# 64 FR 52696: Suitability Determination for Donors of Human Cellular and Tissue-Based Products

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URL: https://www.frixlaw.com/law-library/statutes/FR_PRORULE_99-25378

## Section

- **Citation:** 64 FR 52696
- **Heading:** Suitability Determination for Donors of Human Cellular and Tissue-Based Products
- **Jurisdiction:** Federal
- **Kind:** Regulations
- **Status:** In force
- **Text as of:** August 14, 2026
- **Source:** Compiled text
- **Location:** Federal Register / Vol. 64 / 64 FR 52696

## Text

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 210, 211, 820, and 1271

[Docket No. 97N-484S]

Suitability Determination for Donors of Human Cellular and
Tissue-Based Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing new
regulations to require manufacturers of human cellular and tissue-based
products to screen and test the donors of cells and tissue used in
those products for risk factors for and clinical evidence of relevant
communicable disease agents and diseases. Human cellular and tissue-
based products are products that contain or consist of human cells or
tissues and that are intended for implantation, transplantation,
infusion, or transfer. As part of this regulatory action, the agency is
proposing to amend the current good manufacturing practice (CGMP)
regulations that apply to human cellular and tissue-based products
regulated as drugs, medical devices, and/or biological products to
incorporate the new donor-suitability procedures into existing good
manufacturing practice (GMP) regulations. The agency is taking this
action to provide more appropriate oversight for the wide spectrum of
human cellular and tissue-based products that are marketed now or may
be marketed in the future. The agency's action would improve protection
of the public health and increase public confidence in new
technologies, while permitting significant innovation and keeping
regulatory burden to a minimum.

DATES: Submit written comments on the proposed rule on or before
December 29, 1999. Submit written comments on the information
collection provisions on or before November 1, 1999.
the future. The agency's action would improve protection
of the public health and increase public confidence in new
technologies, while permitting significant innovation and keeping
regulatory burden to a minimum.

DATES: Submit written comments on the proposed rule on or before
December 29, 1999. Submit written comments on the information
collection provisions on or before November 1, 1999.

ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852. Submit written comments on the information
collection provisions to the Office of Information and Regulatory
Affairs, OMB, New Executive Office Bldg., 725 17th St. NW., Washington,
DC 20503, Attn: Wendy Taylor, Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT: Paula S. McKeever, Center for
Biologics Evaluation and Research (HFM-17), Food and Drug
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448, 301-827-6210.

SUPPLEMENTARY INFORMATION:

I. Introduction

FDA is in the process of establishing a comprehensive new system
of regulating human cellular and tissue-based products. The term
``human cellular and tissue-based products'' encompasses an array of
medical products derived from the human body and used for repair,
reproductive, replacement, or other therapeutic purposes. Skin,
tendons, bone, heart valves, and corneas have long been used as
replacements for damaged or diseased tissues. Semen, ova, and embryos
are transferred for reproductive purposes. Currently, some human
cellular and tissue-based products are being developed for new
therapeutic uses. For example, scientists are studying the use of
manipulated human cells to treat viral infections, Parkinson's disease,
and diabetes, among other conditions and diseases. FDA's new regulatory
program will cover all of these products, including those currently
regulated as ``human tissue intended for transplantation'' under part
1270 (21 CFR part 1270)
eing developed for new
therapeutic uses. For example, scientists are studying the use of
manipulated human cells to treat viral infections, Parkinson's disease,
and diabetes, among other conditions and diseases. FDA's new regulatory
program will cover all of these products, including those currently
regulated as ``human tissue intended for transplantation'' under part
1270 (21 CFR part 1270). (The proposed regulatory definition of a human
cellular or tissue-based product, and exceptions from the definition,
will be discussed in greater detail later in this document.)
In February 1997, the agency announced its regulatory plans in two
documents: ``Reinventing the Regulation of Human Tissue'' and ``A
Proposed Approach to the Regulation of Cellular and Tissue-Based
Products'' (hereinafter referred to as the ``proposed approach
document''). FDA requested written comments on its proposed approach
and, on March 17, 1997, held a public meeting to solicit information
and views from the interested public (62 FR 9721, March 4, 1997).
In the Federal Register of May 14, 1998 (63 FR 26744), FDA
proposed an establishment registration and product listing system for
manufacturers of human cellular and tissue-based products (hereinafter
referred to as the ``proposed registration rule.'') The proposed
registration rule was the first in a series of rules that the agency
intends to propose to implement its new approach to these products. The
proposed registration rule would require manufacturers of human
cellular and tissue-based products to register with the agency, to list
their products, and to submit regular updates. The rule defines ``human
cellular and tissue-based product,'' sets out exceptions to this
definition, e.g., vascularized human organs and certain minimally
manipulated bone marrow, and describes certain types of establishment
that would not be subject to the registration and listing requirement
-based products to register with the agency, to list
their products, and to submit regular updates. The rule defines ``human
cellular and tissue-based product,'' sets out exceptions to this
definition, e.g., vascularized human organs and certain minimally
manipulated bone marrow, and describes certain types of establishment
that would not be subject to the registration and listing requirement.
In addition, the rule proposes criteria for regulation of a human
cellular or tissue-based product solely under section 361 of the Public
Health Service Act (the PHS Act) (42 U.S.C. 264), rather than as a
drug, device, and/or biological product. Relevant portions of the
proposed registration rule are discussed in this proposed rule as
necessary, and the definitions contained in the proposed registration
rule are reprinted in their entirety in section III.B.1 of this
document.
As another step toward accomplishing its regulatory objectives,
the agency recently issued a request for proposed standards and
supporting data relating to certain stem-cell products (63 FR 2985,
January 20, 1998).
FDA now proposes to require manufacturers of certain human
cellular and tissue-based products to screen and test the donors of
cells and tissues used in those products for risk factors for and
clinical evidence of relevant communicable disease agents and diseases.
The proposed regulations are intended as safeguards to prevent the
transmission of communicable diseases that may occur with the use of
cells and tissues from infected donors.
In acting to increase the safety of the nation's supply of human
cellular and tissue-based products, FDA is also seeking to avoid
unnecessary regulation. Thus, consistent with the proposed approach
document, the agency has tailored the proposed testing and screening
requirements to the degree of communicable disease risk associated with
the various types of human cellular and tissue-based products
ting to increase the safety of the nation's supply of human
cellular and tissue-based products, FDA is also seeking to avoid
unnecessary regulation. Thus, consistent with the proposed approach
document, the agency has tailored the proposed testing and screening
requirements to the degree of communicable disease risk associated with
the various types of human cellular and tissue-based products. The
testing and screening for donors of cells and tissues that pose a high
degree of communicable disease risk will be more extensive than for
donors of cells and tissues with lesser risk. Where the risk is quite
low (e.g., cells or tissues used autologously), FDA will recommend
testing and screening, but will not require them; however, certain
labeling will be required.
As outlined in the proposed approach document, the agency is
implementing its regulatory plan for human cellular and tissue-based
products in a step-by-step fashion. Following the publication of this
proposed rule, the agency intends to propose current good tissue
practice ``CGTP'' regulations to address concerns about the proper
handling, storage, and processing of human cellular and tissue-based
products. The donor-suitability regulations now being proposed would be
placed in new part 1271, along with the regulations covering
registration, CGTP, and other areas, e.g., establishment inspection and
enforcement. Proposed part 1271 will eventually supersede part 1270,
which contains current regulations governing infectious-disease
testing, donor screening, and recordkeeping for human tissue intended
for transplantation. At the completion of the rulemaking process, FDA
intends to revoke part 1270.

II. Donor Suitability

A. Part 1270 and the Need for Expanded Donor-Suitability Requirements
enforcement. Proposed part 1271 will eventually supersede part 1270,
which contains current regulations governing infectious-disease
testing, donor screening, and recordkeeping for human tissue intended
for transplantation. At the completion of the rulemaking process, FDA
intends to revoke part 1270.

II. Donor Suitability

A. Part 1270 and the Need for Expanded Donor-Suitability Requirements

In the early 1990's, serious issues arose about the safety of
human tissue used for transplantation. Concern focused on the potential
for disease transmission through the transplantation of tissues from
donors infected with the human immunodeficiency virus (HIV) or one of
the hepatitis viruses. In 1993, FDA acted in response to this immediate
need to protect the public health by issuing an interim rule requiring
the donors of human tissue intended for transplantation to be screened
and tested for HIV types 1 and 2, hepatitis B (HBV), and hepatitis C
(HCV) (58 FR 65514, December 14, 1993). That rule, codified at part
1270, covered human tissue that was not regulated as a human drug,
biological product, or medical device; reproductive tissue and several
other categories of products were also excluded (Sec. 1270.3(j)). In
response to comments submitted on the interim rule, FDA modified and
clarified the requirements. In the Federal Register of July 29, 1997
(62 FR 40429), FDA issued a final rule replacing the interim rule
(hereinafter referred to as the ``tissue final rule'').
When it issued the regulations in part 1270, FDA envisioned
replacing them, at a future date, with more extensive requirements with
respect to infectious-disease control (58 FR 65514 at 65516).
Consistent with these intentions, the agency is now proposing
regulations that would expand on the current testing and screening
requirements in two ways. First, the proposed regulations would
increase the number of products covered by the screening and testing
requirements
, at a future date, with more extensive requirements with
respect to infectious-disease control (58 FR 65514 at 65516).
Consistent with these intentions, the agency is now proposing
regulations that would expand on the current testing and screening
requirements in two ways. First, the proposed regulations would
increase the number of products covered by the screening and testing
requirements. Second, the proposed regulations would require screening
and testing for additional diseases. (The present rulemaking affects
only the screening and testing

components of part 1270. Other requirements will be the subject of
future rulemaking, e.g., the requirement in Sec. 1270.31 for written
procedures and the enforcement provisions in part 1270 subpart D.)
Because of their nature as derivatives of the human body, all
human cellular and tissue-based products pose a potential risk of
transmitting communicable diseases. For example, HIV, HBV, and HCV have
been detected in human tissue, including bone, skin, corneas, and
semen. In proposing to establish a unified regulatory approach for
human cellular and tissue-based products, the agency is responding to
the concern about communicable disease transmission that is common to
all such products. The proposed testing and screening provisions would
be applicable to human cellular and tissue-based products that are
regulated under section 201 of the Federal Food, Drug, and Cosmetic Act
(the act) (21 U.S.C. 321 et. seq.) and/or section 351 of the PHS Act
(42 U.S.C. 262) as medical devices, drugs, and/or biological products.
The proposed testing and screening provisions would also apply to human
cellular products and products containing human reproductive cells or
tissues, including some products not currently subject to Federal
regulation. In addition, tissues currently regulated under part 1270
would be brought under the scope of the new regulations
C. 262) as medical devices, drugs, and/or biological products.
The proposed testing and screening provisions would also apply to human
cellular products and products containing human reproductive cells or
tissues, including some products not currently subject to Federal
regulation. In addition, tissues currently regulated under part 1270
would be brought under the scope of the new regulations.
When part 1270 was issued as an interim rule, FDA was acting
swiftly to counter the transmission of three serious disease agents,
HIV, HBV, and HCV, by the transplantation of human tissue. In this
rulemaking, the agency seeks to establish a more comprehensive system
for preventing the spread of those and other diseases transmissible by
implantation, transplantation, infusion, or transfer of human cellular
and tissue-based products. The proposed regulation would require,
except in certain limited situations, screening and testing for all
``relevant'' communicable disease agents and diseases. (The criteria
for considering a disease to be ``relevant'' are discussed later in
section III.C.1 of this document.) For example, FDA is now proposing to
require that donors of tissue and cells be tested for syphilis and
screened for transmissible spongiform encephalopathies (TSE) including
Creutzfeldt-Jakob Disease (CJD). In addition, donors of viable,
leukocyte-rich cells or tissues would be tested for human T-cell
lymphotrophic virus type I and type II (HTLV-I/II) and Cytomegalovirus
(CMV), which are considered ``cell-associated viruses.'' FDA is
proposing to require that donors of reproductive cells and tissue be
tested for Neisseria gonorrhea and Chlamydia trachomatis, which have
been transmitted through artificial insemination, and screened for
sexually transmitted and genitourinary diseases that could contaminate
reproductive cells and tissue during recovery and then be transmitted
to the recipient of those cells or tissues and/or to the fetus.

B. Legal Authority
reproductive cells and tissue be
tested for Neisseria gonorrhea and Chlamydia trachomatis, which have
been transmitted through artificial insemination, and screened for
sexually transmitted and genitourinary diseases that could contaminate
reproductive cells and tissue during recovery and then be transmitted
to the recipient of those cells or tissues and/or to the fetus.

B. Legal Authority

FDA is proposing to issue these new regulations under the
authority of section 361 of the PHS Act. Under that section, FDA may
make and enforce regulations necessary to prevent the introduction,
transmission, or spread of communicable diseases between the States or
from foreign countries into the States. (See sec. 1, Reorg. Plan No. 3
of 1966 at 42 U.S.C. 202 for delegation of section 361 authority from
the Surgeon General to the Secretary, Health and Human Services; see 21
CFR 5.10(a)(4) for delegation from the Secretary to FDA.) Intrastate
transactions may also be regulated under section 361 of the PHS Act.
(See Louisiana v. Mathews, 427 F. Supp. 174, 176 (E.D. La. 1977).)
Certain diseases are transmissible through the implantation,
transplantation, infusion, or transfer of human cellular or tissue-
based products derived from donors infected with those diseases. In
order to prevent the introduction, transmission, and spread of such
diseases, FDA considers it necessary to take appropriate measures to
prevent the use of cells or tissues from infected donors. Thus, the
agency is proposing that, prior to the use of most human cellular or
tissue-based products, the manufacturer would be required to determine
the suitability of the donor of cells or tissues based on the results
of screening and testing for relevant communicable diseases
DA considers it necessary to take appropriate measures to
prevent the use of cells or tissues from infected donors. Thus, the
agency is proposing that, prior to the use of most human cellular or
tissue-based products, the manufacturer would be required to determine
the suitability of the donor of cells or tissues based on the results
of screening and testing for relevant communicable diseases. Under the
proposed regulations, a donor who tests repeatedly reactive for a
particular disease agent, or who possesses clinical evidence of or risk
factors for such a disease, would be considered unsuitable, and cells
and tissues from that donor would not ordinarily be used.
FDA's directive, under section 361 of the PHS Act, is to prevent
the introduction, transmission, and spread of communicable diseases.
Specifically, these regulations are intended to prevent the
transmission of communicable disease through the implantation,
transplantation, infusion, or transfer of human cellular or tissue-
based products. However, as discussed in the proposed registration
rule, all human cellular and tissue-based products pose some risk of
carrying pathogens that could cause disease in recipients and family
members or other close contacts of recipients, health care personnel,
and other handlers of tissue. This broader concern for the spread of
communicable disease is reflected in certain labeling requirements
proposed in these regulations and in the criteria for identifying a
relevant communicable disease. Although FDA recognizes that regulations
exist that are specifically designed to protect employees who may come
in contact with infectious materials (see 29 CFR 1910.1030, 42 CFR
72.6, and 49 CFR 171.180), the agency does not consider its proposed
regulations to be in conflict with those other regulations currently in
effect. However, the agency has made an effort to be consistent with
the terminology used in these other regulations, e.g., ``Infectious
Substances'' and Biohazard legend
es who may come
in contact with infectious materials (see 29 CFR 1910.1030, 42 CFR
72.6, and 49 CFR 171.180), the agency does not consider its proposed
regulations to be in conflict with those other regulations currently in
effect. However, the agency has made an effort to be consistent with
the terminology used in these other regulations, e.g., ``Infectious
Substances'' and Biohazard legend.
Authority for the enforcement of section 361 of the PHS Act is
provided by section 368 of the PHS Act (42 U.S.C. 271). Under section
368(a), any person who violates a regulation prescribed under section
361 of the PHS Act may be punished by imprisonment for up to 1 year, a
fine of not more than $1,000, or both (42 U.S.C. 271(a)). In addition,
Federal District Courts have jurisdiction to enjoin individuals and
organizations from violating regulations implementing section 361 of
the PHS Act.
Under sections 501(a)(2)(B) and (h) and 520(f)(1) of the act (21
U.S.C. 351(a)(2)(B) and (h) and 360j(f)(1)), drugs and devices are
subject to CGMP requirements designed to ensure, among other things,
product safety. Currently, no specific CGMP regulations exist with
respect to human cellular and tissue-based products regulated as drugs
or devices that delineate testing and screening procedures for
communicable diseases. (See parts 210 et seq. and 820 (21 CFR parts 210
and 820).) Nevertheless, FDA considers communicable disease testing and
screening to be steps in the manufacturing process that are crucial to
the safety of such products. As a result, FDA proposes to amend the
existing CGMP regulations for drugs in parts 210 and 211 (21 CFR part
211) and the quality system regulations for devices in part 820 (21 CFR
part 820), which include CGMP requirements, to incorporate the testing
and screening provisions of proposed part 1271 subpart C
be steps in the manufacturing process that are crucial to
the safety of such products. As a result, FDA proposes to amend the
existing CGMP regulations for drugs in parts 210 and 211 (21 CFR part
211) and the quality system regulations for devices in part 820 (21 CFR
part 820), which include CGMP requirements, to incorporate the testing
and screening provisions of proposed part 1271 subpart C. In proposing
these amendments, FDA is relying on the authority provided by section
361 of the PHS Act to issue regulations to prevent the spread of
communicable disease, as well as its authority under the act to

issue CGMP regulations (21 U.S.C. 351(a)(2)(B) and (h) and 360j(f)(1)).
Under proposed Sec. 210.1(c), the manufacturer of a human cellular
or tissue-based product regulated as a drug or biological drug would be
required to comply with the donor-suitability procedures in proposed
part 1271, subpart C. Likewise, under proposed Sec. 820.1, the
manufacturer of a human cellular or tissue-based product regulated as a
device would be required to comply with the same procedures. (Existing
regulations and policy determine whether a product is a drug,
biological product, and/or device). If the manufacturer failed to
follow the CGMP or quality system requirements, including the testing
and screening procedures in proposed part 1271, the product would be
adulterated under the act.
Section 375 of the PHS Act provides for Federal oversight of the
nation's Organ Procurement and Transplantation Network and section 379
of the PHS Act authorizes the National Bone Marrow Donor Registry. The
Health Resources and Services Administration (HRSA) currently
administers both of these programs. Given HRSA oversight in these
areas, vascularized human organs and minimally manipulated bone marrow
(as defined in proposed Sec. 1271.3(e)) for unrelated allogeneic use
are specifically excluded from the proposed and final regulations on
human cellular and tissue-based products.

III. Summary of the Proposed Regulation
ices Administration (HRSA) currently
administers both of these programs. Given HRSA oversight in these
areas, vascularized human organs and minimally manipulated bone marrow
(as defined in proposed Sec. 1271.3(e)) for unrelated allogeneic use
are specifically excluded from the proposed and final regulations on
human cellular and tissue-based products.

III. Summary of the Proposed Regulation

A. Purpose and Scope (Proposed Sec. 1271.1)

FDA is proposing that donor-suitability regulations would apply to
all establishments covered by the proposed registration rule. In the
proposed registration rule, FDA discussed its proposed system for
regulating human cellular and tissue-based products. In particular, the
agency proposed to distinguish between two groups of human cellular and
tissue-based products: those that would be regulated solely under the
authority of section 361 of the PHS Act (``361 products''), and those
regulated under the act and/or section 351 of the PHS Act as drugs,
medical devices and/or biological products as well as section 361 of
the PHS Act.
Section 1271.1 of the proposed registration rule states that
manufacturers of both 361 products and products regulated as drugs or
devices and/or biological products under the act and/or section 351 of
the PHS Act would be required to comply with the proposed registration
and listing procedures. The criteria for regulation of a human cellular
or tissue-based product as a 361 product are set out in Sec. 1271.10 of
the proposed registration rule. Section 1271.20 of the proposed
registration rule sets out exceptions from the registration and listing
requirements.
FDA is now making several modifications to proposed Secs. 1271.1,
1271.10, and 1271.20 as they appeared in the proposed registration rule
and is proposing a new Sec. 1271.15. To improve clarity, FDA has
divided section 1271.1 into separate paragraphs on scope and purpose
and has added cross-references to other pertinent regulations
t exceptions from the registration and listing
requirements.
FDA is now making several modifications to proposed Secs. 1271.1,
1271.10, and 1271.20 as they appeared in the proposed registration rule
and is proposing a new Sec. 1271.15. To improve clarity, FDA has
divided section 1271.1 into separate paragraphs on scope and purpose
and has added cross-references to other pertinent regulations. FDA has
also changed the heading of proposed Sec. 1271.10 to ``Establishments
subject to this part; criteria for regulation of human cellular and
tissue-based products solely under section 361 of the PHS Act.'' The
phrase ``nontissue or noncellular'' has been removed from proposed
Sec. 1271.10(c). Proposed Sec. 1271.10(d) has been reorganized,
although its meaning has not changed. Proposed Sec. 1271.10 now
describes human cellular and tissue-based products regulated solely
under section 361 of the PHS Act as those products that: Are minimally
manipulated, are not promoted or labeled for any use other than a
homologous use, are not combined with or modified by the addition of
any component that is a drug or a device; and either do not have a
systemic effect or have a systemic effect and are for autologous use,
are for a family-related allogeneic use, or are for reproductive use.
FDA expects that comments on the four criteria in proposed Sec. 1271.10
will be submitted in response to the proposed registration rule, and
foresees that each of the four criteria will be modified for greater
clarity. For example, the agency is considering clarifying or modifying
the term ``systemic effect'' in proposed Sec. 1271.10(d) because of
potential ambiguities. FDA is concerned that products that have local
metabolic effects, e.g., neurons used to replace or supplement neurons
in the brain, warrant regulation under the act and/or section 351 of
the PHS Act
ria will be modified for greater
clarity. For example, the agency is considering clarifying or modifying
the term ``systemic effect'' in proposed Sec. 1271.10(d) because of
potential ambiguities. FDA is concerned that products that have local
metabolic effects, e.g., neurons used to replace or supplement neurons
in the brain, warrant regulation under the act and/or section 351 of
the PHS Act. The agency invites comments on whether ``systemic effect''
adequately characterizes those products that warrant the more stringent
level of regulation or whether another term or terms would more
accurately describe such products.
FDA is proposing a new Sec. 1271.15 to describe those products
that would be regulated under the act and/or section 351 of the PHS Act
and to reference the subparts of part 1271 that will be applicable to
those products.
FDA is also modifying proposed Secs. 1271.1, 1271.10, and 1271.20
so that they refer not simply to registration and product listing
requirements but to all of the requirements that will be contained in
part 1271 when rulemaking for the entire part is complete. With these
changes, the regulatory framework that was described in the proposed
approach document and developed in the proposed registration rule would
be extended, as intended, to cover donor-suitability requirements now
being proposed as well as other requirements to be proposed later. The
agency is seeking to craft the modifications to these sections to
obviate the need for further adjustments in later rulemaking. To that
end, the new language refers to compliance ``with the other
requirements contained in this part.''
FDA intends that the procedures in part 1271 that would apply to
human cellular and tissue-based products regulated as drugs, devices
and/or biological products are the proposed registration and listing
procedures, the donor-suitability procedures now being proposed, and
the CGTP procedures to be proposed in the future
ers to compliance ``with the other
requirements contained in this part.''
FDA intends that the procedures in part 1271 that would apply to
human cellular and tissue-based products regulated as drugs, devices
and/or biological products are the proposed registration and listing
procedures, the donor-suitability procedures now being proposed, and
the CGTP procedures to be proposed in the future. Therefore, the agency
is now proposing to modify proposed Sec. 1271.1 to add the statement
that manufacturers of human cellular and tissue-based products
regulated under the act and/or section 351 of the PHS Act are required
to comply with the donor-suitability procedures and the CGTP procedures
in part 1271 in addition to all other applicable regulations.

B. Definitions (Proposed Sec. 1271.3)

1. Definitions Contained in the Proposed Registration Rule
Section 1271.3(a) through (h) of the proposed registration rule
contain definitions of terms used in the registration and listing
regulations. Because some of the terms defined in the proposed
registration rule are used in the donor-suitability regulations now
being proposed, the agency is reprinting proposed Sec. 1271.3(a)
through (h) as follows to facilitate understanding of the rule now
being proposed.
(a) Autologous use means the implantation, transplantation,
infusion, or transfer of a human cellular or tissue-based product
back into the individual from whom the cells or tissue comprising
such product were removed.
uitability regulations now
being proposed, the agency is reprinting proposed Sec. 1271.3(a)
through (h) as follows to facilitate understanding of the rule now
being proposed.
(a) Autologous use means the implantation, transplantation,
infusion, or transfer of a human cellular or tissue-based product
back into the individual from whom the cells or tissue comprising
such product were removed.
(b) Establishment means a place of business under one
management, at one general physical location, that engages in the
manufacture of human cellular or tissue-based products. The term
includes, among others, facilities that engage in contract

manufacturing services for a manufacturer of human cellular or
tissue-based products. The term also includes any individual,
partnership, corporation, association, or other legal entity engaged
in the manufacture of human cellular or tissue-based products,
except that an individual engaged solely in the procurement or
recovery of cells or tissues or under contract to a registered
establishment is not required to independently register.
(c) Family-related allogeneic use means the implantation,
transplantation, infusion, or transfer of a human cellular or
tissue-based product into a first-degree blood relative of the
individual from whom cells or tissue comprising such product were
removed.
(d) Homologous use means the use of a cellular or tissue-based
product for replacement or supplementation and:
(1) For structural tissue-based products, occurs when the
tissue is used for the same basic function that it fulfills in its
native state, in a location where such structural function normally
occurs; or
(2) For cellular and nonstructural tissue-based products,
occurs when the cells or tissue is used to perform the function(s)
that they perform in the donor.
lacement or supplementation and:
(1) For structural tissue-based products, occurs when the
tissue is used for the same basic function that it fulfills in its
native state, in a location where such structural function normally
occurs; or
(2) For cellular and nonstructural tissue-based products,
occurs when the cells or tissue is used to perform the function(s)
that they perform in the donor.
(e) Human cellular or tissue-based product means a product
containing human cells or tissues or any cell or tissue-based
component of such a product. The following products are not
considered human cellular or tissue-based products and
establishments that manufacture only one or more of the following
would not be subject to the registration or listing provisions of
this part:
(1) Vascularized human organs for transplantation;
(2) Whole blood or blood components or blood derivative
products subject to listing under part 607 of this chapter;
(3) Secreted or extracted human products, such as milk,
collagen, and cell factors;
(4) Minimally manipulated bone marrow;
(5) Ancillary products used in the propagation of cells or
tissues; or
(6) Cells, tissues or organs derived from animals.
(f) Manufacture means, but is not limited to, any or all steps
in the recovery, screening, testing, processing, storage, labeling,
packaging, or distribution of any human cellular or tissue-based
product.
(g) Minimal manipulation means: (1) For structural tissue,
processing that does not alter the original relevant characteristics
of the tissue relating to the tissue's utility for reconstruction,
repair, or replacement; and
(2) For cells or nonstructural tissues, processing that does
not alter the relevant biological characteristics of cells or
tissues.
man cellular or tissue-based
product.
(g) Minimal manipulation means: (1) For structural tissue,
processing that does not alter the original relevant characteristics
of the tissue relating to the tissue's utility for reconstruction,
repair, or replacement; and
(2) For cells or nonstructural tissues, processing that does
not alter the relevant biological characteristics of cells or
tissues.
(h) Transfer means the placement of human reproductive cells or
tissues into a human recipient.
Since proposing the previous definitions, FDA has reconsidered the
definition in proposed Sec. 1271.3(e) of ``human cellular or tissue-
based product,'' and has determined that it is too broad. For example,
the definition might be construed to include many in vitro diagnostic
products. The agency is adding language to the proposed definition to
clarify that the products covered by the definition (and thus by these
proposed regulations) are those that are intended for implantation,
transplantation, infusion, or transfer into a human recipient. The
agency is also adding language to specifically exclude in vitro
diagnostic products as defined in 21 CFR 809.3(a) from the definition
of human cellular or tissue-based product. In addition, the agency is
deleting the reference in Sec. 1271.3(e) to the registration and
listing provisions of part 1271. Minimally manipulated bone marrow has
been clarified by adding ``for homologous use and not combined with or
modified by the addition of any component that is a drug or a device.''
Also, the agency is clarifying that, although secreted or extracted
human products such as milk, collagen, and cell factors are not
considered to meet the definition of human cellular or tissue-based
product, semen is considered a human cellular or tissue-based product
because it contains germ cells. The definition also contains several
other minor clarifications and corrections.
2. New Definitions
The agency is now proposing to define additional terms and to list
them in Sec
h as milk, collagen, and cell factors are not
considered to meet the definition of human cellular or tissue-based
product, semen is considered a human cellular or tissue-based product
because it contains germ cells. The definition also contains several
other minor clarifications and corrections.
2. New Definitions
The agency is now proposing to define additional terms and to list
them in Sec. 1271.3(i) through (ee). The agency intends to place all
definitions relevant to proposed part 1271 in proposed Sec. 1271.3.
Thus, in subsequent rulemakings, the agency may propose to define more
terms in that section.
Many of the terms now proposed to be defined in proposed
Sec. 1271.3 are currently defined in Sec. 1270.3. In several instances,
the definition now being proposed is the same as that in Sec. 1270.3 or
is only modified slightly for clarity, e.g., ``donor'' and
``responsible person'' in proposed Sec. 1271.3(n) and (w),
respectively. Although the proposed definitions of colloid and
crystalloid remain substantially the same as in Sec. 1270.3(c) and (e),
the agency specifically requests comments on the appropriateness of
these definitions, including whether it is appropriate to define these
terms in the regulations.
The definitions of some other terms (e.g., donor medical history
interview and physical assessment) have been significantly modified to
accommodate the broader range of infectious diseases covered by this
proposed regulation. Additional terms are newly defined in proposed
Sec. 1271.3 (Biohazard legend, directed donor, embryo, gamete, relevant
communicable disease agent or disease, urgent medical need,
xenotransplant, and close contact). Where relevant, proposed
definitions are discussed as follows, with the requirements to which
the defined terms relate.
The definition of ``summary of records'' in proposed
Sec. 1271.3(x) is a modification of the definition of the same term in
Sec. 1270.3(w). As in Sec
r, embryo, gamete, relevant
communicable disease agent or disease, urgent medical need,
xenotransplant, and close contact). Where relevant, proposed
definitions are discussed as follows, with the requirements to which
the defined terms relate.
The definition of ``summary of records'' in proposed
Sec. 1271.3(x) is a modification of the definition of the same term in
Sec. 1270.3(w). As in Sec. 1270.3(w), the agency proposes to define
``summary of records'' as containing a list of all tests performed for
relevant communicable disease agents and the results of those tests,
and the name and address of the establishment that made the donor-
suitability determination. However, FDA has recently received comments
from manufacturers of human tissue intended for transplantation on
other aspects of the definition of ``summary of records'' in
Sec. 1270.3(w). These comments assert that, because a processor or
distributor may use multiple testing laboratories, the requirement in
Sec. 1270.3(w) that a summary of records contain the identity of the
testing laboratory is unduly burdensome; similar objections were raised
to the requirement for listing all relevant medical records reviewed.
Such information, it was asserted, would be available from the
establishment that made the donor-suitability determination. FDA has
considered these concerns, and is proposing a new, less burdensome
definition. Under the proposed definition, the summary of records would
be redefined as: (1) A statement that communicable disease testing was
performed by a laboratory or laboratories certified under the Clinical
Laboratory Improvement Amendments of 1988 (CLIA); (2) a listing and
interpretation of the results of all communicable disease tests
performed; (3) a statement describing the types of records which may
have been reviewed as part of the relevant medical records; and (4) the
name and address of the establishment determining the suitability of
the donor of cells or tissues
ied under the Clinical
Laboratory Improvement Amendments of 1988 (CLIA); (2) a listing and
interpretation of the results of all communicable disease tests
performed; (3) a statement describing the types of records which may
have been reviewed as part of the relevant medical records; and (4) the
name and address of the establishment determining the suitability of
the donor of cells or tissues. Upon request by FDA, or other interested
persons, the establishment that made the donor-suitability
determination will be expected to promptly furnish the name and address
of the testing laboratory and a list of all relevant medical records
reviewed.

C. General Requirements

1. Determination of Donor Suitability (Proposed Sec. 1271.50)
Proposed Sec. 1271.50 sets out the fundamental requirement of
these proposed regulations: The donor-suitability determination. Except
in certain specified situations, a human cellular or tissue-based
product may not be implanted, transplanted, infused, or

transferred until the donor of the cells or tissue for the product has
been determined to be suitable.
The determination of whether a donor is suitable or unsuitable
would be made by a responsible person, as defined in proposed
Sec. 1271.3(w), and would be based on the results of required donor
screening and testing. ``Donor screening'' refers to a review of the
donor's relevant medical records, as defined in proposed
Sec. 1271.3(v), for information about the donor that might indicate
past or present infection or risk factors for a relevant communicable
disease agent or disease. ``Donor testing'' refers to performing
laboratory tests on a specimen collected from the donor, generally a
blood sample, to determine whether the donor has been exposed to or is
infected with a relevant communicable disease agent.
Both aspects of the donor-suitability determination are vital
cate
past or present infection or risk factors for a relevant communicable
disease agent or disease. ``Donor testing'' refers to performing
laboratory tests on a specimen collected from the donor, generally a
blood sample, to determine whether the donor has been exposed to or is
infected with a relevant communicable disease agent.
Both aspects of the donor-suitability determination are vital. A
donor may be determined to be suitable only if test results are
negative or nonreactive and screening shows the donor to be free from
risk factors for and clinical evidence of infection due to relevant
communicable disease agents and diseases. Conversely, if either donor
screening or donor testing indicates the presence of a relevant
infectious agent, or risk factors therefor, then the potential donor
must be determined to be unsuitable.
Proposed Sec. 1271.3(y) contains a two-part definition of the term
``relevant communicable disease agent or disease.'' Section
1271.3(y)(1) lists those disease agents and diseases that are
specifically identified in Secs. 1271.75 and 1271.85 as relevant
communicable disease agents and diseases for which the agency is
proposing to require donor screening and/or testing. These are: HIV,
types 1 and 2; HBV; HCV; TSE; Treponema pallidum; HTLV, types I and II;
CMV; Chlamydia trachomatis and Neisseria gonorrhea. In some instances,
FDA has identified a disease agent or disease as relevant for a
particular type of cells or tissue-based product; this distinction is
reflected in the proposed testing and screening requirements in
proposed Secs. 1271.75 and 1271.85.
The second part of the definition describes the criteria for a
communicable disease agent or disease to be considered ``relevant,''
and covers diseases not specifically listed in Sec. 1271.3(y)(1).
First, for a communicable disease agent or disease to be ``relevant,''
its prevalence among donors would have to be sufficient to warrant
screening or testing of all donors
s. 1271.75 and 1271.85.
The second part of the definition describes the criteria for a
communicable disease agent or disease to be considered ``relevant,''
and covers diseases not specifically listed in Sec. 1271.3(y)(1).
First, for a communicable disease agent or disease to be ``relevant,''
its prevalence among donors would have to be sufficient to warrant
screening or testing of all donors. Second, there would need to be a
risk of transmission of the disease agent or disease by a human
cellular or tissue-based product, either to the recipient of the
product or to those people who may handle or otherwise come in contact
with the product, such as medical personnel. Third, the health risks,
measured by morbidity and mortality, posed by the disease would need to
be significant. For example, HIV, HBV, HCV, and Treponema pallidum,
which are listed in Sec. 1271.3(y)(1), all pose significant health
risks. In contrast, although Ureaplasma urealyticum, Mycoplasma
hominis, and Streptococci are organisms that have been transmitted
through artificial insemination procedures, they exist in a great
number of healthy, sexually active adults and their pathogenicity to
the recipient of reproductive cells or tissue is of questionable
clinical significance. Thus, FDA does not consider them to be relevant
communicable diseases or disease agents at this time for the purpose of
this regulation. Finally, for a disease or disease agent to be
considered ``relevant,'' appropriate screening measures would need to
have been developed and/or an appropriate FDA-licensed, approved, or
cleared screening test for donor specimens would need to be available.
Should a new relevant communicable disease agent or disease arise
or be identified, the agency would consider manufacturers to be
required, under proposed Sec. 1271.75(a), to screen donors for the
disease and, under proposed Sec. 1271.80(a), to test donor specimens
for the disease agent, even if the disease agent or disease is not
specified in proposed Secs
cimens would need to be available.
Should a new relevant communicable disease agent or disease arise
or be identified, the agency would consider manufacturers to be
required, under proposed Sec. 1271.75(a), to screen donors for the
disease and, under proposed Sec. 1271.80(a), to test donor specimens
for the disease agent, even if the disease agent or disease is not
specified in proposed Secs. 1271.3(y), 1271.75, or 1271.85. The agency
intends to issue guidance in the future to interpret the term
``relevant communicable disease agent or disease,'' when additional
agents or diseases arise or are identified that meet the definition
under proposed Sec. 1271.3(y).
2. Records of Donor Suitability Determination (Proposed Sec. 1271.55)
Proposed Sec. 1271.55 incorporates requirements that are now found
in (Secs. 1270.21(e) and 1270.33(d) and (f)). Additional recordkeeping
requirements based on other regulations in part 1270 will be proposed
in the future, as part of CGTP's.
Under proposed Sec. 1271.55, manufacturers would be required to
ship a human cellular or tissue-based product accompanied by
documentation of the donor-suitability determination. This requirement
would apply to a human cellular or tissue-based product from a donor
determined to be suitable as well as to a product from a donor
determined to be unsuitable and made available for use under the
provisions of proposed Sec. 1271.65(b), (c), or (d). Manufacturers
would be required to include in the documentation a copy of the donor's
relevant medical records, as defined in proposed Sec. 1271.3(v),
results of testing required under Secs. 1271.80 and 1271.85, and the
name and address of the establishment that made the donor-suitability
determination. Alternatively, the documentation may consist of a
summary of records, as defined in proposed Sec. 1271.3(x)
ld be required to include in the documentation a copy of the donor's
relevant medical records, as defined in proposed Sec. 1271.3(v),
results of testing required under Secs. 1271.80 and 1271.85, and the
name and address of the establishment that made the donor-suitability
determination. Alternatively, the documentation may consist of a
summary of records, as defined in proposed Sec. 1271.3(x). Additional
required documentation would include a statement whether, based on a
review of the results of donor screening and testing, the donor has
been determined to be suitable or unsuitable. In the interest of
confidentiality, the agency is proposing to require that the donor's
name be deleted from the documentation of the donor's suitability
determination that accompanies the product.
FDA recognizes the potentially sensitive nature of information
about a human cell or tissue donor that may be contained in the donor's
relevant medical records. Nothing in this proposed rule is intended to
modify any currently applicable Federal, State, or local regulations
regarding confidentiality. With respect to the agency's handling of
personal medical information, the regulations in part 20 (21 CFR part
20) will continue to apply (see Sec. 20.63).
Proposed Sec. 1271.55(b) would impose record-retention
requirements on the establishment that generates records used in
determining donor suitability and on the establishment that makes the
donor-suitability determination. These records must be made available
for authorized inspection by or upon request from FDA. Records that can
be readily retrieved from another location by electronic means would be
considered ``retained.'' FDA envisions that various methods of
recordkeeping could be employed to meet the terms of Sec. 1271.55(b),
so long as suitable reader and photocopying equipment were readily
available. For example, records might be retained electronically, as
original paper records, or as true copies, such as photocopies,
microfiche, or microfilm
ocation by electronic means would be
considered ``retained.'' FDA envisions that various methods of
recordkeeping could be employed to meet the terms of Sec. 1271.55(b),
so long as suitable reader and photocopying equipment were readily
available. For example, records might be retained electronically, as
original paper records, or as true copies, such as photocopies,
microfiche, or microfilm.
Proposed Sec. 1271.55(b) would require that records be retained at
least 10 years after the date of implantation, transplantation,
infusion, or transfer of the product. If that date is not known,
however, then records would be retained at least 10 years after the
product's distribution, disposition, or expiration, whichever is
latest.
The agency notes that, given concerns about TSE transmission from
dura

mater, it may be prudent to hold records relating to donations of dura
mater for longer than 10 years, although the optimal period is not
known at this time. The latency period between receipt of a dura mater
graft and onset of TSE has been reported to be as long as 16 years
(Morbidity and Mortality Weekly Report, 46:1066, November 14, 1997). If
new information should be obtained in the future about TSE, then review
of the original screening and testing information about dura mater
donors could be invaluable. The agency requests comments on whether
records relating to donors of dura mater should be required to be held
for a period longer than 10 years and what that period should be.
3. Quarantine Pending Determination of Donor Suitability (Proposed
Sec. 1271.60)
In order to prevent the use of human cellular and tissue-based
products prior to a donor-suitability determination, Sec. 1271.60
proposes requirements for quarantine. ``Quarantine'' is defined in
proposed Sec
a mater should be required to be held
for a period longer than 10 years and what that period should be.
3. Quarantine Pending Determination of Donor Suitability (Proposed
Sec. 1271.60)
In order to prevent the use of human cellular and tissue-based
products prior to a donor-suitability determination, Sec. 1271.60
proposes requirements for quarantine. ``Quarantine'' is defined in
proposed Sec. 1271.3(t) as ``the storage or identification of a human
cellular or tissue-based product, in order to prevent improper release,
in a physically separate area clearly identified for such use, or
through use of other procedures, such as automated designation.''
As provided in proposed Sec. 1271.60, manufacturers would be
required to keep human cellular and tissue-based products in
quarantine, and clearly identify such products as being in quarantine,
until completion of the donor-suitability determination. A manufacturer
who ships a product before it is available for release or distribution
(as in the case of shipment by the procurer to the processor) would be
required to ship the product under quarantine and accompanied by
records identifying the donor, indicating that the donor-suitability
determination has not been completed, and stating that the product may
not be implanted, transplanted, infused, or transferred until
completion of the donor-suitability determination. Donor identification
may be accomplished by assigning a donor number.
4. Quarantine and Disposition of Human Cellular or Tissue-based
Product From an Unsuitable Donor (Proposed Sec. 1271.65)
If a donor is determined to be unsuitable, then under proposed
Sec. 1271.65 the manufacturer would be required to keep in quarantine
any human cellular or tissue-based product from that donor. In this
situation, quarantine would require physical separation of the product
from all other products until it is destroyed, or until it is used
under the provisions of proposed Sec. 1271.65(b), (c), or (d).
Proposed Sec
ined to be unsuitable, then under proposed
Sec. 1271.65 the manufacturer would be required to keep in quarantine
any human cellular or tissue-based product from that donor. In this
situation, quarantine would require physical separation of the product
from all other products until it is destroyed, or until it is used
under the provisions of proposed Sec. 1271.65(b), (c), or (d).
Proposed Sec. 1271.65 (b) sets out the limited circumstances in
which the proposed regulations would not bar the implantation,
transplantation, infusion, or transfer of human cellular and tissue-
based products from unsuitable donors. In three situations, the agency
is proposing that the recipient and his or her physician may decide
whether to use the human cellular or tissue-based product.
The first exception is for family-related allogeneic use. Family-
related allogeneic use is defined in Sec. 1271.3(c) of the proposed
registration rule as the implantation, transplantation, infusion, or
transfer of a human cellular or tissue-based product into a first-
degree blood relative of the individual from whom cells or tissue
comprising such product were removed. Under the second exception, a
person could choose to receive a product containing reproductive tissue
from a directed donor who had been determined to be unsuitable.
(Proposed Sec. 1271.3(m) defines ``directed donor'' as a living person
who is the source of cells or tissue designated for a specific
potential recipient of a human cellular or tissue-based product.) The
third exception is for cases where an urgent medical need exists and is
documented. Urgent medical need is defined in proposed Sec. 1271.3(z)
as the situation where no comparable human cellular or tissue-based
product from a suitable donor is available and, without the product,
the recipient is likely to suffer serious morbidity.
However, use in each of these circumstances is conditioned on
compliance with certain safeguards
an urgent medical need exists and is
documented. Urgent medical need is defined in proposed Sec. 1271.3(z)
as the situation where no comparable human cellular or tissue-based
product from a suitable donor is available and, without the product,
the recipient is likely to suffer serious morbidity.
However, use in each of these circumstances is conditioned on
compliance with certain safeguards. First, in order to protect those
people who may handle the product, the manufacturer would be required
to label such products with a Biohazard legend. (A Biohazard legend is
shown in proposed Sec. 1271.3(i) and is used to mark products that
present ``a known or suspected relevant communicable disease risk.'')
Second, the manufacturer of the product would be responsible for
documenting that: (1) The physician using the product was notified of
the results of testing and screening, (2) the physician authorized the
use of the product, (3) the physician agreed to explain the
communicable disease risks associated with the product to the recipient
or the recipient's legally authorized representative, and (4) the
physician agreed to obtain from the recipient or the recipient's
legally authorized representative consent to use the product. In
proposing these exceptions that would not prohibit, in certain cases,
the use of products from an unsuitable donor, it is FDA's intention to
delegate to the potential recipient and his or her physician the
responsibility for comparing the relative risks and benefits. The
agency specifically seeks comment on the scope of the exceptions and
the proposed safeguards that FDA has crafted
duct. In
proposing these exceptions that would not prohibit, in certain cases,
the use of products from an unsuitable donor, it is FDA's intention to
delegate to the potential recipient and his or her physician the
responsibility for comparing the relative risks and benefits. The
agency specifically seeks comment on the scope of the exceptions and
the proposed safeguards that FDA has crafted. For example, does the
exception for directed reproductive tissue donors provide a reasonable
accommodation for a woman who wishes to choose the genetic father of
her child? Should the exception be further broadened to permit a woman
to select an anonymous donor with a known high risk behavior or,
conversely, does the exception provide sufficient protection for the
woman and her potential child?
FDA recognizes that, just as there may be urgent medical
situations that might justify the use of a human cellular or tissue-
based product from an unsuitable donor, so the need may arise to use a
human cellular or tissue-based product before the donor-suitability
determination has been completed. Proposed Sec. 1271.65(c) sets out the
limited, emergency circumstances in which the proposed regulations
would not prohibit the implantation, transplantation, infusion, or
transfer of such a product. The emergency provisions of Sec. 1271.65(c)
are similar to those in Sec. 1271.65(b), with some modifications
appropriate to the different characteristics of the situation. In
particular, a product made available for use pending completion of the
donor-suitability determination must be accompanied by information on
the status of the required screening and testing. In addition,
Sec. 1271.65(c) includes the requirement that the donor-suitability
determination be completed during or after the use of the product, and
that the manufacturer inform the physician of the results of that
determination.
Under proposed Sec
ing completion of the
donor-suitability determination must be accompanied by information on
the status of the required screening and testing. In addition,
Sec. 1271.65(c) includes the requirement that the donor-suitability
determination be completed during or after the use of the product, and
that the manufacturer inform the physician of the results of that
determination.
Under proposed Sec. 1271.65(d), nonclinical uses of a human
cellular or tissue-based product from an unsuitable donor would not be
prohibited, e.g., use for educational or research purposes. A
manufacturer would be required to label a product used under the
provisions of Sec. 1271.65(c) as ``For Nonclinical Use Only'' and with
the Biohazard legend shown in proposed Sec. 1271.3(i).

D. Donor Screening (Proposed Sec. 1271.75)

The determination of donor-suitability is based on the results of
two different evaluations: Screening and testing. Donor screening
involves the review of a variety of possible sources

of information about the donor that might indicate that the donor is at
risk for or exhibits clinical evidence of infection due to a relevant
communicable disease.
1. General Requirements
The requirements for donor screening are in proposed Sec. 1271.75.
Under proposed Sec. 1271.75(a), the manufacturer would be required to
review the relevant medical records of a donor of cells or tissue for a
human cellular or tissue-based product for risk factors for and
clinical evidence of relevant communicable disease agents and diseases.
Relevant medical records are defined in proposed Sec. 1271.3(v) as a
collection of documents that includes a current donor medical history
interview as defined in proposed Sec. 1271.3(o); a current report of
the physical assessment as defined in proposed Sec
human cellular or tissue-based product for risk factors for and
clinical evidence of relevant communicable disease agents and diseases.
Relevant medical records are defined in proposed Sec. 1271.3(v) as a
collection of documents that includes a current donor medical history
interview as defined in proposed Sec. 1271.3(o); a current report of
the physical assessment as defined in proposed Sec. 1271.3(r) of a
cadaveric donor or a physical examination of a living donor; and, if
available, laboratory test results, medical records, coroner and
autopsy reports, and records or other information received from any
source pertaining to risk factors for relevant communicable disease.
(The proposed definitions for ``relevant medical records,'' ``donor
medical history interview,'' and ``physical assessment'' have been
broadened to refer not only to HIV and hepatitis but instead to
``relevant communicable disease;'' in other respects, except as
otherwise noted, these definitions are substantially the same as those
currently in Sec. 1270.3.)
Under proposed Sec. 1271.3(v), risk factors for communicable
disease may include social behavior, clinical signs and symptoms of a
relevant communicable disease, and treatments related to medical
conditions suggestive of risk for a relevant communicable disease.
Consistent with the approach taken in part 1270, the proposed
regulations do not specify risk factors, as these may change as
knowledge of communicable diseases grows. FDA, together with CDC, is
reviewing the risk factors for transmission of relevant communicable
diseases in light of current scientific knowledge. Based on the results
of the review, FDA plans to specifically describe in a guidance
document risk factors and screening information to assist manufacturers
in complying with the regulation. A notice announcing the availability
of a draft guidance document for public comment will be published in
the Federal Register
of relevant communicable
diseases in light of current scientific knowledge. Based on the results
of the review, FDA plans to specifically describe in a guidance
document risk factors and screening information to assist manufacturers
in complying with the regulation. A notice announcing the availability
of a draft guidance document for public comment will be published in
the Federal Register. The notice will provide instructions for
obtaining copies of the draft guidance document by mail, facsimile, and
the Internet using the World Wide Web. FDA plans to issue a final
guidance document on or about the time of issuance of the final rule.
Under proposed Sec. 1271.75(d), an abbreviated screening procedure
may be used for a living donor who returns to make subsequent donations
and who has already been screened under Sec. 1271.75(a) and (b). This
abbreviated screening would determine whether any changes had occurred
in the donor's medical history since the previous donation that would
make the donor unsuitable, and would require documentation of those
changes. A complete donor-suitability determination procedure would be
required at least once every 6 months.
Under proposed Sec. 1271.3(o), a ``donor medical history
interview'' means a documented dialogue with the donor, if the donor is
living. If the donor is not living or is unable to participate in the
interview, the interview takes place with an individual or individuals
who are knowledgeable about the donor's medical history and relevant
social behavior, such as the donor's next of kin, the nearest available
relative, a member of the donor's household, an individual with an
affinity relationship, and/or the primary treating physician. With
respect to relevant social behavior, the definition states that the
interview includes questions about whether or not the donor met certain
descriptions or engaged in activities or behaviors considered to place
the donor at increased risk for a relevant communicable disease
ember of the donor's household, an individual with an
affinity relationship, and/or the primary treating physician. With
respect to relevant social behavior, the definition states that the
interview includes questions about whether or not the donor met certain
descriptions or engaged in activities or behaviors considered to place
the donor at increased risk for a relevant communicable disease.
The current regulations on human tissue intended for
transplantation contain an exception from the requirement for a donor
medical history interview for corneas obtained under legislative
consent; i.e., in accordance with a State law that allows the medical
examiner or coroner to procure corneal tissue without the consent of
the donor's next of kin (Sec. 1270.21(g)). In response to numerous
comments and discussions about the tissue interim rule, FDA
acknowledged the need for flexibility in the procurement of corneal
tissue under legislative consent, and modified the regulations to
accept as sufficient a physical assessment of the donor in the absence
of a donor medical history interview (62 FR 40429 at 40437).
The regulations now being proposed do not contain an exception
from the donor medical history interview for corneas procured under
legislative consent. FDA recognizes that, when corneal tissue is
procured without the consent of the donor's next of kin, a donor
medical history interview with the donor's next of kin does not
necessarily occur. However, the agency notes that the proposed
definition of donor medical history interview would permit the
interview to be conducted with an individual knowledgeable about the
donor's medical history and relevant social behavior (e.g., primary
treating physician) and would not require an interview with the next of
kin. For this reason, FDA considers that the proposed regulation and
State laws on legislative consent may coexist, and does not intend at
this time to preempt those laws
uld permit the
interview to be conducted with an individual knowledgeable about the
donor's medical history and relevant social behavior (e.g., primary
treating physician) and would not require an interview with the next of
kin. For this reason, FDA considers that the proposed regulation and
State laws on legislative consent may coexist, and does not intend at
this time to preempt those laws. The agency requests that affected
parties submit specific, detailed comments on any potential conflicts
that might make it impossible to comply with both this regulation and
State laws on legislative consent.
Requiring a donor medical history interview for corneas obtained
under legislative consent is necessary to ensure that the risk of
communicable disease transmission is appropriately assessed. To prevent
the transmission of communicable disease, adequate donor screening
measures are necessary, even when approved tests are available.
The necessity of adequate screening for TSE illustrates the
importance of the donor medical history interview. The regulations now
being proposed would require TSE screening for all cell and tissue
donors and, in the case of dura mater donors, a post-mortem physical
assessment for TSE. (In contrast, current regulations on human tissue
intended for transplantation contained in part 1270 do not require
screening or testing for TSE.) Two recent possible transmissions of TSE
by corneal tissue have been reported in Japan and Germany. In addition,
three potential CJD transmissions have been reported in the United
Kingdom, where corneas and sclera from a donor subsequently determined
to have CJD were transplanted into, and then removed from, three
recipients (Ref. 20). Recent cognitive changes and abnormalities in
speech and gait are possible indications of TSE
TSE
by corneal tissue have been reported in Japan and Germany. In addition,
three potential CJD transmissions have been reported in the United
Kingdom, where corneas and sclera from a donor subsequently determined
to have CJD were transplanted into, and then removed from, three
recipients (Ref. 20). Recent cognitive changes and abnormalities in
speech and gait are possible indications of TSE. These and other
behavioral changes that a cell or tissue donor might exhibit prior to
donation would be expected to be uncovered in the donor medical history
interview, but would be less likely to turn up during other parts of
the screening process.
2. Specific Communicable Disease Screening Requirements
Proposed Sec. 1271.75(a)(1) states that the relevant medical
records for a cell or tissue donor shall be reviewed for risk factors
for and clinical evidence of infection due to relevant communicable
disease agents and diseases. Proposed Sec. 1271.75(a)(1) specifically
lists HIV, HBV, HCV, and TSE as relevant communicable disease agents
and

diseases for which such screening is required. These four disease
agents and diseases are listed as the ``minimum'' for which screening
would be required; should a new relevant communicable disease arise or
be identified, the agency would consider manufacturers to be required,
under proposed Sec. 1271.75(a)(1), to screen for the new disease as
well.
Special concerns arise with respect to donors of reproductive
cells or tissue, when those cells or tissue are recovered through
methods that could lead to the transmission of sexually transmitted and
genitourinary diseases. Accordingly, under proposed Sec. 1271.75(b), if
those methods are used, donor screening would be required for risk
factors for and clinical evidence of infection due to sexually
transmitted and genitourinary diseases
of reproductive
cells or tissue, when those cells or tissue are recovered through
methods that could lead to the transmission of sexually transmitted and
genitourinary diseases. Accordingly, under proposed Sec. 1271.75(b), if
those methods are used, donor screening would be required for risk
factors for and clinical evidence of infection due to sexually
transmitted and genitourinary diseases. Certain methods of recovery,
e.g., laparoscopy to recover oocytes, are not directly connected with
the transmission of sexually transmitted and genitourinary diseases,
and would not trigger this requirement.
Special concerns also arise with respect to potential donors who
have received xenotransplants. Xenotransplantation is the
transplantation of live cells, tissues, and/or organs between different
species, such as from a baboon or pig to a human. Because
transplantation necessitates disruption of the recipient's usual
protective physical immunologic barriers, xenotransplantation may
facilitate transmission of known and as yet unrecognized agents to
humans. These can include unknown retroviruses, which may remain latent
for a period of time before causing clinically recognized disease.
Concerns about the potential infectious disease and public health risks
associated with xenotransplantation have been discussed at two recent
FDA meetings (Xenotransplantation Advisory Subcommittee of the Biologic
Response Modifier Advisory Committee, December 17, 1997, and Blood
Products Advisory Committee, March 19, 1998).
Cells or tissue from a xenotransplant recipient could potentially
contain infectious agents transmitted by the xenotransplant. In
addition, the cells or tissues of a person who has been a close contact
of a xenotransplant recipient could contain infectious agents
originating from the xenotransplant. Because of the potential severity
of the risk associated with these situations, the agency is proposing
to require, in Sec
ansplant recipient could potentially
contain infectious agents transmitted by the xenotransplant. In
addition, the cells or tissues of a person who has been a close contact
of a xenotransplant recipient could contain infectious agents
originating from the xenotransplant. Because of the potential severity
of the risk associated with these situations, the agency is proposing
to require, in Sec. 1271.75(a)(2), that medical records be reviewed to
determine whether a potential donor of cells or tissue has received a
xenotransplant or has been a close contact of a xenotransplant
recipient. If so, the donor would be determined to be unsuitable under
proposed Sec. 1271.75(c).
FDA is proposing to define ``xenotransplantation'' in
Sec. 1271.3(aa) as any procedure that involves the use of live cells,
tissues, or organs from a nonhuman animal source, transplanted or
implanted into a human, or used for ex vivo contact with human body
fluids, cells, tissues, or organs that are subsequently given to a
human recipient. Nonliving biological products or materials from
animals, such as porcine heart valves, porcine insulin, and bovine
serum albumin, have been used clinically for decades and would not be
considered xenotransplantation products for purposes of these
regulations. ``Close contacts'' of a xenotransplant recipient would be
defined in proposed Sec. 1271.3(bb) as household members and others
with whom the recipient participates in activities that could result in
exchanges of bodily fluids.

E. Donor Testing
vine
serum albumin, have been used clinically for decades and would not be
considered xenotransplantation products for purposes of these
regulations. ``Close contacts'' of a xenotransplant recipient would be
defined in proposed Sec. 1271.3(bb) as household members and others
with whom the recipient participates in activities that could result in
exchanges of bodily fluids.

E. Donor Testing

In addition to donor screening, the analysis of donor test results
is necessary for a donor-suitability determination. Laboratory tests
conducted on specimens collected from a cell or tissue donor can
indicate whether the donor has evidence of infection due to a relevant
communicable disease agent or disease. Proposed Sec. 1271.80 sets out
the general requirements for donor testing. Disease- and product-
specific requirements are in proposed Sec. 1271.85.
FDA notes that the proposed regulations employ the word
``screening'' in two different contexts. In proposed Secs. 1271.80 and
1271.85, ``screening test'' refers to a laboratory test to determine
exposure to or presence of a relevant communicable disease agent. The
agency has used the term ``screening test'' in the past, e.g.,
Sec. 1270.21, and considers it to be the generally recognized term in
the industry and medical community for this type of initial test. Other
sections of the proposed regulations, e.g., proposed Sec. 1271.75, use
the term ``donor screening'' to refer to the review of the donor's
relevant medical records, as defined in proposed Sec. 1271.3(v). This
use of ``donor screening'' is consistent with part 1270 and with usage
by the industry and medical community.
1. General Requirements (Proposed Sec. 1271.80)
FDA proposes in Sec. 1271.80(a) to require that a donor specimen
be tested for evidence of infection due to relevant communicable
disease agents and diseases, which would include, at a minimum, those
specified in proposed Sec. 1271.85. Proposed Sec
or screening'' is consistent with part 1270 and with usage
by the industry and medical community.
1. General Requirements (Proposed Sec. 1271.80)
FDA proposes in Sec. 1271.80(a) to require that a donor specimen
be tested for evidence of infection due to relevant communicable
disease agents and diseases, which would include, at a minimum, those
specified in proposed Sec. 1271.85. Proposed Sec. 1271.80(a) states
that a specimen from the mother of a fetal or neonatal donor would be
acceptable for testing. The proposed regulation also specifically notes
that the purpose of testing is to adequately and appropriately reduce
the risk of transmission of relevant communicable diseases.
Proposed Sec. 1271.80(b) addresses the timing of the collection of
a donor specimen for testing. The agency proposes to require that the
donor specimen be collected at the time of recovery of cells or tissue
from the donor or within 48 hours after recovery. The agency is
concerned that a specimen collected prior to donation may not
accurately reflect the donor's actual exposure to a relevant
communicable disease at the time of donation. However, the agency
recognizes that there may be certain instances in which it would be
preferable to analyze a donor specimen to determine donor suitability
in advance of recovery of cells or tissue. For that reason, the agency
proposes that, for living donors, a specimen may be collected up to 7
days prior to recovery if: (1) Recovery of the cells or tissue involves
invasive procedures or substantial risk to the donor; (2) implantation,
transplantation, infusion, or transfer of the recovered cells or tissue
is necessary before results of testing performed on a specimen
collected at the time of recovery or post recovery would be available;
or (3) extensive processing of the recovered cells or tissue is
necessary before results of testing performed on a specimen collected
at the time of recovery or post recovery would be available
splantation, infusion, or transfer of the recovered cells or tissue
is necessary before results of testing performed on a specimen
collected at the time of recovery or post recovery would be available;
or (3) extensive processing of the recovered cells or tissue is
necessary before results of testing performed on a specimen collected
at the time of recovery or post recovery would be available.
The agency recognizes that its proposed requirement on the timing
of collection of donor specimens differs from testing practices
currently followed by various industry members, and specifically
requests comments on this proposal. Any comments that propose an
alternative time period should explain how the proffered alternative
balances the agency's concern about the spread of communicable disease
with the practical concerns relating to the coordination of donor
testing and donation.
Under proposed Sec. 1271.80(c), testing would be required to be
performed using FDA-licensed, approved, or cleared donor screening
tests in accordance with the manufacturer's instructions, to adequately
and appropriately reduce the risk of

transmission of relevant communicable disease agents or diseases.
Proposed Sec. 1271.80(c) contains a proviso with respect to Chlamydia
trachomatis and Neisseria gonorrhea, for which testing of certain
donors of reproductive cells and tissues would be required under
proposed Sec. 1271.85(c). At this time there are no FDA-licensed,
approved, or cleared donor screening tests available for those two
disease agents. However, the agency considers that testing for the
disease agents is essential to prevent their spread, and that the use
of tests labeled for the detection of those organisms in an
asymptomatic, low-prevalence population would be adequate and
appropriate until screening tests are available
are no FDA-licensed,
approved, or cleared donor screening tests available for those two
disease agents. However, the agency considers that testing for the
disease agents is essential to prevent their spread, and that the use
of tests labeled for the detection of those organisms in an
asymptomatic, low-prevalence population would be adequate and
appropriate until screening tests are available. Thus, until such time
as appropriate FDA-licensed, approved, or cleared donor screening tests
are available for these disease agents, the required testing would be
performed using tests labeled for detection of the organisms.
Under proposed Sec. 1271.80(d), a donor whose specimen tests
repeatedly reactive or positive on a test required under proposed
Sec. 1271.85 must be determined to be unsuitable. (Repeatedly reactive
means initially reactive, then reactive in at least one of two
duplicate tests with the same manufacturer's test kit.) Proposed
Sec. 1271.80(d)(1)(i) and (d)(1)(ii) set out two exceptions to this
general rule. Under the first exception, a repeatedly reactive test for
CMV will not make a donor unsuitable unless additional testing shows
the presence of an active infection. This exception is being proposed
because, although a donor with active CMV poses a risk of CMV
transmission, a donor's past infection with the virus does not
necessarily present such a risk. The results of CMV testing would
accompany the product, under proposed Sec. 1271.55(a)(1)(i), or would
be contained in the summary of records that accompanies the product,
and should be reviewed by the physician prior to use of the product.
The agency believes that the provision of information on CMV status in
the materials accompanying the product will be sufficient to allow
physicians to make informed decisions about the use of the product in
particular patients' circumstances. The agency specifically requests
comments on this approach
companies the product,
and should be reviewed by the physician prior to use of the product.
The agency believes that the provision of information on CMV status in
the materials accompanying the product will be sufficient to allow
physicians to make informed decisions about the use of the product in
particular patients' circumstances. The agency specifically requests
comments on this approach.
The second exception is for a donor whose specimen has tested
repeatedly reactive on a non-Treponemal screening test for syphilis and
negative on a specific Treponemal confirmatory test. FDA is proposing
this exception because it recognizes that non-Treponemal screening
tests, which do not test directly for the disease agent, frequently
provide false-positive results. Negative results from a Treponemal
confirmatory test, which is more specific and, thus, more accurate,
will be considered to override an initial false positive.
Blood loss from a potential donor, followed by transfusion or
infusion, may result in plasma dilution that affects test results.
Plasma dilution is defined in proposed Sec. 1271.3(s) as a decrease in
the concentration of the donor's plasma proteins and circulating
antigens or antibodies resulting from the transfusion of blood or blood
components and/or infusion of fluids. Proposed Sec. 1271.80(d)(2) sets
out the requirements for assessing whether a specimen from a donor from
whom blood loss has occurred is acceptable. (In the absence of an
acceptable specimen, a donor must be determined to be unsuitable.) A
specimen taken after blood loss but before the transfusion or infusion
is acceptable. In addition, in certain instances an established
procedure to calculate dilution (an algorithm) may be used. Proposed
Sec. 1271.80(d)(2) is based closely on Sec. 1270.20(h)(2) and (h)(3).
FDA discussed the provisions of Sec
e absence of an
acceptable specimen, a donor must be determined to be unsuitable.) A
specimen taken after blood loss but before the transfusion or infusion
is acceptable. In addition, in certain instances an established
procedure to calculate dilution (an algorithm) may be used. Proposed
Sec. 1271.80(d)(2) is based closely on Sec. 1270.20(h)(2) and (h)(3).
FDA discussed the provisions of Sec. 1270.20(h)(2) and (h)(3) in the
tissue final rule (see 62 FR 40429 at 40435 through 40436), and the
guidance document that accompanied that rule contains information on
plasma dilution and algorithms.
2. Specific Requirements (Proposed Sec. 1271.85)
Proposed Sec. 1271.85 sets out specific requirements with respect
to donor testing. Proposed Sec. 1271.85(a), (b), and (c) identify the
minimum relevant communicable disease agents for which testing is
required. Proposed Sec. 1271.85(d) contains retesting requirements for
donors of certain reproductive cells or tissues.
The proposed requirements in Sec. 1271.85(a) cover all cells and
tissues that are not subject to a regulatory exception from the testing
requirement. Under proposed Sec. 1271.85(a), a specimen from a donor of
viable or nonviable cells or tissue would be required to be tested for
evidence of infection due to: HIV type 1, HIV type 2, HBV, HCV, and
Treponema pallidum.
In addition to the testing required under proposed
Sec. 1271.85(a), a donor of viable, leukocyte-rich cells or tissues
would be required under proposed Sec. 1271.85(b) to be tested for
evidence of infection due to: HTLV types I and II, and CMV. The agency
is proposing to make the distinction between cells and tissues that are
rich in leukocytes and those that are not, because the transmission of
certain disease agents, such as HTLV types I and II, and CMV, depends
on the presence of viable leukocytes. Stem cells and reproductive cells
and tissue, e.g., semen, are examples of leukocyte-rich cells or
tissue
V types I and II, and CMV. The agency
is proposing to make the distinction between cells and tissues that are
rich in leukocytes and those that are not, because the transmission of
certain disease agents, such as HTLV types I and II, and CMV, depends
on the presence of viable leukocytes. Stem cells and reproductive cells
and tissue, e.g., semen, are examples of leukocyte-rich cells or
tissue. In contrast, FDA does not consider corneas, skin, heart valves,
dura mater, bone, tendons, ligaments, or cartilage to be leukocyte-
rich. The agency specifically requests comments on whether the term
``leukocyte-rich'' needs additional clarification.
Proposed Sec. 1271.85(c) would require testing for donors of
reproductive cells or tissue, in addition to those required by proposed
Sec. 1271.85(a) and (b). Proposed Sec. 1271.85(c)(1) identifies
Chlamydia trachomatis and Neisseria gonorrhea as relevant genitourinary
disease agents for which testing would be required. However, testing
for Chlamydia trachomatis and Neisseria gonorrhea would not be required
if the reproductive cells or tissue are procured 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. FDA
is requesting comments and supporting data on whether other
genitourinary disease agents should be considered relevant.
Proposed Sec. 1271.85(a), (b), and (c) specify that the purpose of
testing is to adequately and appropriately reduce the risk of
transmission of relevant communicable diseases. Thus, any test
performed under proposed Sec. 1271.85 must be chosen with this purpose
in mind. The regulation specifies that testing shall be performed using
FDA-licensed, approved, or cleared screening tests in accordance with
the manufacturers' instructions
cify that the purpose of
testing is to adequately and appropriately reduce the risk of
transmission of relevant communicable diseases. Thus, any test
performed under proposed Sec. 1271.85 must be chosen with this purpose
in mind. The regulation specifies that testing shall be performed using
FDA-licensed, approved, or cleared screening tests in accordance with
the manufacturers' instructions.
The following list represents FDA's current thinking on the
appropriate FDA-licensed, approved, or cleared screening tests that
should be used to adequately and appropriately reduce the risk of
transmission of relevant communicable disease agents or diseases:
(1) HIV, type 1: FDA-licensed screening test for anti-HIV-1:
(2) HIV, type 2: FDA-licensed screening test for anti-HIV-2:
(3) HBV: FDA-licensed screening test for hepatitis B surface
antigen (HBsAg);
(4) HCV: FDA-licensed screening test for anti-HCV;
(5) Treponema pallidum: FDA-cleared serological test for syphilis;
(6) Human T-lymphotropic virus, types I and II: FDA-licensed
screening test for anti-HTLV I/II; and
(7) Cytomegalovirus: FDA-cleared test for anti-CMV.

In the case of HBV, there are two types of screening test: A test
for the surface antigen and a test for the core antibody. Currently,
the appropriate test to reduce the possibility of transmission of HBV
to a recipient is the surface antigen test because it is a marker of
infectivity. Thus, ``FDA-licensed screening test for HBsAg'' appears on
the previous list as an example of a test to be performed for the HBV
virus. Testing for the core antibody alone would not accurately
evaluate the donor for the possibility of transmission, because the
core antibody test could be negative and the donor could still be
infectious. Active infection at the time of donation can only be
adequately evaluated with the use of the surface antigen screening
test, which, if repeatedly reactive, indicates early or chronic HBV
infection
g for the core antibody alone would not accurately
evaluate the donor for the possibility of transmission, because the
core antibody test could be negative and the donor could still be
infectious. Active infection at the time of donation can only be
adequately evaluated with the use of the surface antigen screening
test, which, if repeatedly reactive, indicates early or chronic HBV
infection.
It should be noted that, if the establishment determining the
suitability of the donor is aware of any repeatedly reactive screening
test for a relevant communicable disease agent that indicates the
possible presence of a relevant communicable disease, whether or not
the test is the one best suited to adequately and appropriately reduce
the risk of disease transmission, then the donor of the cellular or
tissue-based product must be determined to be unsuitable under proposed
Sec. 1271.80(d)(1). For example, a repeatedly reactive core antibody
test for HBV, although not required, would make the donor unsuitable.
Proposed Sec. 1271.80(d) would require retesting of the donor at
least 6 months after the date of donation of reproductive cells or
tissues that can reliably be stored. Cells or tissues that can reliably
be stored are those that maintain function and integrity during
storage; some examples include spermatozoa and sperm progenitor cells.
The retesting requirement is designed to address the ``window period''
between the time of infection and the presence of detectable levels of
antibodies to communicable diseases and agents such as HCV. Testing
would not be complete, and thus a donor-suitability determination could
not be made, until the completion of the second round of tests. Under
proposed Sec. 1271.60(a), quarantine for these products would last a
minimum of 6 months, until completion of testing. For donors of
reproductive cells and tissues that can be reliably stored, FDA
considers HBV core antibody screening test to be the most adequate and
appropriate retest for HBV
itability determination could
not be made, until the completion of the second round of tests. Under
proposed Sec. 1271.60(a), quarantine for these products would last a
minimum of 6 months, until completion of testing. For donors of
reproductive cells and tissues that can be reliably stored, FDA
considers HBV core antibody screening test to be the most adequate and
appropriate retest for HBV.
For all other banked tissue and cells from living donors, FDA
recommends but does not propose to require that, where appropriate and
feasible, all donors (or mothers of fetal or neonatal donors) be
retested 6 months after donation and that the banked cells and tissue
be kept in quarantine pending retesting.
3. Dura Mater
CJD, a type of TSE, is a rare, but invariably fatal, degenerative
disease of the central nervous system characterized by progressive
dementia. Recent reports link the transmission of CJD to recipients of
human cadaveric dura mater, particularly allografts manufactured by one
company prior to 1987. Thus, FDA proposes to require, in
Sec. 1271.85(e), that an assessment be performed for donors of dura
mater to detect evidence of TSE.
On March 27, 1997, the World Health Organization (WHO) recommended
a ban on the use of human dura mater as an implant because of reports
of CJD in a limited number of recipients. Since FDA had established
safeguards and guidelines in 1990 to minimize the possibility of such
infections, the agency announced on March 31, 1997, that it would not
restrict the distribution of FDA-cleared dura mater allografts.
On October 6, 1997, FDA's Transmissible Spongiform Encephalopathy
Advisory Committee (TSEAC) discussed the existing safeguards and
additional safeguards that needed to be in place to prevent the
transmission of CJD by human cadaveric dura mater. The TSEAC's
recommendations were transmitted to industry through an FDA letter to
manufacturers on March 6, 1998. After comments were received, FDA
revisited the issues with TSEAC on April 16, 1998
m Encephalopathy
Advisory Committee (TSEAC) discussed the existing safeguards and
additional safeguards that needed to be in place to prevent the
transmission of CJD by human cadaveric dura mater. The TSEAC's
recommendations were transmitted to industry through an FDA letter to
manufacturers on March 6, 1998. After comments were received, FDA
revisited the issues with TSEAC on April 16, 1998. Based upon the
recommendations of the TSEAC at this meeting, the following represent
proposed procedures for complying, at the present time, with the
testing requirements of proposed Sec. 1271.85(e) and the screening
requirements of proposed Sec. 1271.75(a)(4).
After the dura mater has been removed, a full brain autopsy of the
donor of dura mater, including gross and histological examination,
should be performed by a qualified neuropathologist, to identify
evidence of TSE changes. Testing to detect protease-resistant prion
protein (PrP-RES) either by immunohistochemistry or Western Blot, is
currently a research (investigational use) tool, as there is no FDA-
approved or validated test for screening TSE in brain tissue. However,
a negative test is considered significant in increasing the level of
confidence that the brain and the dura mater are free of TSE. FDA
encourages validation of this test. Manufacturers should continue to
monitor scientific developments and should incorporate this test if and
when it becomes approved for this intended use.
Donors of dura mater should be subject to a consistent screening
protocol, including a donor medical history interview that includes
questions relevant to TSE risk, as mentioned in the human tissue
guidance.
FDA intends to address other recommendations of the TSEAC in
future proposed regulations on CGTP's
nd should incorporate this test if and
when it becomes approved for this intended use.
Donors of dura mater should be subject to a consistent screening
protocol, including a donor medical history interview that includes
questions relevant to TSE risk, as mentioned in the human tissue
guidance.
FDA intends to address other recommendations of the TSEAC in
future proposed regulations on CGTP's. These include a standard
protocol for procuring dura mater, prevention of cross-contamination,
use of either a NaOH protocol or other procedure that has been
validated to reduce infectivity while preserving clinical utility,
archiving of a sample of brain and dura mater tissues, and
recordkeeping and tracking requirements.
4. Corneal Tissue
The possibility that corneal tissue may transmit TSE is discussed
in section III.D.1 of this document. Although the agency is proposing
to require that, for donors of dura mater, an assessment designed to
detect evidence of TSE be performed, the recommended method of
accomplishing this assessment involves a full brain autopsy, including
gross and histological examination, and definitive results are not
available for several weeks. At present, this type of testing does not
appear feasible for cornea donors, because under present conditions of
storage in the United States, corneas must be transplanted within days
of procurement in order to maintain their integrity and function. The
agency requests comment on the feasibility of testing for TSE in donors
of corneal tissue.

F. Exceptions (Proposed Sec. 1271.90)
ral weeks. At present, this type of testing does not
appear feasible for cornea donors, because under present conditions of
storage in the United States, corneas must be transplanted within days
of procurement in order to maintain their integrity and function. The
agency requests comment on the feasibility of testing for TSE in donors
of corneal tissue.

F. Exceptions (Proposed Sec. 1271.90)

1. Exceptions From the Requirement for a Donor Suitability
Determination
Proposed Sec. 1271.90(a) identifies two situations in which a
determination of donor suitability would not be required. In the case
of banked cells and tissues for autologous use, cells and tissues are
removed from a patient and stored for later use in the same patient.
Because the risk of the patient's contracting a new communicable
disease from cells or tissues taken from his or her own body is
extremely low, FDA is not requiring communicable disease testing or
screening. (Any handling and storage requirements for such cells or
tissue may be addressed later, in the proposed CGTP regulation.)
However, as a general safety measure, FDA recommends that

autologous donors be subjected to the same testing and screening as
proposed under Secs. 1271.75, 1271.85, and 1271.90 for allogeneic
donors of comparable human cellular or tissue-based products.
The second situation in which FDA is recommending but not
requiring testing is for reproductive cells or tissue donated by a
sexually intimate partner of the recipient. In this case, the recipient
will likely have been routinely exposed to the donor's semen or other
body fluids. Although some screening and testing of the donor and
recipient may be appropriate, FDA believes that this should be the
responsibility of the attending physician and the donor and the
recipient.
2. Labeling Requirements
Although screening and testing would not be required in the two
above situations, FDA is proposing certain labeling requirements
d to the donor's semen or other
body fluids. Although some screening and testing of the donor and
recipient may be appropriate, FDA believes that this should be the
responsibility of the attending physician and the donor and the
recipient.
2. Labeling Requirements
Although screening and testing would not be required in the two
above situations, FDA is proposing certain labeling requirements.
In order to protect those people who may handle the human cellular
or tissue-based product, the manufacturer would be required to label a
product as ``NOT EVALUATED FOR INFECTIOUS SUBSTANCES'' unless all donor
screening and testing applicable to a comparable human cellular or
tissue-based product under proposed Secs. 1271.75, 1271.80, and 1271.85
are performed. Thus, if screening and testing results are negative, but
not all of the testing and screening that would be required under
proposed Secs. 1271.75, 1271.80, and 1271.85 are performed, then the
product would be labeled ``NOT EVALUATED FOR INFECTIOUS SUBSTANCES.''
However, if any screening or testing is performed, and the results
indicate the presence of relevant communicable disease agents, or risk
factors for and/or clinical evidence of relevant communicable disease,
then the product would be labeled with the Biohazard legend shown in
proposed Sec. 1271.3(i).
In addition, the manufacturer would be required to label
autologous banked cells and tissues as ``FOR AUTOLOGOUS USE ONLY.''
Such a label would help prevent inadvertent allogeneic administration.

G. Drug and Device Amendments (Secs. 210.1, 210.2, 211.1, 820.1)
te the product. (References to the
requirements in proposed part 1271 are also proposed to be added to
Secs. 210.2 and 211.1, to bring those regulations in conformity with
the changes in Sec. 210.1.) Comparable amendments are being proposed
for Sec. 820.1 to achieve the same result with respect to human
cellular and tissue-based products regulated as devices.

IV. Analysis of Economic Impacts

FDA has examined the impacts of the proposed rule under Executive
Order 12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612),
and under the Unfunded Mandates Reform Act (Public Law 104-4).
Executive Order 12866 directs agencies to assess all costs and benefits
of available regulatory alternatives and, when regulation is necessary,
to select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The Regulatory
Flexibility Act requires agencies to analyze whether a rule may have a
significant impact on a substantial number of small entities and, if it
does, to analyze regulatory options that would minimize the impact. The
Unfunded Mandates Reform Act requires that agencies prepare a written
statement under section 202(a) of anticipated costs and benefits before
proposing any rule that may result in an expenditure by State, local,
and tribal governments, in the aggregate, or by the private sector, of
$100 million (adjusted annually for inflation in any one year).
The agency believes that this final rule is consistent with the
principles identified in Executive Order 12866. OMB has determined that
the final rule is a significant regulatory action as defined by the
Executive Order and so is subject to review
ate, local,
and tribal governments, in the aggregate, or by the private sector, of
$100 million (adjusted annually for inflation in any one year).
The agency believes that this final rule is consistent with the
principles identified in Executive Order 12866. OMB has determined that
the final rule is a significant regulatory action as defined by the
Executive Order and so is subject to review. Because the rule does not
impose mandates on State, local, or tribal governments, or the private
sector, that will result in an expenditure in any one year of $100
million or more, FDA is not required to perform a cost-benefit analysis
according to the Unfunded Mandates Reform Act.
The Regulatory Flexibility Act requires agencies to prepare a
Regulatory Flexibility Analysis for each rule unless the agency
certifies that the rule will not have a significant economic impact on
a substantial number of small entities. As explained in section IV.C of
this document, the agency believes that most of the facilities would
not be significantly affected by the proposed rule because they are
already performing the infectious disease screening and testing and
recordkeeping that is being proposed. However, FDA does not have
sufficient data to characterize the size distribution and other
relevant features of small entities involved in reproductive tissue and
the impact on these entities is uncertain. FDA has therefore prepared
an Initial Regulatory Flexibility Analysis.

A. Objectives and Basis of the Proposed Action
sease screening and testing and
recordkeeping that is being proposed. However, FDA does not have
sufficient data to characterize the size distribution and other
relevant features of small entities involved in reproductive tissue and
the impact on these entities is uncertain. FDA has therefore prepared
an Initial Regulatory Flexibility Analysis.

A. Objectives and Basis of the Proposed Action

FDA is proposing this action as the next step in the regulation of
the rapidly evolving industry of human cellular and tissue-based
products. This proposed rule focuses on the first of three general
areas of regulation proposed in the approach to cellular and tissue-
based products, i.e., preventing unwitting use of contaminated tissues
with the potential for transmitting infectious diseases such as AIDS
and hepatitis. While acting to increase the safety of the nation's
supply of human cellular and tissue-based products, FDA is proposing
regulations that would avoid unnecessary requirements. The agency has
designed the screening and testing regulations for the specific type
and use of each cellular or tissue-based product that would minimize
regulatory burden while maintaining safety.
In this rulemaking, the agency is proposing to broaden its
regulatory oversight over all human cellular and tissue-based products,
including reproductive cells and tissue. This action is focused on the
prevention of diseases transmitted by specific cellular or tissue-based
products by implantation, transplantation, infusion, or transfer of any
cellular or tissue-based product. For example, FDA is
his rulemaking, the agency is proposing to broaden its
regulatory oversight over all human cellular and tissue-based products,
including reproductive cells and tissue. This action is focused on the
prevention of diseases transmitted by specific cellular or tissue-based
products by implantation, transplantation, infusion, or transfer of any
cellular or tissue-based product. For example, FDA is

now proposing to require cell and tissue donors to be tested for
syphilis and screened for TSE. Donors of viable, leukocyte-rich cells
or tissue would also be tested for HTLV types I and II, and CMV.
Because communicable disease agents can be transmitted by semen and
other genitourinary secretions, FDA is proposing to require that donors
of reproductive cells and tissue be screened and tested for sexually
transmitted diseases. FDA proposes to amend the existing CGMP
regulations for drugs and devices to incorporate the screening and
testing requirements in proposed part 1271 subpart C. FDA is relying on
the authority provided by section 361 of the PHS Act to issue
regulations to prevent the spread of communicable disease, as well as
its authority under the act to issue CGMP regulations (21 U.S.C.
351(a)(2)(B) and (h) and 360j(f)(1)). FDA has reviewed related Federal
rules and has not identified any rules that duplicate, overlap, or
conflict with the proposed rule.

B. The Type and Number of Entities Affected
vided by section 361 of the PHS Act to issue
regulations to prevent the spread of communicable disease, as well as
its authority under the act to issue CGMP regulations (21 U.S.C.
351(a)(2)(B) and (h) and 360j(f)(1)). FDA has reviewed related Federal
rules and has not identified any rules that duplicate, overlap, or
conflict with the proposed rule.

B. The Type and Number of Entities Affected

The proposed rule would require manufacturers of human cellular
and tissue-based products, including human tissue intended for
transplantation, to screen and test donors of cells and tissue used in
those products. The rule would require that donors be screened and
tested for risk factors for and clinical evidence of relevant
communicable disease agents and diseases. The proposed rule would apply
to a range of activities conducted at facilities such as tissue banks,
blood banks, eye banks, semen banks, infertility treatment facilities,
and cord blood banks. However, the number of entities that would be
required to comply with this proposal is difficult to ascertain because
the agency has not previously regulated certain human cellular and
tissue-based products. Although the agency has proposed to require
manufacturers of human cellular and tissue-based products to register
and list their products and to identify their manufacturer steps, this
information will not be available for some time. Consequently, the
agency's estimates rely heavily on information obtained from various
trade organizations related to the human cellular and tissue-based
industry.
As shown in Table 1 of this document, the estimated numbers of
facilities affected by the proposed rule are derived from varied
industry sources. The Eye Bank Association of America (EBAA) represents
about 108 eye banks, which are estimated to be about 95 percent of eye
banks in the United States
ained from various
trade organizations related to the human cellular and tissue-based
industry.
As shown in Table 1 of this document, the estimated numbers of
facilities affected by the proposed rule are derived from varied
industry sources. The Eye Bank Association of America (EBAA) represents
about 108 eye banks, which are estimated to be about 95 percent of eye
banks in the United States. The American Association of Tissue Banks
(AATB) lists approximately 60 accredited tissue banks and projects an
additional 40 to 60 members not accredited. As of May 1998, CBER has
record of 132 registered blood bank facilities listing ``stem cell'' as
a type of product or establishment. The National Marrow Donor Program
(NMDP), which includes establishments that recover peripheral blood
stem cells, lists approximately 101 donor centers (these establishments
are associated with the American Association of Blood Banks (AABB) or
the Foundation for the Accreditation of Hematopoietic Cell Therapy
(FAHCT)). Although there is no single national organization that keeps
track of the number of facilities for umbilical cord blood banking, FDA
estimates that there are approximately 25 cord blood banks currently
operating in the United States. These facilities would also seek
accreditation through FAHCT or AABB.
In addition, the proposed rule would apply to facilities involved
with reproductive tissue, primarily fertility centers and sperm banks
that collect and process donor oocytes or donor sperm. The American
Society of Reproductive Medicine (ASRM) has a membership of
approximately 300 fertility centers, about 280 of which have provided
reports to the 1995 Society for Assisted Reproductive Technology (SART)
registry. The ASRM also has a 1996 list of approximately 110 sperm
banks operating in the United States
ters and sperm banks
that collect and process donor oocytes or donor sperm. The American
Society of Reproductive Medicine (ASRM) has a membership of
approximately 300 fertility centers, about 280 of which have provided
reports to the 1995 Society for Assisted Reproductive Technology (SART)
registry. The ASRM also has a 1996 list of approximately 110 sperm
banks operating in the United States. Although ASRM has published
guidelines for donor screening and other aspects of oocyte donation,
and for therapeutic donor insemination, ASRM does not exercise
oversight or provide accreditation of facilities that collect donor
tissue or use these tissue products in infertility treatment.

C. Nature of the Impact

The proposed rule includes requirements for donor screening, donor
testing, recordkeeping and quarantine of cells and tissue. Donor
screening would involve the review of relevant medical records to
include a medical history interview (particularly pertaining to
communicable disease risk), a current report of a physical assessment
for cadaveric donors, and a physical examination for living donors. For
living repeat donors, a complete donor-suitability determination
procedure would be required at least once every 6 months. The proposed
rule would require that a donor specimen be tested for evidence of
infection due to relevant communicable disease agents and diseases,
with testing conducted within a specified time of recovery of cells or
tissue. In general, a donor may be determined suitable if free from
risk factors for and clinical evidence of infection due to relevant
communicable disease agents and diseases, and if the required testing
is negative or nonreactive.
The proposed rule would also require recordkeeping of donor-
suitability determinations
,
with testing conducted within a specified time of recovery of cells or
tissue. In general, a donor may be determined suitable if free from
risk factors for and clinical evidence of infection due to relevant
communicable disease agents and diseases, and if the required testing
is negative or nonreactive.
The proposed rule would also require recordkeeping of donor-
suitability determinations. Manufacturers would be required to ship
human cellular and tissue-based products accompanied by documentation
of donor-suitability status, including a copy of the donor's relevant
medical records, results of required testing and the name and address
of the establishment that made the suitability determination. The
proposed rule requires that establishments that generate records used
in donor-suitability determinations retain those records for at least
10 years after the date of the product's use or distribution. The
proposed rule would also require that cell and tissue-based products be
quarantined until a determination of donor suitability is made, and
that products be clearly labeled as under quarantine during that
period. The rule would hold manufacturers responsible for the
appropriate labeling and documentation of cells or tissue from a donor
who is found to be unsuitable.
The extent of the economic impact is expected to be minor for most
of these establishments, because the leading industry associations have
already established standards for screening that, in most cases, meet
or exceed the criteria specified in the proposed rule; and because
existing FDA regulations already apply to certain human tissue intended
for transplantation (see part 1270). Table 1 of this document lists the
types of donor cells and tissue that will be affected by the proposed
rule and the associated facilities that collect and bank these tissue
products
creening that, in most cases, meet
or exceed the criteria specified in the proposed rule; and because
existing FDA regulations already apply to certain human tissue intended
for transplantation (see part 1270). Table 1 of this document lists the
types of donor cells and tissue that will be affected by the proposed
rule and the associated facilities that collect and bank these tissue
products. Table 1 also provides estimates of the number of
establishments affected by the proposed rule and the estimated
percentage of establishments already in compliance with current
industry standards for donor screening and testing. The lists of
specific donor screening and testing requirements proposed by FDA can
be compared with those currently required by the industry associations.

Table 1.--Type and Number of Establishments Affected and Percentage Already in Compliance With Industry Standards for Donor Suitability Screening and
Testing
--------------------------------------------------------------------------------------------------------------------------------------------------------
Relevant Industry Association
Type of Human Donor Tissue Type of Entities Affected (and Standards Compared to FDA Proposed Estimated Percent Entities in
Estimated Total Number) Regulations Compliance with Industry Standards
--------------------------------------------------------------------------------------------------------------------------------------------------------
Nonreproductive Tissue

--------------------------------------------------------------------------------------------------------------------------------------------------------
Eye tissue Eye banks 21 CFR part 1270 and FDA proposed 100%
108 EBAA members (114 total) (s1,s2,s3)\1\
(t1,t2,t3,t5)\2\
EBAA
(s1 through s3)\1\
(t1 through t3)\2\
Pericardium, dura mater, heart Tissue banks 21 CFR part 1270 and FDA proposed 100%
valves, skin allograft, bone 60 AATB members (110 total) (s1 through s3)\1\
allograft, other viable (t1,t2,t3,t5)\2\
AATB
(s1 throu
-------------
Eye tissue Eye banks 21 CFR part 1270 and FDA proposed 100%
108 EBAA members (114 total) (s1,s2,s3)\1\
(t1,t2,t3,t5)\2\
EBAA
(s1 through s3)\1\
(t1 through t3)\2\
Pericardium, dura mater, heart Tissue banks 21 CFR part 1270 and FDA proposed 100%
valves, skin allograft, bone 60 AATB members (110 total) (s1 through s3)\1\
allograft, other viable (t1,t2,t3,t5)\2\
AATB
(s1 through s3)\1\
(t1 through t5)\2\
Stem cells; peripheral blood Marrow donor centers FDA proposed 100%
132 FDA registered facilities (s1 through s3)\1\
donor centers (101 total) (t1 through t6)\2\
collection centers (114 total) AABB/FAHCT
(s1 through s3)\1\
(t1 through t6)\2\
Stem cells; umbilical cord blood Cord blood banks (25 total) FDA proposed 100%
(s1 through s3)\1\
(t1 through t6)\2\
AABB/FAHCT
(s1 through s3)\1\
(t1 through t6)\2\
--------------------------------------------------------------------------------------------------------------------------------------------------------

Reproductive Tissue

--------------------------------------------------------------------------------------------------------------------------------------------------------
Donor oocyte, embryos ART facilities & associated labs FDA proposed Unknown
281 in 1995 SART report (300 total) (s1 through s3)\1\
(t1,t2,t3,t5)\2\
ASRM, CAP
(s1)\1\
(t1,t2,t3,t5)\2\
Donor sperm Sperm banks FDA proposed 10% Unknown
4 in 1996 AATB survey (110 total) (s1 through s3)\1\
(t1 through t8)\2\
AATB
(s1 through s3)\1\
(t1 through t8)\2\
ASRM
(s1)\1\
(t1,t2,t3,t5,t7,t8)\2\
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Screening for: s1: HIV, s2: hepatitis, s3: CJD
\2\ Laboratory Tests: t1: anti-HIV-1-2, t2: anti-HCV, t3: HBsAg, t4: anti-HTLV-1, t5: syphilis, t6: CMV, t7: Neisseria gonorrhea, t8: Chlamydia
trachomatis
ASRM
(s1)\1\
(t1,t2,t3,t5,t7,t8)\2\
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Screening for: s1: HIV, s2: hepatitis, s3: CJD
\2\ Laboratory Tests: t1: anti-HIV-1-2, t2: anti-HCV, t3: HBsAg, t4: anti-HTLV-1, t5: syphilis, t6: CMV, t7: Neisseria gonorrhea, t8: Chlamydia
trachomatis

Based on communications with representatives of several industry
associations and facility managers, FDA estimates that the number of
facilities currently in compliance with industry standards for donor
screening and testing approaches 100 percent for several affected types
of tissue product. Facilities handling reproductive tissue are the
primary exception to this finding, and also represent the greatest area
of uncertainty for this analysis. There is currently no single reliable
source of information on fertility center or sperm bank compliance with
AATB standards or ASRM guidelines. A small percentage of sperm banks
are members of the AATB and are known to comply with that
organization's requirements for screening and testing, but little is
known about the standards for screening used at other facilities.
Because this information is essential for the estimation of economic
impact, FDA requests detailed industry comment on current donor
screening and testing practices in these facilities.
In addition to the proposed donor screening and testing, the
proposed rule is expected to require facility staff time to align
current quarantine, sample labeling and recordkeeping systems with the
requirements of the proposed rule. As shown in Table 2 of this
document, all of the industry associations already specify requirements
for these procedures. With the exception of facilities handling
reproductive tissue, the current industry standards adopted by most
facilities are at least as stringent as those included in the proposed
rule.
sample labeling and recordkeeping systems with the
requirements of the proposed rule. As shown in Table 2 of this
document, all of the industry associations already specify requirements
for these procedures. With the exception of facilities handling
reproductive tissue, the current industry standards adopted by most
facilities are at least as stringent as those included in the proposed
rule.

Table 2.--Correspondence of FDA-proposed Requirements to Current Industry Standards for Specimen Quarantine,
Labeling, and Recordkeeping
----------------------------------------------------------------------------------------------------------------
FDA-Proposed AATB Current EBAA Current AABB Current FAHCT Current ASRM Current
----------------------------------------------------------------------------------------------------------------
Quarantine X1 X1 X1 X1 Donor sperm; not
oocyte
----------------------------------------------------------------------------------------------------------------
Labeling X1 X1 X1 X1 X1
----

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Source: Frix Law Library, https://www.frixlaw.com/law-library/statutes/FR_PRORULE_99-25378. Check the current official text before relying on it. Not legal advice.