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December 23, 2002

Dockets Management Branch (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 20852

Re: Docket \# 02D-0266

Dear Sir or Madam:

The American Academy of Ophthalmology (AAO) is providing these comments
in response to the FDA's draft *"Guidance for Industry: Preventive
Measures to Reduce the Possible Risk of Transmission of
Creutzfeldt-Jakob Disease (CJD and Variant Creutzfeldt-Jakob Disease
(vCJD) by Human Cells, Tissues, and Cellular and Tissue-Based Products
(HCT/Ps)"* \[1\]. The AAO is the largest national membership association
of ophthalmologists, medical doctors who provide comprehensive eye care,
including medical, surgical and optical care. More than 90 percent of
practicing U.S. ophthalmologists are Academy members. The mission of the
American Academy of Ophthalmology is to advance the lifelong learning
and professional interests of ophthalmologists to ensure that the public
can obtain the best possible eye care. The AAO places the benefit of our
patients and the public health foremost in considering the effects of
the proposed Guidance for Industry.

**Basis for Development of Deferral Guidelines**

In formulating new donor exclusionary criteria, both risk-benefit and
cost-benefit analyses must be performed to derive the greatest positive
impact on public health. These must include the significant positive
effect that corneal transplantation has on the quality of life for the
tens of thousands of blind Americans whose sight is restored through
corneal transplantation every year. The AAO is concerned that some of
the exclusionary criteria listed in the draft guidance document will
have a significant negative impact on the availability of corneal tissue
without increasing the safety of the donor pool.

The AAO supports formulation of guidelines based on the precautionary
principle: If there are means for reducing risk, they should be
implemented. However, the perception that the safety of the tissue is
increased by imposing more restrictive exclusionary criteria does not
reflect the reality that many of the proposed guidelines will do nothing
to increase the safety of the tissue. They will only exclude donors,
decreasing the availability of corneas for human transplantation. Some
of the deferral criteria proposed in the Guidance for Industry document
lack a sound scientific basis. The Transmissible Spongiform
Encephalopathies Advisory Committee (TSEAC) has thus far declined to
recommend specific donor exclusionary criteria because of the lack of
information about transmission of CJD and vCJD by cornea and other
tissues and their potential effect on the donor pool \[2\]. Further,
many of the draft criteria are derived from processes that apply to
blood donation. Cornea procurement is fundamentally different from the
blood donation process. The effect on the blood supply from deferral of
a blood donor can be recouped by the large pool of remaining donors who
can repeatedly donate. Cornea donors are one-time, cadaveric donors. A
cornea donor deferral can not be recouped.

In 2001, approximately 46,000 corneas were provided for transplantation
by United States eye banks \[3\]. Due to strict eye banking medical
standards and exclusionary criteria, over twice that many donor corneas
were procured in order to provide the tissue for these procedures. The
future supply of corneal tissue is uncertain, given the increasing
prevalence of LASIK surgery, which renders the cornea unsuitable for
transplantation.

**Risk Under Current Regulations/Standards Is Extremely Low**

While the AAO recognizes the potential for transmission of prion disease
via human tissues, there has only been one confirmed case of CJD
transmission via corneal transplantation reported in the medical
literature \[4\]. This case occurred in an era preceding the institution
of eye banking medical standards (in 1980) and arose from tissue that
was not procured by an eye bank. Currently, Eye Bank Association of
America (EBAA) medical standards \[5\] exclude use of tissue for human
transplantation from donors that have a history suggestive of a
potential for increased risk of CJD or transmissible encephalitis. These
exclusionary criteria include:

-   Death of unknown cause

-   Death with neurological disease of unestablished diagnosis

-   Dementia, unless due to cerebrovascular disease, brain tumor, or
    head trauma. Donors with toxic- or metabolic-induced dementia may be
    acceptable only if approved on a case by case basis by the eye
    bank's Medical Director after consultation.

-   Subacute sclerosing panencephalitis

-   Progressive multifocal leukoencephalopathy

-   Congenital rubella

-   Reyes syndrome

-   Active viral encephalitis or encephalitis of unknown origin or
    progressive encephalopathy

-   Rabies

-   Recipients of human pituitary-derived growth hormone (pit-hGH)
    during the years from 1963-1985

-   Recipients of non-synthetic dura mater grafts

The risk of a corneal donor with CJD appearing in the donor pool prior
to screening is 0.045 cases per year in the United States \[6\]. Any
donor with an established diagnosis of CJD or dementia due to prion
disease should be excluded by the above criteria. Further, there have
been no reported cases of CJD or vCJD transmission via corneal
transplant in the 28 years since the initial report in 1974.

Valid Additions to the Exclusionary Criteria

Despite the extremely low prevalence of CJD (one per million) and vCJD
(one known case) in the United States, concern for the potential
introduction of the prion agent into the donor pool is warranted under
the precautionary principle. The AAO therefore supports the draft
guidelines proposing ineligibility of any donor who:

-   Has been diagnosed with vCJD or any other form of CJD;

-   Is at increased risk for CJD; (Donors are considered to be at
    increased risk for CJD if they have received a dura mater
    transplant, human pituitary-derived growth hormone, or have one or
    more blood relatives diagnosed with CJD.)

**Screening for Travel Abroad**

The following exclusionary criteria are troubling, as they will
disqualify a large number of donors without decreasing risk:

-   Spent three months or more cumulatively in the U.K. from the
    beginning of 1980 through the end of 1996;

-   Is a current or former U.S. military member, civilian military
    employee, or dependent of a military member or civilian employee who
    resided at U.S. military bases in Northern Europe (Germany, U.K.,
    Belgium, and the Netherlands) for 6 months or more from 1980 through
    1990, or elsewhere in Europe (Greece, Turkey, Spain, Portugal, and
    Italy) for 6 months or more from 1980 through 1996;

-   Lived cumulatively for 5 years or more in Europe from 1980 until the
    present

We posit that these criteria would exclude a significant number of
corneal donors, even when the travel history is clear. The EBAA is
currently conducting a survey of eye banks at the FDA's request to
determine the magnitude of this problem. Further, it is likely to be
difficult or impossible to obtain complete information regarding dates
and cumulative lengths of stay in Europe. Unlike blood donors, cornea
donors are all cadaveric. A medical and social history must be obtained
from family members or significant others rather than directly from the
donor. If donors whose family members are uncertain about the details of
the donor's travel history are deferred, we would expect an even larger
number of donors to be eliminated. Given that there has been only one
case of vCJD reported in the United States, these deferrals will not
decrease risk. We are aware that other regulatory agencies have
different policies. Canada, for example, considered this issue and
decided not to defer donors based on residency in the U.K. or other
high-risk countries.

**Brain Biopsy Requirement Lacks Scientific Basis**

We have specific objections to some of the following exclusionary
criteria, as they lack a scientific basis and would exclude a large
number of donors:

-   You should determine to be ineligible any donor who has been
    diagnosed with dementia or any degenerative or demyelinating disease
    of the central nervous system (CNS) or other neurological disease of
    unknown etiology; (HCT/Ps from donors with dementia confirmed by
    gross and microscopic examination of the brain to be caused by
    cerebrovascular accident, brain tumor, head trauma, or
    toxic/metabolic dementia and who are confirmed not to have evidence
    of TSE on microscopic examination of the brain may be acceptable
    based on an evaluation by the Medical Director.)

We agree with excluding donors who have been diagnosed with dementia or
any degenerative or demyelinating disease of the CNS or other
neurological disease of unknown etiology. However, the requirement for
gross and microscopic examination of the brain to confirm one of the
more specific diagnoses and to rule out evidence of TSE would eliminate
a large percentage of the donor pool without significantly reducing the
risk of transmission of disease. Since corneal tissue must be
transplanted quickly, before the results of a brain biopsy can be
obtained, the requirement of a brain biopsy would eliminate all of these
cases as potential donors. The results of an FDA-requested survey of
EBAA member eye banks to determine the impact on the donor pool is
currently pending. However, we believe this requirement would
significantly reduce the number of surgically transplantable donor
corneas. Alternative biopsy techniques, such as transorbital sampling,
may be faster, but are not sensitive enough to reliably detect prion
disease, and would therefore increase costs without increasing the
safety of the tissue.

Further, the diagnosis of dementia due to cerebrovascular accident,
brain tumor, head trauma, or toxic/metabolic dementia is made with a
high degree of specificity and sensitivity based on clinical grounds and
supporting clinical laboratory and neuroimaging data. Gross and
microscopic examination of the brain is not necessary to confirm these
diagnoses. Given the extremely low incidence of CJD in the U.S.
population, brain biopsy to exclude findings of TSE is unlikely to
detect any cases in donors with known other etiologies for dementia.
According to a study co-authored by Paul Brown, M.D., former Chair of
the TSEAC, it is more likely for a donor with preclinical prion disease
to pass the exclusionary criteria for dementia than it is for a donor to
have concurrent prion disease plus dementia due to one of the above
cited etiologies \[7\]. Even if brain biopsy were performed on every
donor, its sensitivity for detection of prion disease in preclinical
cases is unknown. Requiring a brain biopsy on every donor would,
however, eliminate the risk of disease transmission by completely
eliminating the availability of any viable corneal tissue due to the
delay inherent in the test procedure. Consider also that brain biopsy is
not required in other jurisdictions, such as the United Kingdom and
Canada.

We recommend that these exclusionary criteria be amended to read as
follows:

-   "You should determine to be ineligible any donor who has been
    diagnosed with dementia or any degenerative or demyelinating disease
    of the central nervous system (CNS) or other neurological disease of
    unknown etiology; (HCT/Ps from donors with dementia confirmed by
    ~~gross and microscopic examination of the brain~~ **[clinical,
    laboratory, and/or neuroimaging criteria]{.underline}** to be caused
    by cerebrovascular accident, brain tumor, head trauma, or
    toxic/metabolic dementia ~~and who are confirmed not to have
    evidence of TSE on microscopic examination of the brain~~ may be
    acceptable based on an evaluation by the Medical Director.)"

**Recipients of U.K. Blood or Blood Components**

There is not an adequate scientific basis for excluding donors who
*"received any transfusion of blood or blood components in the U.K.
between 1980 and the present."* As noted in the FDA draft guidance
document, there have been no known cases of CJD or vCJD transmission to
humans via blood transfusion. At least 20 individuals in the U.K. have
received blood or blood components from donors who later developed vCJD,
with no cases of transmission to date \[8\]. Further, in the U.K.,
recipients of blood or blood components, other than clotting agents, are
not excluded as corneal donors. The possibility of transmission via
blood or blood products in humans or primates remains only theoretical.
Blood or blood products have not been demonstrated to be vehicles for
transmission \[9\]. Therefore, it is premature to exclude donors who
have received blood or blood products in the U.K. We would expect that
this criteria would exclude a significant number of otherwise acceptable
donors. When available, the results of the EBAA CJD high risk survey of
member banks will more accurately quantify the impact of this exclusion.
We recommend the elimination of this criterion.

**Insulin Users**

The exclusion of donors who have *"injected bovine insulin since 1980,
unless you can confirm that the product was not manufactured after 1980
from cattle in the U.K"* is based on theoretical precepts alone, with no
evidence that it would reduce the risk of vCJD transmission. There is no
scientific evidence that prion disease can be transmitted via injection
of bovine-derived insulin. As noted in the draft guidance document: *"No
cases of transmission of vCJD have been reported in recipients of bovine
insulin or other injectable products manufactured in BSE-countries."*

Further, this exclusion would have a major impact on the donor pool. An
analysis of the Minnesota Lions Eye Bank donor records indicated that
12% of all otherwise-eligible donors used insulin, but donor histories
were not able to supply information that could clearly define the type
of insulin used \[10\]. This issue highlights the difference between
living blood donors and cadaveric cornea donors. Unlike a blood donor,
who can give a detailed medical history, a cornea donor's family may not
know every detail of the donor's insulin procurement history. Even in
cases where information was available regarding the type of insulin
used, it was impossible to guarantee that donors had never taken insulin
manufactured from U.K. cattle. If these donors were excluded as well,
the donor pool in Minnesota would be reduced 17% \[10\].

Finally, cornea donors who have used bovine-derived insulin are not
excluded in the United Kingdom. We recommend the elimination of this
deferral criterion.

**Summary**

Many of the proposed deferral guidelines are based on the precautionary
principle, but lack a sound scientific basis indicating that they will
indeed reduce risk. Guideline development must include valid
risk-benefit and cost-benefit analyses, considering quality of life
issues for the tens of thousands of Americans whose sight is restored
every year via corneal transplantation, and the potential for
significantly reducing the size of a donor cornea pool that is already
threatened by the burgeoning popularity of refractive surgery.

The AAO supports the current medical and social history requirements. We
call for a clear and transparent scientific approach to the development
of more stringent screening criteria to reduce the possible risk of
transmission of CJD and vCJD. This process should have input from all
members of the transplant community, including physicians and
recipients. We also encourage a dialogue between the FDA and other
regulatory agencies, such as those in Canada and the U.K., which have
developed different policies based on the differences between blood and
tissues.

We appreciate the opportunity to comment on the proposed draft
guidelines, as well as your serious consideration of our
recommendations.

Sincerely,

David B. Glasser, M.D. Walter Stark, M.D.

Chair, Committee on Eye Banks Chair, Committee for Research, Regulatory,
And External Scientific Relations

H. Dunbar Hoskins, M.D. Michael R. Redmond, M.D.

Executive Vice President President

**References**

1.  Food and Drug Administration. Guidance for Industry: Preventive
    Measures to Reduce the Possible Risk of Transmission of
    Creutzfeldt-Jakob Disease (CJD and Variant Creutzfeldt-Jakob Disease
    (vCJD) by Human Cells, Tissues, and Cellular and Tissue-Based
    Products (HCT/Ps). Draft Guidance. June, 2002.

2.  Transmissible Spongiform Encephalopathy Advisory Committee Quick
    Summary, Topic #2, June 26-27, 2002.

3.  Eye Bank Association of America. Statistical Report, 2002.

4.  Duffy P, et al. Possible person-to-person transmission of
    Creutzfeldt-Jakob disease. New Engl J Med 290:692-3, 1974.

5.  Eye Bank Association of America. Medical Standards, December, 2002.

6.  Hogan RN, et al. Risk of prion disease transmission from ocular
    donor tissue transplantation. Cornea 18(1):2-11, 1999.

7.  Kennedy RH, et al. Eye banking and screening for Creutzfeldt-Jakob
    disease. Arch Ophthalmol 119(5):721-6, 2001.

8.  Transmissible Spongiform Encephalopathy Advisory Committee
    transcripts, January 18-19, 2001.

9.  Weber DJ, et al. Managing the risk of nosocomial transmission of
    prion diseases. Curr Opin Infect Dis 5(4):421-5, 2002.

10. Dale R, et al. Letter. Written comments re: Docket No. 02D-0266,
    August 29, 2002.