[Federal Register: September 30, 1999 (Volume 64, Number 189)]
[Proposed Rules]
[Page 52696-52723]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr30se99-34]

=======================================================================
-----------------------------------------------------------------------

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.

-----------------------------------------------------------------------

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.

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.

[[Page 52697]]

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). (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.
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. 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

     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. Second, the proposed regulations would require screening
and testing for additional diseases. (The present rulemaking affects
only the screening and testing

[[Page 52698]]

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.
     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

     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. 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.
     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. 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

[[Page 52699]]

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

 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. 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. 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. 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.
     (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

[[Page 52700]]

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.
     (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.
     (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. 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. 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. 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

[[Page 52701]]

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. 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. 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. 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). 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.
     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

[[Page 52702]]

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. 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. 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. 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. 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. 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

[[Page 52703]]

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. 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. 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.
     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. 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. 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

[[Page 52704]]

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. 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. 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

     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. 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.
     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

[[Page 52705]]

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. 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.
     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. 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. 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.
     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.

[[Page 52706]]

     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.
     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.
     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. 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. 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)

 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

[[Page 52707]]

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.
     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)

     As discussed in section I of this document, FDA proposes to
require that manufacturers of human cellular or tissue-based products
regulated as drugs, medical devices, and/or biological products comply
with the donor-suitability procedures now being proposed. In a future
proposed rulemaking, the agency plans to propose CGTP's that would be
applicable to these products, as well. The donor-suitability and CGTP
procedures would be considered part of CGMP requirements for drugs and
the Quality System for devices. In order to incorporate these new
procedures, FDA is proposing to amend parts 210 and 211 with respect to
human cellular and tissue-based products regulated as drugs and/or
biological products and part 820 with respect to human cellular and
tissue-based products regulated as devices.
     FDA proposes to amend Sec. 210.1 by adding new paragraph (c),
which would contain the requirement for compliance with the donor-
suitability procedures proposed in part 1271 subpart C and the current
CGTP procedures to be proposed in part 1271 subpart D as part of the
GMP requirements, and which would state that failure to comply with
those or other CGMP's would adulterate 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. 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

     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

[[Page 52708]]

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

     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. 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. 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. 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. 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.

[[Page 52709]]

  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 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

    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.

[[Page 52710]]

  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         X<SUP>1</SUP>                 X<SUP>1</SUP>                 X<SUP>1</SUP>                 X<SUP>1</SUP>                 Donor sperm; not
                                                                                                oocyte
----------------------------------------------------------------------------------------------------------------
Labeling           X<SUP>1</SUP>                 X<SUP>1</SUP>                 X<SUP>1</SUP>                 X<SUP>1</SUP>                 X<SUP>1</SUP>
----------------------------------------------------------------------------------------------------------------
Record Retention   X<SUP>1</SUP>                 X<SUP>1</SUP>                 X<SUP>1</SUP>                 X<SUP>1</SUP>                 Recommended; not
                                                                                                required
----------------------------------------------------------------------------------------------------------------
\1\  ``X'' means corresponds.

    Due to the disparity in the amount of available information and the
potential impact of the rule on nonreproductive versus reproductive
tissue establishments, these two broad categories of tissue
establishments are treated separately in the impact analysis that
follows.
1. Impact on Nonreproductive Tissue Establishments
    (a) Impact of donor screening and testing. As summarized in Table 1
of this document, most nonreproductive tissue establishments are
already in compliance with the proposed FDA donor screening and testing
requirements, as a result of following their own industry association
standards and FDA current regulations. The cost of compliance with
these provisions will be minimal for these establishments.
    (b) Impact of recordkeeping and tissue quarantine. The burden of
recordkeeping and tissue quarantine requirements will reflect the staff
time needed to compare current recordkeeping and facility procedures
with those required by the proposed standard and to make modifications
where needed in current facility procedures. Such changes are expected
to be minor for most nonreproductive tissue establishments.
    FDA estimates that it would take approximately 8 to 40 hours to
compare the proposed regulations against a facility's current
standards. This process would be performed by a staff person who acts
as a regulatory reviewer, a supervisor, or a manager of quality
assurance. Assuming a labor cost of $40 per hour, this standards
reconciliation effort would result in a one-time cost per facility
ranging from $320 to $1,600. Applying this range of cost per facility
to the approximately 380 nonreproductive tissue facilities yields a
potential impact that ranges from $121,600 to $608,000.
2. Impact on Reproductive Tissue Establishments
    (a) Impact of donor screening and testing. As indicated in Table 1
of this document, the current rate of compliance with industry
standards is unknown among reproductive tissue establishments. Thus,
FDA cannot develop a precise estimate of regulatory costs. As an upper
bound figure, however, FDA assumed that 100 percent of facilities
involved with oocyte donation and 80 percent of sperm banks would need
additional screening and testing. Although the out-of-compliance sperm
banks constitute a majority of the firms in that industry, they are
primarily small operations that are estimated to serve only 5 percent
of all sperm donors.
    (i) Oocyte Donor Screening and Testing. The estimated impact of the
proposed rule on establishments involved in oocyte donation is based on
1995 data reported by SART, an organization of assisted reproductive
technology providers affiliated with ASRM. Approximately 70 percent of
ART centers reporting in 1995 had performed at least one cycle of ART
with donor eggs. In 1995, donor eggs were used in approximately 8
percent of all 59,800 ART cycles, or 4,783 cycles. (Although 78 percent
of those cycles used fresh embryos, the proposed quarantine rules would
likely necessitate the use of frozen embryos in all donor cycles, with
some potential associated reduction in the success rate per donor in
vitro fertilization (IVF) cycle (Ref. 1). FDA believes that all
infertility treatment centers already conduct medical exams and
history-taking and perform some laboratory testing prior to egg
retrieval for any potential oocyte donor. Compliance with the proposed
standard, however, may entail adding some additional blood testing and
screening questions to the interview.
    The cost of additional blood work (including HIV 1-2, hepatitis B,
hepatitis C, and syphilis) is estimated at about $123 per donor (Ref.
2). The additional time to interview and record information in donor
screening is estimated to cost about $37, based on the assumption that
approximately half of the required screening is already being done, and
the estimated cost of a full health history interview is $75
($37<difference>  $75/2) (Ref. 3). Thus, the additional cost per
donation is estimated at $160 ($123 + 37). Based on a reported cost of
$11,868 (Ref. 4) per donor oocyte cycle, this cost translates to a 1.3
percent increase (($160 +$11,868)/$11,868) in the cost of therapy per
cycle.
    The cost of screening egg donors will depend on the number of donor
cycles attributable to each screened donor. If each donor contributes
eggs for only one cycle, and the rejection rate is low (assumed to be
0.57 percent, which is the estimated prevalence rate of HBSAG
positivity among parturient women) (Ref. 5), the number of donors to be
tested would be 4,810 (4783/(1-0.0057)). If each donor contributes eggs
for two donor cycles, the number of donors to be screened would be
2,405. These alternative assumptions imply a total cost to U.S.
facilities involved in oocyte donation of from $386,000 to $772,000 per
year, as shown in Table 3 of this document.

  Table 3.--Alternative Oocyte Donation Scenarios and Associated Donor
                             Screening Costs
------------------------------------------------------------------------

------------------------------------------------------------------------
Screen/Test Cost Per     2 ART Cycles Per Donor   1 ART Cycle Per Donor
 Donor                    = 2,405                  = 4,810 Donors
$123.40 + $37.00 =       $386,000 ($160.40 x      $772,000 ($160.40 x
 $160.40                  2,405 = $385,762)        4,810 =$771,524)
------------------------------------------------------------------------

[[Page 52711]]

    (ii) Sperm donor screening and testing. The agency has conducted an
extensive search for current information on the extent of infectious
disease screening for sperm donors, but has found little current
information available. The Congressional Office of Technology
Assessment (OTA) conducted a survey of establishments involved in sperm
donation in 1987, and found that all commercial banks surveyed
performed routine screening and testing for HIV, but only 45 percent of
private physicians included this screening. The most recently available
data includes a list of approximately 110 commercial sperm banks
developed by ASRM in 1996, and a 1996 registration survey of the AATB
that includes data for 4 sperm banks. The agency is aware that some
sperm banks that have applied, but are not yet accredited members of
AATB, are nonetheless following AATB standards. It is also likely that
some other facilities have informally adopted AATB standards. This
analysis assumes that all sperm banks currently perform HIV screening
and testing, as reported by OTA in 1987, and a smaller percentage of
facilities additionally follow all AATB screening and testing
standards.
    Based on recent conversations with sperm banking industry experts,
FDA estimates that the largest 20 sperm banks account for approximately
95 percent of the commercial production of donor sperm, and that these
facilities are compliant with AATB standards for donor screening and
testing. The agency analysis therefore assumes that the 20 largest
facilities, which account for most industry production, will experience
minimal impact; while the remaining 90 facilities, which have extremely
small volumes of production, will be more significantly affected. The
very small sperm banks are described by an industry expert as typically
functioning within a physician office practice (e.g., that of an
obstetrician or gynecologist). The sperm banking in these facilities is
generally offered as an additional service to patients receiving
fertility treatment, and is not the primary line of business within
these establishments.
    The total estimated cost of the proposed screening and testing
procedures for sperm banking facilities is based on the number of sperm
donors who would require screening and testing, and their respective
unit costs. Due to the lack of data on the actual number of sperm
donors, the agency estimated the number based on projected therapeutic
donor insemination TDI demand. The level of TDI demand has likely
changed over time, with advances in treatment for male factor
infertility. For example, the development of intracytoplasmic sperm
injection ISCI used in conjunction with in vitro fertilization has
enabled some couples to forego TDI in favor of ISCI using the male
partner's sperm (Ref. 6). In 1985, an estimated 70,000 women per year
received TDI (Ref. 7), compared to an estimated 171,000 women who
reported ever receiving artificial insemination with donor sperm, in
the National Survey of Family Growth (NSFG) conducted in 1995. If the
NSFG respondents referred only to experience over the past 5 years,
this would translate to approximately 34,200 women receiving TDI per
year. Assuming an average of three cycles of therapy per patient per
year, these data yield an estimated demand for TDI donor units of
approximately 102,600 units per year. This figure is consistent with an
industry expert estimate of current U.S. TDI production of 100,000
units per year.
    Clinical literature indicates that most sperm donor attrition
occurs prior to the blood testing stage of donor screening. For
example, in one study of donor recruitment in which the clinic followed
AATB and ASRM standards, of the total of 199 potential donors initially
recruited, 174 were rejected; 172 of whom were rejected before blood
testing, with only 2 (1 percent) rejected based on the blood test
results (Ref. 8). Based on these findings, the agency assumes that the
number of donors who will require infectious disease testing is
approximately equal to the number of donors needed to supply the level
of demand for TDI. Thus, FDA's estimate is based on the previous TDI
unit demand combined with the maximum number of births per donor
suggested in ASRM guidelines (Ref. 9), the average delivery rate per
cycle of intrauterine insemination, an assumed 10 donated specimens per
donor per year, and 4 donation units per donor specimen (Ref. 10).
These factors yield an estimated 2,565 donors required per year.
Assuming that the number of donors already screened and tested is
proportionate to the volume of production accounted for by facilities
compliant with AATB standards, FDA estimates that approximately 5
percent of all donors (0.05 x 2,565 = 128), or 128 donors per year, may
need to be newly screened and tested to meet the requirements of the
proposed rule.
    The screening cost per donor is assumed to include an initial
medical history and physical, a 6-month followup exam, and an
abbreviated screening at the time of each donation. Based on rates
published on the Internet (Ref. 3), the agency estimates that a full
medical exam may cost $175, a less extensive followup exam will cost
approximately $75 (a published fee for a health history review), and
the abbreviated screening at the time of each donation will cost
approximately $15 (i.e., one-fifth of the time required for a full
history review). One repeat donor visit per year is assumed. Thus, the
total cost of this screening is estimated to be $265 per year per
donor.
    The lab tests for prospective donors include those listed in Table
1 of this document, with 6-month followup blood tests for hepatitis B
and C, HTLV-1, and syphilis. The cost of additional testing, based on
screening test fees published on the Internet (Ref. 2), is $230.16 for
initial complete blood testing, plus $123.40 for followup blood testing
after a 6-month quarantine period, plus $113.30 for bacterial testing.
The total cost of the additional lab work is estimated to be $467 per
donor per year ($230.16 + $123.40 + $113.30 = $466.86). Because these
estimates are based on charges to facility clients, they are likely to
represent an upper bound on actual facility costs. Using these figures,
the estimated total industry cost per year is approximately $94,000
(128 x ($265 + $467) = $93,696).
    (b) Impact of donor recordkeeping and tissue quarantine. The impact
of recordkeeping and tissue quarantine for reproductive tissue
establishments will reflect the staff time required for: (1) A one-time
review and modification of current recordkeeping and facility
procedures to bring them into alignment with the proposed standard, and
(2) on-going, expanded practices for each donor who undergoes screening
and testing to meet the requirements of the proposed rule.
    FDA estimates that the one-time review and alignment of current
facility procedures will require approximately 8 to 40 hours at each
facility. As with nonreproductive tissue facilities, this process would
be performed by a regulatory affairs analyst, a supervisor, or a
manager of quality assurance. Assuming a labor cost of $40 per hour,
this standards reconciliation effort would result in a one-time cost
per facility ranging from $320 to $1,600. This estimate corresponds to
a total one-time cost for all reproductive tissue facilities that
ranges from $131,200 ($320 x (300 + 110)) to $656,000 ($1,600 x (300 +
110)).
    The recurring requirements for tissue quarantine, labeling,
recordkeeping and record retention at reproductive tissue facilities
are based on the estimated staff time needed to create and retain
records of medical history, screening information, and lab testing for
each

[[Page 52712]]

prospective donor from whom specimens are collected. The records must
comply with the information requirements of the proposed rule and are
estimated to require approximately 4 hours per donor per year of
clerical staff time, with an assumed labor cost of $24 per hour for
clerical staff ($96 per donor per year). Table 4 of this document
summarizes the potential range of recurring costs for all reproductive
tissue facilities. As shown, the estimated costs range from $243,000 to
$474,000, depending on the assumed number of donors.

       Table 4.--Range of Recurring Costs for Reproductive Tissue
------------------------------------------------------------------------

------------------------------------------------------------------------
128 sperm donors                     $243,000
1 cycle per egg donor                ((128 + 2,405) x $96 = $243,168)
------------------------------------------------------------------------
128 sperm donors                     $474,000
2 cycles per egg donor               ((128 + 4,810) x $96 = $474,048)
------------------------------------------------------------------------

    The size and range of these estimates reflects the agency's current
lack of information about typical donor practices for reproductive
tissue. If a higher rate of donation per donor is typically achieved by
facilities, compared to that assumed in this analysis, the additional
cost burden may be much lower than these estimates would indicate. More
generally, if the current level of facility donor screening and
recordkeeping is more stringent among reproductive tissue facilities
than assumed in this analysis, the overall cost of compliance with the
proposed rule will be lower than these preliminary estimates suggest.
    Uncertainty about current practice and the level of compliance
results in range estimates of the cost impact of the proposed rule.
However, because most industry sectors already follow industry
standards requiring donor testing and screening, the overall impact is
expected to be small. Table 5 of this document provides a summary of
the impacts across the different industry sectors included in the
analysis. The total annualized cost for the 380 nonreproductive tissue
facilities is estimated to range from $17,000 to $87,000, reflecting
agency uncertainty about the extent of effort devoted to one-time
review and alignment of existing standard operating procedures with the
proposed donor screening rule provisions. This translates to an average
cost of $45 to $229 per facility.
    The annualized cost of compliance for the ART industry ranges from
approximately $631,000 to $1.302 million, reflecting current
uncertainty about the number of oocyte donors and the number of
donations per donor per year. These costs translate to an average cost
of approximately $2,103 ($631,000/300) to $4,340 ($1,302,000/300) per
facility per year. In general, assumed higher rates of donation per
year, or a lower number of total donor oocyte cycles per year, will
result in lower industry costs. By the same token, lower rates of
donation per donor, or higher total donor cycles performed per year,
will result in higher donor screening costs.
    The total annualized cost impact on the sperm banking industry is
based on an estimated TDI demand of approximately 102 thousand units
per year, and assumed current compliance of the top 20 commercial
banks, which account for approximately 95 percent of industry
production. The total annualized costs range from approximately
$111,000 to $131,000. These industry totals yield an average annualized
cost range of $1,234 ($111,000/(110-20)) to $1,456 ($131,000/(110-20))
per facility estimated to be noncompliant with the proposed standard.

                           Table 5.--Donor Suitability Cost Analysis Summary Table\1\
----------------------------------------------------------------------------------------------------------------
                                                                                             Total Annualized
           Type of Facility              Total One-time Cost      Total Recurring Cost           Cost\2\
----------------------------------------------------------------------------------------------------------------
                     Nonreproductive Tissue--Eye Tissue, Conventional Tissue, and Stem Cell

----------------------------------------------------------------------------------------------------------------
(a) Donor screening and testing               Minimal                  Minimal                  Minimal
(b) Recordkeeping and tissue           $121,600 to $608,000            Minimal           $17,000 to $87,000
 quarantine
----------------------------------------------------------------------------------------------------------------

                                       Reproductive Tissue--ART Facilities

----------------------------------------------------------------------------------------------------------------
(a) Donor screening and testing               Minimal           $386,000 to $772,000     $386,000 to $772,000
(b) Recordkeeping and tissue           $96,000 to $480,000      $231,000 to $462,000     $245,000 to $530,000
 quarantine
ART subtotal                           $96,000 to $480,000      $617,000 to $1,234,000   $631,000 to $1,302,000
----------------------------------------------------------------------------------------------------------------

                                        Reproductive Tissue--Sperm Banks

----------------------------------------------------------------------------------------------------------------
(a) Donor screening and testing               Minimal                  $94,000                  $94,000
(b) Recordkeeping and tissue           $35,200 to $176,000             $12,000           $17,000 to $37,000
 quarantine
Sperm subtotal                         $35,200 to $176,000            $106,000           $111,000 to $131,000
----------------------------------------------------------------------------------------------------------------

[[Page 52713]]

                                              Total Tissue Industry

----------------------------------------------------------------------------------------------------------------
Total                                  $252,800 to $1,264,000   $723,000 to $1,340,000   $759,000 to $1,520,000
----------------------------------------------------------------------------------------------------------------
\1\ Rounded to the nearest thousand
\2\ At 7% interest rate over 10 years

D. Estimated Benefits of Proposed Rule

    The proposed action would provide oversight for the full spectrum
of human cellular and tissue-based products that are now marketed and
may be marketed in the future. This action is intended to improve
protection of the public health and increase public confidence in new
technologies, while permitting significant innovation and imposing
minimal regulatory burden. An important benefit of the rule will be the
establishment of a consistent standard of safety to help ensure
equivalent protection from transmissible diseases for all recipients of
therapy involving cellular and tissue-based products, regardless of the
health condition for which they are being treated. The proposed rule
would help minimize risk to all patients of exposure to several life-
threatening, in some cases incurable, diseases including HIV, HBV, HCV,
CJD and others. These risks would be minimized through validated
screening procedures, lab tests, and adequate labeling to avoid
unwitting use of unsafe specimens. Each of the infectious diseases
screened (see Table 1 of this document) will provide added patient
safety protection and public health benefit.
    The risks of disease transmission vary by type of cellular and
tissue-based product. Donor screening, testing, and other measures to
reduce the risks of transmission for various types of tissue will
correspondingly yield a different relative reduction in disease risk.
For example, expansion of blood donor screening and improved laboratory
tests have dramatically reduced the risk of blood transfusion-
transmitted disease. The risk of HIV infection has dropped from a
reported 1 in 100 units in some U.S. cities to approximately 1 in
680,000 units. The risk of transmission of HBV has been reduced from 1
in 2,100 to 1 in 63,000 units, and the transmission risk for HCV has
been lowered from 1 in 200 units in the early 1980's to the current
level of 1 in 100,000 units (Ref. 11). These levels of risk reduction
based on blood donors, offer an illustration of the kind of
improvements in safety that might be achieved through improved and
expanded screening of donors.
    As described earlier, most nonreproductive tissue establishments
are assumed to be already compliant with the proposed rule and
therefore have already achieved the level of intended risk reduction.
The discussion of benefits resulting from the proposed rule will
therefore focus on some key areas of risk and potential benefit of the
proposed requirements for reproductive tissue recipients. The
discussion that follows will consider the risks of sexual transmission
of disease that will be reduced through expanded screening among
reproductive tissue donors, focusing on the reduced risk of two life-
threatening chronic diseases that can be transmitted through donor
tissue: HBV and HCV.
    The expansion of screening among reproductive tissue donors is
expected to produce important reductions in disease risk, as evidenced
by the apparent reductions in HIV risk that have already been achieved
through screening. The risk of HIV transmission through TDI appears to
be much lower since screening for HIV was recommended by the Center for
Disease Control and Prevention (CDC) in 1985. A total of six documented
and two possible cases have been reported to the CDC as of December
1996 (Ref. 7).
    The risks of transmitting HBV and HCV through reproductive tissue
should be substantially reduced as a result of donor screening, based
on the significance of self-reported risk factors as predictors of the
findings of blood screening for HBV and HCV (Ref. 12). Compared to HCV,
HBV presents a higher risk of sexual transmission. In 1991,
heterosexual activity is reported to account for 41 percent of all
cases of HBV (Ref. 13). HBV transmission has also been reported by use
of TDI; in 1982 a physician used semen from an unscreened donor (later
found to carry HBsAg) to inseminate several women, one of whom later
developed HBV (Ref. 14).
    HBV-infected mothers can transmit the disease to their infants.
Forty-two percent of infants born to women with HBsAg positivity
(adjusted for HBeAg status) are at risk of HBV infection, and an
additional 30 percent of infants born to HBsAg-positive mothers become
infected between 1 and 5 years of age. Prospective studies of infected
infants or young children, indicate that 25 percent will die from
primary hepatocellular carcinoma (PHC) or cirrhosis as adults. The
lifetime medical cost per case of PHC and cirrhosis is estimated to be
$96,500 (Ref. 15). An analysis of the cost-effectiveness of prenatal
screening and testing of mothers, with vaccination for positive
screens, estimates that such screening and intervention would prevent
69 percent of the chronic HBV infections acquired perinatally or later
in life (Ref. 16). This rate of effectiveness may provide an indication
of the potential benefit of HBV screening in the proposed rule.
    The risk of sexual transmission is estimated to be lower for HCV,
compared to HBV. The CDC estimates the rate of transmission from female
to male partners, and the rate of transmission from mother to child, to
each be approximately 5 percent. However, there is no vaccine
intervention available for HCV, although interferon-alpha therapy has
been found effective in eliminating the virus for at least some
patients and drug combinations (e.g., Interferon and Ribovirus) may be
even more effective. Although most patients infected with HCV are
relatively healthy during most of their lives, an estimated 30 percent
of those infected will eventually die of liver-related causes; an
estimated 8,000 patients per year (Ref. 15). The average cost of care
per year for persons with liver disease from chronic HCV is estimated
to range from $24,600 for patients without interferon-alpha therapy to
$26,500 per year for those receiving a 12-month course of therapy. The
latter is estimated to provide patients with an additional 0.37
quality-adjusted life-years (Ref. 16).
    Screening third-party tissue donors is expected to significantly
reduce the excess morbidity and mortality caused by hepatitis B and C.
As noted earlier, there are an estimated 2,405 to 4,810 oocyte donors
and 2,565 sperm donors

[[Page 52714]]

per year. If these populations experience recently reported prevalence
rates for HVC (9.8 percent) and HBV (27.6 percent) (Ref. 12), then
screening for significant risk factors and disease markers will result
in reduced HBV and HCV exposures for the patient population at risk.
The population at risk each year is estimated to include 1,600 to 4,700
women undergoing IVF with donor eggs, and 1,300 newborns delivered as a
result of this therapy\1\; and 34,200 to 70,000 women receiving TDI,
and 8,800 newborns delivered as a result of that therapy.
---------------------------------------------------------------------------

    \1\ The range of 1,600 to 4,700 IVF patients is based on a
reported 4,783 cycles of IVF with donor egg reported for 1995,
varying the assumed number of cycles of therapy per patient. The
number of newborns is based on an assumed average delivery rate of
19.6 percent per cycle.
---------------------------------------------------------------------------

E. Initial Regulatory Flexibility Analysis

    FDA's objectives and authority for issuing the proposed rule are
described in section II of this document. Based on its initial
analysis, FDA finds that a substantial number of the establishments
required to comply with this proposed rule may be small business
entities, particularly facilities involved with reproductive tissue
products. The Small Business Administration defines a small business in
this SIC industry sector to be an establishment with $5 million or less
in annual receipts (Ref. 17). The economic impact analysis presented in
section IV.C of this document includes estimates of the number of
entities to which the proposed rule will apply. Each set of facilities
involved in the tissue banking sectors includes some facilities that
would be classified as small business entities.
    A 1995 study of conventional tissue banks (Ref. 18) reports average
annual revenues of $1.23 million per facility. Most nonreproductive
tissue facilities are assumed to have a comparable level of average
revenues. Reproductive tissue experts estimate that 65 percent of ART
facilities have average revenues of approximately $2.5 million per year
and the remaining 35 percent have average revenues of $11.5 million per
year. Industry experts also estimate that 19 of the 20 largest sperm
banks have average annual revenues of approximately $2 million per
year, and 1 of the 20 largest facilities has annual revenues greater
than $5 million. Thus, the majority of tissue facilities are small
entities. Nevertheless, as noted in the preceding cost analysis, most
of these facilities would not be significantly impacted by the proposed
rule, because they are already performing the proposed infectious
disease screening and recordkeeping.
    Table 6 of this document presents estimates of the average cost per
facility as a percentage of average annual revenues. In addition to
facility revenues Table 6 presents the estimated annual practice income
for Ob/Gyn practices, because some operate a small donor sperm bank as
an additional service to patients, but may not currently comply with
the screening and testing requirements of the proposed rule. The
estimated annual revenue of $252,000 per year for individual physician
practices is based on the mean physician income of $215,000 after
expenses and before taxes for the Ob/Gyn specialty category reported in
the 1992 American Medical Association survey (Ref. 19), adjusted to
1998 assuming an average annual wage inflation of 2.7 percent, based on
yearly rates reported by the Bureau of Labor Statistics.

   Table 6.--Estimated Annualized Cost per Facility as a Percentage of
                        Estimated Annual Revenue
------------------------------------------------------------------------
    Number of
 Facilities That        Average        Average Annual    Annualized Cost
May Be Classified   Annualized Cost      Revenue per    as Percentage of
as Small Entities     per Facility        Facility       Annual Revenue
------------------------------------------------------------------------
  Nonreproductive Tissue--Eye Tissue, Conventional Tissue and Stem Cell

------------------------------------------------------------------------
380-all            $45 to $229        $1.2 million      0.004 to 0.019%
 potentially
 small
------------------------------------------------------------------------
                   Reproductive Tissue--ART Facilities

------------------------------------------------------------------------
195 (65% of 300    $2,103 to $4,340   $2.5 million      0.08 to 0.17%
 facilities)
------------------------------------------------------------------------
                    Reproductive Tissue--Sperm Banks

------------------------------------------------------------------------
19-larger          $1,234 to $1,456   $2.0 million      0.06 to 0.08%
 commercial banks
90-physician       $1,234 to $1,456   $252,000          0.5 to 0.6%
 practice-based
 banks
------------------------------------------------------------------------

    As noted in Table 6 of this document, the greatest cost will be
incurred by facilities involved with reproductive tissue. Nevertheless,
the estimated impact on most small facilities does not appear to be
significant. The expected increase in cost per facility ranges up to
0.6 percent of annual revenues. However, if current practices actually
involve a much lower level of infectious disease screening than assumed
in this analysis, the impact of the proposed screening and testing
requirements would be higher than expected. Because accurate
information on current industry practices is essential for a valid
assessment of economic impact, FDA requests detailed industry comment
on its estimate of the number of affected small facilities and their
current donor screening, testing, tissue quarantine, and recordkeeping
practices.
    Although the proposed rule would impose some costs on small
entities involved in the manufacture of cellular and tissue-based
products, the agency believes that the proposed approach represents an
effective means of protecting patient safety and public health in the
collection of donor cells and tissue for manufacture. The less
burdensome alternatives to the proposed approach involve fewer
requirements for small entities (the vast majority of facilities in
this industry), but fail to provide fundamental aspects of product
safety. For example, reliance on published FDA guidance for donor
suitability screening and testing, rather than establishing a
regulatory requirement, would provide the agency with no basis for
ensuring compliance. Thus, agency guidance may have no greater
influence than current industry voluntary standards, which have similar
provisions, but have failed to persuade all facilities to adopt
comprehensive screening and testing practices. FDA's guidance, alone,
therefore, would not be expected to provide adequate public protection
from the safety risks

[[Page 52715]]

associated with infected donor-derived products.
    Another alternative would involve the waiving of some of the donor
screening and testing requirements for small facilities. However, as
noted previously, nearly all facilities in this industry are small.
Moreover, this alternative would increase tissue product safety risks,
if small facilities that currently screen and test donors on a
voluntary basis choose to discontinue this practice due to an FDA-
granted waiver. For example, waiving a requirement for donor screening
would eliminate an extremely cost-effective first-tier level of safety
protection because prospective donors deferred or disqualified at this
stage need not undergo further testing. Similarly, waiving the proposed
requirements for blood testing would expose patients, as well as tissue
facility and medical staff, to avoidable risks of infectious disease
that may be undocumented in a patient's medical history, or be unknown
to, or not mentioned by the living donor or donor family during
screening.
    A waiver of the requirements for tissue quarantine to allow for the
window period of donor infectivity prior to detection through blood
tests would expose product recipients and the public to risks of
infectious disease agents that cannot be immediately detected through
most currently available blood tests (e.g., tests for HIV and HCV).
Recordkeeping for donor screening and testing is also critical to
product recipient and public safety. Adequate documentation and record
retention ensure that cellular and tissue-based products can be tracked
to their source in the event of infection or other adverse reactions
that result from donor tissue characteristics.
    In summary, the agency believes that abridged requirements for
donor screening and testing, based on voluntary standards or facility
size criteria, would provide inadequate protection against the risk of
infectious disease. Most notably, the absence of regulation allows
reproductive tissue facilities to omit the proposed screening and
testing of tissue donors that is routinely completed for other cellular
and tissue-based products, thus exposing infertility patients to a
disproportionate risk of several life-threatening infectious disease
agents.
    To alleviate the impact on small entities while continuing to
protect public health, the agency is proposing to recommend, but not
require, that manufacturers follow screening and testing procedures for
relevant communicable disease agents and diseases when a cellular or
tissue-based product is used in the same person from whom it is
obtained, or in a sexually intimate partner of a reproductive-tissue
donor. A recommendation is considered adequate in this instance because
the risk of disease transmission from such activities is believed
minimal.
    Under the proposed rule, small entities involved with reproductive
tissue will be required to meet the same safety and quality standards
as large reproductive tissue facilities and other cellular and tissue-
based product manufacturers, regardless of size. The specific
requirements for donor screening and testing, the required
recordkeeping, and the required types of professional skills are
described in the economic analysis provided previously. This analysis
includes an accounting of all major cost factors, with the exception of
the reduced potential liability currently encountered by those
reproductive tissue facilities that fail to provide the level of
protection from infectious disease that is considered a standard of
good practice in other sectors of the tissue-based product industry.
The relevant Federal rules that are related to the proposed rule are
discussed in section II of this document. This economic analysis
provides a summary of the private industry standards that overlap the
proposed Federal standard, but as discussed, there is no current
regulation of reproductive tissue that would duplicate the proposed
rule. Consequently, FDA finds that the proposed regulation would
enhance both public health and public confidence in the safety and
utility of transplanted cells and tissues, while imposing only a
minimum burden on the affected industry sectors.

V. The Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-
3520). A description of these provisions is shown as follows with an
estimate of the annual reporting and recordkeeping burden. Included in
the estimate is the time for reviewing the instructions, searching
existing data sources, gathering and maintaining the data needed, and
completing and reviewing each collection of information.
    FDA invites comments on: (1) Whether the proposed collection of
information is necessary for the proper performance of FDA's functions,
including whether the information will have practical utility; (2) the
accuracy of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including through the use of
automated collection techniques, when appropriate, and other forms of
information technology.
    Title: Documentation and Reporting of Suitability Determination for
Donors of Human Cellular and Tissue-based Products.
    Description: Under the authority of section 361 of the PHS Act, FDA
is proposing new regulations to require manufacturers of 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. FDA is
proposing that donor suitability determination regulations apply to all
establishments covered by the proposed registration rule. The
determination of whether a donor is suitable or unsuitable would be
made by a responsible person and would be based on the results of
required donor screening and testing. 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 certain
provisions. The accompanying documentation would contain a copy of the
donor's relevant medical records, results of testing, the name and
address of the establishment that made the donor suitability
determination, and a statement whether, based on the results of the
screening and testing of the donor, the donor has been determined to be
suitable or unsuitable. With the use of a product from an unsuitable or
incompletely tested donor, documentation by the manufacturer would be
required showing that the recipient's physician was notified of the
screening and testing results, the physician authorized the use of the
product after determining there is an urgent medical need, the
recipient or the recipient's legal representative was informed of the
communicable disease risk, and the recipient or the recipient's legal
representative consented to use of the product.
    The agency proposes to require that records be retained at least 10
years instead of the current 5 years. This

[[Page 52716]]

increase in retention time is necessary because certain cellular and
tissue-based products have storage periods longer than 5 years. In
addition, advances in medical technology have created opportunities for
diagnosis and therapy for up to 10 years after recipient exposure to a
donor later determined to be at risk for communicable disease agents or
diseases.
    These proposed provisions are intended as safeguards to prevent the
transmission of communicable diseases that may occur with the use of
cells and tissues from infected donors. Through this action FDA will
improve its ability to protect the public health by controlling the
spread of communicable disease.
    Description of Respondents: Manufacturers of cellular and tissue-
based products.
    Based upon recent information from trade organizations related to
the manufacturing of products utilizing cells and tissues and the
agency's experience, FDA has estimated the following burden for each
provision that describes a collection of information.
    In the proposed registration rule, the agency proposed Sec. 1271.10
and estimated the burden of collection of information under that
provision. In this proposed rule, the agency is modifying proposed
Sec. 1271.10. Consequently, a revised estimate for the reporting burden
is provided as follows. Although the modifications to proposed
Sec. 1271.10 do not effect the original burden estimates, new
information from trade associations supports an increase in the
estimate of affected manufacturers from 680 to 806. Under proposed
Sec. 1271.10 each manufacturer would be required to update its product
listings twice a year. For each update, the agency estimates
approximately 0.75 hours to complete.
    Under proposed Sec. 1271.55(a), approximately 857 manufacturers
(224 manufacturers of conventional and eye tissue, 157 manufacturers of
peripheral and cord blood stem cell products, 410 manufacturers of
reproductive tissue, and 66 manufacturers of products regulated under
the act and/or section 351 of the PHS Act) would be required to provide
a summary of records. An estimated total of 523,231 cells and tissues
(approximately 309,000 conventional tissue products, 86,000 eye tissue
products, 6,031 stem cell products, and 122,200 reproductive cells and
tissue products) are manufactured into products per year. The agency
estimates that for each product, a manufacturer will expend
approximately 0.5 hours to prepare the summary of records.
Manufacturers of conventional and eye tissue are currently required to
provide a summary of records under Sec. 1270.33(d), which proposed
Sec. 1271.55(a) would replace.
    Under proposed Sec. 1271.65(c)(2), when a cellular or tissue-based
product is used prior to completion of screening and testing due to an
urgent medical need, a manufacturer would provide a list of the
completed and incomplete results with the product. This would be a new
practice for 731 manufacturers. Out of 791 manufacturers who could be
affected by this provision, approximately 60 manufacturers follow this
procedure as usual and customary practice under AATB standards and
would not be affected by this proposed section. The agency believes
that the use of a product from an unsuitable or incompletely tested
donor when there is an urgent medical need may occur approximately once
a year and that each listing should result in approximately 0.25 hours
to complete.
    Under proposed Sec. 1271.50(b), documentation of donor suitability
would be required for the first time for approximately 410
manufacturers. Out of a total of 791 manufacturers of cellular and
tissue-based products, there would be no added burden for approximately
381 manufacturers who document donor suitability as usual and customary
practice under the trade organization standards. In table 5 of this
document, FDA estimates that Sec. 1271.50(b) would impose a new
collection of information requirement on 410 manufacturers of
reproductive cellular and tissue-based products, each of which would
document the suitability of an estimated 11 donors per year, or 4,640
donors, expending approximately 5 hours per document for a total of 55
hours per manufacturer per year.
    Under proposed Sec. 1271.55(b), manufacturers would be required to
retain records for 10 years. The requirement would affect 410
manufacturers of reproductive cells and tissues. Three hundred and
eighty-one of a total 791 manufacturers already retain records for a
minimum of 10 years as usual and customary practice under trade
organization standards. FDA estimates 0.5 hours per manufacturer to
annually retain records. This estimate reflects an average of time that
would be necessary to create records for retention from advanced
methods of recordkeeping, such as electronic formatting which can
improve the ability of manufacturers to more easily retain and retrieve
records, to copying records onto microfiche.
    Under proposed Secs. 1271.65(b)(3) and (c)(3), when a product that
is unsuitable or not fully screened or tested is used, approximately
791 manufacturers of cellular and tissue-based products would be
required to document notice of the results of testing and screening to
the physician, the authorization from the physician after determining
there is an urgent medical need, the agreement from the physician to
explain the risk to the recipient, and to obtain consent from the
recipient before using the product. The agency estimates that such
documentation would occur approximately once annually per manufacturer
and that each manufacturer would expend approximately 2.0 hours to
create such document.

                                  Table 7.--Estimated Annual Reporting Burden<SUP>1</SUP>
----------------------------------------------------------------------------------------------------------------
                                                      Annual
         21 CFR Section               No. of       Frequency per   Total Annual      Hours per      Total Hours
                                    Respondents      Response        Responses       Response
----------------------------------------------------------------------------------------------------------------
1271.10                               806               2           1,612               0.75        1,209
1271.55(a)                            857             610.5       523,231               0.5       261,615.5
1271.65(c)(2)                         731               1             731               0.25          183
Total                                                                                             263,007.5
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

[[Page 52717]]

                                Table 8.--Estimated Annual Recordkeeping Burden<SUP>1</SUP>
----------------------------------------------------------------------------------------------------------------
                                                      Annual
         21 CFR Section               No. of       Frequency per   Total Annual      Hours per      Total Hours
                                   Recordkeepers   Recordkeeping      Records      Recordkeeper
----------------------------------------------------------------------------------------------------------------
1271.50(b)                            410              11           4,640              55          22,550
1271.55(b)                            410              11           4,640               5.5         2,255
1271.65(b)(3) and (c)(3)              791               1             791               0.5           395.5
Total                                                                                              25,200.5
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    The agency estimates that there will be no new or significant
increase in maintenance costs for the maintenance of records for the
proposed 10-year period instead of the current 5-year retention period,
because modern storage technology has markedly reduced the space needed
to store records.
    Under section 1320.3(c)(2) of the PRA the labeling requirements in
proposed Secs. 1271.65(c)(2) and (d), and 1271.90(b) and (c) do not
constitute collection of information because information required to be
on the labeling is originally supplied by FDA to the manufacturers for
the purpose of disclosure to the public to help ensure a safe product
supply and protect public health.
    The reporting of screening and testing results to the consignee in
proposed Sec. 1271.65(c)(4) does not constitute collection of
information burden because it is the customary and usual practice or
procedure of all manufacturers to conduct screening and testing and
provide the results to the consignee.
    In compliance with section 3507(d) of the PRA of 1995 (44 U.S.C.
3507(d)), the agency has submitted a copy of this proposed rule to OMB
for review of the information collection provisions.

VI. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.

VII. Request for Comments and Proposed Effective Date

    Interested persons may, on or before December 29, 1999, submit to
the Dockets Management Branch (address above) written comments
regarding this proposal, except that comments regarding information
collection provisions should be submitted in accordance with the
instructions in section V of this document. Two copies of any comments
on issues other than information collection are to be submitted, except
that individuals may submit one copy. Comments are to be identified
with the docket number found in brackets in the heading of this
document. Received comments may be seen in the office above between 9
a.m. and 4 p.m., Monday through Friday.
    FDA is proposing to delay the compliance date of all final rules
implementing the proposed regulatory approach to human cellular and
tissue-based products until the concluding final rule for registration,
donor suitability, and CGTP has been published in the Federal Register.
FDA will announce the compliance date for the final rules in a future
issue of the Federal Register.

VIII. References

    The following references have been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
    1. CDC, 1995 ART Fertility Clinic Reports at ``www.cdc.gov/
nccdphp/drh/arts/introduc.htm''.
    2. Published fee for blood testing, including Hepatitis B and
Hepatitis C, HIV 1-2, HTLV-1, and syphilis, reported for direct
donor screening by The Sperm Bank of California, at
``www.thespermbankofca.org/fees96.htm''.
    3. The Sperm Bank of California at ``www.thespermbankofca.org/
fees96.htm''.
    4. Van Voorhis, B. J., A. E. T. Sparks, B. D. Allen, et al.
``Cost-effectiveness of Infertility Treatments: A Cohort Study,''
Fertility and Sterility, vol. 67, No. 5, May 1997, pp. 830-836.
    5. Margolis, H. S., P. J. Coleman, R. E. Brown, E. E. Mast, S.
H. Sheingold, and J. A. Arevalo, ``Prevention of Hepatitis B Virus
Transmission by Immunization: An Economic Analysis of Current
Recommendations,'' Journal of the American Medical Association, vol.
274, No. 15, 1995, pp. 1201-1208.
    6. The National Summary of CDC 1995 ART Fertility Clinic Reports
estimates that 11 percent of the ART therapy performed included ICSI
at ``www.cdc.gov/nccdphp/drh/arts/introduc.htm''.
    7. Wortley, P. M., T. A. Hammett, and P. L. Fleming, ``Donor
Insemination and Human Immunodeficiency Virus Transmission,''
Obstetrics & Gynecology, vol. 91, No. 4, 1998, pp. 515-518.
    8. Sidhu, R. S., R. K. Sharma, S. Kachoria, C. Curtis, and A.
Agarwal, ``Reasons for Rejecting Potential Donors from a Sperm Bank
Program,'' Journal of Assisted Reproduction and Genetics, vol.14,
No. 6, 1997, pp. 354-360.
    9. The American Fertility Society, ``Guidelines for Therapeutic
Donor Insemination: Sperm,'' Fertility and Sterility, vol. 62, No.
5, November 1994, pp. 101s-104s.
    10. Government Accounting Office, Human Tissue Banks: FDA Taking
Steps to Improve Safety, but Some Concerns Remain, GAO/HEHS-98-25.
    11. AuBuchon, J. P., J. D. Birkmeyer, and M. P. Busch, ``Safety
of the Blood Supply to the United States: Opportunities and
Controversies,'' Annals of Internal Medicine, vol. 127, No. 10,
November 1997, vol. 127, No. 10.
    12. Kaur, S., L. Rybicki, B. R. Bacon, J. L. Gollan, V. K.
Rustgi, W. D. Carey and the National Hepatitis Surveillance Group,
``Performance Characteristics and Results of a Large-Scale Screening
Program for Viral Hepatitis and Risk Factors Associated with
Exposure to Viral Hepatitis B and C: Results of the National
Hepatitis Screening Survey,'' Hepatology, vol. 24, No. 5, 1996, pp.
979-986.
    13. Kane, M., ``Epidemiology of Hepatitis B Infection in North
America,'' Vaccine, vol. 13, Supplement 1: 1995, pp. s16-s17.
    14. Guinan, M. E., ``Artificial Insemination by Donor: Safety
and Secrecy,'' Journal of the American Medical Association, vol.
173, No. 11, March 1995, pp. 890-891.
    15. U.S. Centers for Disease Control and Prevention, 1997.
    16. Kim, W. R., J. J. Poterucha, J. E. Hermans, T. M. Therneau,
E. R. Dickson, R. W. Evans, and J. B. Gross, Jr., ``Cost-
effectiveness of 6 and 12 Months of Interferon-<greek-a> Therapy for
Chronic Hepatitis C,'' Annals of Internal Medicine, vol. 127, No.
10, November 1997.
    17. U.S. Small Business Administration, Table of Size Standards,
March 1, 1996, Major Group 80--Health Services.
    18. Prottas, J., ``A study of the Tissue Procurement and
Distribution System of the United States,'' Brandeis University,
FDA/HRSA contract No. 240-090-0048, October 1995.
    19. American Medical Association, Socioeconomic Characteristics
of Medical Practice, Table 47, p. 150, 1994.
    20. Hogan, R. N. et al., ``Risk of Prion Disease Transmission
From Ocular Donor

[[Page 52718]]

Tissue Transplantation,'' Cornea, vol. 18, No. 1, pp. 2-11, 1999.

List of Subjects

21 CFR Part 210

    Drugs, Packaging and containers.

21 CFR Part 211

    Drugs, Labeling, Laboratories, Packaging and containers,
Prescription drugs, Reporting and recordkeeping requirements,
Warehouses.

21 CFR Part 820

    Medical devices, Reporting and recordkeeping requirements.

21 CFR Part 1271

    Human cellular and tissue-based products, Communicable diseases,
HIV/AIDS, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, it is proposed to amend 21 CFR Chapter
I as follows:

I. Parts 210, 211, and 820 are amended as follows:

PART 210--CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING,
PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL

    1. The authority citation for 21 CFR part 210 is revised to read as
follows:

    Authority: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42
U.S.C. 216, 262, 263a, 264.

    2. Section 210.1 is amended by adding paragraph (c) to read as
follows:

Sec. 210.1  Status of current good manufacturing practice regulations.

 * * * * *
    (c) Owners and operators of establishments engaged in the recovery,
screening, testing, processing, storage, labeling, packaging or
distribution of human cellular or tissue-based products, as defined in
Sec. 1271.3(e) of this chapter, that are regulated as drugs under the
act and/or biological products under section 351 of the Public Health
Service Act are subject to the donor suitability and current good
tissue practice procedures set forth in part 1271 subparts C and D of
this chapter, in addition to the regulations in this part and in parts
211 through 226 of this chapter. Failure to comply with any regulation
set forth in this part, in parts 211 through 226 of this chapter, in
part 1271 subpart C of this chapter, or in part 1271 subpart D of this
chapter shall render such a human cellular or tissue-based product
adulterated under section 501(a)(2)(B) of the act, and such product, as
well as the person who is responsible for the failure to comply, shall
be subject to regulatory action.
    3. Section 210.2 is revised to read as follows:

Sec. 210.2  Applicability of current good manufacturing practice
regulations.

    (a) The regulations in this part and in parts 211 through 226 of
this chapter as they may pertain to a drug, in parts 600 through 680 of
this chapter as they may pertain to a biological product for human use,
and in part 1271 of this chapter as they may pertain to a human
cellular or tissue-based product that is regulated as a drug and/or
biological product shall be considered to supplement, not supersede,
each other, unless the regulations explicitly provide otherwise. In the
event that it is impossible to comply with all applicable regulations
in these parts, the regulations specifically applicable to the drug in
question shall supersede the more general.
    (b) If a person engages in only some operations subject to the
regulations in this part, in parts 211 through 226 of this chapter, in
parts 600 through 680 of this chapter, and in part 1271 of this
chapter, and not in others, that person need only comply with those
regulations applicable to the operations in which he or she is engaged.

PART 211--CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED
PHARMACEUTICALS

    4. The authority citation for 21 CFR part 211 is revised to read as
follows:

    Authority: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42
U.S.C. 216, 262, 263a, 264.
    5. Section 211.1 is amended by revising paragraph (b) to read as
follows:

Sec. 211.1  Scope.

 * * * * *
    (b) The current good manufacturing practice regulations in this
chapter as they pertain to drug products, in parts 600 through 680 of
this chapter, as they pertain to biological products for human use, and
in part 1271 of this chapter, as they pertain to human cellular or
tissue-based products that are regulated as drugs and/or biological
products shall be considered to supplement, not supersede, the
regulations in this part unless the regulations explicitly provide
otherwise. In the event it is impossible to comply with applicable
regulations both in this part and in other parts of this chapter, in
parts 600 through 680 of this chapter, or in part 1271 of this chapter,
the regulation specifically applicable to the drug product in question
shall supersede the regulation in this part.
 * * * * *

PART 820--QUALITY SYSTEM REGULATION

    6. The authority citation for 21 CFR part 820 is revised to read as
follows:

    Authority: 21 U.S.C. 351, 352, 360, 360c, 360d, 360e, 360h,
360i, 360j, 360l, 371, 374, 381, 383; 42 U.S.C. 216, 262, 263a, 264.
    7. Section 820.1 is amended by adding two sentences to the end of
paragraph (a)(1) and by revising the second sentence in paragraph (c)
to read as follows:

Sec. 820.1  Scope.

    (a) Applicability. (1) *  *  * Manufacturers of human cellular or
tissue-based products, as defined in Sec. 1271.3(e) of this chapter,
that are regulated as medical devices under the act are subject to this
part and are also subject to the donor-suitability procedures set forth
in part 1271 subpart C of this chapter and current good tissue practice
procedures in part 1271 subpart D of this chapter. In the event that it
is impossible to comply with all applicable regulations in parts 820
and 1271 of this chapter, the regulations specifically applicable to
the device in question shall supersede the more general.
 * * * * *
    (c) *  *  * The failure to comply with any applicable provision in
this part or in part 1271 subpart C or D of this chapter renders a
device adulterated under section 501(h) of the act. *  *  *
* * * * *

II. Part 1271 as proposed in the Federal Register of May 14, 1998
(63 FR 26744) is amended as follows:

PART 1271--HUMAN CELLULAR AND TISSUE-BASED PRODUCTS

    1. The authority citation for 21 CFR part 1271 is revised to read
as follows:

    Authority: 42 U.S.C. 216, 243, 263a, 264, 271.
    2. The heading for part 1271 is revised to read as set forth above.
    3. Section 1271.1 is revised to read as follows:

Sec. 1271.1  Purpose and scope.

    (a)  Purpose. The purpose of this part, in conjunction with
Secs. 207.20(f), 210.1(c), 210.2, 807.20(e), and 820.1(a) of this
chapter, is to establish procedures to prevent the introduction,
transmission, and spread of communicable diseases and to create a

[[Page 52719]]

unified registration and product listing system for establishments that
manufacture human cellular and tissue-based products.
    (b) Scope. Manufacturers of human cellular and tissue-based
products regulated solely under the authority of section 361 of the
Public Health Service Act (the PHS Act) are required by this part to
register and list their products with the Food and Drug
Administration's (FDA's) Center for Biologics Evaluation and Research,
and to comply with the other requirements contained in this part. Under
Secs. 207.20(f) and 807.20(e), manufacturers of human cellular and
tissue-based products regulated under section 351 of the PHS Act and/or
the Federal Food, Drug, and Cosmetic Act (the act) are required to
register and list their products following the procedures in subpart B
of this part; under Secs. 210.1(c), 210.2, 211.1(b), and 820.1(a),
manufacturers of those products are required to comply with the donor-
suitability procedures in subpart C of this part and current good
tissue practice procedures in subpart D of this part in addition to all
other applicable regulations.
    4. Section 1271.3 is amended by revising paragraph (e), and by
adding paragraphs (i) through (ee) to read as follows:

Sec. 1271.3  Definitions.

 * * * * *
    (e) Human cellular or tissue-based product means a product
containing or consisting of human cells or tissues that is intended for
implantation, transplantation, infusion, or transfer into a human
recipient, e.g., cadaveric ligament, skin, dura mater, heart valve,
cornea, hematopoietic stem cells derived from peripheral and cord
blood, manipulated autologous chondrocytes, and spermatozoa. The
following products are not considered human cellular or tissue-based
products:
    (1) Vascularized human organs for transplantation;
    (2) Whole blood or blood components or blood derivative products
subject to listing under parts 607 and 207 of this chapter,
respectively;
    (3) Secreted or extracted human products, such as milk, collagen,
and cell factors; except that semen is considered a human cellular or
tissue-based product;
    (4) Minimally manipulated bone marrow for homologous use and not
combined with or modified by the addition of any component that is a
drug or a device;
    (5) Ancillary products used in the manufacture of cellular or
tissue-based products;
    (6) Cells, tissues, and organs derived from animals other than
humans; and
    (7) In vitro diagnostic products as defined in Sec. 809.3(a) of
this chapter.
* * * * *
    (i) Biohazard legend appears on packaging as follows and is used to
mark products that present a known or suspected relevant communicable
disease risk.

[GRAPHIC] [TIFF OMITTED] TP30SE99.031

    (j) Blood component means any part of human blood separated by
physical or mechanical means.
    (k) Colloid means:
     (1) A protein or polysaccharide solution, such as albumin,
dextran, or hetastarch, that can be used to increase or maintain
osmotic (oncotic) pressure in the intravascular compartment; or
    (2) Certain blood components such as plasma and platelets.
    (l) Crystalloid means a balanced salt and/or glucose solution used
for electrolyte replacement or to increase intravascular volume, such
as saline solution, Ringer's lactate solution, or 5 percent dextrose in
water.
    (m) Directed donor means 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.
    (n) Donor means a person, living or dead, who is the source of
cells or tissue for a human cellular or tissue-based product.
    (o) Donor medical history interview means a documented dialogue
with the donor, if living or, if the donor is not living or is unable
to participate in the interview, with an individual or individuals
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 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.
    (p) Embryo means the product from fertilization of the oocyte to
the 8th week of development.
    (q) Gamete means a male or female germ cell; i.e., spermatocyte or
oocyte.
    (r) Physical assessment means a limited autopsy or recent
antemortem or postmortem physical examination of the donor to assess
for signs or symptoms of a relevant communicable disease and for signs
or symptoms suggestive of any risk factor for such disease.
    (s) Plasma dilution means 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.
    (t) Quarantine means 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.
    (u) Reconstituted blood means the blood produced by the
extracorporeal resuspension of a blood unit labeled as ``Red Blood
Cells'' through the addition of colloids and/or crystalloids to produce
a product with a hematocrit in the normal range.
    (v) Relevant medical records means a collection of documents that
includes a current donor medical history interview; a current report of
the

[[Page 52720]]

physical assessment of a cadaveric donor or the physical examination of
a living donor; and, if available, the following:
    (1) Laboratory test results (other than results of testing for
relevant communicable disease agents required under this subpart);
    (2) Medical records;
    (3) Coroner and autopsy reports; and
    (4) Records or other information received from any source
pertaining to risk factors for relevant communicable disease (e.g.,
social behavior, clinical signs and symptoms of relevant communicable
disease, and treatments related to medical conditions suggestive of
risk for relevant communicable disease).
    (w) Responsible person means a person who is authorized to perform
designated functions for which he or she is trained and qualified.
    (x) Summary of records means a condensed version of the records of
required screening and testing and contains:
     (1) A statement that the 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.
    (y) Relevant communicable disease agent or disease means:
    (1) One of the following disease agents or diseases:
    (i) Human immunodeficiency virus, types 1 and 2;
    (ii) Hepatitis B virus;
    (iii) Hepatitis C virus;
    (iv) Human transmissible spongiform encephalopathies, icluding
Creutzfeldt-Jakob disease;
    (v) Treponema pallidum;
    (vi) Human T-lymphotropic virus, types I and II;
    (vii) Cytomegalovirus;
    (viii) Chlamydia trachomatis; and
    (ix) Neisseria gonorrhea.
    (2) A disease agent or disease not listed in paragraph (z)(1) of
this section:
    (i) That is sufficiently prevalent among potential donors to
warrant screening or testing of all donors;
    (ii) For which there is a risk of transmission 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;
    (iii) That poses significant health risks, as measured by morbidity
and mortality; and
    (iv) For which appropriate screening measures have been developed
and/or an appropriate screening test for donor specimens has been
licensed, approved, or cleared for such use by FDA and is available.
    (z) Urgent medical need means that no comparable human cellular or
tissue-based product is available and the recipient is likely to suffer
serious morbidity without the product.
    (aa) Xenotransplantation means 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.
    (bb) Close contacts means household members and others with whom
the recipient participates in activities that could result in exchanges
of bodily fluids.
    (cc) Act means the Federal Food, Drug, and Cosmetic Act.
    (dd) PHS Act means the Public Health Service Act.
    (ee) FDA means the Food and Drug Administration.
    5. Section 1271.10 is revised to read as follows:

Sec. 1271.10  Establishments subject to this part; criteria for
regulation of human cellular and tissue-based products solely under
section 361 of the PHS Act.

    The owner or operator of an establishment, foreign or domestic,
that manufactures a human cellular or tissue-based product, whether or
not the product enters into interstate commerce, is required under this
part to register with FDA, to submit to the agency a list of each human
cellular or tissue-based product manufactured, and to comply with the
other requirements of this part, if the product:
    (a) Is minimally manipulated;
    (b) Is not promoted or labeled for any use other than a homologous
use;
    (c) Is not combined with or modified by the addition of any
component that is a drug or a device; and
    (d)(1) Either does not have a systemic effect; or
    (2) Has a systemic effect, and--
    (i) Is for autologous use;
    (ii) Is for a family-related allogeneic use; or
    (iii) Is for reproductive use.
    6. Section 1271.15 is added to read as follows:

Sec. 1271.15  Criteria for regulation of human cellular and tissue-
based products under the act and/or section 351 of the PHS Act.

    Human cellular or tissue-based products that are regulated as
drugs, devices and/or biological products under the act and/or section
351 of the PHS Act, and the establishments that manufacture those
products, are subject to all applicable regulations in title 21,
chapter 1. In conjunction with those regulations, the procedures in
part 1271, subparts B, C, and D shall be followed, as specified in
Secs. 207.20(f), 210.1(c), 210.2, 211.1(b), 807.20(e), and 820.1(a) of
this chapter. A human cellular or tissue-based product is regulated
under the act and/or section 351 of the PHS Act if it:
    (a) Is more than minimally manipulated;
    (b) Is promoted or labeled for any use other than a homologous use;
    (c) Is combined with or modified by the addition of any component
that is a drug or a device; or
    (d) Has a systemic effect and--
    (1) Is not for autologous use;
    (2) Is not for a family-related allogeneic use; and
    (3) Is not for reproductive use.
    7. Section 1271.20 is revised to read as follows:

Sec. 1271.20  Establishments not required to comply with the
requirements of this part.

    The following establishments are not required to register, list, or
meet the other requirements of this part:
    (a) Establishments that use human cellular or tissue-based products
solely for nonclinical scientific or educational purposes;
    (b) Establishments that remove human cellular or tissue-based
products from an individual and implant such cells or tissues into the
same individual during the same surgical procedure;
    (c) Carriers who accept, receive, carry, hold, or deliver human
cellular or tissue-based products in the usual course of business as
carriers;
    (d) Establishments that do not, recover, screen, test, process,
label, package, or distribute, but only receive or store human cellular
or tissue-based products solely for pending scheduled implantation,
transplantation, infusion, or transfer within the same facility.
    8. Subpart C, consisting of Secs. 1271.50 through 1271.90, is added
to read as follows:

Subpart C--Donor Suitability

Sec.
1271.50  Determination of donor suitability.
1271.55  Records of donor suitability determination.

[[Page 52721]]

1271.60  Quarantine pending determination of donor suitability.
1271.65   Quarantine and disposition of human cellular or tissue-
based product from a donor determined to be unsuitable.
1271.75  Donor screening.
1271.80  Donor testing; general requirements.
1271.85  Donor testing; specific requirements.
1271.90  Exceptions from the requirement of donor suitability
determination; labeling requirements.

Subpart C--Donor Suitability

Sec. 1271.50  Determination of donor suitability.

    (a) Except as provided under Secs. 1271.65 and 1271.90 of this
subpart, a human cellular or tissue-based product shall not be
implanted, transplanted, infused, or transferred until the donor of the
cells or tissue for the product has been determined to be suitable. In
the case of an embryo, donor suitability shall be determined for both
the oocyte donor and the sperm donor.
    (b) Donor suitability shall be determined and documented by a
responsible person as defined in Sec. 1271.3(w).
    (c) A determination that a donor is suitable or unsuitable shall be
based upon the results of donor screening in accordance with
Sec. 1271.75 and donor testing in accordance with Secs. 1271.80 and
1271.85.
    (d) A donor may be determined to be suitable if:
    (1) The results of donor screening in accordance with Sec. 1271.75
indicate that the donor is free from risk factors for and clinical
evidence of infection due to relevant communicable disease agents and
diseases and is neither a xenotransplant recipient nor a close contact
of a xenotransplant recipient; and
    (2) The results of donor testing for relevant communicable disease
agents in accordance with Secs. 1271.80 and 1271.85 are negative or
nonreactive.

Sec. 1271.55  Records of donor suitability determination.

    (a) A human cellular or tissue-based product from a donor
determined to be suitable or from a donor determined to be unsuitable
and made available for use under the provisions of Sec. 1271.65(b),
(c), or (d) shall be accompanied by documentation of the donor-
suitability determination required by Sec. 1271.50 from which the
donor's name has been deleted. This documentation shall include:
    (1)(i) A copy of the donor's relevant medical records, as defined
in 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; or
    (ii) A summary of records, as defined in Sec. 1271.3(x); and
    (2) A statement whether, based on the results of donor screening
and testing, the donor has been determined to be suitable or
unsuitable.
    (b) The establishment that generates records used in determining
donor suitability and the establishment that makes the donor-
suitability determination shall retain such records and shall make them
available for authorized inspection by or upon request from FDA.
Records that can be readily retrieved from another location by
electronic means are considered ``retained.'' Records shall be retained
at least 10 years after the date of implantation, transplantation,
infusion, or transfer of the product, or if the date of implantation,
transplantation, infusion, or transfer is not known, then records shall
be retained at least 10 years after the date of the product's
distribution, disposition, or expiration, whichever is latest.

Sec. 1271.60  Quarantine pending determination of donor suitability.

    (a) A human cellular or tissue-based product shall be kept in
quarantine, as defined in Sec. 1271.3(t), until completion of the
donor-suitability determination required by Sec. 1271.50. For
reproductive cells and tissues that can reliably be stored, quarantine
shall last until completion of the testing required under
Sec. 1271.85(d).
    (b) A human cellular or tissue-based product in quarantine pending
completion of a donor-suitability determination shall be clearly
identified as in quarantine and shall be easily distinguishable from
products that are available for release and distribution.
    (c) A human cellular or tissue-based product shipped before it is
available for release or distribution shall be kept in quarantine and
shall be accompanied by records identifying the donor (e.g., by donor
number), stating 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.

Sec. 1271.65  Quarantine and disposition of human cellular or tissue-
based product from a donor determined to be unsuitable.

    (a) If the donor of the cells or tissue for a human cellular or
tissue-based product is determined to be unsuitable based on the
results of required testing and/or screening, the product shall be kept
in quarantine and physically separated from all other products until
destruction or other disposition in accordance with paragraph (b) or
(c) of this section is accomplished.
    (b)(1) Except as provided in paragraph (b)(4) of this section, a
human cellular or tissue-based product from a donor who has been
determined to be unsuitable, based on the results of required testing
and/or screening, is not prohibited by this subpart C of this part from
use for implantation, transplantation, infusion, or transfer under the
following circumstances:
     (i) The product is for family-related, allogeneic use, as defined
in Sec. 1271.3(c);
    (ii) The product contains reproductive tissue from a directed
donor, as defined in Sec. 1271.3(m); or
    (iii) There is a documented urgent medical need as defined in
Sec. 1271.3(aa).
    (2) A human cellular or tissue-based product made available for use
under the provisions of paragraph (b)(1) of this section shall be
labeled with the Biohazard legend shown in Sec. 1271.3(i).
    (3) The manufacturer of a human cellular or tissue-based product
used under the provisions of paragraph (b)(1) of this section shall
document that:
    (i) The physician using the product was notified of the results of
testing and screening;
    (ii) The physician authorized the use of the product;
    (iii) The physician agreed to explain the communicable disease
risks associated with the use of the product to the recipient or the
recipient's legally authorized representative; and
    (iv) The physician agreed to obtain from the recipient or the
recipient's legally authorized representative consent to use the
product.
    (4) A human cellular or tissue-based product from a donor who is
identified under Sec. 1271.75(a)(2) as either having received a
xenotransplant or having been a close contact of a xenotransplant
recipient shall not be made available for use under the provisions of
paragraph (b)(1) of this section.
    (c)(1) A human cellular or tissue-based product from a donor for
whom the donor-suitability determination has not yet been completed is
not prohibited by this subpart C from use for implantation,
transplantation, infusion, or transfer if there is a documented urgent
medical need as defined in Sec. 1271.3(z).
    (2) A human cellular or tissue-based product made available for use
under the provisions of paragraph (c)(1) of this section shall be
labeled ``NOT EVALUATED FOR INFECTIOUS SUBSTANCES'' and shall be
accompanied by a statement of:

[[Page 52722]]

    (i) The results of donor screening required under Sec. 1271.75, if
complete;
    (ii) The results of any testing required under Sec. 1271.80 or
Sec. 1271.85 that has been completed; and
    (iii) A list of any testing required under Sec. 1271.80 or
Sec. 1271.85 that has not yet been completed.
    (3) The manufacturer of a human cellular or tissue-based product
used under the provisions of paragraph (c)(1) of this section shall
document that:
    (i) The physician using the product was notified that the testing
and screening were not complete;
    (ii) The physician authorized the use of the product after
determining there is an urgent medical need;
    (iii) The physician agreed to explain the communicable disease
risks associated with the use of the product to the recipient or the
recipient's legally authorized representative; and
    (iv) The physician agreed to obtain from the recipient or the
recipient's legally authorized representative consent to use the
product.
    (4) In the case of a human cellular or tissue-based product used
under the provisions of paragraph (c)(1) of this section, the donor-
suitability determination shall be completed during or after the
emergency use of the product, and the manufacturer shall inform the
physician of the results of the determination.
    (d) A human cellular or tissue-based product from a donor who has
been determined to be unsuitable, based on the results of required
testing and/or screening, is not prohibited by this subpart C of this
part from use for nonclinical purposes, provided that it is labeled:
    (1) ``For Nonclinical Use Only''; and
    (2) With the Biohazard legend shown in Sec. 1271.3(i).

Sec. 1271.75  Donor screening.

    (a)(1) Except as provided under Sec. 1271.90, the relevant medical
records of a donor of cells or tissue for a human cellular or tissue-
based product shall be reviewed for risk factors for and clinical
evidence of relevant communicable disease agents and diseases
including, at a minimum, the following:
    (i) Human immunodeficiency virus;
    (ii) Hepatitis B virus;
    (iii) Hepatitis C virus; and
    (iv) Human transmissible spongiform encephalopathies including
Creutzfeldt-Jakob disease.
    (2) Except as provided under Sec. 1271.90, the relevant medical
records of a donor of cells or tissue for a human cellular or tissue-
based product shall be reviewed to determine whether the donor has
received a xenotransplant or has been a close contact of a
xenotransplant recipient.
    (b) Except as provided under Sec. 1271.90, the relevant medical
records of a donor of reproductive cells or tissue shall be reviewed
for risk factors for and clinical evidence of infection due to relevant
sexually transmitted and genitourinary diseases that can be transmitted
with the recovery of the reproductive cells or tissue including at a
minimum Chlamydia trachomatis and Neisseria gonorrhea, in addition to
the relevant communicable disease agents and diseases for which
screening is required under paragraph (a) of this section.
    (c) A donor who is identified as having risk factors for or
clinical evidence of any of the relevant communicable disease agents or
diseases for which screening is required under paragraph (a)(1) or (b)
of this section, or is identified under paragraph (a)(2) of this
section as either a xenotransplant recipient or a close contact of a
xenotransplant recipient, shall be determined to be unsuitable.
    (d) An abbreviated donor screening procedure that determines and
documents any changes in the donor's medical history including relevant
social behavior since the previous donation that would make the donor
unsuitable may be used for a living donor of human cellular and tissue-
based products on subsequent donations. An abbreviated donor screening
procedure may be used only when a complete donor screening procedure
has been performed within the previous 6 months.

Sec. 1271.80  Donor testing; general requirements.

    (a) To adequately and appropriately reduce the risk of transmission
of relevant communicable diseases, and except as provided under
Sec. 1271.90, a donor specimen shall be tested for evidence of
infection due to relevant communicable disease agents in accordance
with paragraph (c) of this section. At a minimum, testing shall be
performed for those relevant communicable disease agents specified in
Sec. 1271.85. In the case of a fetal or neonatal donor, a specimen from
the mother is generally acceptable for testing.
    (b) Except as provided in paragraphs (d)(2) and (d)(3) of this
section, the donor specimen shall be collected at the time of recovery
of cells or tissue from the donor or within 48 hours after recovery,
except that the specimen from a living donor 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.
    (c) Testing shall be performed using appropriate 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; provided that, until such time as appropriate FDA-licensed,
approved, or cleared donor screening tests for Chlamydia trachomatis
and for Neisseria gonorrhea are available, FDA-licensed, approved, or
cleared tests labeled for the detection of those organisms in an
asymptomatic, low-prevalence population shall be used. Tests
specifically labeled for cadaveric specimens shall be used instead of a
more generally labeled test when applicable and when available. Testing
shall be performed by a laboratory certified to perform testing on
human specimens under the CLIA.
    (d) The following donors shall be determined to be unsuitable:
    (1) A donor whose specimen tests repeatedly reactive or positive on
a test for a relevant communicable disease agent in accordance with
Sec. 1271.85, except for:
    (i) A donor whose specimen tests repeatedly reactive for
cytomegalovirus (CMV) and additional testing does not show the presence
of an active infection, or
    (ii) A donor whose specimen tests reactive on a non-Treponemal
screening test for syphilis and negative on a specific Treponemal
confirmatory test;
    (2) A donor from whom blood loss is known or suspected to have
occurred and who received a transfusion or infusion of more than 2,000
milliliters (mL) of blood (i.e., whole blood, reconstituted blood, or
red blood cells) or colloids within 48 hours, or more than 2,000 mL of
crystalloids within 1 hour, or any combination thereof prior to the
collection of a specimen from the donor for testing, unless:
    (i) A specimen taken from the donor after blood loss but before the
transfusion or infusion is available for

[[Page 52723]]

relevant communicable disease testing; or
    (ii) An algorithm designed to ensure that plasma dilution
sufficient to affect test results has not occurred is utilized to
evaluate the volumes administered in the 48 hours prior to collecting
the specimen from the donor;
    (3) A donor who is 12 years of age or younger and has received any
transfusion of blood, colloids, and/or crystalloids prior to the
recovery of the cells or tissue, unless:
    (i) A specimen taken from the donor before the transfusion or
infusion is available for relevant communicable disease testing; or
    (ii) An algorithm designed to ensure that plasma dilution
sufficient to affect test results has not occurred is utilized to
evaluate the volumes administered in the 48 hours prior to collecting
the specimen from the donor.

Sec. 1271.85  Donor testing; specific requirements.

    (a) To adequately and appropriately reduce the risk of transmission
of relevant communicable diseases, and except as provided under
Sec. 1271.90, a specimen from a donor of viable or nonviable cells or
tissue for a human cellular or tissue-based product shall be tested for
evidence of infection due to relevant communicable disease agents
including, at a minimum, the communicable disease agents listed as
follows.
    (1) Human immunodeficiency virus, type 1;
    (2) Human immunodeficiency virus, type 2;
    (3) Hepatitis B virus;
    (4) Hepatitis C virus; and
    (5) Treponema pallidum.
    (b) To adequately and appropriately reduce the risk of transmission
of relevant communicable diseases, and except as provided under
Sec. 1271.90, a specimen from a donor of viable, leukocyte-rich cells
or tissue shall be tested for evidence of infection due to the relevant
cell-associated communicable disease agents including, at a minimum,
the communicable disease agents listed as follows, in addition to the
relevant communicable disease agents for which testing is required
under paragraph (a) of this section.
    (1) Human T-lymphotropic virus, type I;
    (2) Human T-lymphotropic virus, type II; and
    (3) Cytomegalovirus.
    (c) To adequately and appropriately reduce the risk of transmission
of relevant communicable diseases, and except as provided under
Sec. 1271.90, a specimen from a donor of reproductive cells or tissue
shall be tested for evidence of infection due to relevant genitourinary
disease agents. Testing shall include, at a minimum, the communicable
disease agents listed in paragraphs (c)(1) and (c)(2) of this section,
in addition to the relevant communicable disease agents for which
testing is required under paragraphs (a) and (b) of this section.
However, 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, then tests for the communicable disease agents listed in
paragraphs (c)(1) and (c)(2) of this section are not required. Minimum
testing for genitourinary disease agents include:
    (1) Chlamydia trachomatis; and
    (2) Neisseria gonorrhea.
    (d) Except as provided under Sec. 1271.90, at least 6 months after
the date of donation of reproductive cells or tissue that can be
reliably stored, a new specimen shall be taken from the donor and
retested for evidence of infection due to the relevant communicable
disease agents for which testing is required under paragraphs (a), (b),
and (c) of this section.
    (e) For donors of dura mater, an assessment designed to detect
evidence of transmissible spongiform encephalopathy shall be performed.

Sec. 1271.90  Exceptions from the requirement of donor suitability
determination; labeling requirements.

    (a) For the following human cellular and tissue-based products, a
determination of donor suitability under Sec. 1271.50 is not required,
and donor screening under Sec. 1271.75, and testing under Secs. 1271.80
and 1271.85 are recommended but not required:
    (1) Banked cells and tissues for autologous use;
    (2) Reproductive cells or tissue donated by a sexually-intimate
partner of the recipient for reproductive use.
    (b) If all screening and testing applicable to a comparable human
cellular or tissue-based product under Secs. 1271.75, 1271.80, and
1271.85 are not performed on the donor of a human cellular or tissue-
based product listed in paragraph (a) of this section, the product
shall be labeled ``NOT EVALUATED FOR INFECTIOUS SUBSTANCES.'' If any
screening or testing is performed on a donor of a human cellular or
tissue-based product listed in paragraph (a) of this section, and the
results indicate the presence of relevant communicable disease agents
and/or risk factors for or clinical evidence of relevant communicable
disease agents or diseases, the product shall be labeled with the
Biohazard legend shown in Sec. 1271.3(i).
    (c) Banked cells and tissues for autologous use shall be labeled
``FOR AUTOLOGOUS USE ONLY.''

    Dated: February 19, 1999.
Jane E. Henney,
Commissioner of Food and Drugs.
    Dated: August 29, 1999.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 99-25378 Filed 9-29-99; 8:45 am]
BILLING CODE 4160-01-F