[Federal Register Volume 64, Number 189 (Thursday, September 30, 1999)]
[Proposed Rules]
[Pages 52696-52723]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-25378]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 210, 211, 820, and 1271

[Docket No. 97N-484S]


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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

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

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

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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

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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

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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         X1                 X1                 X1                 X1                 Donor sperm; not
                                                                                                oocyte
----------------------------------------------------------------------------------------------------------------
Labeling           X1                 X1                 X1                 X1                 X1
----------------------------------------------------------------------------------------------------------------
Record Retention   X1                 X1                 X1                 X1                 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  $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 Burden1
----------------------------------------------------------------------------------------------------------------
                                                      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 Burden1
----------------------------------------------------------------------------------------------------------------
                                                      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- 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