-90.

9.  Hogan, RN; Brown, P, et al. Risk of prion disease transmission from
    ocular donor tissue transplantation. *Cornea.* 1999; 18(1): 2-11.
    (\***enclosed**)

10. Brown P, Gibbs CJ, Jr., et al. Human Spongiform Encephalopathy: The
    National Institutes of Health series of 300 cases of experimentally
    transmitted disease. Annals of Neurology 1994; 35(5):513-529.
    (\***enclosed)**

11. Human Tissue Intended for Transplantation. Final rule. 62 Federal
    Register 40429-40447; July 29, 1997.

12. Guidance for Screening and Testing of Donors of Human Tissue
    Intended for Transplantation, July 1997.

13. Guidance for the Preparation of a Premarket Notification Application
    for Processed Human Dura Mater, October 1999.

14. Guidance for Industry: Validation of Procedures for Processing of
    Human Tissues Intended for Transplantation, March 2002.
    (\***enclosed**)

> <http://www.fda.gov/cber/tissue/docs.htm>

15. Suitability of Donors of Human Cellular and Tissue-Based Products;
    Proposed Rule (64 FR 52696) September 30, 1999. (\***enclosed**)

> <http://www.fda.gov/cber/rules/suitdonor.pdf>.

16. Current Good Tissue Practice for Manufacturers of Human Cellular and
    Tissue-Based Products; Inspection and Enforcement; Proposed Rule (66
    FR 1508), January 6, 2001. (\***enclosed**)

> <http://www.fda.gov/cber/rules/gtp010801pr.htm>.

# CHARGE

FDA asks the TSEAC to evaluate the appropriateness of several measures
and controls to prevent the transmission of TSEs to the recipients of
human cells, tissues, and cellular and tissue-based products. The TSEAC
might consider whether FDA should recommend imposing donor eligibility
criteria in addition to screening potential donors for CJD, vCJD, and
risk factors for these diseases, as discussed in more detail in topic 2
below, such as setting an upper age limit for donors or excluding donors
who died of head trauma. FDA recognizes that recommending such
exclusions might seriously reduce tissue supply.

The TSEAC might also consider whether the agency should recommend that
an autopsy---or failing that, a brain biopsy validated to show that it
is predictive of an autopsy diagnosis of TSE\-\--be performed on some or
all HCT/P cadaveric donors.

In addition, FDA asks the TSEAC to consider the appropriateness of
requiring that specified methods be introduced to prevent contamination
and cross-contamination by TSE agents during recovery and processing of
HCT/Ps. Should the agency recommend or require any specific procedures
to decontaminate surfaces and instruments, or require manufacturing
steps to remove and/or inactivate TSE agents in HCT/Ps? Should
co-mingling of HCT/Ps from different donors during manufacturing ever be
permitted? If so, what controls should FDA require in assessing whether
a request for an exemption from the proposed pooling prohibition should
be granted?

Finally, FDA asks the TSEAC to comment on the design of TSE agent
clearance studies validating the effectiveness of methods to prevent
contamination and cross-contamination of HCT/Ps by TSE agents.

[QUESTIONS]{.underline}

1.  **Which of the following measures and controls is (are) appropriate
    to prevent TSE agent transmission to the recipients of human cells,
    tissues, and cellular and tissue-based products?**

    A.  Recommend additional donor eligibility criteria:

        -   Upper age limit

        -   Head trauma exclusion

        -   Negative brain autopsy or biopsy

    B.  Recommend specified methods for HCT/P recovery and/or processing
        to prevent contamination and cross-contamination:

        -   Decontamination of instruments and surfaces used for
            recovery and processing

        -   Methods for removal and/or inactivation of TSE agents from
            accidentally contaminated HCT/Ps

        -   Single-donor aseptic processing or permit pooled processing
            under certain circumstances with adequate controls

    C.  Other

2.  **Please comment on the design of a satisfactory TSE agent clearance
    study for HCT/Ps, in terms of the following criteria:**

    A.  Suitable TSE agent strains and animal models

    B.  Accept measurement of abnormal forms of prion protein alone or
        require assays for infectivity

    C.  Accept substantial reduction (how much?) or require complete
        elimination of detectable prion protein and/or infectivity

    D.  Accept a single validated method or require that more than one
        validated method for eliminating TSE agents be included in the
        study

    E.  Other