[Federal Register Volume 69, Number 101 (Tuesday, May 25, 2004)]
[Rules and Regulations]
[Pages 29786-29834]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-11245]



[[Page 29785]]

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

Part II





Department of Health and Human Services





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



Food and Drug Administration



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



21 CFR Parts 210, 211, 820, and 1271



Eligibility Determination for Donors of Human Cells, Tissues, and 
Cellular and Tissue-Based Products; Final Rule and Notice

  Federal Register / Vol. 69, No. 101 / Tuesday, May 25, 2004 / Rules 
and Regulations  

[[Page 29786]]


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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 210, 211, 820, and 1271

[Docket No. 1997N-0484S]
[RIN 0910-AB27]


Eligibility Determination for Donors of Human Cells, Tissues, and 
Cellular and Tissue-Based Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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

SUMMARY: The Food and Drug Administration (FDA) is requiring human 
cell, tissue, and cellular and tissue-based product (HCT[sol]P) 
establishments to screen and test cell and tissue donors for risk 
factors for, and clinical evidence of, relevant communicable disease 
agents and diseases. The agency is amending the current good 
manufacturing practice (CGMP) and quality system (QS) regulations that 
apply to HCT[sol]Ps regulated as drugs, medical devices, and/or 
biological products to clarify the role of the new donor-eligibility 
regulations in relation to existing CGMP regulations. By preventing the 
transmission of communicable disease by the wide spectrum of HCT[sol]Ps 
that are marketed now or may be marketed in the future, the agency's 
action will improve protection of the public health and increase public 
confidence in new technologies.

DATES: This rule is effective May 25, 2005. This rule is applicable to 
cells and tissues recovered on or after May 25, 2005.

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:

Table of Contents

I. Introduction
    A. Background
    B. Legal Authority
II. Highlights of the Final Rule
    A. Plain Language
    B. New Terminology and Definitions
    C. Other Highlights
III. Comments on the Proposed Rule and FDA's Responses
    A. General
    B. Amendments to 21 CFR Parts 210, 211, and 820
    C. Definitions (Sec.  1271.3)
    D. Part 1271, Subpart C--Donor-Eligibility
    E. Economic Impacts
IV. Analysis of Economic Impacts
    A. Objectives and Basis of the Proposed Action
    B. The Type and Number of Entities Affected
    C. Nature of Impacts
    D. Benefits of the Final Rule
    E. Small Entity Impacts and Analysis of Alternatives
V. Environmental Impact
VI. Federalism Assessment
VII. The Paperwork Reduction Act of 1995
VIII. References

I. Introduction

    This final rule is part of a comprehensive new system of regulation 
for HCT[sol]Ps. The goal of the new approach is to improve protection 
of the public health without imposing unnecessary restrictions on 
research, development, or the availability of new products. 
Consolidating the regulation of HCT[sol]Ps into one regulatory program 
is expected to lead to increased consistency and greater efficiency. 
Together, these planned improvements will increase the safety of 
HCT[sol]Ps, and public confidence in their safety. We intend to make 
the good tissue practice final rule, which has not yet published but 
which FDA intends to issue soon, effective 1 year after publication of 
this rule. Once both this rule and the good tissue practice regulations 
are in effect, FDA's comprehensive regulatory framework will be 
complete.

A. Background

    In 1997, FDA proposed a new approach to the regulation of 
HCT[sol]Ps (62 FR 9721, March 4, 1997). (The term ``HCT[sol]P'' is 
defined at Sec.  1271.3(d) (21 CFR 1271.3(d).) To improve the 
regulation of HCT[sol]Ps, we announced our intention to establish a 
comprehensive regulatory program for HCT[sol]Ps, contained in part 1271 
(21 CFR part 1271). In accordance with the tiered, risk-based approach 
that we proposed, some HCT[sol]Ps would be regulated only under these 
new regulations, while others would also be regulated as drugs, 
devices, and/or biological products.
    To implement the proposed approach, we issued three proposed rules:
     Establishment Registration and Listing for Manufacturers 
of Human Cellular and Tissue-Based Products (the registration proposed 
rule) (63 FR 26744, May 14, 1998);
     Suitability Determination for Donors of Human Cellular and 
Tissue-Based Products (the donor-suitability proposed rule) (64 FR 
52696, September 30, 1999); and
     Current Good Tissue Practice for Manufacturers of Human 
Cellular and Tissue-Based Products; Inspection and Enforcement (the 
CGTP proposed rule) (66 FR 1508, January 8, 2001).
    We published a final rule entitled ``Human Cells, Tissues, and 
Cellular and Tissue-Based Products; Establishment Registration and 
Listing,'' in the Federal Register on January 19, 2001 (the 
registration final rule) (66 FR 5447). The registration final rule put 
into place general provisions pertaining to the scope and applicability 
of part 1271. These provisions are contained in subpart A of part 1271, 
along with a section that contains definitions applicable to all of 
part 1271 (Sec.  1271.3). The registration final rule requires cell and 
tissue establishments to register with us and submit a list of their 
HCT[sol]Ps; the procedures for registration and listing are contained 
in subpart B of part 1271.
    Some sections of the registration final rule became effective on 
April 4, 2001. Under those provisions, we now receive registration and 
listing information from establishments that engage in the recovery, 
screening, testing, processing, storage, or distribution of human 
tissue intended for transplantation (as described in Sec.  
1271.3(d)(1)). The effective date for the remaining sections was 
January 21, 2003, by which time we expected to have completed 
rulemaking for all of part 1271 (66 FR 5447 at 5448). At that time, the 
registration and listing requirements would have become effective for 
all other HCT[sol]Ps (as described in Sec.  1271.3(d)(2)). However, we 
recognized that unanticipated delays in completing the rulemaking for 
the remainder of part 1271 could occur, and we noted that, should the 
rulemaking proceedings be delayed past the 2-year timeframe, we would 
consider whether to maintain the 2-year effective date for the 
HCT[sol]Ps described in Sec.  1271.3(d)(2) or whether to extend that 
date for some or all of these HCT[sol]Ps (66 FR 5447 at 5449). Since 
the rulemaking proceedings were delayed past the original 2-year 
effective date of January 21, 2003, we delayed the effective date of 
Sec.  1271.3(d)(2) until January 21, 2004 (68 FR 2690, January 21, 
2003). After the definition became final on January 21, 2004, we issued 
an interim final rule excepting human dura mater and human heart valve 
allografts from the scope of the definition of ``human cells, tissues, 
or cellular or tissue-based products (HCT[sol]Ps)'' (69 FR 3823, 
January 27, 2004). We took this action to assure that these products, 
which were subject to the Federal Food, Drug, and Cosmetic Act (the 
act) and therefore regulated under the current good

[[Page 29787]]

manufacturing practice regulations set out in the quality system 
regulations in part 820 (21 CFR part 820), were not released from the 
scope of those regulations before a more comprehensive regulatory 
framework applicable to HCT[sol]Ps, including donor eligibility 
requirements, good tissue practice regulations, and appropriate 
enforcement provisions, is fully in place. When that comprehensive 
framework is in place, we intend that human dura mater and human heart 
valve allografts will be subject to it. We intend to revoke the interim 
final rule at that time.
    We are now making final the donor-suitability proposed rule that 
was proposed on September 30, 1999. (For reasons discussed in comment 
26 of this document, we refer in this final rule to donor 
``eligibility'' rather than ``suitability.'') The comment period for 
that proposed rule closed on December 29, 1999. On April 18, 2000, we 
reopened the comment period for an additional 90 days. We took this 
step in response to requests for an extension of the comment period as 
well as to provide sufficient time for State officials to participate 
in the rulemaking (65 FR 20774, April 18, 2000).
    Because of their nature as derivatives of the human body, 
HCT[sol]Ps pose a risk of transmitting communicable diseases. For this 
reason, this final rule requires that most cell and tissue donors be 
tested and screened for evidence of relevant communicable disease 
infection. It also contains other related requirements (e.g., on 
records, quarantine, storage, and labeling). These donor-eligibility 
requirements, which locate in subpart C of part 1271, are part of the 
core requirements applicable both to HCT[sol]Ps regulated solely under 
these regulations and section 361 (the 361 HCT[sol]Ps) of the Public 
Health Service Act (the PHS Act) and to those HCT[sol]Ps also subject 
to regulation as drugs, devices, and/or biological products. As part of 
this rulemaking, we are also amending the drug CGMP regulations and the 
device QS regulations to clarify the role of the donor-eligibility 
requirements in the manufacture of HCT[sol]Ps subject to regulation as 
drugs, devices, and/or biological products.
    Since the publication of the donor-suitability proposed rule, we 
have continued to obtain current and accurate information on the risks 
of communicable-disease transmission by HCT[sol]Ps and the most 
appropriate testing and screening measures. To this end, we have met 
with FDA's Transmissible Spongiform Encephalopathies Advisory Committee 
(TSEAC) (January 18 to 19, 2001, and June 26 to 27, 2002); the Blood 
Products Advisory Committee (BPAC) (December 13 to 14, 2001, and March 
14 to 15, 2002); and the Centers for Disease Control and Prevention 
(CDC) (June 26 to 27, 2000). We have placed information on these 
meetings in the docket for this rulemaking.
    We have used the information obtained at those meetings to develop 
a draft guidance document on determining donor eligibility entitled 
``Eligibility Determination for Donors of Human Cells, Tissues, and 
Cellular and Tissue-Based Products'' (the donor-eligibility draft 
guidance). Elsewhere in this issue of the Federal Register, we announce 
the availability of that draft guidance, and solicit comments on its 
contents. We have also developed draft guidance on screening for 
Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease 
(vCJD) entitled ``Guidance for Industry: Preventive Measures to Reduce 
the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) 
and Variant Creutzfeldt-Jakob Disease (vCJD) by Human Cells, Tissues, 
and Cellular and Tissue-Based Products (HCT[sol]Ps)'' (the CJD draft 
guidance) (67 FR 42789, June 25, 2002). We intend to combine the donor-
eligibility draft guidance with the CJD draft guidance, and to issue a 
single final guidance document.

B. Legal Authority

    We are issuing these new regulations under the authority of section 
361 of the PHS Act (42 U.S.C. 264). Under that section, by delegation 
from the Surgeon General and the Secretary of Health and Human 
Services, 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. Intrastate 
transactions affecting communicable disease transmission may also be 
regulated under section 361 of the PHS Act. (See Louisiana v. Mathews, 
427 F. supp. 174, 176 (E.D. La. 1977).)
    It is especially important to recognize that HCT[sol]P 
manufacturing inevitably has interstate effects. HCT[sol]Ps recovered 
in one State may be sent to another for processing, then shipped for 
use throughout the United States, or beyond. FDA has been involved in 
many recalls where HCT[sol]Ps processed in a single establishment have 
been distributed in many States.
    Section 361 of the PHS Act authorizes FDA to issue regulations 
necessary to prevent the introduction, transmission, or spread of 
communicable diseases. Communicable diseases include, but are not 
limited to, those transmitted by viruses, bacteria, fungi, parasites, 
and transmissible spongiform encephalopathy agents.
    Certain diseases are transmissible through the implantation, 
transplantation, infusion, or transfer of HCT[sol]Ps derived from 
donors infected with those diseases. To prevent the introduction, 
transmission, or spread of such diseases, we consider it necessary to 
take appropriate measures to prevent the use of cells or tissues from 
infected donors. Thus, these regulations require that, before the use 
of most HCT[sol]Ps, the cell or tissue donor must be determined to be 
eligible to donate, based on the results of screening and testing for 
relevant communicable diseases. In most cases, a donor who tests 
reactive for a particular disease, or who possesses clinical evidence 
of or risk factors for such a disease, would be considered ineligible, 
and cells and tissues from that donor would not ordinarily be used.
    In addition to regulations governing the testing and screening of 
donors for relevant communicable disease and quarantine and storage of 
HCT[sol]Ps, FDA has also determined that regulations requiring 
establishments to maintain certain records related to HCT[sol]Ps and to 
establish standard operating procedures are necessary to prevent the 
introduction, transmission, or spread interstate of communicable 
disease. A single donor may be the source of a large number of 
HCT[sol]Ps. For example, it may be discovered, long after the donation 
and transplantations have been completed, that a donor of HCT[sol]Ps 
transplanted into a large number of recipients had a relevant 
communicable disease. Although it might be too late to prevent the 
recipients' infections, it would not be too late to for the recipient 
to obtain treatment and take steps to avoid infecting others, such as 
close family members. However, unless adequate records were maintained, 
and maintained for the period of time throughout which infections may 
be identified, it would be impossible to identify the recipients 
potentially infected by the donor's HCTPs. This would be a critical 
breakdown in the prevention of disease transmission. Accordingly, FDA 
determined that the maintenance and retention of records are necessary 
to prevent the interstate introduction, transmission, and spread of 
communicable disease. Since some diseases, such as transmissible 
spongiform encephalopathies (TSEs), appear to have a long latency 
period, FDA has determined that a 10-year record retention period is 
necessary.
    Similarly, it is necessary for establishments to establish, 
maintain,

[[Page 29788]]

and follow procedures related to the prevention of communicable 
disease. The agency has determined that these provisions are necessary 
to ensure that the important protections created by these regulations 
are actually effected and are not simply empty promises. Only 
manufacturing conducted in accordance with established procedures can 
assure that HCT[sol]Ps meet the standards in these rules. If 
standardized processes are not developed and used, mistakes, 
inevitably, are made. Moreover, review of procedures can be critical to 
determining the cause of a disease transmission. Without that analysis, 
it would be impossible to prevent a future occurrence, with possibly 
fatal consequences.
    These regulations are intended to prevent the transmission of 
communicable disease through the implantation, transplantation, 
infusion, or transfer of HCT[sol]Ps. However, as noted in the 
registration and donor-suitability proposed rules, all HCT[sol]Ps pose 
some risk of carrying pathogens that could cause disease in health-care 
personnel, other handlers of tissue, recipients, and family members or 
other contacts of recipients (63 FR 26744 and 64 FR 52696 at 52698). 
This broader concern for the spread of communicable disease is 
reflected in certain labeling requirements in these regulations and in 
the criteria for identifying a relevant communicable disease. We 
recognize 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 173.196), and we do not 
consider these regulations to be in conflict with those other 
regulations currently in effect. However, we have made an effort to be 
consistent with the terminology used in these other regulations; e.g., 
``Infectious Substances'' and the Biohazard legend.
    Under section 361 of the PHS Act, FDA is authorized to enforce the 
regulations it issues to prevent the introduction, transmission, or 
spread of communicable diseases interstate through such means as 
inspection, disinfection, sanitation, destruction of animals or 
articles found to be so infected or contaminated as to be sources of 
dangerous infection in human beings, and other measures that may be 
necessary. In addition, under section 368(a) of the PHS Act, any person 
who violates a regulation prescribed under section 361 of the PHS Act 
may be punished by imprisonment for up to 1 year. Individuals may also 
be punished for violating such a regulation by a fine of up to $100,000 
if death has not resulted from the violation or up to $250,000 if death 
has resulted. For organizational defendants, fines range up to $200,000 
and $500,000. Individuals and organizations also face possible 
alternative fines based on the amount of gain or loss (18 U.S.C. 3559 
and 3571(b) through (d)). Federal District Courts also have 
jurisdiction to enjoin individuals and organizations from violating 
regulations implementing section 361 of the PHS Act. (See Califano v. 
Yamasaki, 442 U.S. 682, 704-05 (1979); United States v. Beatrice Foods 
Co., 493 F.2d 1259, 1271-72 (8th Cir. 1974), cert. denied, 420 U.S. 961 
(1975).) Under sections 501(a)(2)(B) and (h), and 520(f)(1) of the 
Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 351(a)(2)(B) 
and (h), and 21 U.S.C. 360j(f)(1)), drugs (including biological 
products) and devices (including biological products) are subject to 
CGMP requirements designed to ensure, among other things, product 
safety (21 U.S.C. 351(a)(2)(B) and (h), and 21 U.S.C. 360j(f)(1)). The 
authorities supporting the CGMP and QS regulations are also applicable 
when the CGMP and QS regulations apply to an HCT[sol]P regulated as a 
drug, biological product, or device. Currently, the CGMP and QS 
regulations applicable to HCT[sol]Ps regulated as drugs or devices do 
not delineate testing and screening procedures for communicable 
diseases. (See parts 210, 211, and 820 (21 CFR parts 210, 211, and 
820).) Nevertheless, we consider communicable-disease testing and 
screening to be steps in the manufacturing process that are crucial to 
the safety of such products. As a result, we are amending the existing 
CGMP regulations for drugs in parts 210 and 211 and the QS regulations 
for devices in part 820, which include CGMP requirements, to make clear 
that the testing and screening provisions of part 1271 subpart C apply 
to HCT[sol]Ps regulated as drugs, devices, and/or biological products.
    Under Sec.  210.1(c), the manufacturer of an HCT[sol]P regulated as 
a drug, including a biological product that is a drug under the act, 
must comply with the donor-eligibility procedures in part 1271, subpart 
C. Failure to follow the CGMP requirements, including the testing and 
screening procedures in part 1271, would make the product adulterated 
under the act. In issuing this regulation, FDA is relying on the drug 
CGMP authorities (in particular, section 501(a)(2)(B) of the act (21 
U.S.C. 351(a)(2)(B)), as well as section 361 of the PHS Act. Under 
Sec.  820.1(a)(1), the manufacturer of an HCT[sol]P regulated as a 
device, including a biological product that is a device under the act, 
must comply with the same procedures.
    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 (42 
U.S.C. 274c and 274k). The Health Resources and Services Administration 
(HRSA) currently administers both of these programs. Given HRSA 
oversight in these areas, vascularized human organs (to include 
vascularized subparts of human organs) and minimally manipulated bone 
marrow (as defined in Sec.  1271.3(d)(2)) for unrelated allogeneic use 
are specifically excluded from these final regulations.

II. Highlights of the Final Rule

    This final rule requires establishments to make donor-eligibility 
determinations for cell and tissue donors, based on donor screening and 
testing for relevant communicable disease agents and diseases (Sec.  
1271.45). The regulations cover how to screen and test donors 
(Sec. Sec.  1271.75, 1271.80, and 1271.85), as well as how to make the 
donor-eligibility determination (Sec.  1271.50). The term ``relevant 
communicable disease agent or disease'' is defined at Sec.  1271.3(r). 
The rule also contains related requirements pertaining to procedures 
(Sec.  1271.47); records (Sec.  1271.55); quarantine (Sec.  1271.60); 
and storage of HCT[sol]Ps from ineligible donors (Sec.  1271.65). Two 
of these provisions describe situations where it is not prohibited to 
use an HCT[sol]P from an ineligible donor or a donor who has not yet 
been determined eligible (Sec. Sec.  1271.60 and 1271.65). Exceptions 
from the requirement for making a donor-eligibility determination 
appear in Sec.  1271.90.
    The donor-eligibility draft guidance that may be found elsewhere in 
this Federal Register is intended to assist establishments in complying 
with the requirements of this final rule and contains details that are 
not in the regulation. Although not binding, the draft guidance 
presents the agency's current thinking on the topics covered. For 
example, whereas the regulation requires an establishment to screen 
donors for risk factors, the draft guidance specifies what we consider 
those risk factors to be. Similarly, the draft guidance contains 
recommendations on which tests to use to comply with the testing 
requirements in Sec. Sec.  1271.80 and 1271.85. The draft guidance also 
identifies several additional disease agents or diseases that we 
believe meet the definition of relevant communicable disease agent or

[[Page 29789]]

disease. We welcome comments on the draft guidance. As scientific 
knowledge is developed, new tests are introduced, and additional 
relevant communicable disease agents and diseases are identified, we 
intend to follow the good guidance practices set out in Sec.  10.115 to 
modify the donor-eligibility guidance so that it remains current.

A. Plain Language

    In the Federal Register of June 10, 1998 (63 FR 31885), the 
Presidential Memorandum on Plain Language in Government Writing was 
issued. The goal of the plain language initiative is to publish 
government documents that are easier to understand.
    In response to this initiative, we have written the donor-
eligibility regulation in plain language. We have taken the following 
actions:
     Written the regulation in question-and-answer format;
     Reorganized some regulatory sections for greater clarity; 
and
     Followed other plain-language conventions, such as using 
``must'' instead of ``shall.''
    The resulting codified language is easier to read and understand 
than the proposed regulation. These editorial changes are for clarity 
only and do not change the substance of the requirements.

B. New Terminology and Definitions

    In the registration final rule, we discussed our decision to 
replace the term ``human cellular or tissue-based products'' with 
``human cells, tissues, and cellular and tissue-based products'' 
(abbreviated HCT[sol]Ps) (66 FR 5447 at 5455). For consistency, we have 
made the same change in this final rule.
    In response to comments, we have changed the term ``donor 
suitability'' to ``donor eligibility.''
    In addition, we have made several changes to the definition of 
``relevant communicable disease agent or disease'' with respect to 
prevalence. We intend the new language to cover both intentional and 
unintentional release of infectious agents.
    We have also modified the definition of ``directed donor'' and 
changed the term to ``directed reproductive donor.''
    We have deleted the definitions of ``xenotransplantation'' and 
``close contacts.''

C. Other Highlights

    This final rule contains other changes from the proposed rule. 
These changes are listed as follows:
     Provisions in Sec.  1271.47, originally proposed in the 
CGTP proposed rule, require that HCT[sol]P establishments establish and 
maintain procedures for the steps they perform in determining donor 
eligibility, including testing and screening;
     The requirement for donor retesting 6 months after 
donation now applies only to anonymous semen donors. In addition, you 
do not have to obtain a specimen for testing at each donation from a 
repeat anonymous donor, so long as you do not release the donation 
unless the donor has been retested (at least 6 months post donation). 
Directed donations of semen are excepted from the retesting 
requirement;
     Physical separation between HCT[sol]Ps from ineligible and 
eligible donors is no longer required;
     We have removed the requirement that a physician must 
consent to the use of an HCT[sol]P from an ineligible donor;
     You must screen all donors for Treponema pallidum and some 
donors for Human T-lymphotropic virus (HTLV) (in addition to testing);
     You must screen donors for ``communicable disease risks 
associated with xenotransplantation.'' Under the proposed rule, receipt 
of a xenotransplantation product would have made a donor ineligible 
under all circumstances. Now, receipt of a xenotransplantation product 
no longer overrides the special circumstances, listed in Sec.  
1271.65(b)(1), under which use of an HCT[sol]P from an ineligible donor 
is not prohibited;
     We have modified the requirements applicable to testing 
for Cytomegalovirus (CMV);
     If the donor is one month of age or younger, you must test 
a specimen from the birth mother;
     The requirements on timing of specimen collection allow 7 
days before or after recovery, or for donors of peripheral blood stem 
progenitor cells only, up to 30 days before recovery, if specimen 
collection at the time of recovery is not feasible; and
     Required testing can be performed by a laboratory that has 
met requirements equivalent to those imposed by the Clinical Laboratory 
Improvement Amendments of 1988 (CLIA), as determined by the Centers for 
Medicare and Medicaid Services (CMS).

III. Comments on the Proposed Rule and FDA's Responses

    We received over 500 comments on the proposed rule.
    Some comments raised issues relating to the general provisions in 
subpart A of part 1271 or the registration and listing procedures in 
subpart B, and we considered those comments in drafting the 
registration final rule (66 FR 5447 at 5450, January 19, 2001). For 
example, in that final rule we discussed comments on dispute resolution 
(66 FR 5447 at 5451); homologous use (66 FR 5447 at 5458); the practice 
of medicine (66 FR 5447 at 5452); minimal manipulation (66 FR 5447 at 
5457); the definition of ``family-related allogeneic use'' (66 FR 5447 
at 5454); the terms ``human cellular or tissue-based product'' and 
``manufacture'' (66 FR 5447 at 5455 and 5456); the regulation of bone 
allografts (66 FR 5447 at 5457); establishments not required to comply 
with part 1271 (66 FR 5447 at 5460); and the frequency of updates (66 
FR 5447 at 5460 and 5461). If we considered an issue in the 
registration final rule, we are not reiterating our response here.
    Several comments submitted to the docket for the CGTP proposed rule 
raised issues that are appropriately addressed in this final rule. We 
respond to those comments in comments 32, 48, 49, and 59, and in the 
discussion of Sec.  1271.47 in section III.D.3 of this document.
    We received two requests for an extension of the comment period. On 
April 18, 2000, a document was published in the Federal Register 
reopening the comment period for an additional 90 days (65 FR 20774).

A. General

    (Comment 1) We received various comments expressing general 
approval of the proposed rule. One comment applauded us for addressing 
concerns of vital interest to the protection of the public health. 
Another comment expressed continued support for our efforts to design a 
comprehensive regulatory program for HCT[sol]Ps, and agreed that 
screening and testing of donors constitutes a vital component of such a 
program. Other comments supported our goal of preventing the 
transmission of communicable diseases through donor screening and 
testing. One comment supported requiring semen banks to comply with the 
proposed screening and testing regulations.
    We also received comments voicing general criticism of the proposed 
rule and of our comprehensive regulatory approach to cells and tissues. 
Some comments described the proposed rule as unnecessary or burdensome. 
One comment asserted that the regulations were inconsistent with the 
Congressionally supported ``least burdensome'' practice of regulation.
    (Response) We acknowledge and appreciate the supportive comments. 
This rule contains important requirements that will help prevent the 
transmission of communicable diseases by HCT[sol]Ps. Moreover, it forms 
a vital

[[Page 29790]]

component of the new tiered, risk-based regulatory program, which will 
be superior to the patchwork of requirements that it replaces. As 
discussed in greater detail in section IV of this document, this rule 
is consistent with Executive Order 12866, which, in its eleventh 
Principle of Regulation applicable to Federal rulemaking, requires FDA 
to ``* * * tailor its regulations to impose the least burden on society 
* * * consistent with obtaining the regulatory objectives.'' FDA has 
designed this regulatory program to impose only appropriate, and 
appropriately limited, burdens.
    For example, the compliance expectations for a small medical 
practice that provides artificial insemination are commensurate with 
the communicable disease risks associated with its activities. If the 
practice is limited to artificial insemination using either semen from 
an anonymous or directed reproductive donor obtained from a semen bank 
(Sec.  1271.15(d)), or semen recovered at the practice and immediately 
used to inseminate the donor's sexually intimate partner (Sec.  
1271.15(e)), then the risks are minimal and the practice is not 
required to comply with part 1271. If the semen is not immediately 
transferred to a donor's sexually intimate partner but instead is 
stored (raising concerns about possible cross-contamination during 
storage), the practice would not be eligible for the exception under 
Sec.  1271.15(e) and would need to comply with the requirements in part 
1271 subpart B (registration and listing) and in applicable sections of 
subpart C (minimal standard operating procedures, minimal 
recordkeeping, and specific labeling for stored reproductive cells or 
tissue from sexually intimate partners if not screened or tested). 
Additional risks are associated with the recovery of semen from an 
anonymous or directed reproductive donor for artificial insemination; 
practitioners who perform these services are not eligible for the 
exception under Sec.  1271.15(d) and must comply with both subpart B 
(registration and listing) and all of subpart C (donor screening and 
testing, standard operating procedures, recordkeeping, and labeling) in 
part 1271. FDA intends to provide further detailed guidance regarding 
these risk-based approaches.
    We have striven to establish regulations that provide public health 
protection without imposing an undue burden on regulated industry. In 
this sense, they are also entirely consistent with the requirement for 
``least burdensome'' regulation of devices set out in section 205(a) 
and (b) of the Food and Drug Administration Modernization Act of 1997.
    (Comment 2) Several comments asked that provisions be made for 
HCT[sol]Ps collected before the effective date of this regulation and 
opposed retrospective application of the new regulations.
    (Response) This regulation will apply to cells and tissues 
recovered on or after the effective date of the regulation.
    (Comment 3) One comment urged us to coordinate our donor screening 
requirements with those of other countries.
    (Response) We support the long-term goal of international 
harmonization. In the process of developing this final rule, we have 
reviewed standards from other countries and met with representatives 
from the European Union, Australia, Japan, and other nations. The 
requirements in place in other countries are diverse and rarely static, 
reflecting the fact that other countries may have screening needs 
different from those in the United States and different tests available 
to them. The challenge of achieving consistency is underscored by the 
European Commission's announcement of the need for a new directive on 
human tissue, intended to replace the current myriad of 15 differing--
and sometimes nonexistent--national laws on the subject. On June 19, 
2002, the Commission of European Communities put forth a ``Proposal for 
a Directive of the European Parliament and of the Council on setting 
standards of quality and safety for the donation, procurement, testing, 
processing, storage, and distribution of human tissues and cells.'' 
Completion of this directive is expected to take several years. We 
applaud this effort and will continue to follow developments in tissue 
regulation throughout the world. However, at this time, our primary 
goal is to put into place the basic safeguards set out in this rule, an 
effort that may provide a starting point for further harmonization 
efforts.
    (Comment 4) Several comments stated that the rule would conflict 
with the rule concerning privacy of health care information proposed by 
the Department of Health and Human Services (HHS) on November 3, 1999. 
The privacy rule was subsequently finalized on December 28, 2000 (65 FR 
82462), and amended on August 14, 2002 (67 FR 53182).
    (Response) The Department regulations on privacy of health care 
information (the Privacy Rule) were codified at 45 CFR parts 160 and 
164. The Privacy Rule does not include the procurement or banking of 
organs, blood (including autologous), sperm, eyes or any other tissue 
or human product within the definition of health care and the 
establishments that perform such activities are not considered health 
care providers when conducting these functions (65 FR 82462 at 82477, 
December 28, 2000). In addition, the Privacy Rule authorizes health 
care providers who are subject to the Privacy Rule to ``disclose 
protected health information to organ procurement organizations or 
other entities engaged in the procurement, banking or transplantation 
of cadaveric organs, eyes, or tissue for the purpose of facilitating 
organ, eye or tissue donation and transplantation'' (45 CFR 
164.512(h)). The preamble to the Privacy Rule notes that, when an 
individual has not previously authorized release of protected health 
information, this provision of the Privacy Rule ``* * * is intended to 
allow covered entities [those subject to the privacy rule] to initiate 
contact with organ and tissue donation and transplantation 
organizations to facilitate transplantation of cadaveric organs, eyes, 
and tissues'' (65 FR 82464 at 82534). The Privacy Rule further 
authorizes covered entities to disclose protected health information to 
persons subject to the jurisdiction of FDA with respect to an FDA-
regulated product or activity for which that person has responsibility, 
for the purpose of activities related to the quality, safety or 
effectiveness of such FDA-regulated product or activity (45 CFR 
164.512(b)(1)(iii)). Finally, we further note that in the event that 
one of the previously mentioned provisions is not applicable, covered 
entities may disclose protected health information pursuant to an 
authorization from the individual or the individual's personal 
representative (45 CFR 164.502(a)(1)(iv) and (g)(1), and 164.508). For 
these reasons, we do not believe that the Privacy Rule conflicts with 
this final rule.
    However, FDA has considered the impact of this donor-eligibility 
final rule on patient privacy. We have deleted the requirement that 
relevant patient records accompany an HCT[sol]P, requiring instead a 
summary of records. We made this change in response to concerns about 
privacy.
    (Comment 5) One comment stated that, in the proposed rule, FDA 
improperly ``relied'' on provisions of the registration proposed rule. 
Another comment objected to the rulemaking process, asserting that we 
circumvented the usual departmental review process before publishing 
the proposed rule.
    (Response) We disagree with both comments. In the proposed rule, 
the agency did not ``rely'' on the registration

[[Page 29791]]

proposed rule, but merely described another ongoing, related, 
rulemaking. Moreover, we made clear that the provisions of the 
registration proposed rule we referenced in the preamble to the donor-
suitability proposed rule were merely proposals. The agency received 
comments related to those proposals in the donor suitability docket. 
When we finalized those provisions in the registration final rule, we 
considered comments received in the donor suitability docket, as well 
as in the registration docket (66 FR 5447 at 5450). With respect to the 
second comment, we disagree that we followed anything other than our 
usual review process; however, we note that these procedures constitute 
department practice and are not required by regulation by law or 
regulation.
    (Comment 6) One comment cited a potential conflict with the 
regulation issued by CMS requiring hospitals to notify organ 
procurement organizations (OPOs) upon patients' death or imminent death 
(42 CFR 482.45). The comment pointed out that OPOs might, in some 
instances, determine donor eligibility for tissue donors. The comment 
asserted that FDA does not regulate OPOs and questioned who would be 
accountable for compliance with FDA regulations.
    (Response) We disagree that there is a conflict between the 
regulations in part 1271 and CMS's regulation of OPOs; we also disagree 
that OPOs are exempt from FDA regulations. The determination of donor 
eligibility is a key function of an HCT[sol]P manufacturing 
establishment. Therefore, although human organs are excluded from the 
definition of HCT[sol]P, and thus not covered by the regulations in 
part 1271, any OPO that performs any part of any HCT[sol]P 
manufacturing function, is subject to the regulations in part 1271. 
Such an OPO must register with the agency and comply with all 
applicable regulations in part 1271; thus, an OPO that screens tissue 
donors must do so in compliance with the regulations in part 1271 on 
donor screening. If an OPO performs no tissue manufacturing functions, 
it would not be subject to these regulations.
    (Comment 7) One comment recommended that we set allowable limits 
for additives to allograft tissues, such as glycerol.
    (Response) We decline to set a specific limit on such additives in 
these regulations. We point out, however, that one of the criteria in 
Sec.  1271.10 for regulation of an HCT[sol]P solely under section 361 
of the PHS Act and part 1271 is that the manufacture of the HCT[sol]P 
does not involve the combination of the cell or tissue component with a 
drug or a device, except for a sterilizing, preserving, or storage 
agent, and then only if the addition of the agent does not raise new 
clinical safety concerns with respect to the HCT[sol]P. Should an 
additive raise new safety concerns or, as in the case of glycerol, be 
for any purpose other than sterilizing, preserving, or storage, the 
HCT[sol]P would be subject to regulation under the act and/or section 
351 of the PHS Act, and FDA would consider allowable limits of chemical 
additives in the context of the premarket review process.
    (Comment 8) One comment asserted that tissue banks should audit 
their domestic and international tissue recovery and distribution 
intermediaries to assure accountability to the same standards that they 
themselves uphold.
    (Response) We agree that documentation of these audits would help 
assure our goals of protecting the public health. Audits and other ways 
of ensuring accountability are addressed in the CGTP proposed rule.
    (Comment 9) One comment supported the establishment of a central 
registry for tracking all reproductive tissue donors to locate donors 
and recipients in an emergency.
    (Response) We encourage interested parties to explore methods of 
tracking donors, donations, and recipients, including the establishment 
of such a central registry. However, we do not propose to require such 
a registry at this time.
    (Comment 10) One comment asked that the regulations clarify the 
responsibilities of reproductive tissue banks and client depositors 
with respect to length of storage of tissue and the right of a bank to 
destroy tissue of noncompliant depositors.
    (Response) The requested clarification is beyond the scope of these 
regulations, which concern communicable disease transmission and not 
provisions of agreements between HCT[sol]P establishments and 
individual clients that are unrelated to communicable disease 
transmission.
    (Comment 11) One comment questioned why these regulations do not 
address the use of cellular material other than from the patient in in-
vitro fertilization. Another comment supported restrictions on gene, 
ooplasm, and nuclear transfer.
    (Response) We recognize the comments' concerns and are addressing 
these issues in contexts outside of this rulemaking.

B. Amendments to 21 CFR Parts 210, 211, and 820

    We proposed amending Sec. Sec.  210.1 and 820.1 to require 
manufacturers of HCT[sol]Ps regulated as drugs, medical devices, and/or 
biological products to comply with the donor-eligibility procedures in 
subpart C and the current good tissue practice (CGTP) procedures in 
subpart D of part 1271. (We also proposed minor amendments, for 
consistency, to Sec. Sec.  210.2 and 211.1.) The donor-eligibility and 
CGTP procedures would be considered part of CGMP requirements for drugs 
and the QS requirements for devices.
    The proposed amendment to Sec.  210.1 stated that failure to comply 
with the donor-eligibility, CGTP, or other CGMP regulations would 
render adulterated, under section 501(a)(2)(B) of the act, an HCT[sol]P 
regulated as a drug and/or biological product, and the HCT[sol]P, as 
well as the person responsible for the failure to comply, would be 
subject to regulatory action. The proposed amendments to Sec.  820.1 
were comparable, stating in part that the failure to comply with any 
applicable donor-eligibility, CGTP, or QS regulation would render a 
device adulterated under section 501(h) of the act.
    We received no comments on the proposed amendments.
    We are finalizing the proposed modifications to Sec. Sec.  211.1(b) 
and 820.1(a), which add a cross-reference to the regulations in part 
1271. As finalized, Sec.  211.1(b) applies to HCT[sol]Ps that are also 
regulated as drugs or biological products subject to the drug current 
good manufacturing practice (CGMP) regulations in parts 210 and 211, 
and Sec.  820.1(a) applies to HCT[sol]Ps that are also regulated as 
devices subject to the QS regulations in part 820.
    In response to a comment submitted on the CGTP proposed rule that 
asserted that the ``impossible to comply'' language in proposed Sec.  
1271.150(c) did not provide useful guidance, we have modified this 
provision by replacing the ``impossible to comply'' language with more 
specific wording referring to a conflict between applicable regulations 
in different parts. In the event of a conflict between applicable 
regulations in part 1271 and regulations in parts 210, 211, or 820, the 
regulations specifically applicable to the product in question will 
supersede the more general regulations. Because the ``impossible to 
comply'' language is contained in related provisions in other parts we 
have made the same change to these provisions to ensure consistency. 
This new language is intended for

[[Page 29792]]

purposes of clarity. The ``impossible to comply'' language in our 
current regulations was not the subject of complaints by regulated 
establishments. With the revised language, FDA intends to continue to 
interpret the standard reasonably and does not intend to impose 
unreasonable burdens on establishments.
    We note that the phrase ``impossible to comply'' has been used for 
products other than HCT[sol]Ps since FDA first issued the device CGMP 
regulations in 1978 (43 FR 31508, July 21, 1978). Two months later, FDA 
used the phrase in the drug CGMP regulations (43 FR 45014, September 
29, 1978). FDA explained in the preamble to the drug regulations that 
``impossible to comply'' encompasses situations where regulations 
contradict or conflict each other (43 FR 45014 at 45029).
    The new language on a conflict between applicable regulations 
replaces the phrase ``impossible to comply'' in Sec. Sec.  210.2(a), 
211.1(b), 820.1(a), and 820.1(b). (Although a revision to Sec.  
820.1(b) was not proposed, it is now necessary to revise that paragraph 
for consistency with Sec.  820.1(a).) The new language pertains only to 
conflicts that occur between applicable regulations in one part (e.g., 
part 211) and applicable regulations in another part (e.g., part 1271) 
and not between regulations within one part (e.g., between two 
regulations in part 211). FDA believes that, in the event of such a 
conflict, the more specifically applicable regulation would be found in 
part 1271.
    We are also finalizing proposed Sec.  210.1(c), which would provide 
that the failure to comply with any applicable provision in part 1271, 
subparts C and D, would render a drug adulterated under section 
501(a)(2)(B) of the act.
    We have made minor revisions to the wording of the proposed 
amendments to Sec. Sec.  210.1(c), 210.2, 211.1(b), and 820.1(a). These 
changes include the addition of a reference to section 361 of the PHS 
Act in Sec. Sec.  210.1(c) and 820.1(a). We have also clarified in 
Sec.  210.1(c) that screening refers to donor screening and that 
testing includes donor testing.
    However, we are not finalizing proposed Sec.  820.1(c) in this 
rule, which would have provided that the failure to comply with any 
applicable provision in part 1271, subparts C and D, would render a 
device adulterated under section 501(h) of the act. The act requires 
FDA to follow special procedures when issuing regulations under the 
device good manufacturing practice (GMP) authority; those procedures 
are not applicable to regulations issued under the CGMP authority for 
drugs. Before issuing regulations establishing requirements under 
section 520(f) of the act, the act requires FDA to submit the proposed 
regulations for review by an advisory committee meeting the criteria 
established in section 520(f)(3). However, FDA's advisory committee for 
device GMP regulations has not met since April 29, 1997, and only six 
of the required nine seats are currently filled. Although the agency 
believes it would be desirable to include a provision such as proposed 
Sec.  820.1(c), we believe it is not absolutely necessary to the 
regulatory scheme. When the device GMP advisory committee has been 
fully reconstituted, FDA may consider submitting proposed Sec.  
820.1(c) for its consideration. In the meantime, FDA intends to enforce 
violations of part 1271, subparts C and D, under the enforcement 
provisions contained in section 368 of the PHS act (42 U.S.C. 271), and 
the general equitable powers of the Federal courts.
    Finally, we note that the references to part 1271 in these sections 
(Sec. Sec.  210.1, 210.2, 211.1, and 820.1) refer to ``applicable'' 
provisions of part 1271. In the event that the final CGTP rule provides 
that any or all provisions in that rule are not being implemented for 
certain HCT[sol]Ps, those CGTP provisions would not be ``applicable'' 
for those HCT[sol]Ps.

C. Definitions (Sec.  1271.3)

    We have grouped all definitions pertinent to part 1271 in a single 
definitions section (Sec.  1271.3), among the general provisions of 
subpart A.
    We received no comments on the proposed definitions of the 
following terms, and those definitions appear in the final rule either 
unchanged or with only minor changes for consistency in terminology 
(i.e., references to HCT[sol]Ps): Biohazard legend (Sec.  1271.3(h)), 
blood component (Sec.  1271.3(i)), donor (Sec.  1271.3(m)), plasma 
dilution (Sec.  1271.3(p)), responsible person (Sec.  1271.3(t)), act 
(Sec.  1271.3(v)); PHS Act (Sec.  1271.3(w)); and FDA (Sec.  
1271.3(x)). For clarity, we have added the phrase ``of a cadaveric 
donor'' to the term ``physical assessment,'' but have made no other 
change to that definition (Sec.  1271.3(o)).
    We received no comments on the proposed definitions of the terms 
``embryo'' and ``gamete,'' but have deleted those definitions from this 
final rule as unnecessary; ``gamete'' is not used in the codified 
provisions and ``embryo'' is generally understood. We received no 
comments on the term ``reconstituted blood,'' but have deleted the term 
from the final rule because of its potential to cause confusion. We 
have incorporated the substance of the proposed definition of ``summary 
of records'' into Sec.  1271.55 and so have deleted the definition of 
that term from the final rule. We received no comments on that 
definition. We also received no comments on the proposed definition of 
``quarantine,'' and it remains unchanged in this final rule (Sec.  
1271.3(q)); however, comments on the quarantine provisions in Sec.  
1271.60 are addressed in section III.D.6 of this document.
1. Colloid (Sec.  1271.3(j)) and Crystalloid (Sec.  1271.3(k))
    Proposed Sec.  1271.3(k) defined ``colloid,'' and proposed Sec.  
1271.3(l) defined ``crystalloid.'' Both are terms used in Sec.  1271.80 
with respect to plasma dilution. Although we specifically requested 
comments on the appropriateness of these definitions, no comments were 
submitted.
    For greater accuracy, we have made minor changes to the language of 
each definition. The final rule contains a two-part definition of 
``colloid'' in Sec.  1271.3(j). Under the first part, a colloid is 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. We have deleted the word 
``certain'' from the second part of the definition, so that it now 
reads: ``Blood components such as plasma and platelets.''
    The final rule replaces the word ``balanced'' in the proposed 
definition of crystalloid with ``isotonic,'' so that the definition now 
refers to an isotonic 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.
2. Directed Reproductive Donor (Sec.  1271.3(l))
    The proposed rule contained a definition of ``directed donor,'' a 
term used in proposed Sec.  1271.65(b) to describe a situation in which 
the use of reproductive cells or tissue from an ineligible donor would 
not be prohibited. In considering the comments on Sec.  1271.65(b), 
discussed in greater detail in section III.C.5 of this document, we 
concluded that, for clarity, we should limit the definition of 
``directed donor'' to donors of reproductive cells and tissue and 
change the term to ``directed reproductive donor.'' Because the term 
``directed reproductive donor'' is used only in the context of the 
donation of reproductive cells and tissue, these changes do not affect 
the scope of the exception.

[[Page 29793]]

    As proposed, a directed donation involved the designation of a 
specific potential recipient. We have maintained this part of the 
definition in the final rule.
    (Comment 12) Our review of comments indicated that there was some 
confusion about whether the designation of a specific recipient could 
take place in the context of anonymous semen donation (i.e., a 
situation in which the donor and recipient do not know each other).
    (Response) We did not intend for the term ``directed donor'' to 
refer to anonymous donations. Rather, our intention was to respect the 
existence of relationships between people. To recognize existing 
relationships between donors and recipients, we have added language to 
the definition of ``directed reproductive donor'' to indicate that, in 
a directed donation, the donor knows and is known by the recipient 
before donation.
    We have also clarified the definition by noting that directed 
reproductive donors do not include sexually intimate donors, who are 
excepted from screening and testing requirements under Sec.  1271.90. 
This change is intended to make clear that, for the purpose of this 
rule, there are three categories of reproductive donors, subject to 
three different sets of requirements listed as follows: (1) The 
anonymous donor, to whom all the donor-eligibility requirements apply; 
(2) the directed reproductive donor, whose reproductive cells and 
tissue may be used even if the donor is determined ineligible; and (3) 
the sexually intimate partner, for whom testing and screening are not 
required (discussed in section III.D.11 of this document).
    (Comment 13) One comment requested that we define an additional 
category of anonymous semen donor, the ``Identification Revealed 
Donor.'' Under this kind of donation, the identity of an anonymous 
semen donor may be revealed to the child and/or mother at some point 
after birth. (We also received comments supporting this type of 
arrangement.) The comment suggested a related change to proposed Sec.  
1271.75 so that screening for risk factors for relevant communicable 
diseases would not be required for donors whose identities may be 
revealed later.
    (Response) Donor identification is outside our jurisdiction and 
unrelated to the purpose of this rule, which is to prevent the 
transmission of communicable disease. For these reasons, this rule does 
not address any agreements that might be entered into for revealing a 
donor's identity at a future time.
    We note that the suggested change to the screening requirement in 
Sec.  1271.75 would exempt the anonymous donors described in the 
comment from screening for risk factors for human immunodeficiency 
virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), human 
transmissible spongiform encephalopathy (TSE), including CJD and vCJD, 
Treponema pallidum, HTLV, Chlamydia trachomatis, and Neisseria 
gonorrhea. We cannot justify this exception on public health grounds. 
Whether or not the identity of an anonymous donor may be revealed later 
has no bearing on the appropriate screening and testing of that donor. 
For the prevention of the transmission of communicable disease, the 
same requirements should apply to all anonymous donors.
    We have distinguished between directed reproductive donors and 
anonymous donors to respect the existence of relationships between 
people who know each other and have made a joint decision for the 
recipient to conceive a child. In contrast to the directed reproductive 
donor who has an existing relationship with the recipient, only the 
potential for a future relationship exists for the anonymous donors 
described in the comment. Under the identification-revealed donation 
arrangement described in the comment, there is no relationship between 
donor and recipient at the time of donation. The recipient does not 
even know the name of the donor at the time of the donation, and may 
never learn the donor's identity at all. For these reasons, we decline 
to add a new definition for ``identification revealed donor.''
3. Donor Medical History Interview (Sec.  1271.3(n))
    The donor medical history interview is one of the relevant medical 
records that are reviewed in the donor screening process. We proposed 
to define ``donor medical history interview'' as a documented dialog 
with the donor, if living, or, if the donor is not living or is unable 
to participate in the interview, with an individual knowledgeable about 
the donor's medical history and relevant social behavior (proposed 
Sec.  1271.3(o)). The proposed definition provided examples of possible 
interviewees and described the questions to be asked about relevant 
social behavior
    (Comment 14) Several comments asserted that the proposed definition 
of donor medical history interview implies that an in-person, face-to-
face interview would be required. One comment assumed that the 
definition includes communications with friends and life partners.
    (Response) A donor medical history interview means a ``documented 
dialog.'' You may conduct such a dialog in person, by telephone, or 
through written or other forms of communication that allow the exchange 
of information between interviewer and interviewee. The interview 
method should allow the interviewer to ask followup questions to 
collect necessary information or to clarify responses. In the case of a 
living donor, a face-to-face interview is generally the most effective 
way to conduct a dialog.
    We agree that the definition may include communications with 
friends and life partners, if they are knowledgeable about the donor's 
medical history and relevant social behavior.
    We note that the definition of ``donor medical history interview'' 
is among the provisions of this final rule that we have redrafted for 
clarity and plain language reasons. The meaning of the definition 
remains unchanged.
4. Relevant Communicable Disease Agent or Disease (Sec.  1271.3(r))
    Proposed Sec.  1271.3(y) contained a 2-part definition of 
``relevant communicable disease or disease agent.'' The first part 
listed those disease agents and diseases that are specifically 
identified in Sec. Sec.  1271.75 and 1271.85 as relevant communicable 
diseases for which screening and testing would be required. These are 
as follows: HIV, types 1 and 2; HBV; HCV; TSE, including CJD and vCJD; 
Treponema pallidum; HTLV, types I and II; CMV; Chlamydia trachomatis 
and Neisseria gonorrhea. The proposed rule noted that in some 
instances, FDA had identified a disease agent or disease as relevant 
for a particular type of HCT[sol]P and that this distinction was 
reflected in the proposed testing and screening requirements in 
Sec. Sec.  1271.75 and 1271.85 (64 FR 52696 at 52701). For clarity, we 
have reorganized the list of identified relevant communicable disease 
agents and diseases in the first part of the definition (Sec.  
1271.3(r)(1)) according to tissue type. Thus, for example, HIV, types 1 
and 2, is listed as relevant for all cells and tissues; HTLV, types I 
and II, is listed as a cell-associated disease agent or disease 
relevant for viable, leukocyte-rich cells and tissues; and Chlamydia 
trachomatis is listed as a disease agent or disease of the 
genitourinary tract relevant for reproductive cells and tissues. This 
is an organizational change and not substantive.

[[Page 29794]]

    The second part of the proposed definition described criteria for 
other communicable diseases or disease agents to be considered 
``relevant.'' The proposed criteria related to prevalence, transmission 
risk, significance of health risk, and the availability of appropriate 
screening and/or testing methods. We have made changes to several 
aspects of this part of the definition, discussed in comments 16 
through 19 of this document.
    ``Relevant communicable disease agent or disease'' is defined in 
the final rule at Sec.  1271.3(r)
    (Comment 15) One comment stated that we had not sufficiently 
demonstrated the need to expand agency oversight to include diseases in 
addition to HIV and hepatitis. Another comment asserted that 
transmission of CJD and syphilis (Treponema pallidum) via cornea 
transplants is rare or nonexistent.
    (Response) When we issued part 1270 as an interim rule in 1993, 
among other reasons, we were acting swiftly to counter the transmission 
of three serious disease agents, HIV, HBV, and HCV (64 FR 52696 at 
52698). One reason for the inclusion of more diseases and disease 
agents in the proposed rule and this final rule is that the new rules 
cover more types of cells and tissues than were subject to part 1270. 
These additional cells and tissues pose additional risks of 
transmitting communicable disease. For example, we are now requiring 
you to test donors of viable, leukocyte-rich tissue for HTLV and CMV; 
this requirement did not previously exist, because part 1270 did not 
cover such viable, leukocyte-rich HCT[sol]Ps as semen and hematopoietic 
stem/progenitor cells. Similarly, we are now requiring that you test 
donors of reproductive tissue for Neisseria gonorrhea and Chlamydia 
trachomatis, a requirement that did not exist under part 1270, which 
did not cover reproductive tissue.
    We proposed to add TSE (including CJD and vCJD) and syphilis to the 
list of disease agents and diseases for which donors of all types of 
cells and tissues would be required to undergo screening and/or 
testing, because these two diseases present significant health risks. 
We disagree with the assertion that testing is unnecessary due to the 
infrequency of transmission. With respect to CJD, there have been over 
100 transmissions of CJD from dura mater worldwide (including 3 in the 
United States) and 1 transmission from cornea (in addition to 2 
possible transmissions), and the number of cases of vCJD is rising. 
With respect to syphilis, several factors could be responsible for the 
lack of reports of syphilis transmission via organs, tissues, or cells, 
including the use of antibiotics during tissue processing and the 
storage of tissues at low temperature. (Treponema pallidum does not 
survive when stored at 4 [deg]C for more than 48 to 72 hours.) However, 
these factors might not always be in place; i.e., antibiotics might not 
be used, and fresh bone grafts might not be stored under time and 
temperature conditions that would kill the organism, if present. 
Because of the potential for transmission by cells and tissue, 
including cornea, of both CJD and syphilis, we are maintaining the 
screening and testing requirements in the final rule.
    (Comment 16) Several comments asked about the procedure we would 
use to identify additional relevant communicable disease agents and 
diseases under the second part of the definition. Two comments asserted 
that we should specify that procedure, and that, except in cases of 
real urgency, the agency must afford interested parties prior notice 
and an opportunity to comment before adding a new disease agent or 
disease to the list. According to these comments, providing for such 
input would provide the following results: (1) Reveal scientific 
complexities otherwise unknown to FDA, (2) allow us to avoid imposing 
an additional testing obligation where no test is available, and (3) 
help avert the unnecessary destruction of tissues in inventory. Some 
comments stated that tissue establishments would have a difficult time 
identifying a new relevant communicable disease agent or disease under 
the four factors set out in the proposed rule. In the absence of 
guidance by the agency, establishments might feel forced to conduct 
testing that was not supported by the risk, due to liability concerns.
    (Response) We agree that public participation in these issues is 
important. We intend to issue guidance in accordance with the good 
guidance practices set out in Sec.  10.115 to advise you when, in the 
agency's view, a new relevant communicable disease agent or disease 
exists. Good guidance practices provide the public with an opportunity 
to comment on guidance before its implementation, except when the 
agency determines that prior public participation is not feasible or 
appropriate (e.g., in a public health emergency). When FDA issues 
guidance for immediate implementation, the public is invited to comment 
after publication. In suitable situations, we will hold public meetings 
or consult with advisory committees to help us identify communicable 
disease agents or diseases for which donor screening and testing should 
be performed.
    We also believe that, by issuing guidance, the agency will assist 
small tissue establishments, which may not be in a position to track 
the prevalence of emerging diseases and disease agents in a timely 
manner. Through guidance, FDA will perform an important communications 
function and assist small tissue establishments in meeting their 
regulatory obligations to test and screen for relevant communicable 
diseases and disease agents.
    Under the final rule, whether or not a disease or disease agent is 
``relevant'' under the rule will still be measured by the factors set 
out in Sec.  1271.3(r)(2)(i), (r)(2)(ii), and (r)(2)(iii), taken 
together. We recognize that, due to a variety of circumstances, you may 
not be aware of every instance when a disease or disease agent meets 
these factors. We therefore intend to clarify the application of these 
criteria in guidance. FDA's role in issuing guidance is to provide 
notice that the definitional elements appear to be met. FDA's 
notification will take the form of guidance and will not constitute a 
rule. In an enforcement action involving testing and screening for a 
new relevant communicable disease or disease agent, FDA's 
identification in guidance of the disease or disease agent would not be 
dispositive of the issue of whether it meets the factors set out in 
Sec.  1271.3(r)(2)(i), (r)(2)(ii), and (r)(2)(iii). In such an action, 
FDA would have to establish that the disease met those factors.
    (Comment 17) One comment asserted that the application of 
``relevant'' is subject to FDA's sole determination, which is further 
complicated by FDA's interpretation of terms such as ``risk'' and 
``appropriate screening.'' The comment asserted that these terms are 
not sufficiently defined, and that relevant risk is broadly applied and 
does not sufficiently address risk by specific tissue. Another comment 
stated that ``relevant disease risk'' is overly broad and would subject 
all tissue entities to unfair malpractice claims, leaving the system 
vulnerable and subject to unnecessary costs. The comment further opined 
that the mere hypothetical threat of a disease or agent would make it 
eligible for required screening and testing.
    (Response) The rule establishes factors that must be met before a 
disease agent or disease is ``relevant'' under this rule. As explained 
in comment 16 of this document, we intend to follow good guidance 
practices to notify you that the agency believes additional relevant 
communicable disease agents or

[[Page 29795]]

diseases exist. This will provide the opportunity for public 
participation in the process.
    We disagree with those comments that question the terms ``relevant 
disease risk'' and ``relevant risk.'' These are not terms that we used 
in the proposed definition of relevant communicable disease agent or 
disease, and they do not appear in the final definition.
    With respect to the comment on requiring testing and screening for 
a disease that poses a ``mere hypothetical threat,'' screening and 
testing would be required only when supported by a sound scientific 
basis. Identifying a relevant communicable disease agent or disease 
will entail an evaluation of the risk of the disease based on the 
criteria in Sec.  1271.3(r)(2). Establishments would not be required to 
determine independently which disease agents and diseases meet the 
definition of ``relevant communicable disease agent or disease,'' and 
could simply follow FDA guidance concerning communicable diseases or 
disease agents newly identified as relevant. Establishments could also 
participate in FDA's identification process, for example by commenting 
on draft and final guidances. Such FDA guidances would identify disease 
agents or diseases which, in the agency's view, meet the standards for 
``relevant communicable disease or disease agent.'' Each guidance would 
describe effective, and thus ``appropriate,'' screening practices, and 
would list recommended tests, if there are available and effective 
tests that have been licensed, approved, or cleared by FDA.
    (Comment 18) One comment asserted that the term ``prevalent'' is 
not sufficiently defined. Another comment asked at which point and by 
whom a disease would be designated sufficiently prevalent among 
potential donors.
    (Response) We have made several changes to the definition of 
``relevant communicable disease agent or disease'' with respect to 
prevalence.
    First, we have made the question of prevalence and/or incidence 
part of the evaluation of the risk of transmissibility of a 
communicable disease agent or disease. We have implemented this change 
by dividing the question of risk of transmissibility into the following 
two parts: (1) Is the disease or disease agent potentially 
transmissible by an HCT[sol]P? and (2) does the disease or disease 
agent have sufficient incidence and/or prevalence to affect the 
potential donor population? This change is reflected in Sec.  
1271.3(r)(2)(i). Both questions are important in considering whether to 
require testing and/or screening for a communicable disease or disease 
agent; grouping them will ensure that both factors are considered 
together.
    We believe that the factors set out in Sec.  1271.3(r)(2)(i), 
(r)(2)(ii), and (r)(2)(iii) should be considered as a whole. This 
approach is useful in explaining the concept of prevalence/incidence. 
On the one hand, a highly prevalent but relatively harmless disease 
agent might not be considered relevant. For example, some communicable 
diseases (e.g., Ureaplasma urealyticum, a disease of the genitourinary 
tract) are prevalent, but their pathogenicity to cell and tissue 
recipients is of questionable clinical significance. For this reason, 
we do not currently consider Ureaplasma urealyticum to be a relevant 
communicable disease agent. On the other hand, testing or screening 
might be required for a less prevalent but particularly virulent agent. 
Examples of communicable diseases that are less prevalent, yet pose 
extremely significant health risks, are TSE and HIV-2.
    The second change we have made is to modify the proposed language 
on prevalence so that it now refers to ``sufficient incidence and/or 
prevalence to affect the potential donor population.'' Whereas 
prevalence refers to the number of existing cases over a period of 
time, incidence refers to the number of new cases. Both prevalence and 
incidence are important indicators of the risk that a potential 
HCT[sol]P donor could be infected with a particular disease or disease 
agent, and that HCT[sol]Ps from that donor could transmit the disease.
    The third change we have made is to identify an alternative to 
prevalence. Under Sec.  1271.3(r)(2)(i)(B), a relevant communicable 
disease or disease agent is one that ``* * * either (1) has sufficient 
incidence and/or prevalence to affect the potential donor population, 
or (2) may have been released accidentally or intentionally in a manner 
that could place donors at risk of infection.''
    We intend this new language to cover both intentional and 
unintentional release of infectious agents. Although prevalence/
incidence remains an important consideration in determining whether a 
communicable disease or disease agent should be considered relevant, we 
recognize that when an infectious agent is released, whether by 
accident or purposefully (e.g., to inflict harm), we may not 
immediately have adequate information to assess the prevalence of the 
disease or disease agent. In this instance, where we have information 
about the release of an infectious agent, and the other prongs of the 
definition are met, it is important for the agency to be able to 
respond promptly by issuing guidance on testing and screening without 
awaiting the accumulation of data on prevalence.
    In response to the second comment, which asked at which point and 
by whom would a disease be designated sufficiently prevalent among 
potential donors, we discuss in comment 16 of this document, the 
procedures we will follow to communicate the agency's conclusions 
concerning when a disease or disease agent meets the definition of 
relevant communicable disease or disease agent.
    (Comment 19) One comment asked us to define ``significant'' health 
risk. This comment asserted that the term is vague and subject to 
misinterpretation.
    (Response) In response to this comment, we have replaced the phrase 
with more specific language in Sec.  1271.3(r)(2)(ii). The definition 
now states that a relevant communicable disease agent or disease is one 
that could be fatal or life-threatening, could result in permanent 
impairment of a body function or permanent damage to body structure, or 
could necessitate medical or surgical intervention to preclude 
permanent impairment of body function or permanent damage to a body 
structure. This more specific description is modeled on language used 
in the agency's regulations on medical device reporting (see 21 CFR 
803.3(bb)).
5. Relevant Medical Records (Sec.  1271.3(s))
    Donor screening involves the review of relevant medical records for 
risk factors for, and clinical evidence of, a relevant communicable 
disease agents and diseases. Proposed Sec.  1271.3(v) would define 
``relevant medical records'' as a collection of documents that includes 
a current donor medical history interview and a current report of the 
physical assessment of a cadaveric donor or the physical examination of 
a living donor. The proposed definition listed additional records that 
would be considered relevant medical records if they were available.
    (Comment 20) One comment opposed including, in the definition of 
``relevant medical records,'' a current report of a physical assessment 
or examination. The comment asserted that these evaluations are of 
minimal utility, particularly if the available exam was not performed 
to look for evidence of specific disease, and suggested that the 
requirement be moved to the ``if available'' part of the definition.
    (Response) We disagree with this comment. There are clear physical 
findings that could indicate that a donor either has a relevant 
communicable

[[Page 29796]]

disease or exhibits signs of risk factors for such a disease. Examples 
include jaundice, lymphadenopathy, or needle marks. The donor-
eligibility draft guidance that accompanies this final rule lists 
physical findings that would suggest if a cadaveric or living donor 
could have a relevant communicable disease and that should be looked 
for in the physical assessment or examination.
    (Comment 21) Five comments questioned the need for a physical 
examination of a cord blood donor. Three of these recommended that the 
requirement not apply to cord blood donors, but only to HCT[sol]Ps for 
which the physical examination is relevant to the safety of the donor 
or the HCT[sol]P. Two comments proposed requiring only a limited 
physical examination.
    (Response) We disagree with the suggestion that it is unnecessary 
to conduct a physical examination of a cord blood donor. A physical 
examination could reveal risk factors for or the presence of a relevant 
communicable disease.
    We note that the purpose of the physical examination is to assess 
for signs of a relevant communicable disease and for signs suggestive 
of any risk factor for a relevant communicable disease. The donor-
eligibility draft guidance announced elsewhere in this Federal Register 
provides further information on physical evidence of relevant 
communicable diseases that may be observed during the physical 
examination of a living donor.
    (Comment 22) One comment asserted that the scope of medical records 
should be limited to information pertaining to relevant communicable 
diseases. The comment expressed concern that a potentially significant 
finding would be lost in the minutiae. The comment cited autopsy 
results as an example of a record that does not add significant value 
to the donor screening process, noting also that certain products need 
to be released before coroner and autopsy reports are available.
    (Response) We agree that the scope of medical records that you 
review in donor screening is limited to information pertaining to 
relevant communicable diseases. We disagree, however, with the 
assertion that autopsy results do not provide significant information. 
On the contrary, an autopsy can lead to the discovery of subclinical 
evidence of relevant communicable diseases (e.g., liver disease may 
indicate hepatitis). We understand that certain HCT[sol]Ps need to be 
released before autopsy results are available (e.g., corneas). However, 
autopsy results are an important component of a donor's relevant 
medical records, and you must review them if they are available at the 
time of the donor-eligibility determination.
    (Comment 23) Other comments recommended that the definition of 
``relevant medical records'' be limited to processing records, health 
histories, and the infectious disease test results of the donor. These 
comments expressed concern that the definition includes the donor's 
medical records ``if available.'' This comment urged us to make the 
summary of records the sole set of documents required to accompany the 
product.
    (Response) We agree that the summary of records should be the sole 
set of documents required to accompany an HCT[sol]P, and we have 
modified Sec.  1271.55, as discussed in greater detail in comment 29 of 
this document. However, for the purposes of donor screening, we 
continue to believe that a larger range of information should be 
considered, including the donor's medical records, if available. For 
that reason, we have not changed the list of documents that make up the 
relevant medical records.
6. Urgent Medical Need (Sec.  1271.3(u))
    Under proposed Sec.  1271.65(b) and (c), an HCT[sol]P from an 
ineligible donor could be used in cases of urgent medical need. We 
proposed to define ``urgent medical need'' as meaning that no 
comparable HCT[sol]P is available and the recipient is likely to suffer 
serious morbidity without the product.
    (Comment 24) One comment requested that we add to the definition of 
``urgent medical need'' the requirement that the risk of morbidity with 
use of the product be considerably less than without the product.
    (Response) We decline to make this change. We expect that doctors 
will use their professional judgment to balance the risk of using an 
HCT[sol]P against the risk of not using it.
    We have, however, modified the definition of ``urgent medical 
need'' to include the risk of death, in addition to the risk of serious 
morbidity. The risk of death is clearly more urgent than the risk of 
serious morbidity and should have been included in the proposed 
definition.
7. Xenotransplantation Product Recipient and Intimate Contact of a 
Xenotransplantation Product Recipient
    Proposed Sec.  1271.75(a)(2) would require you to determine whether 
a potential donor has received a xenotransplant (now called a 
xenotransplantation product) or has been a close contact of such a 
recipient. We proposed to define ``xenotransplantation'' and ``close 
contact'' in proposed Sec.  1271.3(aa) and (bb).
    (Comment 25) Several comments requested clarification of the 
definitions of ``xenotransplantation'' and ``close contacts,'' 
including the meaning of ``live cells'' and ``ex vivo,'' two terms used 
to define xenotransplantation. One comment preferred the term 
``intimate contact'' to ``close contact.'' We were also asked to 
provide examples of activities that could result in exchanges of bodily 
fluids, a factor in the proposed definition of close contact.
    (Response) The final rule does not contain definitions of 
``xenotransplantation'' or ``close contact.'' These terms are relevant 
to the determination under Sec.  1271.50, concerning whether the donor 
presents communicable disease risks associated with 
xenotransplantation. We now explain our current understanding of 
``xenotransplantation,'' ``xenotransplantation product,'' 
``xenotransplantation product recipient,'' and ``intimate contact of a 
xenotransplantation product recipient'' in the donor-eligibility draft 
guidance announced elsewhere in this issue of the Federal Register.
    The terminology used in the accompanying guidance, and the 
definitions provided, are consistent with guidance on 
xenotransplantation developed by the Public Health Service (PHS) and by 
FDA (PHS Guideline on Infectious Disease Issues in Xenotransplantation; 
Availability (66 FR 8120, January 29, 2001); Draft Guidance for 
Industry: Precautionary Measures to Reduce the Possible Risk of 
Transmission of Zoonoses by Blood and Blood Products from 
Xenotransplantation Product Recipients and Their Intimate Contacts (67 
FR 6266, February 11, 2002). In the accompanying guidance, we describe 
``xenotransplantation'' as any procedure that involves the 
transplantation, implantation, or infusion into a human recipient of 
either of the following: (1) Live cells, tissue, or organs from a 
nonhuman animal source; or (2) Human body fluids, cells, tissues, or 
organs that have had ex vivo contact with live nonhuman animal cells, 
tissues, or organs. By ``live cells'' we mean cells that have the 
ability to metabolize or divide. By ``ex vivo'' we mean outside of an 
individual's body.
    We agree with the comment that the term ``intimate contact'' is 
preferable to ``close contact,'' because it is more specific. The 
donor-eligibility draft guidance describes ``intimate contact of a 
xenotransplantation product recipient'' as a person who has engaged

[[Page 29797]]

in activities that could result in the intimate exchange of body fluids 
with a xenotransplantation product recipient. Examples of intimate 
contacts include, but are not limited to, sexual partners, household 
members who share razors or toothbrushes, and health care workers or 
laboratory personnel with repeated percutaneous, mucosal, or other 
direct exposures. Mere sharing of domicile or casual contact, such as 
hugging or kissing without the exchange of saliva, would not be 
interpreted as intimate contact.

D. Part 1271, Subpart C--Donor Eligibility

    Subpart C of part 1271 contains the donor-eligibility requirements 
for HCT[sol]Ps, including donor screening and testing.
1. General
    (Comment 26) We received comments urging the use of a term other 
than ``unsuitable'' to describe a reproductive tissue donor with risk 
factors for relevant communicable disease.
    (Response) ``Suitability'' is a term with wide usage in tissue and 
blood establishments. We understand, however, that when the term 
``unsuitable'' is applied to a donor, it may take on an unintended 
meaning. For that reason, we have decided to substitute the more 
neutral terms ``donor eligibility,'' ``eligible donor,'' and 
``ineligible donor'' throughout this final rule. Like the donor-
suitability determination in the proposed rule, the donor-eligibility 
determination will be based on both screening and testing. A donor is 
``ineligible'' if either screening or testing indicates the presence of 
a communicable disease or risk factor for a communicable disease. 
Throughout this rule, we refer to the ``donor-suitability proposed 
rule,'' but in all other instances, even references to the provisions 
of that rule, we now refer to ``donor eligibility.''
2. What Requirements Does This Subpart Contain? (Sec.  1271.45)
    In this final rule, we have added Sec.  1271.45 (``What 
requirements does this subpart contain?''). Section 1271.45(a) states 
that subpart C sets out requirements for determining donor eligibility, 
and points out that the requirements in subpart C are a component of 
CGTP requirements.
    Section 1271.45(b) requires a determination of eligibility, based 
on donor screening and testing for relevant communicable disease agents 
and diseases, for all donors of cells or tissue used in HCT[sol]Ps, 
except as provided under Sec.  1271.90. Section 1271.45(b) also states 
that, in the case of an embryo or of cells derived from an embryo, a 
donor-eligibility determination is required for both the oocyte donor 
and the semen donor. We have moved this requirement from proposed Sec.  
1271.50(a). We have also extended the proposed requirement, which 
referred only to embryos, to cells derived from an embryo. Although 
this meaning was implicit in the proposed language, we have made this 
change for greater clarity.
    Section 1271.45(c) prohibits the implantation, transplantation, 
infusion, or transfer of an HCT[sol]P unless the cell or tissue donor 
has been determined to be eligible, except as provided under Sec. Sec.  
1271.60(d), 1271.65(b), and 1271.90. This was originally proposed in 
Sec.  1271.50(a).
    Section 1271.45(d) states that, if you are an establishment that 
performs any function described in subpart C, you must comply with the 
requirements that are applicable to that function.
3. What Procedures Must I Establish and Maintain? (Sec.  1271.47)
    In this final rule, we have added Sec.  1271.47 (``What procedures 
must I establish and maintain?''). This reflects an organizational 
change, but is not substantive. General requirements for establishing 
and maintaining procedures were proposed as part of the GTP proposed 
rule (Sec.  1271.180). These proposed requirements would apply to all 
significant steps in the manufacture of HCT[sol]Ps, including donor 
screening and testing. However, in finalizing the donor-eligibility 
rule, we have decided that a separate provision on procedures specific 
to the donor-eligibility requirements of subpart C is warranted. To 
consolidate procedural requirements within the donor-eligibility 
requirements, and to remind you that you must develop procedures for 
testing and screening, we have added Sec.  1271.47. Final section Sec.  
1271.47 is based on proposed Sec.  1271.180, but tailored to be 
specific to donor-eligibility requirements. (In this final rule, we 
sometimes refer to procedures as standard operating procedures (SOPs).)
    For greater clarity and ease of reading, we have divided the 
proposed language into paragraphs. Paragraph (a) of Sec.  1271.47 
requires that you establish and maintain written procedures for all 
steps that you perform in testing, screening, determining donor 
eligibility, and complying with all other requirements in subpart C. 
Paragraph (a) of Sec.  1271.47 incorporates an explanation of the 
phrase ``establish and maintain.'' This definition was proposed in the 
GTP proposed rule under Sec.  1271.3(ll); we received no comments on 
the proposed definition. Paragraph (b) of Sec.  1271.47 requires that a 
responsible person must review and approve all procedures before 
implementation. Under paragraph (c) of Sec.  1271.47, written 
procedures must be readily available to personnel. Paragraph (d) of 
Sec.  1271.47 contains requirements relating to departures from 
established procedures. Paragraph (e) of Sec.  1271.47 states that an 
establishment may adopt current standard procedures, provided that 
certain conditions are met.
    Section 1271.47 reflects the following changes to proposed Sec.  
1271.180, made in response to comments submitted to the GTP proposed 
rule docket:
    All steps. Proposed Sec.  1271.180 would require procedures for 
``all significant steps'' that an establishment performs. One comment 
asked for examples of what constitutes a ``significant step'' and asked 
how it differs from ``any step.''
    A ``significant'' step is not considered different from ``any or 
all steps,'' as the latter term is used in the definition of 
``manufacture'' in Sec.  1271.3(e). For this reason, we have removed 
the word ``significant,'' and Sec.  1271.47(a) refers instead to ``all 
steps.''
    Periodic review. Proposed Sec.  1271.180 would require 
establishments to review and, if necessary, revise all procedures at 
least once in a 12-month period. One comment objected to the 
specificity of this requirement, citing the more flexible requirements 
in the CGMP and QS regulations.
    We agree with this comment and note that the comparable 
requirements in the CGMP and QS regulations (Sec. Sec.  211.100 and 
820.40) do not require an annual review of procedures. For this reason, 
we are deleting the proposed requirement, Sec.  1271.47 does not 
contain a requirement for an annual review of procedures.
    Departures from procedures. We have replaced the term ``deviation'' 
with ``departure'' in this final rule to prevent confusion with 
HCT[sol]P deviation reporting in the CGTP proposed rule. Several 
comments objected to the proposed requirement that departures from 
procedures be authorized in advance, because departures are not 
foreseeable and cannot be authorized before they occur. One comment 
suggested requiring a justification for the departures to be recorded 
at the time of the occurrence, and requiring approval of the departures 
by a responsible person before release of the tissue.
    We agree with these comments and have modified the requirement in

[[Page 29798]]

accordance with the suggestion. Section 1271.47(d) now requires an 
establishment to record and justify any departure from a procedure 
relevent to preventing risks of communicable disease transmission at 
the time of its occurrence, rather than before. The provision further 
states that the establishment must not make available for distribution 
any HCT[sol]P from a donor whose eligibility is determined under such a 
deviation unless a responsible person has determined that the departure 
does not increase the risk of communicable disease transmission through 
the use of the HCT[sol]P.
    Archiving of obsolete procedures. Proposed Sec.  1271.180 would 
require obsolete procedures to be archived for at least 10 years. One 
comment suggested that a longer retention period of 10 years after 
transplantation would be more appropriate and consistent with record 
retention requirements in Sec.  1271.270 (which also appear in proposed 
Sec.  1271.55).
    We have deleted archiving obsolete procedures as a requirement, but 
we recommend that establishments archive their obsolete procedures so 
that they may reference at any time and as needed a specific procedure 
used for manufacturing a specific HCT[sol]P that is still available for 
use and in storage.
4. How Do I Determine Whether a Donor Is Eligible? (Sec.  1271.50)
    Proposed Sec.  1271.50 sets out basic requirements with respect to 
the donor-eligibility determination. Under proposed Sec.  1271.50(b), 
the determination would be required to be performed by a responsible 
person. Under proposed Sec.  1271.50(b), the responsible person would 
determine a donor to be eligible if the following requirements are met: 
(1) The results of donor screening indicated that the donor was 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 are negative or nonreactive.
    Final Sec.  1271.50 reflects changes in screening for 
xenotransplantation made in Sec.  1271.75, discussed in comment 48 of 
this document.
    (Comment 27) Two comments supported the provision in proposed Sec.  
1271.50 that required a determination of eligibility to be based on 
both screening and testing. These comments further asserted that 
requiring both screening and testing for all prospective donors would 
assure that a prospective donor who is deemed unsuitable, and who is 
covered by proposed Sec.  1271.65, nevertheless, would be subject to 
mandatory testing.
    (Response) We agree that you must base a donor-eligibility 
determination on both screening and testing. If the screening shows the 
presence of a risk factor, the donor becomes ineligible and there is no 
reason to conduct the testing. Thus, we disagree that testing is 
mandatory where screening indicates a risk factor for a relevant 
communicable disease and use under Sec.  1271.65 is not sought. To 
require testing in the case of a donor already determined ineligible 
based on screening would impose an unnecessary expense.
    If the screening does not reveal any risk factors, the testing 
should be conducted to determine the donor's eligibility. We also agree 
that, if donor screening indicates a risk factor, and you wish to use 
the HCT[sol]P from the ineligible donor under the provisions of Sec.  
1271.65(b), you must complete all required testing.
    (Comment 28) One comment asked whether a person who has tested 
positive for a treatable communicable disease could donate reproductive 
tissue.
    (Response) A living donor who tests positive for a relevant 
communicable disease is ineligible to donate, but could become eligible 
to donate reproductive tissue in the future after successful treatment 
of the disease. In the donor-eligibility draft guidance, we make 
recommendations concerning the length of time following treatment of 
various communicable diseases after which a donor could become eligible 
to donate.
5. What Records Must Accompany an HCT[sol]P After the Donor-Eligibility 
Determination Is Complete? (Sec.  1271.55)
    Proposed Sec.  1271.55(a) would require documentation of the donor-
eligibility determination to accompany the HCT[sol]P. This 
documentation would include a copy of the donor's relevant medical 
records, results of required testing, and the name and address of the 
establishment that made the determination. Alternatively, the HCT[sol]P 
could be accompanied by a summary of records (defined in proposed Sec.  
1271.3(x)). In both instances, the donor's name must be deleted from 
the documentation. Proposed Sec.  1271.55(b) would require that the 
establishment that generated the records used in the eligibility 
determination, and the establishment that made the determination, 
maintain the records for 10 years and make them available for FDA 
inspection.
    (Comment 29) Several comments described as burdensome the 
requirement in proposed Sec.  1271.55(a) that a copy of the donor's 
relevant medical records accompany an HCT[sol]P. One comment questioned 
the confidentiality of information in these records, even with the 
donor's name redacted. Other comments urged us to require only that a 
summary of records accompany an HCT[sol]P, to ensure patient privacy 
and the appropriate use of a patient's medical records. Another comment 
supported our decision to require deletion of the donor's name.
    (Response) To increase confidentiality protections, we have removed 
the provision in Sec.  1271.55 for relevant medical records to 
accompany an HCT[sol]P. The regulation now requires only that the 
summary of records accompany the HCT[sol]P. We note that this change 
affects only the documentation that accompanies the HCT[sol]P; it does 
not affect the requirement in Sec.  1271.75(a) to review relevant 
medical records.
    As redrafted, Sec.  1271.55(a) requires that, once a donor-
eligibility determination has been made, the HCT[sol]P must be 
accompanied by: (1) A distinct identification code affixed to the 
HCT[sol]P container, e.g., alphanumeric, that relates the HCT[sol]P to 
the donor and to all records pertaining to the HCT[sol]P and, except in 
the case of autologous or directed reproductive donations, does not 
include an individual's name, social security number, or medical record 
number; (2) a statement whether, based on the results of screening and 
testing, the donor has been determined to be eligible or ineligible; 
and (3) a summary of the records used to make the donor-eligibility 
determination. We have specified that the distinct identification code 
must be affixed to the HCT[sol]P container (rather than attached by a 
tie-tag) because it is crucial that this information never become 
separated from the HCT[sol]P. Instead of defining ``summary of 
records'' in Sec.  1271.3, as proposed, we describe in Sec.  1271.55(b) 
that the summary of records must contain the following components: (1) 
A statement that the testing was performed by a laboratory certified to 
perform such testing on human specimens under the Clinical Laboratory 
Improvement Amendments of 1988 or that has met equivalent requirements 
as determined by the Centers for Medicare and Medicaid Services; (2) a 
listing and interpretation of the results of all communicable disease 
tests performed; and (3) the name and address of the establishment that 
made the donor-eligibility determination. We have

[[Page 29799]]

removed the requirement for a statement describing the types of 
records, which may have been reviewed as part of the relevant medical 
records, because it did not add useful information about the particular 
HCT[sol]P. We note that the requirement to list and interpret all 
communicable disease tests refers not just to those tests required 
under this rule, but would also include any nonrequired communicable 
disease tests that have been performed.
    We have added one item to the list of information in the summary of 
records, in the case of an HCT[sol]P from a donor, ineligible based on 
screening, that is released under the provisions of Sec.  1271.65(b), 
the summary of records must contain a statement noting the reason or 
reasons for the determination of ineligibility. This information will 
greatly assist practitioners in weighing the risks of using an 
HCT[sol]P from an ineligible donor and in explaining risks to the 
recipient.
    The final regulation, at Sec.  1271.55(c), states that the records 
that accompany the HCT[sol]P must not include the donor's name and 
other personal information that might identify the donor.
    (Comment 30) One comment asked whether separate records would be 
required for all batches of HCT[sol]Ps made from a single cell bank.
    (Response) If you make multiple batches from a single cell bank, 
you may maintain a single set of donor-eligibility records for the cell 
bank. However, each HCT[sol]P from that cell bank must be accompanied 
by a copy of the summary of records.
    (Comment 31) One comment asserted that it is important to permit a 
tissue bank to qualify a donor as eligible and then to certify that 
eligibility to the establishment that further processes the cells or 
tissue without providing specific donor information. This comment also 
asserted that a mechanism should provide traceability through use of a 
donor number that can be used to trace the cells or tissue to the 
tissue bank if necessary.
    (Response) Under Sec.  1271.55, an HCT[sol]P must be accompanied by 
a summary of records that indicates the conclusions of the donor-
eligibility determination and that does not contain information that 
could identify the donor. We have added the requirement for a distinct 
identification code, e.g., alphanumeric, that relates the HCT[sol]P to 
the donor and to all records pertaining to the HCT[sol]P and, except in 
the case of autologous or directed reproductive donation, does not 
include an individual's name, social security number, or medical record 
number. This requirement is consistent with the tracking requirements 
of the CGTP proposed rule.
    (Comment 32) One comment supported the requirement in proposed 
Sec.  1271.55(b) that records regarding gamete donation be kept 10 
years.
    (Response) We appreciate this comment and have maintained the 
requirement, in Sec.  1271.55(d), that donor-eligibility records must 
be maintained for 10 years.
    The record retention requirements in Sec.  1271.55(d) have been 
reorganized and clarified. In several instances, we have modified the 
requirements for consistency with the more general records requirements 
of the GTP rule. For example, proposed Sec.  1271.55(b) would require 
records to 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 * * * at least 10 years after the date of the product's 
distribution, disposition, or expiration, whichever is latest.'' Three 
comments submitted to the GTP docket pointed out that similar language 
in proposed Sec.  1271.270(e) is confusing.
    Accordingly, we have revised the relevant language in proposed 
Sec.  1271.55(b) by replacing the words ``implantation, 
transplantation, infusion, or transfer'' with ``administration.'' 
Section 1271.55(d) now reads ``You must retain the records pertaining 
to a particular HCT[sol]P at least 10 years after the date of its 
administration, or if the date of administration is not known, then at 
least 10 years after the date of the HCT[sol]P's distribution, 
disposition, or expiration, whichever is latest.''
    We have made several other changes to the record retention 
requirements that both improve the language and also increase 
consistency with the proposed GTP rule. Final Sec.  1271.55(d) requires 
that all records must be accurate, indelible, and legible; this 
language is consistent with the proposed GTP rule (proposed Sec.  
1271.270(a)). Similarly, Sec.  1271.55(d) sets out a more specific list 
of required documentation than appeared in the proposed rule; as in 
proposed Sec.  1271.270(c), Sec.  1271.55(d) specifies that you must 
maintain documentation of the results and interpretation of all testing 
and screening for relevant communicable disease and disease agents; the 
name and address of the testing laboratory or laboratories; 
documentation of the donor-eligibility determination; the name of the 
responsible person who made the determination; and the date of the 
determination. (No comments were received on either of these issues.)
    We have also incorporated into Sec.  1271.55(d) the requirement 
that information on the identity and relevant medical records of the 
donor must be in English, or, if in another language, must be 
translated into English. We received two comments on the docket for the 
GTP rule about the English language requirement in proposed Sec.  
1271.270(c). One comment stated that the proposed language implied that 
the original non-English record may be destroyed, and suggested 
revising the regulation to indicate that the original may be in any 
language and should be retained, but that a copy translated into 
English should also be kept. Another comment asserted that we should 
stipulate that the English translation requirement applies to products 
distributed within the United States.
    We disagree that the proposed regulation implies that an original 
record that is not in English can be destroyed, and for this reason we 
have added the codified language that the information on the identity 
and relevant medical records of the donor must be retained. You must 
maintain the original documentation, whether or not the documentation 
is in English. These requirements apply to all HCT[sol]Ps that are 
imported into the United States, for distribution within the United 
States, and that are shipped under Sec.  1271.60(c) into the United 
States for processing or other manufacture before distribution in 
another country.
    (Comment 33) One comment requested that we change proposed Sec.  
1271.55(b) to require that any party involved in the collection, 
processing, or transplantation of an HCT[sol]P be allowed access to the 
donor's medical records.
    (Response) The purpose of the language, as proposed, was to ensure 
FDA's access to records supporting a donor-eligibility determination. 
Because of concerns about maintaining the confidentiality of patient 
information, we decline to expand the provision to require an 
establishment to make medical records available to any party involved 
in the collection, processing, or transplantation of the HCT[sol]P.
6. What Quarantine and Other Requirements Apply Before the Donor-
Eligibility Determination Is Complete? (Sec.  1271.60)
    Proposed Sec.  1271.60 contained provisions for quarantine of 
HCT[sol]Ps pending the donor-eligibility determination. Proposed Sec.  
1271.60(a) stated that, ``* * * [f]or reproductive cells and tissues 
that can reliably be

[[Page 29800]]

stored, quarantine shall last until completion of the testing required 
under Sec.  1271.85(d).'' (In Sec.  1271.85(d), we proposed to require 
retesting of the donor of such reproductive cells or tissue at least 6 
months after the date of donation.)
    (Comment 34) One comment supported the provision in Sec.  1271.60 
that permits, under certain safeguards, shipping of material that is in 
quarantine.
    (Response) We have maintained this provision in the final rule.
    (Comment 35) Many comments opposed any quarantine requirement for 
embryos. These comments disputed the communicable disease risks 
associated with embryos. They also cited increased costs from a 
quarantine; decreased success rates through use of frozen embryos; 
adverse effects on patients from a quarantine requirement; logistical 
concerns associated with retesting; and other possible consequences of 
a quarantine requirement, including loss of embryos.
    Some comments asserted that current screening practices are 
adequate. Others asserted that FDA was interfering with the practice of 
medicine or criticized our approach as having a potentially negative 
effect on the field of reproductive medicine. Many comments suggested 
alternative approaches, such as optional quarantine, mandatory 
insurance coverage for infertility, and creation of an embryo bank. One 
comment described a clinically effective program using frozen embryos 
that was instituted to help ensure patient confidentiality.
    (Response) We also received comments opposed to quarantining 
oocytes. Some comments distinguished between oocytes and semen based on 
differences in communicable disease risk, cryopreservation success, 
availability, cost, and other factors.
    We have considered the many comments received on the retesting and 
quarantine requirements and have decided to clarify our intentions with 
respect to embryos and oocytes. In the preamble to the proposed rule, 
we stated that reproductive cells and tissues that can reliably be 
stored are those that maintain function and integrity during storage. 
As examples, we listed spermatozoa and sperm progenitor cells (64 FR 
52696 at 52706). Given technologies at the time, we did not assert that 
embryos or oocytes could reliably be stored. Thus, we did not intend 
the quarantine and retesting requirement to apply to embryos or 
oocytes.
    To clarify the provisions for quarantine and retesting of 
reproductive HCT[sol]Ps, we have deleted the phrase ``reproductive 
cells and tissue that can reliably be stored.'' The 6-month quarantine 
requirement in Sec.  1271.60(a) and the retesting requirement in Sec.  
1271.85(d) applies only to anonymous semen donors.
    We disagree with comments that minimize the communicable disease 
risks associated with reproductive cells and tissue. Among other 
things, these comments assert that there have been no known 
transmissions of disease by ova or embryos or that there is no 
compelling evidence to indicate that human gametes or embryos are 
capable of transmitting infectious disease
    Each cell in the human body has receptors for viruses and bacteria 
and is thus capable of transmitting communicable disease. Even 
avascular tissue has been known to transmit disease (e.g., corneas have 
transmitted HBV). Semen is known to have transmitted HBV and HIV. 
Because embryos are a result of the combining of sperm and ova, they 
have the potential of being contaminated by communicable disease agents 
transmitted by the sperm. Moreover, bacterial contamination and 
transmission of HCV has occurred in assisted reproduction procedures. 
Two cases have been reported of women in France who were HCV antibody 
negative, but seroconverted after undergoing assisted reproductive 
technology (ART) procedures. The cause of transmission was theorized to 
be cross-contamination by health care workers (Lesourd, F., et al., 
``Transmissions of Hepatitis C Virus During the Ancillary Procedures 
for Assisted Conception,'' Human Reproduction, vol. 15, no. 5 pp. 1083-
1085, (2000)).
    Because there is a risk that ova and embryos could transmit 
disease, this risk should not be ignored. Given the lack of oversight 
and reporting requirements to date, it is difficult to know whether 
incidents of transmission of disease by ova or embryos have occurred.
    (Comment 36) Many comments objected to the application of the 
quarantine and retesting requirements to directed semen donations. 
These comments pointed out that, under the proposed regulation, semen 
from a directed donor would have to be quarantined for 6 months pending 
retesting of the donor. Comments asserted that this would effectively 
bar the use of fresh semen in directed donations. Some comments cited 
problems with sperm cryopreservation and noted a higher conception rate 
with fresh semen than with frozen semen. Other comments pointed out the 
delay in conception that would result from quarantine. Some comments 
asserted that the proposed provisions would encourage people to perform 
inseminations without medical assistance and safety screening.
    (Response) On December 14, 2001, we asked the BPAC whether, 
compared with fresh semen, the use of cryopreserved semen for 
artificial insemination reduces pregnancy rates per cycle. After a 
presentation of data, the committee agreed that the practice of 
cryopreserving semen for artificial insemination does reduce pregnancy 
rates.
    In light of the comments and the opinion of the BPAC, we have 
reconsidered whether to require quarantine and retesting in directed 
semen donation. The requirement to retest the donor was intended to 
provide an important added measure of protection by addressing the 
``window period'' between the time of infection and the presence of 
detectable levels of antigens and/or antibodies to communicable 
diseases and agents such as HIV. However, we recognize that semen from 
different donors varies in its ability to withstand cryopreservation. 
Because of the variability in whether a particular donor's sperm will 
survive the freeze/thaw process, a requirement for quarantine could 
defeat the intentions of the directed reproductive donor and intended 
recipient who have made a joint decision for the recipient to conceive 
a child. Accordingly, we have modified the regulation to except 
directed semen donors from the 6-month retesting requirement in Sec.  
1271.85(d). Because of this change, the requirement in Sec.  1271.60(a) 
that semen be quarantined until the completion of retesting under Sec.  
1271.85(a) no longer applies to directed semen donations.
    7. How Do I Store an HCT[sol]P From a Donor Determined to Be 
Ineligible, and What Uses of the HCT[sol]P Are Not Prohibited? (Sec.  
1271.65)
    Proposed Sec.  1271.65(a) would require HCT[sol]Ps from ineligible 
donors to be kept in quarantine and physically separate from other 
HCT[sol]Ps until destruction or other permissible disposition was 
accomplished. Proposed Sec.  1271.65(b) described three situations in 
which these regulations would not prohibit the use of an HCT[sol]P from 
an ineligible donor, and additional requirements that would apply in 
those instances. The three cases were as follows: (1) Family-related, 
allogeneic use; (2) directed donation of reproductive cells or tissue; 
and (3) urgent medical need. Under proposed Sec.  1271.65(c), the use 
of an HCT[sol]P from a donor for whom the donor-eligibility

[[Page 29801]]

determination had not yet been completed would not have been prohibited 
in cases of urgent medical need. (For organizational consistency, we 
have moved that provision to Sec.  1271.60 of this final regulation, 
which deals with HCT[sol]Ps pending the donor-eligibility 
determination.) Finally, proposed Sec.  1271.65(d) would impose special 
labeling requirements on HCT[sol]Ps used under Sec.  1271.65(b).
    Proposed Sec.  1271.65(b)(4) would prohibit making available an 
HCT[sol]P from a xenotransplantation product recipient or an intimate 
contact of a xenotransplantation product recipient for use in the 
special circumstances set out elsewhere in paragraph (b) (family-
related, allogeneic use; directed donation of reproductive cells or 
tissue; and urgent medical need). Throughout this final rule, we have 
adopted a more flexible approach to screening for xenotransplantation 
than proposed. This new approach is intended to recognize that 
different kinds of xenotransplantation may present different degrees of 
risk and to provide us with the ability to respond appropriately to 
these differences as the field of xenotransplantation develops. The 
absolute prohibition in proposed paragraph (b)(4) is not consistent 
with this new flexibility in approach, and so we have deleted it from 
Sec.  1271.65.
    (Comment 37) Several comments questioned how to comply with the 
requirement that HCT[sol]Ps from ineligible donors be kept physically 
separate from other HCT[sol]Ps. Some comments asserted that physical 
separation would require additional refrigerator storage units, 
presenting an unnecessary cost and space burden. These comments 
questioned the benefit of physically separate storage, suggested that 
quarantine alone should be sufficient, or requested that we delete the 
physical separation requirement. One comment asked whether storing in 
vapor phase nitrogen or encasing units in plastic bags is sufficient to 
prevent cross-contamination.
    (Response) We have revised Sec.  1271.65(a) to delete the 
requirement for physical separation. Section 1271.65(a) now 
incorporates language from the definition of quarantine; however, the 
term ``quarantine'' is no longer used in paragraph (a), because we 
believe it is more appropriately reserved for HCT[sol]Ps awaiting the 
outcome of the donor-eligibility determination. Section 1271.65(a) now 
requires you either to store or identify HCT[sol]Ps from ineligible 
donors in a physically separate area clearly identified for such use or 
to follow other procedures that prevent improper release, such as 
automated designation, until destruction of the HCT[sol]P or other 
disposition in accordance with Sec.  1271.65(b) or (c).
    As revised, Sec.  1271.65(a) now provides establishments with 
flexibility in achieving the goal of preventing the improper release of 
HCT[sol]Ps from ineligible donors. You may choose to keep HCT[sol]Ps 
from ineligible donors in a physically separate area clearly identified 
for such use. Such physical separation may include storage on a 
separate shelf in a refrigerator or freezer that also contains other 
shelves storing HCT[sol]Ps in quarantine pending the donor-eligibility 
determination and shelves storing HCT[sol]Ps from eligible donors. A 
separate refrigerator or freezer may not be necessary.
    Alternatively, Sec.  1271.65(a) allows you to use other procedures 
that prevent improper release. Such procedures could include automated 
designation to prevent improper release. For example, some 
establishments label HCT[sol]Ps with bar codes and store the HCT[sol]Ps 
in freezers that maintain a constant temperature. Moving the products 
to a separate storage area would risk transient warming. Instead, the 
HCT[sol]Ps remain in the original storage area and are tracked by a 
validated computer system that maintains information on the results of 
screening and testing. At the time of release of the HCT[sol]P, the 
establishment activates the computer system to assure identification 
and retrieval of the specific HCT[sol]P for the intended recipient. 
This is an example of a system of automated designation that could 
satisfy the requirements of Sec.  1271.65(a).
    The provisions of the CGTP proposed rule would require you to 
establish and maintain procedures for the control of storage areas to 
prevent such problems as cross-contamination and improper release 
(proposed Sec.  1271.260(a)).
    As for the comment regarding vapor phase nitrogen and plastic bags, 
limited scientific evidence exists to show the effectiveness of 
measures such as overwrap bags or storage in the vapor phase of liquid 
nitrogen to reduce the likelihood of cross-contamination. Such measures 
could be used if sufficient evidence exists of their ability to 
minimize the risk of cross-contamination.
    (Comment 38) One comment urged us to delete the exception for 
family-related, allogeneic use, arguing that the urgent medical need 
exception would apply for both related and unrelated stem/progenitor 
cell donors. Another comment supported the concept that hematopoietic 
stem/progenitor cell donors who are related to the recipient should be 
held to the same standards as unrelated donors with respect to 
screening and testing for communicable disease.
    (Response) Although we recognize that the urgent medical need 
exception might apply in some instances of donations between family 
members, we decline to make the change requested by the first comment. 
Our intention in crafting the exception was to recognize that, in some 
situations, a recipient and his or her physician might weigh the risks 
of using an HCT[sol]P from an ineligible family member in the absence 
of an urgent medical need, if such an action were in keeping with the 
family's wishes; this exception, with its added safeguards, would allow 
them to do so.
    We agree with the second comment that the same screening and 
testing requirements should apply to donors of hematopoietic stem/
progenitor cells who are related to the recipient as to unrelated 
donors, and the final rule is consistent with this view. However, we 
have chosen to defer to the family and physician the decision of 
whether or not to use an HCT[sol]P from a related donor who has been 
determined to be ineligible. For this reason, the regulations do not 
prohibit such use.
    We have rewritten proposed Sec.  1271.65(b)(1) to reflect changes 
made in the registration final rule (66 FR 5447 at 5454). The proposed 
exception for ``family-related, allogeneic use'' extended only to 
first-degree blood relatives; as modified, the exception now extends to 
``allogeneic use in a first-degree or second-degree blood relative.'' 
Our decision, expressed in the registration final rule, to broaden the 
scope of related donors was based on several factors, which also apply 
here. The likelihood of finding a donor with a haplotype identical to 
that of the recipient is greater among blood-related individuals than 
among unrelated individuals. In addition, for certain ethnic groups, it 
is extremely difficult to find an appropriate unrelated donor. Finally, 
registry outcome data for some hematologic malignancies suggest that 
peripheral blood and bone marrow transplant recipients may have a 
better survival rate when transplanted with hematopoietic stem/
progenitor cells from related donors (66 FR 5447 at 5454).
    Parents, children, and siblings are considered first-degree 
relatives. Aunts, uncles, nieces, nephews, first cousins, grandparents, 
and grandchildren are second-degree relatives. Relations by adoption or 
marriage are excluded from Sec.  1271.65(b)(1), because they are not in 
the same genetic pool as blood relatives.
    (Comment 39) We received comments on the proposed provision for 
directed

[[Page 29802]]

donation of HCT[sol]Ps from ineligible donors. Elsewhere in this rule, 
we respond to comments on the definition of directed reproductive donor 
and on the applicability of retesting requirements to directed 
donations of reproductive cells and tissues.
    One comment on proposed Sec.  1271.65 praised the directed donor 
provision as appropriate. This comment stated that the directed donor 
provisions should also apply when a woman seeks a second child by the 
same anonymous donor with known high-risk behavior.
    (Response) We disagree that the directed reproductive donor 
provisions of Sec.  1271.65(b) extend to anonymous donation. As 
discussed in comment 13 of this document, the term ``directed 
reproductive donor'' does not apply to anonymous donations, but to 
situations where the donor knows, and is known by, the recipient. 
Moreover, under this final rule, all potential anonymous semen donors 
must be screened for risk factors for relevant communicable disease, 
including high-risk behavior; potential donors with a high-risk 
behavior will be determined ineligible.
    (Comment 40) One comment expressed concern about allowing patients 
and physicians to decide whether to use donated gametes from a directed 
reproductive donor who is found to be ineligible. This comment asserted 
that it is essential that patients be fully informed, and that written 
contracts be signed indicating the possible risks to recipient and 
baby, so that there is complete understanding for the risks involved.
    (Response) It is essential that the patient who chooses to use a 
directed donation from an ineligible donor be fully informed of the 
risks involved. For any use under Sec.  1271.65(b)(1), the 
establishment must notify the physician using the HCT[sol]P from the 
ineligible donor of the results of testing and screening. Under Sec.  
1271.65(b), the HCT[sol]P must be labeled prominently with the 
Biohazard legend and must bear the statement ``WARNING: Advise patient 
of communicable disease risks,'' and, in the case of reactive test 
results, ``WARNING: Reactive test results for (name of disease agent or 
disease).'' In the case of reproductive HCT[sol]Ps, this includes risk 
to the baby. We have removed the proposed requirement for the 
establishment to document that the physician agreed to explain the 
communicable disease risks associated with the use of the HCT[sol]P to 
the recipient or the recipient's legally authorized representative and 
that the physician agreed to obtain from the recipient or the 
recipient's legally authorized representative consent to use the 
HCT[sol]P. We decline to require a written contract between physician 
and patient. We know that physicians are under legal and ethical 
restrictions, requiring them to discuss the risks of communicable 
disease transmission stemming from the use of HCT[sol]Ps. We rely on 
physicians to meet these obligations when obtaining consent to 
procedures involving HCT[sol]Ps from patients and their legal 
representatives.
    (Comment 41) One comment on directed donations of reproductive 
cells or tissue praised FDA for adding clarity to a process that has 
created confusion for donors and patients. This comment endorsed the 
procedures in proposed Sec.  1271.65(b), but objected to the proposed 
requirement for physician consent. The comment asserted that the 
patient has the right to make his or her own decisions about medical 
treatment, that physician consent is unnecessary because of other 
standards of physician conduct, and that some physicians may withhold 
consent for invalid reasons.
    (Response) In light of this comment, we have reconsidered the 
necessity of requiring documentation of the physician's authorization 
of the use of an HCT[sol]P from an ineligible donor in the directed 
reproductive donor situation, as well as in cases of urgent medical 
need or use in a first- or second-degree blood relative. Our decision 
is not based on an evaluation of patients' rights, but on the 
observation that, in each of these situations, a physician will be 
closely involved in the decision to use the HCT[sol]P from the 
ineligible donor. For this reason, no additional requirement to obtain 
physician consent is necessary.
    For the same reasons, we have also removed the requirement for 
physician authorization from the provisions governing use of an 
HCT[sol]P for urgent medical need before completion of the donor-
eligibility determination (Sec.  1271.60(d)).
    (Comment 42) Several comments strongly supported the urgent medical 
need provision in proposed Sec.  1271.65(b) and (c). Some comments 
commended the structuring of the proposed regulations, noting that the 
transplanting physician and the informed patient may deem appropriate a 
tissue that is positive for infectious disease when comparing 
alternatives, particularly in a matter of life or death or other 
emergency medical situations. One comment asserted that the transplant 
physician must be the ultimate authority for the use of tissues from 
all donors and noted that the prevalence of CMV positivity in the 
normal donor population will make this exception widely used.
    (Response) We have maintained the provisions for urgent medical 
need, although, as noted, the provisions governing use pending the 
donor-eligibility determination have been moved to Sec.  1271.60. (To 
ensure that the physician receives sufficient information about the 
risks of the HCT[sol]P, Sec.  1271.60(d)(2) requires that an HCT[sol]P 
from a donor for whom the eligibility determination is not complete be 
accompanied by results of donor screening and testing that have been 
completed, as well as a list of any screening or testing that has not 
yet been completed.)
    We also note that, under the final regulation, you are not required 
to determine a donor ineligible on the basis of a reactive CMV test, 
but under Sec.  1271.85(b)(2) you must establish and maintain an SOP 
governing the release of an HCT[sol]P from a donor whose specimen tests 
reactive for CMV. Thus, it will be unnecessary to invoke the urgent 
medical need provisions to use an HCT[sol]P from a donor who has tested 
positive for CMV. (See the discussion in comment 60 of this document.)
    (Comment 43) One comment asserted that labeling tissue ``untested 
for Biohazard'' might cause transportation issues, because commercial 
carriers are reluctant to transport a container labeled ``Biohazard.'' 
The comment recommended that the proposed regulations clarify that the 
tissue container, not necessarily the tissue transport container, be 
labeled ``untested for Biohazard.''
    (Response) The labeling requirements in this final regulation apply 
to the labeling of the HCT[sol]P. (An HCT[sol]P made available under 
Sec.  1271.60(d) must be labeled ``NOT EVALUATED FOR INFECTIOUS 
SUBSTANCES,'' and an HCT[sol]P made available under Sec.  1271.65(b) 
must bear the Biohazard legend; in both instances, the label must 
state: ``WARNING: Advise patient of communicable disease risks.'') 
Other regulations, e.g., those issued by the Department of 
Transportation, may apply to the shipping container.
8. How Do I Screen a Donor? (Sec.  1271.75)
    Proposed Sec.  1271.75(a) would require screening of all donors, 
except as provided in Sec.  1271.90, for risk factors for, and clinical 
evidence of, relevant communicable disease agents and diseases, 
including, at a minimum, HIV, HBV, HCV, and TSE, including CJD and 
vCJD. Under proposed Sec.  1271.75(b), donors of reproductive cells or 
tissue would be screened for genitourinary diseases that can be 
transmitted with

[[Page 29803]]

the recovery of reproductive cells or tissues, including at a minimum 
Chlamydia trachomatis and Neisseria gonorrhea. Under proposed Sec.  
1271.75(c), donors would also be screened for xenotransplantation or 
close contact with a xenotransplantation product recipient. And 
proposed Sec.  1271.75(d) would allow establishments to follow an 
abbreviated donor screening procedure when a complete donor screening 
had been performed within the previous 6 months.
    We have deleted the phrase ``at a minimum'' from Sec.  1271.75(a) 
and (b), because it might give the impression that screening is 
required only for those relevant communicable diseases listed in Sec.  
1271.75. Although at this time we only require screening for those 
listed diseases, additional diseases may be identified as relevant in 
the future. As discussed in comment 16 of this document, we intend to 
issue guidance that notifies you when we have identified additional 
relevant communicable diseases that appear to meet the definition in 
Sec.  1271.3(r)(2).
    Section 1271.75, as finalized, requires the establishment that 
performs donor screening to review the donor's relevant medical records 
for risk factors for, and clinical evidence of, relevant communicable 
disease agents and diseases. For consistency with testing requirements, 
we have added the requirements that you screen all donors for Treponema 
pallidum (Sec.  1271.75(a)(1)) and that you screen donors of viable, 
leukocyte-rich cells or tissue for relevant cell-associated 
communicable diseases, including HTLV (Sec.  1271.75(b)). These 
additional screening requirements impose only a minimal burden. We 
describe screening factors for these relevant communicable diseases in 
the donor-eligibility draft guidance.
    (Comment 44) Proposed Sec.  1271.75(a)(1) would require screening 
of all donors for human TSE, including CJD. We received several 
comments on this provision. One comment supported the proposed 
screening requirements as written. Another comment stated that the 
agency should make clear whether it intends procurers of human tissue 
to apply the policies in the draft guidance for blood donors issued on 
November 23, 1999. Other comments argued that semen and oocytes should 
be exempt from screening for TSE, or questioned why the screening is 
applied to all donors, not just donors of dura mater or cornea. One 
comment expressed concern that particular symptoms of TSE, such as 
changes in speech or gait, are not specific to TSE.
    (Response) Given the severity of TSE, the lack of an approved test, 
and the lack of information about the tissue distribution of the vCJD 
agent in humans, we continue to believe that it is necessary to screen 
all prospective donors for risk factors. In January 2001, we asked the 
TSEAC to evaluate the risk of transmission of vCJD through the 
transplantation, implantation, infusion, or transfer of HCT[sol]Ps. The 
committee agreed that, compared to the risk of transmission of vCJD by 
blood transfusion, there is a significant risk of transmission of vCJD 
from HCT[sol]Ps.
    We recognize that the potential for transmission appears to differ 
between different types of HCT[sol]Ps, with the greatest risk 
associated with corneas and dura mater. Nevertheless, you must screen 
all donors for TSE, for the previously listed reasons. This screening 
would include questions about risk factors for sporadic CJD and vCJD, 
and donors would be subject to exclusion based on those factors. We 
also recognize that some TSE symptoms are not specific to TSE. The 
specific symptoms to watch for are discussed in the CJD draft guidance.
    (Comment 45) The proposed regulations did not contain an exception 
from the donor medical history interview for corneas procured 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. The preamble to the proposed rule 
stated that 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. We 
noted that the necessity of adequate screening for TSE illustrates the 
importance of the donor medical history interview (64 FR 52696 at 
52703).
    We also noted 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, we considered that the 
proposed regulation and State laws on legislative consent may coexist 
and stated that we did not intend to preempt those laws. We 
specifically requested comments on any potential conflicts that might 
make it impossible to comply with both this regulation and State laws 
on legislative consent.
    We received many comments about the proposed requirement for a 
donor medical history interview. Most of these comments came from eye 
banks.
    Comments from eye banks that supported the proposal described their 
positive experiences performing medical history interviews. One comment 
described a next-of-kin interview that revealed the information that 
the potential donor's sister had died from CJD, information that would 
not have otherwise been obtained. Another comment supported the 
interview as a means of detecting high-risk behavior for diseases other 
than CJD, such as hepatitis and HIV, and said that FDA should carefully 
consider any interview questions relating to TSE with input from 
transplant practitioners and other experts. Several comments cited the 
risk to patients if donors are not screened with an interview. One 
comment from the medical director of an Italian eye bank described a 
positive experience with a recently implemented Italian requirement to 
obtain medical and social information through an interview.
    Some comments criticized the recovery of corneas under legislative 
consent, asserting that autopsy reports are insufficient for assessing 
high-risk behaviors and that donors from medical examiner's or 
coroner's offices have an increased likelihood of high risk behavior. 
One comment asserted that, although part of the justification for 
legislative consent has been that there is a cornea shortage in this 
country, current donation rates have enabled most eye banks to become 
exporters.
    Most comments on this issue opposed a requirement for a donor 
medical history interview for all cornea donors. One comment opposed 
the requirement but appreciated FDA's efforts to help ensure a safe 
supply of donor corneal tissues. Another comment asserted that the 
government should stay out of eye banking.
    Many comments cited benefits of medical examiner laws, and some 
comments expressed the view that the proposed requirement would 
eliminate the procurement of corneas under legislative consent. Some 
expressed concern about diminished cornea supplies. Others asserted 
that the time required for screening would detract from cornea 
viability and quality, and some comments expressed concern about 
decreased access to healthy young corneal material from the medical 
examiner donor pool. Numerous comments cited the added expense of 
performing a medical history interview.
    Many comments asserted that additional screening is unnecessary, or 
disputed the usefulness of an interview. Two comments asserted that the 
medical/social histories performed on

[[Page 29804]]

all cases obtained under legislative consent are just as comprehensive 
as those obtained with a next-of-kin consent and a medical/social 
history questionnaire. Other comments expressed doubt that the 
interview would be effective in screening for CJD or would increase the 
safety of corneal tissue.
    Many comments disputed the risk of CJD transmission via corneas. 
One comment asserted that TSE cases are not brought to the medical 
examiner's office for determination of cause of death. Another comment 
asserted that there is no evidence of any increased risk of disease 
transmission through corneas obtained under legislative consent absent 
a medical history interview and that mandating an interview does not 
appear to have adequate scientific substantiation. Another comment 
stated that CJD is not sufficiently prevalent to warrant testing and 
screening.
    The Eye Bank Association of America (EBAA) commissioned a report, 
which it submitted to the docket, on the occurrence and 
transmissibility of CJD as it relates to cornea transplantation. The 
report concluded, in part, that screening for symptoms of CJD would 
have minimal impact on safety but would reduce the supply of donor 
corneas. One comment objected to the report's conclusion and supported 
a medical/social history interview. On the other hand, one comment 
indicated that, based on the EBAA report, it now recommended that the 
regulation permit corneal donation under legislative consent without a 
donor medical history interview.
    (Response) We have carefully considered the many comments on this 
difficult issue. Since the publication of the proposed rule, our 
concerns about preventing the spread of TSE, including vCJD, have 
increased. We have taken steps to address those concerns by developing 
an agency action plan and issuing new guidance documents, including 
guidance specific to HCT[sol]Ps. In August 2001, HHS also announced a 
TSE action plan. One of FDA's responsibilities under the departmental 
action plan is to review and upgrade our policies designed to prevent 
potential exposure to TSE through blood transfusion or tissue 
transplantation or transmission of TSE through FDA-regulated products. 
(You can find information about the departmental action plan on the 
Internet at http://www.hhs.gov/news/press/2001pres/20010823.html.)
    We developed our action plan for TSE in April 2001. The plan has 
several focus areas, including prevention of exposure to TSE through 
human and animal products, blood transfusion, tissue transplantation, 
and other FDA-regulated products. FDA also wants to establish a 
coordinated education and outreach program to the community, and to 
expand research in TSE. The plan will enhance regulatory tools, and 
help enforce regulations concerning cattle feeding and import 
restrictions. The action plan is posted on the Internet at http://www.fda.gov/oc/oca/roundtable/bse/FDA_actionplan.html.
    Another example of FDA's heightened concern with potential TSE 
transmission is the publication of the guidance entitled ``Revised 
Preventive Measures to Reduce the Possible Risk of Transmission of 
Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease 
(vCJD) by Blood and Blood Products (January 2002),'' available on the 
Internet at http://www.fda.gov/cber/gdlns/cjdvcjd.pdf. This guidance 
recommends blood donor deferrals for travel to the UK and the rest of 
Europe, for military personnel who resided in U.S. military bases in 
Europe, and for receipt of blood in the UK.
    In January 2001, we asked the TSEAC to evaluate the risk of 
transmission of vCJD through the transplantation, implantation, 
infusion, or transfer of HCT[sol]Ps and to compare this risk to that of 
the transfusion of blood and blood products, for which precautionary 
measures have already been adopted. We specifically requested advice on 
how information about residence/travel history could best be obtained 
and noted the relevance of this question to corneas procured under 
legislative consent. The committee agreed that, compared with blood 
transfusion, there is a significant risk of transmission of vCJD from 
HCT[sol]Ps, and noted that dura mater and cornea have the greatest 
risk. A majority of the committee supported deferral for donors of dura 
mater and cornea who had possibly been exposed to the bovine spongiform 
encephalopathy agent, but the committee did not vote on the question of 
whether an interview should be required of all donors.
    Since that meeting of the TSEAC, we have issued a draft guidance 
document entitled ``Draft Guidance for Industry: Preventive Measures to 
Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease 
(CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Human Cells, 
Tissues, and Cellular and Tissue-Based Products (HCT[sol]Ps)'' dated 
June 2002, available on the Internet at http://www.fda.gov/cber/gdlns/cjdvcjd0602.pdf. This draft guidance document contains our current 
recommendations on appropriate donor screening measures for CJD and 
vCJD. This draft guidance was discussed at the TSEAC meeting in June 
2002.
    It would be inconsistent with our level of concern about TSE to 
fail to require a donor medical history interview for some corneas, 
when it is generally agreed that corneas are among the tissues most 
likely to transmit TSE. The information needed to screen for TSE (e.g., 
cognitive changes; travel history) is not the sort that can be obtained 
through an autopsy or through a review of investigators' reports or 
hospital charts.
    Moreover, although the preamble to the proposed rule used TSE to 
illustrate the need for a medical history interview for all cornea 
donors, questions pertaining to other relevant communicable diseases 
would also go unanswered without an interview. We agree with the 
comment that supported the interview as a way of screening for diseases 
other than CJD, such as hepatitis and HIV.
    The EBAA report focused on CJD, and not on other diseases that 
might be screened for, including HIV. The report recommended against 
requiring a donor medical history interview in cases of legislative 
consent. In reaching this conclusion, the report's authors made certain 
assumptions about the diagnosis, course, and prevalence of CJD in the 
cornea donor population, including the frequency of misdiagnosis of 
CJD. As we discuss in this document, varying these assumptions can lead 
to very different conclusions. Moreover, the report analyzed the 
possible effect of supplemental screening applicable to all cornea 
donors, assuming a new screening requirement where none currently 
exists. However, the requirement for a donor medical history interview 
is currently in place with respect to all cornea donations except for 
the small percentage obtained under legislative consent. (The actual 
percentage of cornea donations obtained under legislative consent is 
unknown. The EBAA report used an unsupported value of 10 percent.)
    In evaluating the proposed regulation, the EBAA report considered 
the number of potential cornea donors who might be deferred for CJD 
risk because of the results of supplemental screening but who in fact 
do not have CJD (i.e., the number of all cornea donors who might be 
erroneously excluded). Depending on the assumptions made, the estimated 
number of cornea donors with CJD and the number of donors erroneously 
excluded by screening could vary tremendously. For instance, the 
authors of the report assumed that 1 percent of actual CJD cases would 
be missed, and

[[Page 29805]]

diagnosed as some other neurological disease. They calculated that it 
would take 8.1 years of screening to exclude one actual case of CJD, 
and the numbers of otherwise eligible donors incorrectly excluded by 
screening would range from 18,415 to 73,362 (depending upon the 
specificity of the screening questions). If, instead of 1 percent, we 
make the assumption that 10 percent of cases of CJD would be 
misdiagnosed, then it would take 1.4 years of screening to exclude 1 
actual case of CJD, with 3,219 to 12,876 donors incorrectly excluded. 
Thus, the assumption made by the authors resulted in a calculation of 
approximately six times the number of donors incorrectly excluded as 
under another possible scenario. Furthermore, the EBAA model estimates 
the numbers of incorrectly excluded donors that would result assuming 
that the additional screening would apply to all cornea donors. 
However, the additional screening required under this rule would affect 
only the subset of donors from whom an interview is not currently 
obtained (e.g., corneas obtained under legislative consent).
    Because the report failed to explicitly consider a variety of 
uncertainties in the model assumptions, did not consider the effect of 
the donor medical history interview requirement on the appropriate 
subset of potential donors, and did not include diseases other than CJD 
in the risk assessment, we decline to follow any recommendation based 
on the results.
    We disagree with comments that predict a shortage of corneas 
resulting from this rule. At present, approximately 30 percent of 
corneas recovered in the United States are exported (2002 Eye Banking 
Statistical Report, Eye Bank Association of America). Because any 
estimates of potential reductions in donations under legislative 
consent are quite speculative, we have not included such estimates in 
this response. Even if this final rule led to a reduction in donations 
under legislative consent, we do not anticipate that a shortage would 
result.
    (Comment 46) Although comments expressed concern about the effect 
of the proposed requirement for a donor medical history interview on 
medical examiner laws, we received only a few responses to our request 
for comments on any potential conflicts that might make it impossible 
to comply with both this regulation and State laws on legislative 
consent. One comment agreed with requiring a donor medical history 
interview, but noted that, given privacy considerations, an interview 
with a primary treating physician may be difficult to obtain without 
permission of the deceased and/or the deceased's family. Another 
comment asserted that, for the proposed rule not to conflict with State 
laws on legislative consent, it would have to allow the medical 
examiner or pathologist who performs the autopsy to qualify as an 
``individual knowledgeable about the donor's medical history and 
relevant social behavior'' and to respond to a modified set of history 
questions appropriate to the medical examination. According to the 
comment, other medical and social history would be obtained through the 
case file containing investigator's reports, hospital charts, or other 
sources of donor history.
    (Response) As discussed in section VI of this document, we 
contacted the States to give them the opportunity to comment on any 
possible preemption issues. No States replied to our request.
    In this final rule, we have defined ``donor medical history 
interview'' as a documented dialog about the donor's medical history 
and relevant social behavior, including activities, behaviors, and 
descriptions considered to increase the donor's relevant communicable 
disease risk. If the donor is not living or able to participate in the 
interview, the interview must take place with an individual or 
individuals who are able to provide the information sought in the 
interview. (This language replaces ``individual knowledgeable about the 
donor's medical history and relevant social behavior'' from the 
proposed rule. This change is for purposes of clarity and plain 
language, and it does not affect the definition's meaning.) Examples of 
these individuals who could possibly provide the appropriate 
information include the donor's next-of-kin, the nearest available 
relative, a member of the donor's household, an individual with an 
affinity relationship, or the primary treating physician.
    We continue to believe that the definition of ``donor medical 
history interview'' provides sufficient flexibility to allow for the 
continued recovery of corneas under legislative consent. However, we 
recognize that there may be some difficulty in communicating with the 
primary treating physician without obtaining permission from the 
deceased and/or the family of the deceased, and that therefore this 
final rule may have an effect on the ability of medical examiners and 
coroners to recover corneas under State legislative consent laws. But, 
given the known transmission by corneas of HBV and CJD, and the 
potential for corneas to transmit other communicable diseases, 
including TSE, we have concluded that making an exception from the 
requirement for a donor medical history interview in the case of 
corneas obtained under legislative consent is not justified.
    We disagree with the comment that urged us to interpret the 
definition to include an interview with the medical examiner or 
pathologist who performs the autopsy. Although the medical examiner or 
pathologist will have useful clinical information that should bear on 
the donor-eligibility determination, it is unlikely that this person 
will know the donor well enough to answer questions about his or her 
medical history, travel history, and/or social behavior. Therefore, an 
interview with the medical examiner or pathologist would be inadequate 
to fulfill the interview requirements.
    (Comment 47) In the preamble to the proposed rule, we noted that, 
together with CDC, we were reviewing the risk factors for transmission 
of relevant communicable diseases in light of current scientific 
knowledge. Based on that review, we planned to specifically describe, 
in a guidance document, risk factors and screening information to 
assist establishments in complying with the regulations (64 FR 52696 at 
52703). Although the proposed rule did not specify risk factors, we 
received many comments opposed to a screening factor that would prevent 
men who have had sex with men from donating semen anonymously. (Many 
comments also focused on the proposed requirement to quarantine 
directed donations of reproductive cells and tissue. As discussed in 
comment 36 of this document, we have deleted this requirement from this 
final rule. The final regulations allow the use of fresh semen from 
directed reproductive donors.)
    Some comments disagreed with considering homosexual men to be 
``high risk donors'' and disputed the scientific basis for excluding 
these men as donors. Many comments cited the efficacy of the blood test 
for HIV, with retesting after a 6-month quarantine, although one 
comment noted that HIV antibody testing is imperfect. Many comments 
disputed the public health benefits of the rule, although some 
applauded the agency for trying to craft safeguards to protect the 
public.
    Other comments asserted that the regulations would abridge the 
reproductive, civil, or constitutional rights of both donor and 
recipient, but did not provide an explanation of the scope of those 
rights or a legal analysis of how this rule would affect them. Many 
comments argued that the proposed regulations were discriminatory. Some 
comments

[[Page 29806]]

suggested language for the donor-eligibility draft guidance.
    (Response) In response to the comments suggesting that FDA should 
allow establishments to rely on HIV test results alone, or on 
quarantine and retesting, without screening for risk factors, FDA 
rejects that approach at this time. Although it is reasonable to expect 
that more sensitive nucleic acid amplification testing (NAT) will be 
available soon for reproductive tissue donors, even that testing may 
fail to detect early stage HIV and other infections, particularly 
because the level of viremia may be extremely low in the early stages 
of infection (Refs. 1, 2, and 3). Moreover, even the best test may fail 
to provide an accurate test result due to human error in running the 
test or in linking the test result to the correct donor. Accordingly, 
FDA believes that, based on the current state of testing and current 
knowledge about disease transmission, it is necessary to screen for 
risk factors as well as to test for diseases such as HIV.
    Like the proposed rule, this final rule does not specify risk 
factors. Risk factors and other information about screening are 
contained in the donor-eligibility draft guidance announced elsewhere 
in this Federal Register. We welcome comments on the guidance document.
    In developing the guidance, we have seriously considered the 
comments. To obtain up-to-date information on risk factors, we have 
worked with CDC. CDC performed a literature search and then, on June 26 
and 27, 2000, held a donor suitability consultation to consider whether 
the 1994 ``Guidelines for Preventing Transmission of Human 
Immunodeficiency Virus Through Transplantation of Human Tissue and 
Organs'' (Morbidity and Mortality Weekly Report 1994; 43(RR-8)), should 
be revised with respect to men who have sex with men.
    Approximately 50 persons were invited as consultants. They 
represented transfusion and transplant professional organizations, 
public health experts, donor families, persons receiving transplants, 
ethicists, and donor rights advocates. Representatives of the 
Department of Health and Human Services and its component agencies also 
participated. Observers at the meeting were also encouraged to 
contribute.
    Representatives of CDC presented the scientific literature search 
prepared as a background for the consultation. Presenters compared the 
transmissibility of infection through blood, organs, tissues, and 
reproductive tissues. Data were presented on the incidence and 
prevalence on HIV, HBV, and HCV for specific groups and risk behaviors; 
these data were derived primarily from the literature published between 
1995 and 2000 and from unpublished sources. Data indicated that, 
compared to the general population, the incidence and prevalence rates 
for HIV, HBV, and HCV were substantially higher for heterosexuals 
attending sexually transmitted disease clinics, men who have sex with 
men, commercial sex workers, and injection drug users.
    After the consultation, it was concluded that there is no new data 
that would warrant revising the 1994 guidelines. CDC and others also 
concluded that current data are not sufficient to allow the 
identification of lower-risk subsets of currently excluded population 
groups, and thus, to refine the exclusionary criteria. At the 
consultation, representatives of CDC encouraged the development of new 
data.
    On December 14, 2001, we asked the Center for Biologics Evaluation 
and Research's (CBER) BPAC, whether there are existing data that 
identify subsets of men who have had sex with other men in which the 
incidence and prevalence rates for HIV, HBV, and HCV of the subsets are 
similar to the population at large. By a 10 to 0 vote, the committee 
advised that these data do not exist.
    We have reviewed relevant legal authorities and disagree that these 
regulations discriminate or improperly abridge donor or recipient 
rights. We further note that, since FDA has tailored the rule's 
requirements to take into account an existing relationship between a 
donor and recipient (for example, FDA has not required quarantine and 
retesting for directed reproductive donors, permits the use of 
reproductive tissue from ineligible directed reproductive donors, and 
requires no testing for sexually intimate partners), the comments' 
remaining objections relate almost exclusively to anonymous donations 
of reproductive tissue. We will continue to examine the data on risk 
factors and, as new data are developed that justify changes to our 
guidance, we will make those changes in accordance with good guidance 
practice.
    (Comment 48) Proposed Sec.  1271.75(a)(2) would require screening a 
potential donor to determine if he or she had received a 
``xenotransplant'' or was a ``close contact'' of a xenotransplant 
recipient. Two comments agreed that xenotransplantation recipients 
should be deferred as tissue donors, but asserted that close contacts 
do not need to be deferred. One comment asserted that there have been 
no reports of the spread of zoonoses to close contacts or household 
members. The comment further recommended use of a simplified question 
in donor screening.
    (Response) This final rule adopts a different approach to screening 
for xenotransplantation than proposed. The rule is intended to permit 
the agency added flexibility in responding appropriately to the risks 
presented by different kinds of xenotransplantation as this field 
develops and changes. To this end, we have modified several provisions 
of the final rule with respect to xenotransplantation, including the 
screening requirements set out in Sec.  1271.75. (Changes to the 
definitions and to Sec.  1271.65 are discussed in comment 25 and the 
text before comment 37 of this document.)
    The final rule requires screening for ``communicable disease risks 
associated with xenotransplantation.'' The donor-eligibility draft 
guidance that accompanies this final rule describes those risks. 
Because, at this time, so few xenotransplantations have been performed, 
and much is unknown about the actual risks of xenotransplantation, the 
risks for which you must screen may be potential or hypothetical risks. 
We currently consider both the xenotransplantation product recipient 
and the intimate contact of a xenotransplantation product recipient to 
be at risk for acquiring zoonoses, and, as in the proposed rule, these 
individuals would be ineligible to donate HCT[sol]Ps. However, if 
requested to do so through a request for an exemption from or 
alternative to the regulations under proposed Sec.  1271.155 when 
finalized, we will consider exceptions for certain ex vivo exposures 
(e.g., exposure to a well-characterized cell line, or exposure across a 
physical barrier).
    We have considered the comments' assertion that intimate contacts 
should be eligible for donation, based on the lack of reports of 
zoonosis spread, and we disagree. Given the potential risks associated 
with the spread of diseases from live animal cells, tissues, and 
organs, we believe that the most prudent course at this time is to 
defer intimate contacts, and the donor-eligibility draft guidance 
follows this course. As with hepatitis and HIV, those individuals most 
likely to be infected by a xenotransplantation product recipient with a 
zoonosis are the recipient's intimate contacts. Should that individual 
become infected with a zoonosis, then an HCT[sol]P from that intimate 
contact could transmit the zoonosis to the recipient of that HCT[sol]P.
    The donor-eligibility draft guidance describes the types of 
questions that can

[[Page 29807]]

elicit information on communicable disease risks associated with 
xenotransplantation. We welcome comments on the draft guidance.
    (Comment 49) One comment said that, instead of questioning at the 
time of donation, FDA should require that past xenotransplantation 
product recipients and their next of kin be notified by the medical 
institution performing the clinical trials that they are deferred from 
donating blood and tissues.
    (Response) We agree that a transplant institution should tell a 
xenotransplantation product recipient not to donate blood and tissues 
(e.g., as part of informed consent). The PHS Guideline on Infectious 
Disease Issues in Xenotransplantation (January 19, 2001) recommends 
that xenotransplantation product recipients be instructed not to donate 
blood, blood components, tissues, breast milk, ova, sperm, or any other 
body parts for use in humans. This document further recommends that the 
recipient inform his contacts (now referred to as ``intimate 
contacts'') not to donate.
    However, as an added precaution, an HCT[sol]P donor, or other 
person interviewed in the donor medical history interview, should be 
questioned at the time of HCT[sol]P donation. Unless prodded by the 
question, the donor may not remember that he or she is not supposed to 
donate HCT[sol]Ps. Moreover, another person interviewed in the donor 
medical history interview may not remember the warning against donation 
unless specifically asked about xenotransplantation.
    (Comment 50) Proposed Sec.  1271.75(d) would allow an abbreviated 
donor screening procedure for living donors, as long as complete donor 
screening is performed every 6 months. One comment asserted that it is 
impractical to conduct abbreviated screening at each donation for 
anonymous semen donors and that a complete donor-eligibility 
determination every 6 months is unnecessary. Another comment 
recommended that a complete screening be recorded with each donation 
event. A third comment asked us to revise the regulation to indicate 
that an abbreviated donor screening would not be acceptable if there 
has been a change in screening requirements since the last complete 
screening procedure was performed on the donor.
    (Response) We decline to make the changes suggested by the 
comments. We believe that the requirement for a complete screening 
procedure (i.e., a donor medical history interview), review of medical 
records and physical examination, every 6 months is appropriate because 
in this timeframe a potential donor may develop physical signs of a 
communicable disease that can be detected by examination.
    With an abbreviated screening procedure, a full review of records 
is not necessary, but you must make sure that there have been no 
changes in a donor's risk factors, including high risk behavior, since 
the previous donation. You may accomplish this by having the donor read 
a written list of risk behaviors and asking whether he or she has 
participated in these behaviors.
    With respect to changes in screening requirements, we agree with 
the intent of the comment but disagree that the requested change is 
necessary. Information on screening (e.g., risk factors) is contained 
in guidance that, although not binding, represents our current thinking 
on the topic. If FDA guidance on screening has changed since the last 
donation (for example, if a new risk factor has been added), we 
recommend that you screen in accordance with the new guidance at the 
next scheduled donation following the implementation date of the 
guidance (for example, by screening for the new risk factor).
    We have made several changes to the regulation for clarity. We have 
replaced the phrase ``on subsequent donations'' with ``on repeat 
donations'' to clarify that we intend this abbreviated procedure to 
apply in repeat donation situations (e.g., semen).
    We note that while Sec.  1271.75(d) addresses abbreviated screening 
procedures for repeat donors, the requirements for quarantine, testing, 
and retesting applicable to repeat donations are contained in 
Sec. Sec.  1271.60, 1271.80, and 1271.85. In comment 53 of this 
document, we discuss changes to the testing requirements applicable in 
the repeat donor situation.
9. What Are the General Requirements for Donor Testing? (Sec.  1271.80)
    Proposed Sec.  1271.80 would require an establishment to test donor 
specimens for relevant communicable disease agents, to adequately and 
appropriately reduce the risk of transmission of relevant communicable 
diseases. Among other things, proposed Sec.  1271.80 sets out 
requirements for the timing of specimen collection; the use of FDA-
licensed, approved, or cleared tests; which laboratories could perform 
the required tests; exceptions applicable to certain test results for 
CMV or syphilis; and determining the adequacy of a specimen where the 
donor has received a transfusion or infusion.
    a. Testing of mother. Proposed Sec.  1271.80(a) stated that, in the 
case of a fetal or neonatal donor, a specimen from the mother is 
generally acceptable for testing.
    (Comment 51) One comment emphasized the importance of permitting 
testing of an appropriate specimen from the mother of a fetal or 
neonatal donor. Another comment requested that we require maternal 
tests to be validated as predictive of transmissibility of infection in 
the fetal or neonatal tissue.
    (Response) We have reexamined the proposed language on maternal 
testing and now believe that testing of the mother is preferable to 
testing of the fetal or neonatal donor. We are particularly concerned 
about the possibility that HBV might be transmitted at or around the 
time of birth, or possibly in utero. In such cases, HBV testing of the 
fetus or neonate could lead to a false negative result, but testing of 
the mother would be positive. We have therefore revised Sec.  
1271.80(a) to require that, in the case of a donor 1 month of age or 
younger, you must test a specimen from the birth mother instead of from 
the donor. We note that requiring testing of the mother is consistent 
with the standards of several professional organizations (see, e.g., 
American Association of Blood Banks (AABB) Standards for Hematopoietic 
Progenitor Cell and Cellular Product Services, 3rd edition, 2002; NMDP 
Standards, 17th edition, Sept. 1999; Foundation for the Accreditation 
of Cellular Therapy (FACT)/Netcord International Standards for Cord 
Blood, 2002; FACT Standards for Hematopoietic Progenitor Cell 
Collection, Processing and Transplantation, 2nd edition, 2002). Because 
it is generally accepted that, in most cases, until a month of age the 
same IgG antibodies are present in the mother's blood as in the 
neonate's, we decline to add the requested validation requirement.
    b. Timing of specimen collection. Proposed Sec.  1271.80(b) would 
require collection of the donor specimen at the time of recovery of 
cells or tissue from the donor or within 48 hours after recovery, 
although proposed Sec.  1271.80(b)(1) through (b)(3) would allow 
specimen collection from a living donor up to 7 days before recovery in 
certain situations.
    We received many comments on this provision.
    (Comment 52) One comment recommended that time constraints for 
specimen storage before testing be consistent with test kit 
instructions.
    (Response) We agree. Section 1271.80(c) requires that you follow 
the manufacturer's instructions in

[[Page 29808]]

performing testing. This includes instructions with respect to storage 
time before testing.
    (Comment 53) Numerous comments asserted that the proposed rule was 
too restrictive and requested that we allow more time between 
collection of the specimen and recovery of the cells or tissue. 
Comments concerned with the recovery of peripheral blood stem/
progenitor cells, where recipient conditioning is performed, suggested 
a timeframe of 30 days before recovery of the HCT[sol]P. Other comments 
requested that, for cord blood donors, specimen collection be permitted 
at any time following the donation; another comment requested 7 days. 
One comment requested from 30 to 90 days post-donation for specimen 
collection from a sperm donor, citing expense and natural fluctuations 
in semen sample parameters. Another comment asserted that the proposed 
time limits were too restrictive for oocyte donors. Some comments 
expressed concern that, in the case of cadaveric donors, the 
regulations would not allow testing of specimens collected before death 
(premortem specimens). Other comments asserted that the requirements on 
timing of specimen collection would prohibit the use of pretransfusion 
samples.
    (Response) We agree that more time should be allowed between 
collection of specimens for testing and HCT[sol]P recovery. The final 
rule requires a sample at the time of recovery, when feasible. However, 
if specimen collection at the time of cell or tissue recovery is not 
feasible, you may collect the specimen up to 7 days before or after 
recovery. We decline to rely on testing for communicable diseases 
performed later than 7 days before donation, because the test results 
would not accurately reflect the donor's actual disease exposure at the 
time of donation. Moreover, as the time period between donation and 
specimen collection increases, the chances of mix-ups or difficulties 
with followup also increase. An establishment may choose to perform 
testing before initiating preparatory regimens on the donor (e.g., 
oocyte donors require hormone stimulation), but that earlier testing 
would not replace the testing required by this regulation.
    However, we are making an exception for testing donors of 
peripheral blood stem/progenitor cells. Since the recipient undergoes a 
myeloablative treatment regiment, i.e., high dose chemotherapy and 
total body irradiation, it is important to determine the eligibility of 
the donor before the recipient's treatments begin. At 7 days prior to 
recovery, the treatment of the recipient has already started and the 
decision to proceed is irreversible. Therefore, under Sec.  1271.80(b), 
for donors of peripheral blood stem/progenitor cells only, the 
establishment may collect the donor specimen up to 30 days before 
recovery of the stem/progenitor cells. We understand that the current 
practice of peripheral blood stem/progenitor cell establishments is to 
take a donor specimen on the day of recovery for additional testing, 
and we encourage these establishments to continue this practice, in 
order to permit appropriate followup and treatment if test results are 
positive.
    In response to the comment on semen donation, we have added an 
exception to Sec.  1271.85(d) that will provide flexibility for the 
testing of anonymous, repeat semen donors. We understand that, under 
current practices, establishments do not collect a specimen for testing 
at each donation by a repeat semen donor. As long as a specimen has 
been taken and tested, and the donated semen is quarantined pending the 
results of retesting at least 6 months after donation, it is not 
necessary for us to restrict this practice through these regulations. 
For this reason, we have added an exception to Sec.  1271.85(d) for 
repeat semen donors from whom a specimen has already been collected and 
tested, and for whom retesting is required under Sec.  1271.85(d). We 
reiterate that you must collect a new specimen and test it under Sec.  
1271.85(d) at least 6 months after the donation, and pending the 
completion of that retesting you must quarantine the donated semen 
under Sec.  1271.60(a).
    Under the new regulatory language in Sec.  1271.80(b), which 
permits the collection of a specimen up to 7 days before recovery of 
cells or tissue, you may use a premortem specimen to test a cadaveric 
donor, as long as the specimen is collected within that timeframe. The 
use of specimens taken pretransfusion or preinfusion will continue to 
be allowed, subject to the same 7-day timeframe; use of these specimens 
is discussed in section III.C.8.g of this document.
    c. Approved tests. Proposed Sec.  1271.80(c) would require the use 
of appropriate FDA-licensed, approved, or cleared donor screening tests 
in accordance with the manufacturer's instructions (except that, for 
Chlamydia trachomatis and Neisseria gonorrhea, tests labeled for the 
detection of those organisms in an asymptomatic, low-prevalence 
population must be used until screening tests are available). In 
addition, proposed Sec.  1271.80(c) would require the use of tests 
specifically labeled for cadaveric specimens, when applicable and 
available, instead of more generally labeled donor screening tests.
    (Comment 54) Two comments suggested that Sec.  1271.80(c) describe 
the circumstances in which tissue establishments may use tests that are 
not licensed, cleared, or approved.
    (Response) We decline to make this change. This section requires 
the use of FDA licensed, approved, or cleared screening tests. The use 
of unapproved tests would not meet the requirements of this regulation.
    (Comment 55) One comment urged FDA to work with laboratories and 
manufacturers of diagnostic tests to approve tests for cadaveric 
specimens. Other comments noted that there were no FDA-licensed 
screening kits for cadaveric blood samples. Another comment expressed 
doubts that cadaveric blood tests for corneas would be approved.
    (Response) FDA has encouraged manufacturers of in vitro diagnostic 
products to develop products intended for use with cadaveric specimens. 
Since the publication of the proposed rule, we have licensed test kits 
specifically labeled for use with cadaveric blood specimens. These test 
kits must be used, if applicable, when testing all cadaveric HCT[sol]P 
donors, including cornea donors. A list of licensed test kits for use 
with cadaveric specimens may be found at http://www.fda.gov/cber/products/testkits.htm.
    d. CLIA certification. Proposed Sec.  1271.80(c) stated, in part, 
that testing must be performed by a laboratory certified to perform 
testing on human specimens under the CLIA.
    (Comment 56) Two comments asserted that we should permit testing by 
laboratories that are exempt from CLIA certification.
    (Response) We agree with the comment that not all laboratories that 
comply with CLIA are certified under CLIA. We have revised Sec.  
1271.80(c) to require that required testing must be performed by a 
laboratory that either is certified to perform such testing on human 
specimens under CLIA and 42 CFR part 493, or has met equivalent 
requirements as determined by the CMS. Examples of the latter are 
Veterans Administration hospital laboratories, laboratories in states 
that have received an exemption from CMS, and laboratories accredited 
by certain approved accrediting organizations.
    (Comment 57) Comments also urged us to permit testing by foreign 
laboratories subject to requirements equivalent to or more stringent 
than those imposed by CLIA. One comment

[[Page 29809]]

requested that we consider allowing U.S. citizens access to cord blood 
units from foreign tissue banks, which would not follow CLIA standards 
but would have similarly regulated clinical laboratory testing.
    (Response) We decline to make the change requested because it is 
not feasible for us to identify and assess the equivalence of other 
countries' requirements, keep track of any changes to those 
requirements, and then to ascertain that each foreign tissue bank meets 
those requirements. In contrast, CLIA certification provides a uniform, 
workable mechanism for determining laboratory proficiency. Foreign 
establishments are not prohibited from using domestic CLIA-certified 
laboratories for performing the required testing, and some firms 
operating under part 1270 send samples ahead to the United States for 
testing in CLIA-certified laboratories.
    When we first issued regulations on human tissue, one major concern 
was the distribution in the United States of imported tissue from 
donors who had not been adequately screened and tested to prevent the 
transmission of infectious disease (62 FR 40429 at 40435, July 29, 
1997). The proficiency of the laboratory performing the required 
testing is a key element in assuring the safety of HCT[sol]Ps. 
Certification under CLIA helps to ensure that the laboratory is 
proficient and competent to perform the required tests accurately. 
Moreover, any laboratory, foreign or domestic, may apply for 
certification under CLIA. At this time, we are aware of 21 foreign 
CLIA-certified laboratories.
    e. Ineligible donors. Proposed Sec.  1271.80(d)(1) stated that a 
donor whose specimen tests repeatedly reactive or positive must be 
determined unsuitable.
    We have made several changes to the wording of this paragraph. As 
discussed earlier in this document, ``unsuitable'' is now 
``ineligible.''
    In addition, for consistency with other FDA regulations, we have 
changed ``repeatedly reactive'' to ``reactive.'' As noted in the 
preamble to the proposed rule, repeatedly reactive means initially 
reactive, and then reactive in at least one of two duplicate tests with 
the same manufacturer's test kit (64 FR 52696 at 52705). Deleting the 
word ``repeatedly'' from the regulation should allow for future 
advancements in testing, when the process of repeating an initial 
reactive result in duplicate would no longer be appropriate. This 
modification does not affect the requirement that you follow the 
testing protocol set out in the test kit instructions (Sec.  
1271.80(c)). In other words, if the test kit instructions direct you to 
repeat an initial reactive test result in duplicate, you must do so. In 
such cases, the term ``reactive'' should be understood to mean 
repeatedly reactive.
    Proposed Sec.  1271.80(d)(1) contained two exceptions to the 
general rule that a donor whose specimen tests reactive or positive 
must be determined ineligible. Under the first exception, a reactive 
test for CMV would not make a donor unsuitable unless additional 
testing showed the presence of an active infection. The second 
exception was for a donor whose specimen tested repeatedly reactive on 
a nontreponemal screening test for syphilis and negative on a specific 
treponemal confirmatory test.
    (Comment 58) One comment asserted that FDA should permit 
confirmatory tests to prevail in all cases, arguing that this is 
consistent with medical practice and would prevent discarding 
transplantable tissue. Another comment noted that proposed Sec.  
1271.80(d)(1) contained no exception for HBV, although tests for HBV 
recognize the validity of confirmatory testing in the manufacturer's 
instructions.
    (Response) We disagree that the results of confirmatory tests 
rather than the results of screening tests should determine donor 
eligibility. Confirmatory tests may not be as sensitive as screening 
tests in detecting early infection. Our decision is consistent with the 
agency's policy in blood regulation: For blood donors, supplemental 
testing is used for donor reentry or for donor notification and 
counseling.
    Confirmatory testing for HBV, such as the hepatitis B surface 
antigen (HBsAg) neutralization assay, is valuable for confirming the 
presence of HBsAg in specimens found to be reactive by a screening 
assay, and so can be helpful for donor counseling. However, the 
neutralization assay may not always detect all potentially infectious 
HCT[sol]Ps. Therefore, we are not making an exception in this section 
that would permit a donor-eligibility determination based on HBV 
confirmatory testing.
    (Comment 59) One comment, submitted to the CGTP docket, asked us to 
allow tissue banks to use the results of triplicate testing, performed 
by laboratories for OPOs, when all three tests are negative.
    (Response) If you are using test results of an enzyme immunoassay 
obtained by an OPO, and the test was initially run in triplicate, you 
may interpret three nonreactive results in a single run as a negative 
test result.
    f. Testing for CMV. Proposed Sec.  1271.85(b)(3) would require that 
donors of viable, leukocyte-rich cells or tissue be tested for CMV. 
Proposed Sec.  1271.80(d)(1)(i) would require you to determine 
ineligible a donor whose specimen tests reactive for CMV, unless 
additional testing does not show the presence of an active infection. 
We proposed the exception in Sec.  1271.80(d)(1)(i) 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 (64 
FR at 52705). We noted that the results of CMV testing would accompany 
the HCT[sol]P, and we specifically requested comments on this approach 
(64 FR 52705).
    (Comment 60) One comment noted that the proposed rule did not 
specify a means for assuring that CMV viral shedding is not occurring, 
and suggested that we specify the type of tests to use to determine the 
presence or absence of viral shedding.
    (Response) Considering this comment has led us to conclude that it 
would be difficult to comply with the terms of the exception in 
proposed Sec.  1271.80(d)(1)(i). Therefore, we have made several 
modifications to the final rule with respect to CMV testing. The effect 
of these changes is to require CMV testing of donors of leukocyte-rich 
cells or tissue, while allowing the use of HCT[sol]Ps from CMV-reactive 
donors in some instances.
    First, we have deleted proposed Sec.  1271.80(d)(1)(i) from the 
final rule, and we have removed CMV from the list of relevant 
communicable disease agents and diseases in Sec.  1271.3(r)(1), as well 
as from Sec.  1271.85(b)(3). We have made this change because we 
believe that, as proposed, the rule may have led all donors who test 
reactive for CMV to be disqualified, an undesirable result.
    Second, although we have removed CMV from the list of relevant 
communicable disease agents and diseases in Sec.  1271.3(r)(1), we have 
not removed the requirement for CMV testing from the final rule 
altogether. An HCT[sol]P from a CMV-antibody-reactive donor is capable 
of transmitting CMV to a recipient who tests negative for CMV antibody, 
and in some recipients this can have serious consequences. To prevent 
these consequences, the final rule, at Sec.  1271.85(b)(2), requires 
you to test donors of viable leukocyte-rich cells and tissue for 
evidence of infection due to CMV. Under Sec.  1271.55(b), results of 
testing (including testing for CMV) must accompany an HCT[sol]P.
    The third change we have made in the final rule is to require, in 
Sec.  1271.85(b)(2), that you establish and maintain an SOP governing 
the release

[[Page 29810]]

of an HCT[sol]P from a donor whose specimen tests reactive for CMV. 
This approach will permit the development of procedures that are 
specific to different situations. SOPs might, for example, permit the 
release of an HCT[sol]P from a donor with a CMV-antibody reactive test, 
depending on the CMV status of the recipient. We address the issue of 
the use of HCT[sol]Ps from CMV-reactive donors in the donor-eligibility 
draft guidance, announced elsewhere in this Federal Register.
    (Comment 61) Another comment asked whether a semen bank would be 
able to use a semen donor who tested positive for CMV (IgG) in a CMV 
positive (IgG) recipient.
    (Response) Section 1271.85(b)(2), in part, requires you to 
establish and maintain an SOP governing the release of an HCT[sol]P 
from a donor whose specimen tests reactive for CMV. Thus, your SOP 
would need to address this situation. We discuss the use of semen from 
a donor who tests reactive to CMV (IgG) in the donor-eligibility draft 
guidance announced elsewhere in this Federal Register.
    (Comment 62) One comment suggested that we used the term 
``repeatedly positive'' instead of ``repeatedly reactive'' when 
describing results of CMV testing, because the term ``repeatedly 
reactive'' is not recognized as a CMV screening test result.
    (Response) As discussed, we have changed the wording from 
``repeatedly reactive'' to ``reactive.'' Although the labeling of the 
devices used to perform CMV testing describes results as positive or 
negative, the terms ``positive'' and ``reactive'' are synonymous in 
this context for the purposes of this rule.
    (Comment 63) One comment asserted that, for reproductive cells, it 
is unnecessary to require the CMV status to accompany the product, 
because approximately 40 percent of semen donors are CMV antibody (IgG) 
positive. The comment noted that it is rare for the physician 
conducting the insemination to review this information, and that, for 
this reason, the information is provided only upon request.
    (Response) We disagree. CMV is the most commonly identified cause 
of congenital infection (Krugman S., et al., Infectious Diseases in 
Children, St. Louis, CV Mosby, pp. 8-21, 1985). If a CMV negative 
pregnant woman contracts CMV, the fetus may acquire congenital CMV 
infection. We continue to believe that information about the semen 
donor's CMV status should appear in materials accompanying the 
HCT[sol]P, so that physicians may rely on this information to make 
informed decisions about the use of an HCT[sol]P in a particular 
patient's situation.
    g. Plasma dilution. The transfusion or infusion of blood, colloids, 
or crystalloids may result in plasma dilution, which can affect the 
results of communicable disease testing. Section 1271.3(p) defines 
plasma dilution as a decrease in the concentration of the donor's 
plasma proteins and circulating antigens or antibodies.
    Proposed Sec.  1271.80(d)(2) and (d)(3) would set out requirements 
relating to plasma dilution. We have reorganized those provisions in 
this final rule, and they now appear in paragraph (d)(2).
    The final rule requires you to determine ineligible any donor in 
whom plasma dilution sufficient to affect the results of communicable 
disease testing is suspected, unless you: (1) Test a specimen taken 
before transfusion or infusion (and up to 7 days before recovery of 
cells or tissue), or (2) analyze the extent of plasma dilution, using 
an established procedure called an algorithm. If that analysis rules 
out plasma dilution sufficient to affect test results, then you can 
perform required testing on a specimen taken after transfusion or 
infusion. However, if plasma dilution is sufficient to affect results, 
and no specimen taken before transfusion or infusion is available, then 
the donor is ineligible to donate.
    The final rule gives examples of clinical situations in which you 
must suspect plasma dilution sufficient to affect test results. Under 
Sec.  1271.80(d)(2)(ii)(A), if you know of or suspect blood loss in a 
donor over 12 years of age, transfusions and infusions totaling more 
than 2,000 milliliters (mL) must be suspected of affecting test 
results. Under Sec.  2171.80(d)(2)(ii)(B), any transfusion or infusion 
in a donor 12 years of age or younger must be suspected of affecting 
test results, whether or not blood loss has occurred. These clinical 
situations were set out in the proposed regulation and were based 
closely on Sec.  1270.20(h)(2) and (h)(3).
    However, whereas the proposed rule specified the timeframe for 
these transfusions or infusions as within 48 hours of specimen 
collection (or within 1 hour in the case of crystalloids), the final 
rule sets the timeframe as within 48 hours (or one hour, for 
crystalloids) before death or specimen collection, whichever occurred 
earlier. We have inserted the reference to death to take into account 
those situations where the specimen is collected after death. For 
example, if the specimen is collected 3 days after death, it does not 
make sense to consider transfusions within the 48 hours before specimen 
collection, when the donor would already be dead and would not be 
receiving transfusions. What is relevant in this instance is any 
transfusion or infusion within 48 hours of the donor's death (or one 
hour, for crystalloids).
    As we noted in the guidance document that accompanied part 1270, 
every possible clinical situation cannot be predicted, and there may be 
additional circumstances where plasma dilution sufficient to affect 
test results should be suspected. As restructured, Sec.  1271.80(d)(2) 
recognizes that these other situations exist. In the donor-eligibility 
draft guidance announced elsewhere in this issue of the Federal 
Register, we list additional circumstances in which it may be necessary 
to employ an algorithm.
    A discussion of plasma dilution and algorithms appeared in the 
final rule ``Human Tissue Intended for Transplantation'' issued in the 
Federal Register of July 29, 1997 (see 62 FR 40429 at 40435 through 
40436), and also in a guidance document entitled ``Guidance for 
Screening and Testing of Donors of Human Tissue Intended for 
Transplantation'' dated July 1997. We now refer to those documents. We 
also note that the donor-eligibility draft guidance announced elsewhere 
in this issue of the Federal Register contains information on 
appropriate algorithms.
    (Comment 64) One comment requested clarification of the term 
``blood loss.''
    (Response) By blood loss, we mean bleeding, including internal 
bleeding. Thus, in considering whether blood loss has occurred in a 
potential donor, you should consider both blood lost within the body 
cavity and blood lost outside of the body.
    (Comment 65) One comment questioned how to determine whether to use 
an algorithm due to the 2000 mL limit without actually performing the 
tabulation.
    (Response) You may need to review medical records to make a rough 
determination of the total amount of blood, colloids, or crystalloids 
administered to a potential donor. This threshold determination will 
allow you to decide whether further analysis, using an algorithm, is 
necessary. In an adult with blood loss, if the total exceeds 2,000 mL, 
and administration took place within the timeframes set out in Sec.  
1271.80(d), then you must suspect plasma dilution sufficient to affect 
test results. Section 1271.80(d)(2) would then require you either to 
test a specimen taken before infusion or transfusion or to use an 
appropriate algorithm to analyze further the possibility of plasma 
dilution.

[[Page 29811]]

    (Comment 66) One comment asserted that including the total volume 
of whole blood in calculations does not meet scientific principles, 
because the volume of the red blood cells does not contribute to plasma 
dilution.
    (Response) The calculations that are made to determine if plasma 
dilution has occurred depend upon the category of fluids transfused or 
infused. The three categories are blood (e.g., whole blood, red blood 
cells); colloids (e.g., dextran, plasma, platelets, albumin, 
hetastarch); and crystalloids (e.g., saline, dextrose in water, 
Ringer's lactate). If the donor has received colloids in the 48 hours 
before death or specimen collection, and/or crystalloids in the one 
hour before death or specimen collection, then a comparison of the 
total volume of these fluids with the donor's plasma volume would be 
sufficient to determine if plasma dilution has occurred. However, when 
the fluids transfused are in the ``blood'' category (alone, or in 
combination with colloids and/or crystalloids), a comparison of the 
total volume of these fluids with the donor's blood volume should be 
performed, in addition to a comparison of the total volume of colloids 
and/or crystalloids with the donor's plasma volume.
    In the situation described in the comment, a comparison of the 
estimated volume of plasma contained in whole blood with the donor's 
plasma volume only (without a comparison of the volume of whole blood 
with the donor's blood volume) would underestimate the amount of plasma 
dilution. Thus, a donor might be inappropriately determined to be 
eligible even though plasma dilution sufficient to affect viral marker 
testing had occurred.
    The draft guidance that accompanies this final rule explains which 
calculations should be performed for each category of fluids transfused 
or infused.
    The proposed rule referred to ``reconstituted blood'' under the 
category of fluids called ``blood.'' We have removed the reference to 
``reconstituted blood,'' because we believe it is unnecessary and could 
lead to confusion in performing the necessary calculations (e.g., in 
which one of the three categories should reconstituted blood be 
included?). You should consider reconstituted blood to be whole blood 
for the purpose of Sec.  1271.80(d)(2), and you should include whole 
blood in the category of ``blood'' transfused in the 48 hours before 
death or specimen collection.
10. What Testing Is Required for Different Types of Cells and Tissues? 
(Sec.  1271.85)
    Proposed Sec.  1271.85(a) would require you to test donors of all 
types of cells and tissues for relevant communicable disease agents 
including, at a minimum, HIV, HBV, HCV, and Treponema pallidum. 
Proposed Sec.  1271.85(b) would apply to viable, leukocyte-rich cells 
and tissue and would require testing for relevant cell-associated 
communicable diseases including, at a minimum, HTLV and CMV. Proposed 
Sec.  1271.85(c) would apply to donors of reproductive cells and 
tissues and would require testing for relevant genitourinary disease 
agents, including, at a minimum, Chlamydia trachomatis and Neisseria 
gonorrhea. Proposed Sec.  1271.85(d) would require retesting for semen 
donors. Proposed Sec.  1271.85(e) would require an assessment to detect 
evidence of TSE for donors of dura mater.
    Under the proposed rule, cells or tissues could be subject to more 
than one testing requirement. For example, you would test a donor of 
leukocyte-rich reproductive tissue (e.g., semen) for the diseases 
listed in proposed Sec.  1271.85 (a), (b), and (c).
    The preamble to the proposed rule listed the tests that, according 
to our current thinking, are appropriate to use to test for the disease 
agents and diseases listed in Sec.  1271.85 (64 FR 52696 at 52705 and 
52706). Those testing recommendations are now contained in the donor-
eligibility draft guidance.
    We have deleted the phrase ``at a minimum'' from Sec.  1271.85(a), 
(b), and (c), because it might give the impression that testing is 
required only for those communicable diseases listed in Sec.  1271.85. 
Although at this time we only require testing for these diseases, in 
the future additional diseases may be identified as relevant. As 
discussed in comment 16 of this document, we will issue guidance that 
notifies you when we believe additional relevant communicable diseases 
meet the definition in Sec.  1271.3(r)(2).
    a. Viable and nonviable cells and tissue (Sec.  1271.85(a)). 
Proposed Sec.  1271.85(a) would require donors of all types of cells 
and tissues to be tested for HIV type 1, HIV type 2, HBV, HCV, and 
Treponema pallidum.
    (Comment 67) One comment noted that FDA did not require use of the 
HIV p24 antigen test for HIV screening. The comment described the test 
as easily accessible and inexpensive.
    (Response) We recommend the particular tests to assess HIV 
infection in the donor-eligibility draft guidance, and discuss the HIV 
p24 antigen test.
    (Comment 68) One comment discussed the use of core antibody and 
hepatitis B surface antibody tests to clarify donor HBV infectivity 
when the donor is HBsAg negative and core antibody positive. The 
comment asserted that if the IgM core antibody test is negative, and 
the surface antibody test is positive, this indicates that the donor 
had a past HBV infection that has resolved. The comment also asserted 
that the core antibody (IgG) is not a screening test for HBV 
infectivity, but is a historical test indicating previous infection 
with HBV.
    (Response) Although we agree that, in most cases, a negative IgM 
core antibody test with a reactive surface antibody test indicates a 
past infection, we disagree that this combination of results always 
indicates that the infection has resolved. Rather, this combination of 
results does not indicate whether the donor is infectious.
    In the donor-eligibility draft guidance that accompanies this final 
rule, we recommend that you use the total core antibody (IgG and IgM) 
test to test for HBV in addition to the HBsAg test.
    (Comment 69) One comment noted that the standard screening test for 
HCV in Europe is different from the test FDA listed in the preamble to 
the proposed rule.
    (Response) This comment referred to the use of NAT, which has not 
yet been licensed in this country for the purpose of screening 
cadaveric tissue donors. FDA encourages manufacturers of NAT kits 
licensed for blood donor screening to validate NAT for use with 
cadaveric blood specimens, and to submit the data to FDA to obtain a 
labeling change, to include this intended use. (Recommended tests are 
listed in the donor-eligibility draft guidance.)
    (Comment 70) We received several comments on the requirement for 
syphilis testing (Treponema pallidum). One comment requested that, if 
the agency eliminates syphilis testing for blood donors, it should 
consider eliminating the requirement for tissue donors. Several 
comments opposed requiring syphilis testing for cornea donors, 
asserting that transmission is unlikely or that there is no significant 
health risk to the corneal transplant recipient. One comment supported 
the requirement for cornea donors.
    (Response) We disagree that syphilis testing should not be required 
for cell and tissue donors, including cornea donors, and note that we 
have not eliminated syphilis testing of blood donors. In the final rule 
on testing of blood donors, we noted that comments

[[Page 29812]]

did not provide sufficient supporting data to justify eliminating the 
requirements to test blood and blood components with a serological test 
for syphilis. Moreover, preliminary results from ongoing studies 
indicate that the infectivity of seroreactive donors remains the 
subject of scientific debate. For this reason, we maintained the 
syphilis testing requirement for blood donors (Requirements for Testing 
Human Blood Donors for Evidence of Infection Due to Communicable 
Disease Agents, Final rule (66 FR 31146, June 11, 2001)).
    One comment cited a scientific paper, which we have reviewed 
(Macsai MS, Norris SJ, ``OptiSol Corneal Storage Medium and 
Transmission of Treponema pallidum,'' Cornea, vol. 14(6), pp. 595-600, 
November 1995). The paper reports the results of a rabbit study on the 
effects of storage media on the probability of syphilis transmission. 
Although the media prevented the transmission of syphilis by 
contaminated corneas, transmission occurred when the media was not 
used. This paper does not support the lack of syphilis transmissibility 
by corneas; indeed, it shows the opposite. For this reason, we do not 
believe this study provides sufficient evidence to support eliminating 
the proposed syphilis testing requirement. Moreover, we disagree with 
the comment's assertion that there is no significant health risk to the 
corneal transplant recipient. Although treatable, syphilis remains a 
serious disease.
    b. Leukocyte-rich cells and tissues (Sec.  1271.85(b)). Proposed 
Sec.  1271.85(b) would require testing for HTLV, type I; HTLV, type II; 
and Cytomegalovirus for donors of viable, leukocyte-rich cells and 
tissue.
    (Comment 71) We received several comments on our proposal to 
distinguish between leukocyte-rich cells and tissue and other cells and 
tissue, and on our preamble discussion of which cells and tissues we 
consider leukocyte-rich (64 FR 52696 at 52705). One comment noted that 
the differentiation was helpful. The comment suggested adding cultures 
of certain cell types, such as fibroblasts, to the list of materials 
that are not considered to be leukocyte-rich. Two comments asserted 
that oocytes and embryos are not leukocyte-rich. One comment noted that 
the term ``stem cells,'' listed in the preamble as an example of 
leukocyte-rich cells or tissue, is too broad, and would apply to 
corneal epithelial stem cells, which are not leukocyte-rich. Another 
comment agreed that semen can be characterized as leukocyte-rich tissue 
but asserted that treated or ``washed'' sperm do not pose the same 
disease risks.
    (Response) We agree with the comment requesting a more precise 
description of those stem cells that are rich in leukocytes, and we 
will refer to those cells as hematopoietic stem/progenitor cells. We 
also agree with the comments asserting that oocytes and embryos are not 
leukocyte-rich.
    However, we disagree that sperm that has been treated or washed 
should be treated differently, for the purposes of these testing 
requirements, from semen. The HCT[sol]P initially donated is semen, 
which is leukocyte-rich; thus, the donor must be tested for HTLV-I and 
-II and CMV. The donated semen poses risks; for example, it could 
transmit communicable disease to those handling it, or it could be 
released improperly before further processing. Later processing may 
decrease or remove the leukocytes from the donated semen, but would not 
affect the testing that must be performed on the donor at the time of 
donation. These testing requirements apply at the time of donation, 
regardless of how the HCT[sol]P might later be processed.
    For the same reason, we decline to state whether or not cultures of 
certain cell types, such as fibroblasts, are rich in leukocytes. As 
with semen, the HCT[sol]P initially donated is not the fibroblast, but 
some other tissue from which fibroblasts are isolated. Thus, the 
applicable testing requirements depend on whether or not the donated 
cells or tissue are leukocyte-rich.
    (Comment 72) One comment asserted that HTLV-I/II and CMV testing is 
not relevant to corneal transplants.
    (Response) We agree. As noted in the preamble to the proposed rule 
(64 FR 52696 at 52705), corneas are not rich in leukocytes, so Sec.  
1271.85(b) does not apply to them. The donor-eligibility draft guidance 
contains our current thinking about which cells and tissues are 
leukocyte-rich.
    (Comment 73) One comment asked how to counsel donors of 
reproductive tissue who test positive for HTLV. Another comment noted 
that diagnosis of some infections, such as HTLV, would lead to serious 
consequences for those individuals who test positive.
    (Response) We recognize that it may be difficult to counsel 
patients about the results of HTLV testing; however, the scope of this 
rule does not extend to issues of donor notification.
    (Comment 74) One comment asserted that, because leukocyte-rich, 
nonviable lymphocytes may transmit latent HTLV and CMV, they should be 
tested.
    (Response) We agree that these lymphocytes must be tested. However, 
we do not consider them to be nonviable. Although they do not 
proliferate, they are live cells, which means cells that have the 
ability to metabolize or divide, and thus ``are viable.''
    (Comment 75) One comment asserted that CMV testing is not necessary 
for oocyte donors because the virus does not appear to infect oocytes 
or surrounding cells.
    (Response) We agree that CMV testing is not necessary for oocyte 
donors. Oocytes and embryos are not considered leukocyte-rich.
    c. Reproductive cells and tissues (Sec.  1271.85(c)). Proposed 
Sec.  1271.85(c) would list relevant communicable disease agents and 
diseases of the genitourinary tract for which you would test a donor of 
reproductive cells or tissue. The proposal would exclude reproductive 
cells or tissues 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.
    (Comment 76) One comment asserted that most oocytes are retrieved 
through vaginal ultrasound techniques, so the exception to testing for 
chlamydia and gonorrhea would not apply in most cases.
    (Response) We agree with this comment that, in most instances, 
oocytes are removed transvaginally, and so the exception in Sec.  
1271.85(c) would not apply; thus, testing would be required. However, 
if you use vaginal ultrasound for visualization only, and retrieve the 
oocytes in a way that ensures freedom from contamination with 
infectious disease organisms (e.g., nonvaginal laparoscopy), then the 
exception would apply.
    d. Retesting (Sec.  1271.85(d)). Proposed Sec.  1271.85(d) would 
require retesting of donors of ``reproductive cells or tissue that can 
be reliably stored.''
    We have rewritten this provision to apply only to anonymous donors 
of semen. We discuss the reasons for this change elsewhere in this 
final rule in comment 35 of this document.
    (Comment 77) Several comments expressed concern that retesting 
would be required for all tissues that can be reliably stored, not 
simply reproductive cells and tissue.
    (Response) This was not our intention. As noted previously, Sec.  
1271.85(d) requires retesting only for semen from anonymous donors.
    (Comment 78) The preamble to the proposal recommended that, where 
appropriate and feasible, all living donors of banked tissue be 
retested 6 months after donation (64 FR 52696 at 52706). Several 
comments objected to

[[Page 29813]]

the recommendation and asserted that retesting donors of 
nonreproductive cells and tissue would be onerous, costly, and 
inefficient.
    (Response) At the time of initial testing, a donor may test 
negative but still be in the infectious window period. For this reason, 
retesting living donors of banked tissue 6 months after donation is an 
added safeguard for the prevention and spread of communicable diseases. 
However, in response to the comments, we are not adopting this 
requirement in this final rule.
    e. Dura mater (Sec.  1271.85(e)). Proposed Sec.  1271.85(e) would 
require, for donors of dura mater, an assessment designed to detect 
evidence of TSE. The preamble to the proposed rule described procedures 
for complying with the assessment requirement (see 64 FR 52696 at 
52706). These procedures included, after removal of the dura mater, a 
full brain autopsy of the donor, including gross and histological 
examination, performed by a qualified neuropathologist, to identify 
evidence of TSE changes. The preamble also noted that, although there 
is no FDA-approved or validated test for screening TSE in brain tissue, 
a negative test to detect protease-resistant prion protein (PrP-RES), 
either by immunohistochemistry or Western Blot, is considered 
significant in increasing the level of confidence that the brain and 
the dura mater are free of TSE.
    (Comment 79) Several comments supported the proposed requirement 
and the procedures set out in the preamble. One comment noted that the 
precautions of a full brain autopsy in addition to donor screening and 
medical history are a necessary step until there is an approved 
screening test. One comment asserted that a brain autopsy for dura 
donors is not feasible and recommended a brain biopsy instead. Two 
comments suggested that we change our recommendation that the autopsy 
be performed by a qualified neuropathologist to a qualified 
pathologist.
    (Response) We based the recommendations in the preamble to the 
proposed rule on conclusions reached by FDA's TSEAC at meetings held on 
October 6, 1997, and April 16, 1998. The committee reiterated these 
recommendations at a meeting on January 18, 2001. The committee 
recommended a full brain autopsy of the donor, including gross and 
histological examination, to identify evidence of TSE changes. We agree 
with comments that a brain autopsy is necessary in the absence of an 
appropriate test, and will consider changing the requirement in the 
future if a sufficiently sensitive test is approved. A brain biopsy, 
although less expensive and intrusive, may not provide adequate 
information on TSE changes, because these changes may occur focally in 
the brain. Moreover, it has not been validated as a predictor of TSE. 
For these reasons, we decline to change that aspect of our 
recommendation.
    However, we have reconsidered our proposal that the assessment be 
performed by a qualified neuropathologist. We recognize that many 
institutions do not have a neuropathologist on staff, and that many 
pathologists are qualified to do this assessment. For this reason, we 
now recommend that a qualified pathologist perform the assessment. To 
be qualified, the pathologist needs to have the appropriate training or 
experience to perform the appropriate neuropathologic examination.
    We have modified the regulation slightly to require that the 
assessment performed on donors of dura mater be ``adequate.'' The 
previous discussion provides our current understanding of what would 
constitute an adequate assessment.
    (Comment 80) The preamble to the proposed rule noted that the type 
of TSE testing required for donors of dura mater did not appear 
feasible for cornea donors, and we requested comments on this issue (64 
FR 52696 at 52706).
    Several comments agreed that TSE testing for corneal tissue donors 
is not a feasible option because of the time required for brain autopsy 
or biopsy. The comments also cited concerns about costs and a potential 
decrease in donation rates. One comment noted that the use of all 
available screening components, including the medical screening 
interview, would satisfactorily substitute for TSE testing.
    (Response) Under present conditions of storage in the United 
States, corneas must be transplanted within days of procurement to 
maintain their utility. For this reason, it is not feasible to test 
cornea donors for TSE using current methodologies, and we are not 
imposing a testing requirement at this time. However, under Sec.  
1271.75(a), screening for TSE is required for donors of all types of 
tissues.
    11. Are There Exceptions From the Requirement of Determining Donor 
Eligibility, and What Labeling Requirements Apply? (Sec.  1271.90)
    Proposed Sec.  1271.90 would recommend, but not require, screening 
and testing for banked cells and tissues for autologous use and 
reproductive cells or tissue donated by a sexually intimate partner of 
the recipient for reproductive use. Proposed Sec.  1271.90 would 
require special labeling for these HCT[sol]Ps. We have added 
appropriate warning label requirements to Sec.  1271.90.
    (Comment 81) Several comments supported our proposal to recommend 
that the requirements for infectious disease testing be applied to 
HCT[sol]Ps designated for autologous use. Two comments expressed 
concern that the recommendations in proposed Sec.  1271.90(a) 
pertaining to reproductive tissue would have the same effect as 
requirements.
    We recognize that a codified recommendation may carry more force 
than we intended. For this reason, although we recognize that many 
establishments will screen and test donors of autologous and 
reproductive HCT[sol]Ps that fall within the exceptions in Sec.  
1271.90, and we believe there are valid reasons for doing so, we have 
deleted the recommendation from the codified section.
    (Comment 82) One comment pointed out that the rules of safe 
laboratory operation dictate that laboratory personnel be informed of 
the risks in handling autologous donations. Another comment requested 
that we add to Sec.  1271.90(b) the requirement that these HCT[sol]Ps 
be handled as untested in accordance with Sec.  1271.60.
    Although we agree with the concerns expressed in the comments, we 
decline to amend Sec.  1271.90(b) as suggested by the comments. The 
labeling required in Sec.  1271.90(b) (e.g., ``NOT EVALUATED FOR 
INFECTIOUS SUBSTANCES'') should alert personnel to the risks of these 
HCT[sol]Ps.
    (Comment 83) One comment questioned whether proposed Sec.  
1271.90(a)(2) referred to semen, ova, and embryos.
    (Response) Semen, ova, and embryos are examples of reproductive 
cells and tissues included in Sec.  1271.90(a)(2).
    (Comment 84) Two comments questioned how Sec.  1271.90 would apply 
to individual semen donors who wish to cryopreserve their semen (e.g., 
cancer patients).
    (Response) If the semen donor intends that the cryopreserved sperm 
be used with a sexually intimate partner, then Sec.  1271.90 applies.
    After reviewing these comments, we also realized that cryopreserved 
reproductive cells or tissue for autologous use or for use by a 
sexually intimate partner, originally exempted from the donor screening 
and testing requirements, could be subsequently used for directed 
donation. Therefore, we have added an exception to the rule to 
accommodate individuals whose reproductive options have been restricted 
due to health or infertility.

[[Page 29814]]

 These individuals may not have undergone testing at the time of 
donation, because their intention at that time was autologous use or 
use in a sexually intimate partner. For various reasons, the donor(s) 
cannot make additional donations (e.g., the woman is post-menopausal or 
has her ovaries and uterus removed; the man has undergone chemotherapy, 
which renders him infertile.) To permit use of such cryopreserved cells 
or tissue for directed donation in situations where subsequent 
screening and testing is available, we have added Sec.  1271.90(a)(3).
    Section 1271.90(a)(3) states that cryopreserved cells or tissue for 
reproductive use, which were originally intended for autologous use, or 
use in a sexually intimate partner (and therefore the donor(s) were not 
tested at the time of donation) may subsequently be used for directed 
donation, provided that a donor cannot make additional donations of 
HCT[sol]Ps due to infertility, or health; and appropriate measures are 
taken to screen and test the donor(s) before transfer to the recipient. 
The agency intends to address, in guidance, the appropriate methods for 
screening and testing donors in such circumstances to determine whether 
the HCT[sol]Ps may carry communicable diseases.
    An example is the situation in which a sexually intimate couple 
create embryos, some of which are cryopreserved. The donors were not 
screened and tested at the time of the donation. The woman subsequently 
has her ovaries and uterus surgically removed, due to cancer. The donor 
couple wishes to make a directed donation of the cryopreserved embryos 
to a recipient who is known to one or both of the donors prior to the 
donation. Under Sec.  1271.90(a)(3), the embryos would be eligible for 
directed donation provided the couple can now be screened and tested.
    (Comment 85) One comment opposed the exception in proposed Sec.  
1271.90 for sexually intimate reproductive tissue donors. The comment 
asserted that all reproductive tissue donors should be screened, 
because sexually intimate partners may have escaped exposure to each 
other's bodily fluids.
    (Response) Although we agree that screening and testing may be 
appropriate for sexually intimate partners, and encourage 
establishments to perform screening and testing, we believe that this 
should be the responsibility of the attending physician, the donor, and 
the recipient.

E. Economic Impacts

    (Comment 86) Five comments suggested that we significantly 
underestimated the rule's economic impact and that significant changes 
in the SOPs of all eye banks would be required.
    (Response) We do not agree. Current industry standards meet or 
exceed most of the specifications of this final rule and industry 
consultants have indicated that compliance with these standards is 
nearly 100 percent. Based on this information, we do not believe that 
SOPs will need to be substantively changed as a result of this final 
rule. Furthermore, these comments did not provide any data that refute 
or would cause us to adjust our estimates of the economic impacts.
    (Comment 87) One comment suggested that cost increases are not 
easily absorbed by the not-for-profit eye banking community, and that a 
rule could negatively affect the availability of and/or access to 
services.
    (Response) We do not agree. Many similarities exist between the 
provisions of this final rule and current industry standards. 
Furthermore, our Analysis of Economic Impacts suggests only a minor 
compliance cost burden, which will not significantly affect the 
availability of and/or access to services.
    (Comment 88) One comment suggested that user fees could potentially 
add to the rule's economic impact.
    (Response) A user fee is not a component of this final rule.
    (Comment 89) Two comments stated that the rule will impose 
compliance costs of $10,000 to $20,000 per average tissue and eye bank, 
and that the effects of the regulation on hospitals may push this 
figure higher.
    We do not agree with these estimates of compliance costs. 
Furthermore, we are not able to address their validity as no 
information or data were provided to support them. We are also unable 
to address the rule's effects on hospitals as alluded to by the 
comments, because the comments did not provide any data that would 
allow us to evaluate the alleged effects.
    (Comment 90) One comment objected to our $1.23 million estimate of 
average annual eye bank establishment income and noted that ``* * * 
many U.S. eye banks operate within budgets that are <50% of that 
figure.''
    (Response) We realize that these figures may vary. Our average 
annual income estimate was intended to provide insight as to the 
financial burden of this rule for a representative establishment. Some 
establishments would be expected to have income greater than $1.23 
million and others less than $1.23 million. While we recognize that the 
financial impact of regulations on small business entities is an 
important consideration under The Regulatory Flexibility Act, our 
analysis suggests this final rule will not have a significant economic 
impact.
    (Comment 91) One comment objected to our estimate of the cost of 
testing tissue donors for syphilis, suggesting that such testing will 
cost $15 per donor and that testing 650 donors will increase costs by 
approximately $10,000.
    (Response) We do not dispute these figures. However, there is no 
indication given in the comment as to whether this is a significant 
cost impact, and/or for which types of establishments (i.e., small 
versus large). These figures are accurate, but would be of greater 
value if presented in context, e.g., as a percentage of establishment 
revenues.
    (Comment 92) One comment noted that there was no discussion of the 
costs of the forthcoming ``good manufacturing practices'' rule.
    (Response) We believe the comment is referring to the compliance 
costs associated with the forthcoming CGTP rules, which are not a part 
of this final rule. We will include a full economic analysis of the 
forthcoming CGTPs when that final rule is published.
    (Comment 93) Four comments objected to a quarantine requirement for 
donated oocytes and embryos. These comments suggested that this 
requirement is unnecessary and unacceptable due to the excessive burden 
placed on reproductive clinics, physicians, and patients.
    (Response) The 6-month quarantine requirement for reproductive 
tissues now applies only to semen from anonymous donors, and not to 
oocytes or embryos.
    (Comment 94) One comment suggested that testing and screening of 
oocyte and embryo donors would need to be repeated after a 6-month 
quarantine, resulting in additional costs.
    (Response) This final rule does not require retesting of oocyte and 
embryo donors. Therefore, there is no need to include these costs in 
the economic analysis.
    (Comment 95) One comment suggested that the private sector would 
have to spend more than $100 million per year to comply with this final 
rule, requiring a cost-benefit analysis.
    (Response) We do not agree. Based on our analysis, the costs of 
complying with this final rule are far less than $100 million per year, 
and therefore a cost-benefit analysis is not required. Furthermore, no 
data were provided in the comment to support its estimate of compliance 
costs.
    (Comment 96) Three comments objected to our estimate of the cost of

[[Page 29815]]

screening and testing oocyte donors and suggested that the actual cost 
is much higher.
    (Response) We agree that this cost may be higher, and have revised 
our Analysis of Economic Impacts to reflect the most recent cost data 
available.
    (Comment 97) One comment suggested that our estimate of the cost of 
a donor oocyte cycle is too low.
    (Response) We realize that these figures may vary. However, 
comments from another ART facility indicate that our cost estimate for 
a donor oocyte cycle (originally obtained from a study published in the 
journal Fertility and Sterility) is reasonable (Ref. 26).
    (Comment 98) One comment suggested that our estimate of the average 
revenue of ART centers was too high.
    (Response) We do not agree. The comment assumes the cost of an IVF 
cycle is $10,000, whereas we assume the average cost of an ART cycle is 
$11,868, a more general and somewhat larger number. Furthermore, the 
comment presents a net average revenue estimate for ART facilities, 
after subtracting drug costs and oocyte retrieval fees. In the proposed 
rule, we present a gross average revenue estimate. It is therefore 
unclear that these estimates of average revenue can be meaningfully 
compared.

IV. Analysis of Economic Impacts

    FDA has examined the impacts of this final rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and 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 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 
Regulatory Flexibility Act requires agencies to analyze whether a rule 
may have a significant economic impact on a substantial number of small 
entities and, if it does, to analyze regulatory options that would 
minimize the impact.
    The agency believes that this final rule is consistent with the 
regulatory philosophy and principles identified in Executive Order 
12866. The Office of Management and Budget (OMB) has determined that 
this 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 facilities would not be 
significantly affected by this final rule because they are already 
performing the infectious disease screening and testing and 
recordkeeping that is being required. However, FDA does not have 
sufficient data to fully characterize the size distribution and other 
relevant features of small entities, particularly those involved with 
reproductive HCT[sol]Ps, and the impact on these entities is uncertain. 
The following analysis, along with this preamble, represents FDA's 
Final Regulatory Flexibility Analysis.
    Based on the following economic analysis, FDA estimates that the 
total one-time costs to comply with this final rule will be between 
$0.4 and $2.1 million, and the annual or recurring costs will be 
between $1.8 and $3.5 million. These figures imply a total annualized 
cost estimate of between $1.9 and $3.8 million. The average annualized 
cost per affected entity, expressed as a percentage of average annual 
revenue, ranges from 0.003 to 0.35 percent. FDA has provided ranges of 
cost estimates to account for uncertainty with respect to both the 
number of entities affected, and the degree to which affected entities 
are already performing the activities required by this final rule.

A. Objectives and Basis of the Proposed Action

    FDA is publishing this final rule as the next step in establishing 
regulations for the rapidly evolving HCT[sol]P industry. This final 
rule is needed to prevent unwitting use of contaminated tissues with 
the potential for transmitting infectious diseases, including HIV and 
hepatitis.
    While acting to increase the safety of the nation's supply of 
HCT[sol]Ps, FDA is implementing regulations in a way that will avoid 
unnecessary requirements. To minimize burdens while maintaining safety, 
the agency has designed the screening and testing provisions to vary 
with the specific type and use of each HCT[sol]P. This regulatory 
action is focused on the prevention of disease transmission through 
implantation, transplantation, infusion, or transfer of any HCT[sol]P. 
For example, FDA will now require cell and tissue donors to be tested 
for syphilis and screened for TSE. Donors of viable, leukocyte-rich 
cells or tissue will 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 requiring that certain donors of 
reproductive cells and tissue be screened and tested for sexually 
transmitted diseases. FDA is also amending the existing CGMP 
regulations for drugs and QS regulations for medical devices to clarify 
the scope of the screening and testing requirements in part 1271, 
subpart C.
    FDA's objectives and authority for issuing this final rule are 
described in detail in section II of this document. 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 for drugs (21 
U.S.C. 351(a)(2)(B)). FDA has reviewed related Federal rules and has 
not identified any rules that duplicate, overlap, or conflict with this 
final rule.
    This final rule provides oversight for the full spectrum of 
HCT[sol]Ps that are now marketed and may be marketed in the future. 
This action will improve protection of the public health and increase 
public confidence in new technologies, while imposing a minimal 
regulatory burden. An important benefit of this final rule is that it 
will establish a consistent standard of safety for marginal firms not 
currently following voluntary industry standards and guidelines and 
help to ensure equivalent protection from transmissible diseases for 
all recipients of therapy involving HCT[sol]Ps, regardless of the 
health condition for which they are being treated. This final rule will 
help minimize the risk to all HCT[sol]P recipients of exposure to 
several life-threatening, in some cases incurable, diseases, including 
HIV, HBV, HCV, CJD, HTLV, CMV, and others. These risks will be 
minimized through validated screening procedures, lab tests, 
recordkeeping and adequate product labeling to avoid unwitting use of 
unsafe HCT[sol]Ps.

[[Page 29816]]

B. The Type and Number of Entities Affected

    This final rule requires manufacturers of HCT[sol]Ps to screen and 
test the donors of cells and tissue used in those products. The rule 
requires that donors be screened and tested for risk factors for, and 
clinical evidence of, a relevant communicable disease agents and 
diseases. This final rule applies to a range of activities conducted at 
facilities such as conventional tissue banks, eye banks, semen banks, 
infertility treatment centers, and facilities processing hematopoietic 
stem/progenitor cells.
    Information obtained under the registration final rule forms the 
basis for FDA's estimates of the number of affected eye banks and 
conventional tissue banks. The agency has not yet received all 
registration and listing information from reproductive tissue and 
hematopoietic stem/progenitor cells establishments, because 
registration and listing requirements for such establishments and 
products have not yet gone into effect. The agency's estimates of the 
number of affected eye banks, hematopoietic stem/progenitor cell 
facilities, semen banks and ART facilities rely heavily on information 
obtained from various professional organizations associated with the 
HCT[sol]P industry. Where good statistical data are not available, 
FDA's estimates have incorporated the quantitative judgments of 
individual experts identified through contacts with HCT[sol]P industry 
professional associations.
    As presented in table 1 of this document, FDA has a record of 134 
registered facilities listing eye tissue including 96 eye banks, 93 of 
which are currently accredited by EBAA. FDA also has a record of 166 
registered tissue banks involved in the manufacture of other 
conventional HCT[sol]Ps, e.g., pericardium, dura mater, heart valves, 
skin and bone allografts, fascia, tendons and ligaments (hereafter 
referred to as ``conventional tissue banks''). The American Association 
of Tissue Banks (AATB) lists approximately 75 accredited tissue banks 
and projects an additional 40 to 60 members not accredited.
    Facilities that produce hematopoietic stem/progenitor cell products 
from peripheral blood or umbilical cord blood will also be affected by 
this final rule. FDA finds that available data with which to estimate 
the number of peripheral blood stem/progenitor cell (PBSC) facilities 
and evaluate current practices are quite limited, and the actual number 
of PBSC facilities may range from 200 to 400. As of April 2002, CBER 
has a record of 178 voluntarily registered facilities listing ``stem 
cell'' as a type of product or establishment. The National Marrow Donor 
Program (NMDP), which includes establishments that recover PBSCs, lists 
approximately 92 donor centers and 113 collection centers. 
Approximately 150 facilities involved with PBSC production are 
currently accredited by AABB and an estimated 107 are accredited by the 
Foundation FACT. Industry sources estimate that approximately 80 of 
these facilities have or are seeking dual AABB/FACT accreditation, 
suggesting an unduplicated count of approximately 200 PBSC facilities 
assumed to be accredited by the AABB and/or FACT. However, the number 
and donor screening and testing practices of nonaccredited facilities 
are unknown. The International Bone Marrow Transplant Registry/
Autologous Blood and Marrow Transplant Registry (IBMTR/ABMTR) estimates 
that the total number of blood or bone marrow facilities may be as high 
as 400 (e.g., 200 more than the number estimated to be accredited by 
AABB and/or FACT), but the number of IBMTR/ABMTR-estimated facilities 
that actually process peripheral blood (as opposed to bone marrow) is 
uncertain. For the purposes of this analysis, FDA has assumed that 400 
peripheral blood stem/progenitor cell facilities will be affected by 
this final rule.
    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 umbilical cord blood banks 
currently operating in the United States. These facilities may also 
seek accreditation through AABB or FACT. Based on this information, the 
agency estimates that a total of 425 establishments involved in 
manufacturing hematopoetic stem/progenitor cells would be affected by 
this rule.
    In addition, 67 establishments produce licensed biological products 
or approved medical devices that are currently required to register 
under parts 207 and 807 (21 CFR parts 207 and 807) but would also be 
subject to the provisions of this final rule.
    Finally, this final rule also applies to facilities involved with 
reproductive tissue, primarily semen banks and ART facilities that 
collect and process donor semen or donor oocytes. The American Society 
of Reproductive Medicine (ASRM) has a membership of approximately 400 
fertility centers, 370 of which have provided reports to the 1999 
Society for Assisted Reproductive Technology (SART) registry. The ASRM 
also has a 1996 list of approximately 110 semen 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 (TDI), ASRM does not exercise oversight or provide 
accreditation of facilities that collect donor reproductive tissue or 
use these tissue products in infertility treatment.

C. Nature of the Impact

    This final rule includes requirements for donor screening, donor 
testing, recordkeeping, and quarantine of cells and tissue. Donor 
screening will 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 anonymous semen donors, a complete donor-eligibility 
determination procedure will be required at least once every 6 months. 
This final rule requires 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 eligible 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.
    This final rule also requires recordkeeping for donor-eligibility 
determinations. Manufacturers must ship HCT[sol]Ps accompanied by 
documentation of donor eligibility status, including a summary of 
records that includes the results of the required testing and the name 
and address of the establishment that made the eligibility 
determination. This final rule also requires that HCT[sol]Ps be 
quarantined until a donor-eligibility determination is made, and that 
products be clearly labeled as under quarantine during that period. 
Manufacturers are responsible for the appropriate labeling and 
documentation of HCT[sol]Ps from a donor who is found to be ineligible.
    The economic impact of these requirements is expected to be minor 
because the leading industry associations have already established 
standards for screening, testing and recordkeeping that, in most cases, 
meet or exceed the criteria specified in this final rule, and because 
existing FDA regulations already apply to certain HCT[sol]Ps intended 
for transplantation (see part 1270). Table 1 of this

[[Page 29817]]

document lists the types of HCT[sol]Ps that will be affected by this 
final rule and the associated establishments that manufacture these 
products. Table 1 also provides estimates of the number of 
establishments affected by this final rule and the estimated percentage 
of establishments believed to be following current industry standards 
for donor screening and testing. The lists of specific donor screening 
and testing requirements proposed by FDA can be compared with those 
currently required by the industry associations.

   Table 1.--Type and Number of Establishments Affected and Percentage
   Already in Compliance With Industry Standards for Donor Eligibility
                          Screening and Testing
------------------------------------------------------------------------
                               FDA Regulatory Requirements    Estimated
                  Type of         Compared to Industry       Percent of
                  Entities              Standards            Entities in
Type of Human  Affected (and ------------------------------  Compliance
    Tissue       Estimated                                      With
               Total Number)       FDA          Industry      Industry
                                               Standards      Standards
------------------------------------------------------------------------
NonreproductiveTissue
------------------------------------------------------------------------
Eye tissue     134 FDA        21 CFR part    EBAA (s1       100%
                registered     1270 and       through
                eye tissue     (s1,s2,s3)\1   s3)\1\ and
                facilities,    \ and (t1,     (t1 through
                including 93   t2, t3,        t3)\2\
                EBAA           t5)\2\
                accredited
                eye banks
                (134 total)
------------------------------------------------------------------------
Pericardium,   166 FDA        21 CFR part    AATB (s1       100%
 dura-mater,    registered     1270 and (s1   through
 heart          tissue         through        s3)\1\ and
 valves, skin   banks,         s3)\1\ and     (t1 through
 allograft,     including 75   (t1, t2, t3,   t5)\2\
 bone           AATB           t5)\2\
 allograft,     accredited
 other viable   tissue banks
                (166 total)
------------------------------------------------------------------------
Stem           178 FDA        (s1 through    AABB/FACT (s1  100%
 progenitor     registered     s3)\1\ and     through
 cells;         facilities,    (t1 through    s3)\1\ and
 peripheral     92 NMDP        t6)\2\         (t1 through
 blood          donor                         t6)\2\
                centers, and
                113 NMDP
                collection
                centers (400
                total)
------------------------------------------------------------------------
Stem           Cord blood     (s1 through    AABB/FACT (s1  100%
 progenitor     banks (25      s3)\1\ and     through
 cells;         total)         (t1 through    s3)\1\ and
 umbilical                     t6)\2\         (t1 through
 cord blood                                   t6)\2\
------------------------------------------------------------------------
Licensed       67 FDA         Currently      .............  100%
 biological     registered     regulated                     compliance
 products and   establishmen   under                         with 21 CFR
 approved       ts (67         sections 351                  parts 207
 medical        total)         and 361 of                    and 807
 devices                       the PHS Act,
                               21 CFR parts
                               207 and 807
------------------------------------------------------------------------
Total          792            .............  .............  ............
                Facilities
------------------------------------------------------------------------
ReproductiveTissue
------------------------------------------------------------------------
Donor          370 ART        (s1 through    ASRM/CAP       Unknown
 oocytes,       facilities     s3)\1\ and     (s1)\1\ and
 embryos        and            (t1, t2, t3,   (t1,t2,t3,t5
                associate      t5)\2\         )\2\
                labsin the
                1999 SART
                report (400
                total)
------------------------------------------------------------------------
Donor semen    4 Semen banks  (s1 through    AATB (s1       Unknown
                in 1996 AATB   s3)\1\ and     through
                survey (110    (t1 through    s3)\1\ and
                total)         t8)\2\         (t1 through
                                              t8)\2\ and
                                              ASRM (s1)\1\
                                              and (t1, t2,
                                              t3, t5, t7,
                                              t8)\2\
------------------------------------------------------------------------
Total          510            .............  .............  ............
                Facilities
------------------------------------------------------------------------
\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-I, 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 HCT[sol]Ps. 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 semen bank adherence to 
AATB standards or ASRM guidelines. A small percentage of semen banks 
are members of the AATB and are known to follow that organization's 
requirements for screening and testing, but little is known about the 
standards used at other facilities.
    In addition to the required donor screening and testing, this final 
rule will require facility staff time to align current quarantine, 
labeling, and recordkeeping systems with the new requirements. 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 this final rule.

[[Page 29818]]



  Table 2.--Correspondence of FDA Requirements to Current Industry Standards for Specimen Quarantine, Labeling,
                                              and Record Retention
----------------------------------------------------------------------------------------------------------------
      FDA               AATB                EBAA                AABB                FACT               ASRM
----------------------------------------------------------------------------------------------------------------
Quarantine              X1                  X1                  X1                  X1           X1
----------------------------------------------------------------------------------------------------------------
Labeling                X1                  X1                  X1                  X1           X1
----------------------------------------------------------------------------------------------------------------
Record                  X1                  X1                  X1                  X1           Recommended;
 Retention                                                                                        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 cost 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 
believed to be already in compliance with FDA's new donor screening and 
testing requirements, as a result of following their own industry 
association standards and current FDA regulations. Therefore, 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 under the new standards and to make modifications 
where needed in current facility SOPs related to these activities. Such 
changes are expected to be minor for most nonreproductive tissue 
establishments.
    In the proposed rule, FDA estimated that it would take 
approximately 8 to 40 hours to compare the new regulations against a 
facility's current SOPs and make any necessary modifications. Since we 
received no comments from affected entities, we have retained this 
assumption. This process will 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 (Ref. 23), this 
standards reconciliation effort will result in a one-time cost per 
facility ranging from $320 to $1,600. Applying this range of cost per 
facility to the approximately 792 nonreproductive tissue facilities 
yields an impact that ranges from $253,440 (= $320 x 792) to $1,267,200 
(= $1,600 x 792).
2. Impact on Reproductive Tissue Establishments
    a. Impact of donor screening and testing. As indicated in table 1 
of this document, the number of reproductive tissue facilities 
currently following industry standards is unknown. Thus, FDA cannot 
develop a precise estimate of regulatory costs. To generate an upper 
bound cost estimate, however, FDA assumed that 100 percent of 
facilities involved with oocyte donation and 80 percent of semen banks 
would need to perform additional screening and testing. Although semen 
banks not currently following voluntary industry standards constitute a 
majority of the firms in that industry, they are primarily small 
operations that are estimated to serve only 5 percent of all semen 
donors.
    i. Oocyte donor screening and testing. The estimated impact of this 
final rule on establishments involved in oocyte donation is based on 
1999 data reported by SART, an organization of assisted reproductive 
technology providers affiliated with ASRM. In 1999, donor oocytes were 
used in approximately 10.4 percent of the 86,822 ART cycles reported, 
or 9,066 cycles (Ref. 4). FDA believes that all infertility treatment 
centers already conduct medical exams and history taking and perform 
some laboratory testing before oocyte retrieval for any potential 
donor. Compliance with this final rule, however, may entail further 
blood testing and adding some additional screening questions to the 
interview.
    The cost of additional blood work (including HIV 2, HTLV I and II, 
and CMV IgG and IgM) is estimated at approximately $238.40 per donor 
(Ref. 22). 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 that the estimated cost of a full health history interview is 
$75 ($37 = $75/2) (Ref. 6). Thus, the additional cost per oocyte 
donation is estimated at $275.40 ($238.40 + $37). Based on a reported 
(average) cost estimate of $13,500 (Ref. 22) per donor oocyte cycle, 
this translates into a 2.04 percent increase ($275.40/$13,500) in the 
average cost of therapy per cycle.
    The cost of screening and testing oocyte donors will depend on the 
number of donor cycles attributable to each screened donor. If each 
donor contributes oocytes 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. 7), the number of 
donors to be tested would be 9,118 (9,066/(1-0.0057)). If each donor 
contributes oocytes for two donor cycles, the number of donors to be 
screened would be 4,559. These alternative assumptions imply a total 
cost to U.S. facilities involved in oocyte donation of from $1,255,549 
to $2,511,097 per year, as shown in table 3 of this document.

  Table 3.--Alternative Oocyte Donation Scenarios and Associated Donor
                       Screening and Testing Costs
------------------------------------------------------------------------
  Screening and Testing    2 ART Cycles per Donor  1 ART Cycle per Donor
      Cost per Donor           = 4,559 Donors          = 9,118 Donors
------------------------------------------------------------------------
$275.40                    $1.26 million\1\        $2.5 million\2\
------------------------------------------------------------------------
\1\ $275.40 x 4,559 = $1,255,549
\2\ $275.40 x 9,118 = $2,511,097

    FDA believes that much of the additional screening and testing 
identified in table 3 of this document is already being performed by 
ART clinics. Therefore, these estimates should be viewed as maximum 
expected cost burdens. Furthermore, certain methods of donor oocyte 
recovery, e.g., laparoscopy, are not directly connected with the 
transmission of sexually transmitted and genitourinary diseases and, 
therefore, testing for Neisseria gonorrhea and Chlamydia trachomatis 
would not be required under this final rule. Use of such methods would 
be

[[Page 29819]]

expected to lower the estimated testing costs by approximately $40 per 
oocyte donor.
    ii. Semen donor screening and testing. The agency has conducted an 
extensive search for current information on the extent of infectious 
disease screening for semen donors, but has found little information 
available. The Congressional Office of Technology Assessment (OTA) 
conducted a survey of establishments involved in semen 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 recent available data 
includes a list of approximately 110 commercial semen banks developed 
by ASRM in 1996, and a 1996 registration survey of the AATB that 
includes data for 4 semen banks. Some semen 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 semen 
banks currently perform HIV screening and testing, as reported by OTA 
in 1987, and that a smaller percentage of facilities additionally 
follow all AATB screening and testing standards.
    Based on conversations with semen banking industry experts, FDA 
estimates that the 20 largest semen banks account for approximately 95 
percent of the commercial production of donor semen, and are following 
AATB standards for donor screening and testing. The agency analysis 
therefore assumes that the 20 largest facilities will experience 
minimal impact, while the remaining 90 facilities, which account for 
approximately 5 percent of total industry production, will be more 
significantly affected. These very small semen banks are described by 
an industry expert as typically functioning within a physician office 
practice (e.g., that of an obstetrician or gynecologist). The semen 
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 
requirements for semen banking facilities is based on the number of 
semen donors who would require screening and testing, and their 
respective unit costs. Due to the lack of data on the actual number of 
semen donors, the agency estimated the number based on projected TDI 
demand. The level of TDI demand has likely decreased over time, with 
advances in treatment for male factor infertility. For example, the 
development of intracytoplasmic sperm injection (ICSI) used in 
conjunction with in vitro fertilization (IVF) has enabled some couples 
to forego TDI in favor of ICSI using the male partner's sperm (Ref. 8). 
In 1985, an estimated 70,000 women per year received TDI (Ref. 9), 
compared to an estimated 171,000 women who reported ever receiving 
artificial insemination with donor semen 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.
    The clinical literature indicates that most semen donor attrition 
occurs before the blood testing stage of the donor-eligibility 
determination. 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. 10). For the purposes of this 
analysis, 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. 
11), 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. 12). 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, or 128 donors 
per year (128 = 0.05 x 2,565), may need to be newly screened and tested 
to meet the requirements of this final rule.
    The screening cost per semen 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. 6), the agency estimates that a full 
medical exam costs $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 semen donors include those listed in 
table 1 of this document, with 6-month followup blood tests. The cost 
of additional testing, based on screening test fees published on the 
Internet (Ref. 5), 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. Thus, 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 requirements for reproductive 
tissue establishments will reflect the staff time required for the 
following: (1) A one-time review and modification of current SOPs to 
bring them into alignment with the new standards, and (2) ongoing, 
expanded practices for each donor who undergoes screening and testing 
to meet the requirements of this final rule.
    In the proposed rule, FDA estimated that the one-time review and 
alignment of current facility SOPs will require approximately 8 to 40 
hours at each facility. Since we received no comments from affected 
entities, we have retained this assumption. 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 (Ref. 23), 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 400 ART clinics and 110 semen banks yields a potential one-time 
cost for all reproductive tissue facilities that ranges from $163,200 
($320 x (400 + 110)) to $816,000 ($1,600 x (400 + 110)).
    The estimated cost of the recurring requirements for tissue 
quarantine,

[[Page 29820]]

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 prospective donor from whom specimens are collected. 
These records must comply with the requirements of this final rule and 
are estimated to require approximately 4 hours per donor per year of 
clerical staff time. Assuming a labor cost of $24 per hour (Ref. 24) 
for clerical staff time implies a cost of $96 per donor per year. Table 
4 of this document summarizes the potential range of recurring costs 
for all reproductive tissue facilities. As shown in table 4 of this 
document, the estimated costs range from approximately $450,000 to 
$888,000, depending on the assumed number of oocyte donors.

       Table 4.--Range of Recurring Costs for Reproductive Tissue
 
128 semen donors and 4,559 oocyte-----$449,952\1\-----------------------
 donors (2 ART cycles per donor)
------------------------------------------------------------------------
128 semen donors and 9,118 oocyte     $887,616\2\
 donors (1 ART cycle per donor)
------------------------------------------------------------------------
 
\1\ $449,952 = (128 + 4,559) x $96
\2\ $887,616 = (128 + 9,118) x $96

    The range of these estimates reflects the agency's current lack of 
information about typical donor practices for ART facilities. If a 
higher rate of donation per donor is typically achieved by facilities 
compared to that assumed in this analysis, the cost burden may be much 
lower than these estimates would indicate. More generally, if the 
current level of facility donor screening, testing and recordkeeping is 
more stringent among reproductive tissue facilities than assumed in 
this analysis, the overall cost of compliance with this final rule will 
also be lower than these estimates suggest.
    Uncertainty about current practices results in range estimates of 
the cost impact of this final rule. However, because facilities in most 
HCT[sol]P industry sectors already follow voluntary industry standards 
requiring donor screening and testing, the overall impact is expected 
to be minor. Tables 5 and 6 of this document provide a summary of the 
expected cost impacts across the different industry sectors included in 
the analysis. Table 5 of this document presents costs annualized at 7 
percent interest over 10 years, whereas table 6 of this document 
presents annualized costs for the same time period using a 3 percent 
interest rate. The total annualized cost for the 792 nonreproductive 
tissue facilities is estimated to range from $30,000 to $180,000, 
reflecting agency uncertainty about the extent of effort necessary for 
a one-time review and alignment of existing SOPs with the donor 
screening and testing provisions of this final rule. This translates 
into an average annualized cost of $38 ($30,000/792) to $228 (180,000/
792) per facility.
    The total annualized cost of compliance for the ART industry ranges 
from approximately $1.71 to $3.5 million, reflecting uncertainty about 
the number of oocyte donors, the number of ART cycles per donor per 
year and current screening, testing and recordkeeping practices. These 
costs translate into an average annualized cost of approximately $4,270 
($1.708 million/400) to $8,693 ($3.5 million/400) per facility. In 
general, assumed higher rates of donation per donor, or a lower number 
of total donor cycles per year, will result in lower industry costs. 
Similarly, lower rates of donation per donor, or a greater number of 
total donor cycles per year, will result in higher industry compliance 
costs.
    The total annualized cost impact on the semen banking industry is 
based on an estimated TDI demand of approximately 103 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 $110,000 to $131,000. 
These industry totals yield an average annualized cost range of $1,222 
($110,000/(110-20)) to $1,456 ($131,000/(110-20)) per facility 
currently noncompliant with this final rule.

 Table 5.--Summary Table of Donor Eligibility Cost Analysis at 7 Percent
                        Interest Over 10 Years\1\
------------------------------------------------------------------------
                   Total One-time   Total Recurring    Total Annualized
Type of Facility        Cost              Cost               Cost
------------------------------------------------------------------------
NonreproductiveTissue
------------------------------------------------------------------------
(a) Donor         Minimal           Minimal          Minimal
 screening and
 testing
(b)               $253 to $1,267    Minimal          $36 to $180
 Recordkeeping
 and quarantine
------------------------------------------------------------------------
Reproductive Tissue, ART Facilities
------------------------------------------------------------------------
(a) Donor         Minimal           $1,255 to        $1,255 to $2,511
 screening and                       $2,511
 testing
(b)               $128 to $640      $438 to $875     $456 to $966
 Recordkeeping
 and quarantine
------------------------------------------------------------------------
ART subtotal      $128 to $640      $1,693 to        $1,711 to $3,477
                                     $3,386
------------------------------------------------------------------------
Reproductive Tissue, Semen banks
------------------------------------------------------------------------
(a) Donor         Minimal           $94              $94
 screening and
 testing
(b)               $35 to $176       $12              $17 to $37
 Recordkeeping
 and quarantine
------------------------------------------------------------------------
Semen subtotal    $35 to $176       $106             $111 to $131
------------------------------------------------------------------------
Total Tissue      $416 to $2,083    $1,799 to        $1,858 to $3,788
 Industry                            $3,492
------------------------------------------------------------------------
\1\ All figures in thousands of dollars.


[[Page 29821]]


 Table 6.--Summary Table of Donor Eligibility Cost Analysis at 3 Percent
                        Interest Over 10 Years\1\
------------------------------------------------------------------------
                   Total One-Time   Total Recurring    Total Annualized
Type of Facility        Cost              Cost               Cost
------------------------------------------------------------------------
Nonreproductive Tissue
------------------------------------------------------------------------
(a) Donor         Minimal           Minimal          Minimal
 screening and
 testing
(b)               $253 to $1,267    Minimal          $30 to $149
 Recordkeeping
 and quarantine
------------------------------------------------------------------------
Reproductive Tissue, ART Facilities
------------------------------------------------------------------------
(a) Donor         Minimal           $1,255 to        $1,255 to $2,511
 screening and                       $2,511
 testing
(b)               $128 to $640      $438 to $875     $453 to $950
 Recordkeeping
 and quarantine
------------------------------------------------------------------------
ART subtotal      $128 to $640      $1,693 to        $1,708 to $3,461
                                     $3,386
------------------------------------------------------------------------
Reproductive Tissue, Semen banks
------------------------------------------------------------------------
(a) Donor         Minimal           $94              $94
 screening and
 testing
(b)               $35 to $176       $12              $16 to $33
 Recordkeeping
 and quarantine
------------------------------------------------------------------------
Semen subtotal    $35 to $176       $106             $110 to $127
------------------------------------------------------------------------
Total Tissue      $416 to $2,083    $1,799 to        $1,848 to $3,737
 Industry                            $3,492
------------------------------------------------------------------------
\1\ All figures in thousands of dollars.

D. Benefits of the Final Rule

    The risks of disease transmission vary by type of HCT[sol]P. Thus 
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 testing has 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 1,930,000 units. The risk of transmission 
of HBV has been reduced from 1 in 2,100 to 1 in 137,000 units, and the 
transmission risk for HCV has been lowered from 1 in 200 units in the 
early 1980s to the current level of 1 in 1,000,000 units (Ref. 25). The 
levels of risk reduction associated with blood donation offer an 
illustration of the kind of improvements in safety that might be 
achieved through improved and expanded screening and testing of 
HCT[sol]P donors.
    As described earlier in this document, most nonreproductive tissue 
establishments are assumed to be already compliant with this final rule 
and, therefore, have already achieved much of the potential risk 
reduction. However, some reduction in communicable disease transmission 
risk may still be realized under this final rule for firms that are not 
currently in compliance with the voluntary standards established by 
their respective professional associations. The discussion of benefits 
resulting from this final rule will focus on some key areas of risk and 
the potential benefit of the new requirements for reproductive tissue 
recipients. The discussion that follows will consider the risks of 
transmission of disease that will be reduced through expanded screening 
and testing among reproductive tissue donors, focusing on 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 the risk of disease 
transmission, 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 very low since screening for HIV 
was recommended by CDC in 1985. A total of six documented and two 
possible cases have been reported to the CDC as of December 1996 (Ref. 
9).
    The risks of transmitting HBV and HCV through reproductive tissue 
might also 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 (Refs. 13 and 14). 
Compared to HCV, HBV presents a greater risk of sexual transmission. In 
1991, heterosexual activity was reported to account for 41 percent of 
all cases of HBV (Ref. 15). HBV transmission has also been reported by 
way of TDI. In 1982, a physician used semen from an unscreened donor 
(later found to be carrying HBsAg) to inseminate several women, one of 
whom later developed HBV (Ref. 16).
    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 and 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. 17). 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. 18). This rate of effectiveness may provide an indication 
of the potential benefit of HBV screening required by this final rule.
    The risk of transmission is estimated to be lower for HCV, compared 
to HBV. The CDC estimates the rate of sexual transmission between 
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.,

[[Page 29822]]

Interferon and Ribavirin) have been found to 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. 17). 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 
(QALYs) (Ref. 18).
    Screening reproductive tissue donors is expected to significantly 
reduce the excess morbidity and mortality associated with HBV and HCV. 
As noted previously in this document, there are an estimated 4,559 to 
9,118 oocyte donors and 2,565 semen donors per year. If these 
populations experience recently reported prevalence rates for HCV (1.8 
percent) and HBV (4.9 percent) (Refs. 13 and 14), 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 3,022 to 9,066 women undergoing 
IVF with donor eggs, and 2,285 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 3,022 to 9,066 patients is based on a reported 
9,066 ART cycles using donor oocytes reported for 1999, varying the 
assumed number of cycles per patient. The number of newborns is 
based on an average success rate of 25.2 percent (live births per 
ART cycle).
---------------------------------------------------------------------------

E. Small Entity Impacts and Analysis of Alternatives

    Based on its analysis, FDA found that a substantial number of the 
establishments required to comply with this final rule may be small 
business entities. The Small Business Administration defines a small 
business in this industry sector (NAICS code 621991, Blood and Organ 
Banks) to be an establishment with $8.5 million or less in annual 
receipts (Ref. 19). The economic impact analysis presented in section 
IV.C of this document includes estimates of the number of entities to 
which this final rule will apply. Each sector of the tissue banking 
industry includes some facilities that would be classified as small 
business entities.
    A 1995 study of conventional tissue banks (Ref. 20) reports average 
annual revenues of $1.23 million per facility, which translates into 
$1.45 million per facility (in 2002 dollars) based on inflation data 
reported by the Bureau of Labor Statistics. Most nonreproductive tissue 
facilities are assumed to have a comparable level of average revenues. 
Reproductive tissue industry 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 semen 
banks have average annual revenues of approximately $2 million per 
year, and 1 of the 20 largest facilities has annual revenues greater 
than $8.5 million. Thus, the vast majority of facilities in each 
HCT[sol]P industry sector are small entities. Nevertheless, as noted in 
the preceding cost analysis, most of these facilities will not be 
significantly impacted by this final rule because they are already 
meeting the infectious disease screening and testing and recordkeeping 
requirements.
    Table 7 of this document presents estimates of the average 
annualized cost per affected small facility expressed as a percentage 
of average annual revenues. In addition to facility revenues, table 7 
presents the estimated annual revenue for physician-owned obstetrician/
gynecologist (ob/gyn) practices, because some operate a small donor 
semen bank as an additional service to patients, but may not currently 
comply with all of the requirements of this final rule. The average 
annual practice revenue per self-employed physician in the ob/gyn 
specialty category was reported as $627,000 in 1998 (Ref. 21). This 
translates into $692,000 (in 2002 dollars) based on inflation data 
reported by the Bureau of Labor Statistics.

   Table 7.--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
------------------------------------------------------------------------
792 (all           $38 to $228        $1.45 million     0.003 to 0.016%
 potentially
 small entities)
------------------------------------------------------------------------
Reproductive Tissue, ART Facilities
------------------------------------------------------------------------
260 (65% of 400    $4,270 to $8,694   $2.5 million      0.17 to 0.35%
 facilities)
------------------------------------------------------------------------
Reproductive Tissue, Semen banks
------------------------------------------------------------------------
19 small           $1,222 to $1,456   $2.0 million      0.06 to 0.07%
 commercial banks
------------------------------------------------------------------------
90 small           $1,222 to $1,456   $692,000          0.18 to 0.21%
 physician
 practice-based
 banks
------------------------------------------------------------------------

    As noted in table 7 of this document, the greatest expected 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 cost burden per facility ranges 
up to 0.35 percent of average annual revenues. However, if current 
practices actually involve a much lower level of infectious disease 
screening and testing than assumed in this analysis, the impact of the 
new requirements would be greater than expected.
    Although this final rule will impose some costs on small entities 
involved in the manufacture of HCT[sol]Ps, the agency believes that 
this approach represents an effective means of protecting patient 
safety and public health. The less burdensome alternatives to this 
final rule involve fewer requirements for small entities (the vast 
majority of facilities in the HCT[sol]P industry), but fail to provide 
fundamental assurances of product safety. For example, reliance on

[[Page 29823]]

published FDA guidance for donor eligibility determination, 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 voluntary industry 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 protection from 
the public health risks associated with infected donor-derived 
HCT[sol]Ps.
    Another alternative would involve waiving some of the donor 
screening and testing requirements for small facilities. However, as 
noted previously, the vast majority of facilities in this industry are 
small. Moreover, this alternative would increase the safety risks 
associated with HCT[sol]Ps 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 requirements for blood testing would 
expose patients, as well as tissue facility 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 cadaveric donor's family during screening.
    We also considered waiving the requirement for semen quarantine and 
anonymous donor retesting to detect infections during the window 
period, when a donor's infection may not yet be detectable by blood 
tests. However, this alternative would expose recipients and the public 
to risks from infectious disease agents that cannot be immediately 
detected after exposure through most currently available blood tests 
(e.g., tests for HIV and HCV). Recordkeeping for donor screening and 
testing is also critical to protecting product recipient and public 
safety. Adequate documentation and record retention ensure that 
HCT[sol]Ps 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 transmission through HCT[sol]Ps. Most notably, the 
absence of regulation allows reproductive tissue facilities to omit the 
screening and testing of donors that is routinely performed for other 
types of HCT[sol]Ps, thus exposing patients undergoing infertility 
treatment to a disproportionate risk of exposure to several life-
threatening infectious disease agents.
    To help alleviate the impact on small entities while still 
protecting public health, the agency is not requiring that 
manufacturers follow screening and testing procedures when an HCT[sol]P 
is used in the same person from whom it is obtained, or in a sexually 
intimate partner of a reproductive tissue donor. The agency believes 
the risk of disease transmission from such activities is minimal. 
Further, in the case of reproductive HCT[sol]Ps, the 6-month quarantine 
requirement applies only to semen from anonymous donors and not to 
oocytes and embryos.
    As part of the development process for this final rule, FDA 
conducted an extensive outreach program in an effort to inform affected 
small entities and to request input regarding the potential economic 
impact. Representatives from CBER have given presentations on HCT[sol]P 
donor eligibility related issues at the annual conferences of many of 
the professional associations representing affected entities including 
ASRM, AATB, EBAA, and others. The agency has also engaged in outreach 
activities directed toward interested consumer groups such as RESOLVE 
and the American Infertility Association. At their request, FDA also 
held individual meetings with groups such as ASRM, EBAA and AATB to 
discuss specific concerns regarding the impact of the donor eligibility 
rule. Some of these presentation materials and meeting minutes are 
available on the CBER Web page at http://www.fda.gov/cber/tissue/min.htm. Additional materials associated with the donor eligibility 
rule are available on the Internet at http://www.fda.gov/cber/tissue/docs.htm. Finally, in the proposed rule, FDA requested industry comment 
regarding the assumptions upon which this analysis of economic impacts 
was based. In particular, we requested detailed industry comment 
regarding our estimates of the number and type of entities affected, 
current donor screening and testing practices, and expected compliance 
costs. To the extent possible and appropriate, we have incorporated 
these comments and our responses into the preamble and analysis of 
economic impacts of this final rule.
    Under this final rule, small entities involved with reproductive 
tissue must meet the same safety and quality standards as large 
reproductive tissue facilities and other HCT[sol]P manufacturers. 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 HCT[sol]P industry. The relevant 
Federal rules that are related to this final rule are discussed in 
section II of this document. This economic analysis provides a summary 
of the voluntary industry standards that overlap this final Federal 
standard, but as discussed, there is no current regulation of 
HCT[sol]Ps that will duplicate this final rule. Consequently, FDA finds 
that this final rule will enhance both public health and public 
confidence in the safety and utility of HCT[sol]Ps, while imposing only 
a minimum burden on the affected industry sectors.

V. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) and (j) that this 
action is of a type that is categorically excluded from the preparation 
of an environmental assessment because these actions, as a class, will 
not result in the production or distribution of any substance and 
therefore will not result in the production of any substance into the 
environment.

VI. Federalism Assessment

    Executive Order 13132, dated August 4, 1999, establishes the 
procedure that Federal agencies must follow when formulating and 
implementing policies that have federalism implications. The Executive 
order described nine fundamental federalism principles, stressing the 
importance and sovereignty of State and local governments, and the 
contributions of individual States and communities to the development 
of enlightened public policy. Principles of federalism are inherent in 
the very structure of the Constitution and formalized in and protected 
by the Tenth Amendment. Regulations have federalism implications 
whenever they have a substantial direct effect on the States, on the 
relationship between the National Government and the States, or on the 
distribution of power and responsibilities among the various

[[Page 29824]]

levels of government. Whenever a regulation has this result, the agency 
must prepare a federalism assessment.
    The Executive order directs Federal agencies to:
    1. Encourage States to develop their own policies to achieve 
program objectives and to work with appropriate officials in other 
States;
    2. Where possible, defer to the States to establish standards;
    3. In determining whether to establish uniform national standards, 
consult with appropriate State and local officials as to the need for 
national standards and any alternatives that would limit the scope of 
national standards or otherwise preserve State prerogatives and 
authority; and
    4. Where national standards are required by Federal statutes, 
consult with appropriate State and local officials in developing those 
standards.
    This final rule establishes donor-eligibility and other related 
requirements for HCT[sol]P establishments. In issuing this rule, we 
rely on the authority of section 361 of the PHS Act (42 U.S.C. 264), 
under which we 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. (We also 
rely on our authority to issue CGMP regulations to amend the existing 
CGMP regulations for drugs in 21 CFR parts 210 and 211, which include 
CGMP requirements, to incorporate the testing and screening provisions 
of part 1271 subpart C for HCT[sol]Ps regulated as drugs, and/or 
biological products (see e.g., 21 U.S.C. 351(a)(2)(B)).
    The donor-eligibility proposed rule was published after Executive 
Order 13132 was issued, but before it went into effect. Nevertheless, 
we made a considerable effort after the publication of the proposed 
rule to ensure that States had the opportunity to review the proposed 
rule and submit comments on it. We directed a mailing of the proposed 
rule to State health officials to encourage their comments on the 
proposed rule. We also sent copies of the rule to each State attorney 
general. To provide additional time to the States to comment on the 
proposed rule, we reopened the comment period.
    In the Federal Register document reopening the comment period, we 
noted that we had learned that several States had enacted legislation 
and issued regulations governing tissue donor suitability (65 FR 20774, 
April 18, 2000). Because those laws might conflict with provisions in 
the proposed rule, we invited State officials to participate in the 
rulemaking. We specifically noted that we would appreciate comment on 
the following topics: (1) The need for uniform national standards for 
donor suitability determinations to prevent communicable disease 
transmission through human cellular and tissue-based products, (2) the 
scope of such proposed national requirements and their impact upon 
State laws, (3) FDA's proposal not to preempt State laws on legislative 
consent for cornea transplants, and (4) any issues raised by this 
proposed rule possibly affecting State laws and authorities.
    We received only one comment from a State official. This comment 
addressed abbreviated screening, which is discussed in comment 50 of 
this document. The comment also asked that we require deferral records 
for donors determined to be unsuitable. Reviewing deferral records 
before each donation would only be necessary in the case of living 
donors who could donate more than once, such as semen donors. As part 
of the screening process in Sec.  1271.75, establishments determining 
donor eligibility are required to review the donor's relevant medical 
records, which would identify the donor as an unsuitable donor. 
Therefore, we believe that requiring deferral records would be 
burdensome. We received no comments from State officials on federalism 
issues.
    To the extent that these final regulations cover areas that are 
already subject to Federal regulation, rather than regulation by the 
States, we believe the federalism implications of this final rule are 
minimal or nonexistent, because national standards are already in 
place. Since 1993, there have been Federal regulations on human tissue 
intended for transplantation. These regulations, contained in part 1270 
(21 CFR part 1270), govern donor screening, testing, and other related 
issues. The regulations now being made final replace the regulations in 
part 1270. Although the new donor-eligibility regulations are more 
extensive in their requirements, and apply to a greater range of 
HCT[sol]Ps, many of the establishments that will be required to comply 
with this final rule have been subject to the regulations in part 1270 
or to drug or device regulations.
    However, we acknowledge that this final rule will have an effect in 
those areas where there has been no uniform Federal regulation. For 
example, this rule sets out testing and screening requirements for 
donors of reproductive cells and tissue, an area where there is a range 
of State regulation. Some of the State statutes and regulations that 
have come to our attention focus on the risk of HIV transmission 
through semen donation and are thus more limited in their requirements 
than this final rule, which requires testing and screening for 
additional communicable disease agents and diseases and does not apply 
only to semen (see e.g., Ind. Code 16-41-14-7; Md. Code Ann., Health-
Gen. 18-334(e); 12 Va. Admin. Code 5-90-240, 5-90-250).
    Directed donation of reproductive cells or tissue is another area 
of potential differences between State laws and regulations and this 
final rule, which permits the use of fresh semen from directed 
reproductive donors without retesting of the donor 6 months after 
donation. The final rule is consistent with the California Health and 
Safety Code with respect to directed reproductive donors, but may be 
inconsistent with Indiana law, which appears to require quarantine of 
all semen donations pending retesting 6 months after donation (see Cal. 
Health & Safety Code Sec.  1644.5(c); Ind. Code 16-41-14-7). We note 
that Indiana's more stringent statute may coexist with this final rule.
    To the extent that additional differences may exist between State 
statutes and regulations and this final rule with respect to 
reproductive cells and tissues and other areas where there has not 
previously been Federal regulation, we recognize that there may be a 
federalism impact. However, to the extent there is such an impact, it 
is a necessary part of our effort to institute uniform screening and 
testing requirements, to prevent the introduction, transmission, or 
spread of communicable disease.
    In the proposed rule, we identified a particular area where we 
believed concerns about Federal preemption of State laws could arise: 
Legislative consent, or the recovery of corneas in accordance with 
State laws that allow the medical examiner or coroner to procure 
corneal tissue without the consent of the donor's next of kin (64 FR 
52696 at 52703). The proposed rule did not contain an exception from 
the donor medical history interview for corneas procured under 
legislative consent. We recognized 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. We noted, however, 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 and would not require an interview 
with the next of kin. For that reason, we considered that the proposed

[[Page 29825]]

rule and State laws on legislative consent may coexist, and we stated 
that we did not intend at that time to preempt those laws. We requested 
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.
    Many comments from industry opposed our proposal to require a donor 
medical history interview for all HCT[sol]P donors, including donors of 
corneas recovered under legislative consent, and some disputed our 
assertion that the regulation and State laws could coexist. We address 
those comments in comments 45 and 46 of this document. After 
considering the comments, we continue to consider the donor medical 
history interview necessary for all donors to prevent the introduction, 
transmission, or spread of communicable diseases, and decline to make 
an exception for corneas donated under legislative consent.
    Although we believe the final rule provides sufficient flexibility 
to allow for the continued recovery of corneas under legislative 
consent, we recognize that there may be some difficulty in 
communicating with the primary treating physician without obtaining 
permission from the deceased and/or the family of the deceased, and 
that, therefore, this final rule may have a negative effect on the 
ability of medical examiners and coroners to recover corneas under 
State legislative consent laws. However, given the potential for 
corneas to transmit communicable disease, including TSE, we have 
concluded that making an exception from the requirement for a donor 
medical history interview in the case of corneas obtained under 
legislative consent is not justified.
    This final rule represents the exercise of a core Federal function: 
``* * * prevent[ing] the introduction, transmission, or spread of 
communicable diseases from foreign countries into the States or 
possessions, or from one State or possession into any other State or 
possession'' (section 361(a) of the PHS Act; 42 U.S.C. 264). To prevent 
the transmission of communicable disease in the United States, 
including the interstate transmission of disease, uniform national 
standards on donor testing and screening are necessary. No State 
official commented otherwise. For these reasons, and for the reasons 
discussed previously in this document, this rule is consistent with the 
federalism principles expressed in Executive Order 13132.

VII. The Paperwork Reduction Act of 1995

    This final rule contains information collection provisions that 
have been reviewed by OMB under the Paperwork Reduction Act of 1995 
(the PRA) (44 U.S.C. 3501-3520). (OMB control number 0910-0543 expires 
May 31, 2007.) 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.
    Title: Eligibility Determination for Donors of Human Cells, 
Tissues, and Cellular and Tissue-Based Products.
    Description: Under the authority of section 361 of the PHS Act, FDA 
is requiring HCT[sol]P establishments 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. 
FDA is requiring that donor-eligibility determination regulations apply 
to all establishments described in Sec.  1271.1(b). The documented 
determination of whether a donor is eligible or ineligible is made by a 
responsible person and is based on the results of required donor 
screening, which includes a donor medical history interview (Sec.  
1271.3(n)), and testing (Sec.  1271.50(a)). HCT[sol]P establishments 
are permitted to ship an HCT[sol]P only if it is accompanied by 
documentation of the donor-eligibility determination (Sec.  
1271.55(a)). This requirement applies to an HCT[sol]P from a donor 
determined to be eligible as well as to a product from a donor who is 
determined to be ineligible and made available for use under certain 
provisions. The accompanying documentation must contain a summary of 
records used to determine donor eligibility, and a statement whether, 
based on the results of the screening and testing of the donor, the 
donor is determined to be eligible or ineligible.
    Records used in determining the eligibility of a donor, i.e., 
results and interpretations of screening and testing, the donor 
eligibility determination, the name and address of the testing 
laboratory or laboratories, and the name of the responsible person who 
made the determination and the date, must be maintained (Sec.  
1271.55(d)(1)). If any information on the donor is not in English, the 
HCT[sol]P establishment must retain the original record and the 
statement of authenticity from the translator (Sec.  1271.55(d)(2)). 
HCT[sol]P establishments must retain the records pertaining to 
HCT[sol]Ps at least 10 years after the date of administration, 
distribution, disposition, or expiration, whichever is latest (Sec.  
1271.55(d)(4)).
    When a product is shipped in quarantine, before completion of 
screening and testing, the HCT[sol]P establishment must provide the 
donor identification, a statement that the donor-eligibility 
determination is not completed and that the product is not to be used 
until eligibility determination is completed (Sec.  1271.60(c)). With 
the use of a product from an ineligible or incompletely tested donor 
the following information must accompany the HCT[sol]P: The results of 
any completed donor screening and testing, and a list of any required 
screening and testing not completed. When using an HCT[sol]P from an 
ineligible donor, documentation by the HCT[sol]P establishment is 
required showing that the recipient's physician received notification 
of the screening and testing results (Sec. Sec.  1271.60(d)(3) and 
1271.65(b)(3)).
    An HCT[sol]P establishment also is required to establish and 
maintain procedures for all steps that are performed in determining 
eligibility (Sec.  1271.47(a)), including the use of a product from a 
donor testing positive for CMV (Sec.  1271.85(b)(2)). The HCT[sol]P 
establishment must record any departure from the procedures (Sec.  
1271.47(d)).
    These provisions are intended as safeguards to prevent the 
transmission of communicable diseases that may occur with the use of 
cells and tissue from infected donors. Through this action FDA will 
improve its ability to protect public health by controlling the spread 
of communicable diseases.
    Description of Respondents: HCT[sol]P establishments.
    As required by section 3506(c)(2)(B) of the PRA, we provided an 
opportunity for public comment on the information collection 
requirements of the proposed rule (64 FR at 52715). Under the PRA, OMB 
reserved approval of the information collection burden in the proposed 
rule stating that they will make an assessment in light of public 
comments received on the proposed rule. One comment on the information 
collection burden was submitted to the docket.
    (Comment 99) One comment states that, although FDA invites comments 
on whether the proposed collection of information is necessary for the 
proper performance of FDA's functions, including whether the 
information will have practical utility, there are no data supporting 
any practical utility of the information collection, and that the

[[Page 29826]]

estimated burden of the proposed collection of information is extremely 
low compared to the actual cost.
    (Response) The reporting and recordkeeping information collection 
burdens are necessary to help ensure that the objective of the 
regulations (i.e., to prevent the transmission of communicable 
disease), is fulfilled. This provides information to the consignee or 
user of the product that the donor of the product was adequately and 
appropriately screened and tested for evidence of specific disease 
agents. In addition, this information allows FDA to monitor the 
compliance of HCT[sol]P establishments with the regulations.
    The data described in section V of the proposed rule is not for the 
purpose of supporting the practical utility of the information 
collection, but for demonstrating how the burden is calculated. 
Although the comment states that the calculated burden is low, the 
comment did not offer additional data in support of the comment.
    We estimate the burden of this collection of information as 
follows:

                                 Table 8.--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
                                            Annual
    21 CFR Section          No. of       Frequency per    Total Annual      Hours per Response      Total Hours
                          Respondents      Response         Responses
----------------------------------------------------------------------------------------------------------------
1271.3(n)                 1,302              60              78,136       1.0                          78,136.0
----------------------------------------------------------------------------------------------------------------
1271.55(a)                1,235             787             972,417       0.5                         486,208.5
----------------------------------------------------------------------------------------------------------------
1271.60(c)                1,069             208             222,417       0.5                         111,208.5
----------------------------------------------------------------------------------------------------------------
Total                   ..............  ..............  ................  ......................      675,553.0
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


                               Table 9.--Estimated Annual Recordkeeping Burden\1\
----------------------------------------------------------------------------------------------------------------
                                                    Annual
        21 CFR Section              No. of       Frequency per    Total Annual       Hours per      Total Hours
                                 Recordkeepers  Record-keeping       Records          Record
----------------------------------------------------------------------------------------------------------------
One-Time Burden (Creation of        510               5               2,550              16            40,800
 SOPs) 1271.47(a) and
 1271.85(b)(2)
----------------------------------------------------------------------------------------------------------------
One-time Burden (Review of          792               5               3,960               8            31,680
 existing SOPs for compliance)
----------------------------------------------------------------------------------------------------------------
SOP Update                        1,302               5               6,510               2            13,020
----------------------------------------------------------------------------------------------------------------
1271.47(d)                        1,102               1               1,102               1             1,102
----------------------------------------------------------------------------------------------------------------
1271.55(d)(4)                       195               1                 195             120            23,400
----------------------------------------------------------------------------------------------------------------
1271.50(a)                          510               9               4,640               5            23,200
----------------------------------------------------------------------------------------------------------------
1271.55(d)(1)                       329             162.85           53,579               1            53,579
----------------------------------------------------------------------------------------------------------------
1271.55(d)(2)                     1,302               1               1,302               1             1,302
----------------------------------------------------------------------------------------------------------------
1271.60(d)(3) and                 1,302               1               1,302               2             2,604
 1271.65(b)(3)
----------------------------------------------------------------------------------------------------------------
Total                           ..............  ..............  ................  ..............      190,687
----------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.

    In the proposed rule, we underestimated the number of respondents. 
Based on updated information from FDA's registration data and trade 
organizations, we have revised our estimate of establishments to 
approximately 1,302 (i.e., approximately 166 conventional tissue 
establishments, 134 eye tissue establishments, 425 peripheral and cord 
blood stem/progenitor cell establishments, 510 reproductive tissue 
establishments, and 67 manufacturers of products regulated under the 
act and section 351 of the PHS Act).
    We also have adjusted our estimates for the number of HCT[sol]Ps 
annually produced based on updated information from industry provided 
to us at the time we prepared the final rule.
    Our burden estimates for the annual frequency per response and 
average hours per response are based on institutional experience with 
comparable reporting and recordkeeping provisions for biological 
products. These burden estimates have not changed. Also, we are adding 
burden estimates for Sec. Sec.  1271.3(n) and 1271.47.
    In estimating the burden, we compared the regulations with the 
current voluntary standards of a number of industry organizations, such 
as, AATB, EBAA, AABB, FACT, NMDP, and the College of American 
Pathologists, and the guidelines provided by ASRM. In those cases where 
a voluntary industry standard appears to be equivalent to a regulation, 
we assumed that any reporting or recordkeeping burden is a customary 
and usual business practice of HCT[sol]P establishments who are members 
of those organizations and no additional burden is calculated here.
    Under Sec.  1271.3(n), approximately 1,302 establishments (166 
conventional

[[Page 29827]]

tissue establishments, 134 eye tissue establishments, 425 peripheral 
and cord blood stem/progenitor cell establishments, 510 reproductive 
tissue establishments, and 67 manufacturers of products regulated under 
the act and section 351 of the PHS Act) are required to have a 
documented medical history interview about the donor's medical history 
and relevant social behavior as part of the donor's relevant medical 
records for each of the estimated 78,136 donors (approximately 20,000 
conventional tissue donors, 47,796 eye tissue donors, 5,700 peripheral 
and cord blood stem/progenitor cell donors, and 4,640 reproductive cell 
and tissue donors). We estimate that the time to conduct the interview 
with the donor, if living, or with an individual able to provide the 
information sought in the interview, is 1 hour.
    Under Sec.  1271.55(a), 972,417 HCT[sol]Ps (approximately 750,000 
conventional tissues, 94,186 eye tissues, 6,031 hematopoetic stem/
progenitor cells, and 122,200 reproductive cells and tissues) are 
distributed per year. The agency estimates that, for each HCT[sol]P, 
1,235 establishments (1,302-67 establishments with approved 
applications) will expend approximately 0.5 hours to prepare the 
summary of records. Conventional and eye tissue establishment are 
currently required to provide a summary of records under Sec.  
1270.33(d), which Sec.  1271.55 replaces.
    Under Sec.  1271.60(c), a record consisting of donor identification 
and a statement that the donor-eligibility determination is not 
completed and that the HCT[sol]P is not to be used until the 
determination is completed, must accompany each HCT[sol]P shipped under 
quarantine. We estimate that approximately 1,069 establishments may 
ship an estimated 222,417 HCT[sol]P under quarantine and that the 
preparation of the record would take approximately 0.5 hours.
    We assume that approximately 510 reproductive HCT[sol]P 
establishments would create 5 SOPs under Sec. Sec.  1271.47(a) and 
1271.85(b)(2) for a total of 2,550 records, and we estimate that it 
would take 16 hours per new SOP for a total of 40,800 hours as a 1-time 
burden. We estimate that up to 5 SOPs would already exist for 792 
HCT[sol]P establishments as a result of complying with current 
applicable regulations or following industry organizational standards, 
and that it would take each establishment approximately 8 hours per SOP 
to complete the review for compliance with the requirements for a total 
of 31,600 hours as a 1-time burden.
    Once the SOPs are created, annual SOP maintenance of existing SOPs 
is estimated to involve 2 hours annually per SOP for all HCT[sol]P 
establishments. Annual total hours for maintaining the SOPs is 
estimated at 13,020.
    Under Sec.  1271.47(d), an estimated 1,102 HCT[sol]P establishments 
would take approximately 1 hour to annually document one departure from 
an SOP.
    Under Sec.  1271.55(d)(4), we estimate that 195 HCT[sol]P 
establishments not currently following existing industry standards will 
expend 120 hours (10 hours per month) annually to maintain records for 
10 years.
    Under Sec.  1271.50(a), documentation of donor eligibility is 
required for the first time for approximately 510 reproductive tissue 
establishments. Out of a total of 1,302 establishments of HCT[sol]Ps, 
there would be no added burden for approximately 792 other 
establishments who document donor eligibility as usual and customary 
business practice under the trade organization standards. FDA estimates 
that Sec.  1271.50(a) would impose a new collection of information 
requirement on 510 establishments of reproductive HCT[sol]Ps, each of 
which would document the eligibility of an estimated 9 donors per year, 
or 4,640 donors, expending approximately 5 hours per document.
    Approximately 329 HCT[sol]P establishments would maintain screening 
and testing records under Sec.  1271.55(d)(1) for an estimated 53,579 
donors, which would take approximately one hour per donor.
    For documents originally not in English, approximately 1,302 
HCT[sol]P establishments would maintain a record of translation with an 
authenticity statement by the translator and the original documents. We 
estimate that it would take one hour for each establishment to maintain 
one such document annually.
    Under Sec. Sec.  1271.60(d)(3) and 1271.65(b)(3), when an HCT[sol]P 
that is ineligible or not fully screened or tested is used, 
approximately 1,302 establishments of HCT[sol]Ps are required to 
document the reason for using the product, and notice of the results of 
testing and screening to the physician. The agency estimates that such 
documentation would occur approximately once annually per 
establishments and that each establishment would expend approximately 
2.0 hours to create such document.
    Under section 1320.3(c)(2) of the PRA, the labeling requirements in 
proposed Sec. Sec.  1271.60(d)(2), 1271.65(b)(2), 1271.65(c)(1) and 
(c)(2), 1271.80(b)(1), (b)(2), and (b)(3) and 1271.90(b), do not 
constitute collection of information because information required to be 
on the labeling is originally supplied by FDA to the establishments for 
the purpose of disclosure to the public to help ensure a safe supply of 
HCT[sol]Ps and protect public health.
    The reporting of screening and testing results to the physician in 
Sec.  1271.60(d)(4) does not constitute additional reporting burden 
because it is calculated under the requirement for Sec.  1271.55(a).
    The information collection requirements of the final rule have been 
submitted to OMB for review. Before the effective date of this final 
rule, we will publish a notice in the Federal Register announcing OMB's 
decision to approve, modify, or disapprove the information collection 
provisions in this final rule. An agency may not conduct or sponsor, 
and a person is not required to respond to, a collection of information 
unless it displays a currently valid OMB control number.

VIII. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday. 
(FDA has verified the Web site addresses, but we are not responsible 
for subsequent changes to the Web site after this document publishes in 
the Federal Register.)
    1. Dodd, R. Y., E. P. Notari, and S. L. Stramer, ``Current 
Prevalence and Incidence of Infectious Disease Markers and Estimated 
Window-Period Risk in the American Red Cross Blood Donor 
Population,'' Transfusion, vol. 42(8), pp. 966-72, August 2002.
    2. Stramer, S. L., ``US NAT Yield: Where Are We After Two 
Years?'' Transfusion Medicine, vol. 12, issue 4, pp. 243-253, 2002.
    3. Based on information presented on viral dynamics in early 
seroconversion by Dr. M. P. Busch at the FDA BPAC meeting December 
2002.
    4. CDC, 1999 ART Success Rates: National Summary and Fertility 
Clinic Reports (http://www.cdc.gov/nccdphp/drh/art.htm).
    5. 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 (http://www.thespermbankofca.org/services/fees.htm).
    6. The Sperm Bank of California (http://www.thespermbankofca.org/services/fees.htm).
    7. Margolis, H. S., P. J. Coleman, R. E. Brown, et al., 
``Prevention of Hepatitis B Virus Transmission by Immunization: An 
Economic Analysis of Current Recommendations,'' Journal of the 
American Medical Association, vol. 274, no. 15, pp. 1201-1208, 1995.
    8. CDC, 1995 ART Success Rates: National Summary and Fertility 
Clinic Reports

[[Page 29828]]

estimates that 11 percent of the ART therapy performed included 
ICSI.
    9. Wortley, P. M., T. A. Hammett, and P. L. Fleming, ``Donor 
Insemination and Human Immunodeficiency Virus Transmission,'' 
Obstetrics & Gynecology, vol. 91, no. 4, pp. 515-518, 1998.
    10. Sidhu, R. S., R. K. Sharma, S. Kachoria, et al., ``Reasons 
for Rejecting Potential Donors From a Sperm Bank Program,'' Journal 
of Assisted Reproduction and Genetics, vol. 14, no. 6, pp. 354-360, 
1997.
    11. The American Fertility Society, ``Guidelines for Therapeutic 
Donor Insemination: Sperm,'' Fertility and Sterility, vol. 62, no. 
5, pp. 101s-104s, November 1994.
    12. Government Accounting Office, ``Human Tissue Banks: FDA 
Taking Steps to Improve Safety, but Some Concerns Remain,'' GAO/
HEHS-98-25.
    13. Alter, M. J., D. Kruszon-Moran, O. V. Nainan, et al., ``The 
Prevalence of Hepatitis C Virus Infection in the United States, 1988 
Through 1994,'' New England Journal of Medicine, vol. 341(8), pp. 
556-562, 1999.
    14. McQuillan, G. M., P. J. Coleman, D. Kruszon-Moran, et al., 
``Prevalence of Hepatitis B Virus Infection in the United States: 
The National Health and Nutrition Examination Surveys, 1976 Through 
1994,'' American Journal of Public Health, vol. 89(1), pp. 14-8, 
1999.
    15. Kane, M., ``Epidemiology of Hepatitis B Infection in North 
America,'' Vaccine, vol. 13, suppl. 1, pp. s16-s17, 1995.
    16. Guinan, M. E., ``Artificial Insemination by Donor: Safety 
and Secrecy,'' Journal of the American Medical Association, vol. 
173, no. 11, pp. 890-891, March 1995.
    17. U.S. Centers for Disease Control and Prevention, 1997.
    18. 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-[alpha]'' Therapy for 
Chronic Hepatitis C,'' Annals of Internal Medicine, vol. 127, no. 
10, November 1997.
    19. U.S. Small Business Administration, Office of Size 
Standards, Table of Size Standards, Sector 62--Health Care and 
Social Assistance, February 22, 2002.
    20. 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.
    21. American Medical Association, Center for Health Policy 
Research, Physician Socioeconomic Statistics, 2000-2002 ed., table 
41, p. 83.
    22. Based on information provided by Dr. David Hoffman, NW 
Center for Infertility and Reproductive Endocrinology, August 2001.
    23. U.S. Department of Labor, Bureau of Labor Statistics, Table 
20, Private Industry, Health Services by Occupational Group: 
Employer Costs per Hour Worked for Employee Compensation, 
Professional Specialty Occupations (http://www.bls.gov/ncs/ect/sp/ecechist.pdf), 1994-2001.
    24. U.S. Department of Labor, Bureau of Labor Statistics, Table 
20, Private Industry, Health Services by Occupational Group: 
Employer Costs per Hour Worked for Employee Compensation, Technical 
Occupations (http://www.bls.gov/ncs/ect/sp/ecechist.pdf), 1994-2001.
    25. America's Blood Centers, ``Infectious Risks of Blood 
Transfusion,'' Blood Bulletin, vol. 4, no. 2, December 2001.
    26. 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.

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

    Communicable diseases, HIV/AIDS, Human cells, tissues, and cellular 
and tissue-based products, Reporting and recordkeeping requirements.

0
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, chapter I of title 21 of the Code of 
Federal Regulations is amended as follows:

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

0
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.

0
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, 
donor screening, testing (including donor testing), processing, 
storage, labeling, packaging, or distribution of human cells, tissues, 
and cellular and tissue-based products (HCT[sol]Ps), as defined in 
Sec.  1271.3(d) of this chapter, that are drugs (subject to review 
under an application submitted under section 505 of the act or under a 
biological product license application under section 351 of the Public 
Health Service Act), are subject to the donor-eligibility and 
applicable 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 applicable 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 with respect to the 
manufacture, processing, packing or holding of a drug, renders an 
HCT[sol]P adulterated under section 501(a)(2)(B) of the act. Such 
HCT[sol]P, as well as the person who is responsible for the failure to 
comply, is subject to regulatory action.

0
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 are applicable to a human 
cell, tissue, or cellular or tissue-based product (HCT[sol]P) that is a 
drug (subject to review under an application submitted under section 
505 of the act or under a biological product license application under 
section 351 of the Public Health Service Act); shall be considered to 
supplement, not supersede, each other, unless the regulations 
explicitly provide otherwise. In the event of a conflict between 
applicable regulations in this part and in other parts of this chapter, 
the regulation specifically applicable to the drug product 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

0
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.

0
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

[[Page 29829]]

600 through 680 of this chapter, as they pertain to drugs that are also 
biological products for human use; and in part 1271 of this chapter, as 
they are applicable to drugs that are also human cells, tissues, and 
cellular and tissue-based products (HCT[sol]Ps) and that are drugs 
(subject to review under an application submitted under section 505 of 
the act or under a biological product license application under section 
351 of the Public Health Service Act); supplement and do not supersede 
the regulations in this part unless the regulations explicitly provide 
otherwise. In the event of a conflict between applicable regulations in 
this part and in other parts of this chapter, or 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 more general.
* * * * *

PART 820--QUALITY SYSTEM REGULATION

0
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.

0
7. Section 820.1 is amended by adding two sentences to the end of 
paragraph (a)(1), and by revising paragraph (b) to read as follows:


Sec.  820.1  Scope.

    (a) Applicability. (1) * * * Manufacturers of human cells, tissues, 
and cellular and tissue-based products (HCT[sol]Ps), as defined in 
Sec.  1271.3(d) of this chapter, that are medical devices (subject to 
premarket review or notification, or exempt from notification, under an 
application submitted under the device provisions of the act or under a 
biological product license application under section 351 of the Public 
Health Service Act) are subject to this part and are also subject to 
the donor-eligibility procedures set forth in part 1271 subpart C of 
this chapter and applicable current good tissue practice procedures in 
part 1271 subpart D of this chapter. In the event of a conflict between 
applicable regulations in part 1271 and in other parts of this chapter, 
the regulation specifically applicable to the device in question shall 
supersede the more general.
* * * * *
    (b) The quality system regulation in this part supplements 
regulations in other parts of this chapter except where explicitly 
stated otherwise. In the event of a conflict between applicable 
regulations in this part and in other parts of this chapter, the 
regulations specifically applicable to the device in question shall 
supersede any other generally applicable requirements.
* * * * *

PART 1271--HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED 
PRODUCTS

0
8. The authority citation for 21 CFR part 1271 is revised to read as 
follows:

    Authority: 42 U.S.C. 216, 243, 263a, 264, 271.


Sec.  1271.1  [Amended]

0
9. Section 1271.1 What are the purpose and scope for this part? is 
amended by removing the phrase ``donor-suitability'' and adding in its 
place the phrase ``donor-eligibility'' wherever it appears.

0
10. Section 1271.3 is amended by adding paragraphs (h) through (x) to 
read as follows:


Sec.  1271.3  How does FDA define important terms in this part?

* * * * *
    (h) Biohazard legend appears on the label as follows and is used to 
mark HCT[sol]Ps that present a known or suspected relevant communicable 
disease risk.
[GRAPHIC] [TIFF OMITTED] TR25MY04.000

    (i) Blood component means a product containing a part of human 
blood separated by physical or mechanical means.
    (j) 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) Blood components such as plasma and platelets.
    (k) Crystalloid means an isotonic 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.
    (l) Directed reproductive donor means a donor of reproductive cells 
or tissue (including semen, oocytes, and embryos to which the donor 
contributed the spermatozoa or oocyte) to a specific recipient, and who 
knows and is known by the recipient before donation. The term directed 
reproductive donor does not include a sexually intimate partner under 
Sec.  1271.90.
    (m) Donor means a person, living or dead, who is the source of 
cells or tissue for an HCT[sol]P.
    (n) Donor medical history interview means a documented dialog about 
the donor's medical history and relevant social behavior, including 
activities, behaviors, and descriptions considered to increase the 
donor's relevant communicable disease risk:
    (1) With the donor, if the donor is living and able to participate 
in the interview, or
    (2) If not, with an individual or individuals able to provide the 
information sought in the interview (e.g., 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).
    (o) Physical assessment of a cadaveric donor means a limited 
autopsy or recent antemortem or postmortem physical examination of the 
donor to assess for signs of a relevant communicable disease and for 
signs suggestive of any risk factor for a relevant communicable 
disease.
    (p) 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.
    (q) Quarantine means the storage or identification of an HCT[sol]P, 
to prevent improper release, in a physically separate area clearly 
identified for such use, or through use of other procedures, such as 
automated designation.
    (r) Relevant communicable disease agent or disease means:
    (1)(i) For all human cells and tissues, a communicable disease or 
disease agent listed as follows:
    (A) Human immunodeficiency virus, types 1 and 2;
    (B) Hepatitis B virus;
    (C) Hepatitis C virus;
    (D) Human transmissible spongiform encephalopathy, including 
Creutzfeldt-Jakob disease; and
    (E) Treponema pallidum.
    (ii) For viable, leukocyte-rich cells and tissues, a cell-
associated disease agent or disease listed as follows:
    (A) Human T-lymphotropic virus, type I; and
    (B) Human T-lymphotropic virus, type II.
    (iii) For reproductive cells or tissues, a disease agent or disease 
of the genitourinary tract listed as follows:
    (A) Chlamydia trachomatis; and

[[Page 29830]]

    (B) Neisseria gonorrhea.
    (2) A disease agent or disease not listed in paragraph (r)(1) of 
this section:
    (i) For which there may be a risk of transmission by an HCT[sol]P, 
either to the recipient of the HCT[sol]P or to those people who may 
handle or otherwise come in contact with it, such as medical personnel, 
because the disease agent or disease:
    (A) Is potentially transmissible by an HCT[sol]P and
    (B) Either of the following applies:
    (1) The disease agent or disease has sufficient incidence and/or 
prevalence to affect the potential donor population, or
    (2) The disease agent or disease may have been released 
accidentally or intentionally in a manner that could place potential 
donors at risk of infection;
    (ii) That could be fatal or life-threatening, could result in 
permanent impairment of a body function or permanent damage to body 
structure, or could necessitate medical or surgical intervention to 
preclude permanent impairment of body function or permanent damage to a 
body structure; and
    (iii) 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.
    (s) Relevant medical records means a collection of documents that 
includes a current donor medical history interview; a current report of 
the 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).
    (t) Responsible person means a person who is authorized to perform 
designated functions for which he or she is trained and qualified.
    (u) Urgent medical need means that no comparable HCT[sol]P is 
available and the recipient is likely to suffer death or serious 
morbidity without the HCT[sol]P.
    (v) Act means the Federal Food, Drug, and Cosmetic Act.
    (w) PHS Act means the Public Health Service Act.
    (x) FDA means the Food and Drug Administration.

0
11. Part 1271 is amended by adding subpart C, consisting of Sec. Sec.  
1271.45 through 1271.90, to read as follows:

Subpart C--Donor Eligibility

Sec.

    1271.45 What requirements does this subpart contain?
    1271.47 What procedures must I establish and maintain?
    1271.50 How do I determine whether a donor is eligible?
    1271.55 What records must accompany an HCT[sol]P after the donor-
eligibility determination is complete; and what records must I 
maintain?
    1271.60 What quarantine and other requirements apply before the 
donor-eligibility determination is complete?
    1271.65 How do I store an HCT[sol]P from a donor determined to be 
ineligible, and what uses of the HCT[sol]P are not prohibited?
    1271.75 How do I screen a donor?
    1271.80 What are the general requirements for donor testing?
    1271.85 What donor testing is required for different types of cells 
and tissues?
    1271.90 Are there exceptions from the requirement of determining 
donor eligibility, and what labeling requirements apply?

Subpart C--Donor Eligibility


Sec.  1271.45  What requirements does this subpart contain?

    (a) General. This subpart sets out requirements for determining 
donor eligibility, including donor screening and testing. The 
requirements contained in this subpart are a component of current good 
tissue practice (CGTP) requirements.
    (b) Donor-eligibility determination required. A donor-eligibility 
determination, based on donor screening and testing for relevant 
communicable disease agents and diseases, is required for all donors of 
cells or tissue used in HCT[sol]Ps, except as provided under Sec.  
1271.90. In the case of an embryo or of cells derived from an embryo, a 
donor-eligibility determination is required for both the oocyte donor 
and the semen donor.
    (c) Prohibition on use. An HCT[sol]P must not be implanted, 
transplanted, infused, or transferred until the donor has been 
determined to be eligible, except as provided under Sec. Sec.  
1271.60(d), 1271.65(b), and 1271.90 of this subpart.
    (d) Applicability of requirements. If you are an establishment that 
performs any function described in this subpart, you must comply with 
the requirements contained in this subpart that are applicable to that 
function.


Sec.  1271.47  What procedures must I establish and maintain?

    (a) General. You must establish and maintain procedures for all 
steps that you perform in testing, screening, determining donor 
eligibility, and complying with all other requirements of this subpart. 
Establish and maintain means define, document (in writing or 
electronically), and implement; then follow, review, and as needed, 
revise on an ongoing basis. You must design these procedures to ensure 
compliance with the requirements of this subpart.
    (b) Review and approval. Before implementation, a responsible 
person must review and approve all procedures.
    (c) Availability. Procedures must be readily available to the 
personnel in the area where the operations to which they relate are 
performed, or in a nearby area if such availability is impractical.
    (d) Departures from procedures. You must record and justify any 
departure from a procedure relevant to preventing risks of communicable 
disease transmission at the time of its occurrence. You must not make 
available for distribution any HCT[sol]P from a donor whose eligibility 
is determined under such a departure unless a responsible person has 
determined that the departure does not increase the risks of 
communicable disease transmission through the use of the HCT[sol]P.
    (e) Standard procedures. You may adopt current standard procedures, 
such as those in a technical manual prepared by another organization, 
provided that you have verified that the procedures are consistent with 
and at least as stringent as the requirements of this part and 
appropriate for your operations.


Sec.  1271.50  How do I determine whether a donor is eligible?

    (a) Determination based on screening and testing. If you are the 
establishment responsible for making the donor-eligibility 
determination, you must determine whether a donor is eligible based 
upon the results of donor screening in accordance with Sec.  1271.75 
and donor testing in accordance with Sec. Sec.  1271.80 and 1271.85. A 
responsible person, as defined in Sec.  1271.3(t), must determine and 
document the eligibility of a cell or tissue donor.
    (b) Eligible donor. A donor is eligible under these provisions only 
if:
    (1) Donor screening in accordance with Sec.  1271.75 indicates that 
the donor:

[[Page 29831]]

    (i) Is free from risk factors for, and clinical evidence of, 
infection due to relevant communicable disease agents and diseases; and
    (ii) Is free from communicable disease risks associated with 
xenotransplantation; and
    (2) The results of donor testing for relevant communicable disease 
agents in accordance with Sec. Sec.  1271.80 and 1271.85 are negative 
or nonreactive, except as provided in Sec.  1271.80(d)(1).


Sec.  1271.55  What records must accompany an HCT[sol]P after the 
donor-eligibility determination is complete; and what records must I 
retain?

    (a) Accompanying records. Once a donor-eligibility determination 
has been made, the following must accompany the HCT[sol]P at all times:
    (1) A distinct identification code affixed to the HCT[sol]P 
container, e.g., alphanumeric, that relates the HCT[sol]P to the donor 
and to all records pertaining to the HCT[sol]P and, except in the case 
of autologous or directed reproductive donations, does not include an 
individual's name, social security number, or medical record number;
    (2) A statement whether, based on the results of screening and 
testing, the donor has been determined to be eligible or ineligible; 
and
    (3) A summary of the records used to make the donor-eligibility 
determination.
    (b) Summary of records. The summary of records required by 
paragraph (a)(3) of this section must contain the following 
information:
    (1) A statement that the communicable disease testing was performed 
by a laboratory:
    (i) Certified to perform such testing on human specimens under the 
Clinical Laboratory Improvement Amendments of 1988 (42 U.S.C. 263a) and 
42 CFR part 493; or
    (ii) That has met equivalent requirements as determined by the 
Centers for Medicare and Medicaid Services in accordance with those 
provisions;
    (2) A listing and interpretation of the results of all communicable 
disease tests performed;
    (3) The name and address of the establishment that made the donor-
eligibility determination; and
    (4) In the case of an HCT[sol]P from a donor who is ineligible 
based on screening and released under paragraph (b) of Sec.  1271.65, a 
statement noting the reason(s) for the determination of ineligibility.
    (c) Deletion of personal information. The accompanying records 
required by this section must not contain the donor's name or other 
personal information that might identify the donor.
    (d) Record retention requirements.
    (1) You must maintain documentation of:
    (i) Results and interpretation of all testing for relevant 
communicable disease agents in compliance with Sec. Sec.  1271.80 and 
1271.85, as well as the name and address of the testing laboratory or 
laboratories;
    (ii) Results and interpretation of all donor screening for 
communicable diseases in compliance with Sec.  1271.75; and
    (iii) The donor-eligibility determination, including the name of 
the responsible person who made the determination and the date of the 
determination.
    (2) All records must be accurate, indelible, and legible. 
Information on the identity and relevant medical records of the donor, 
as defined in Sec.  1271.3(s), must be in English or, if in another 
language, must be retained and translated to English and accompanied by 
a statement of authenticity by the translator that specifically 
identifies the translated document.
    (3) You must retain required records and 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.''
    (4) You must retain the records pertaining to a particular 
HCT[sol]P at least 10 years after the date of its administration, or if 
the date of administration is not known, then at least 10 years after 
the date of the HCT[sol]P's distribution, disposition, or expiration, 
whichever is latest.


Sec.  1271.60  What quarantine and other requirements apply before the 
donor-eligibility determination is complete?

    (a) Quarantine. You must keep an HCT[sol]P in quarantine, as 
defined in Sec.  1271.3(q), until completion of the donor-eligibility 
determination required by Sec.  1271.50. You must quarantine semen from 
anonymous donors until the retesting required under Sec.  1271.85(d) is 
complete.
    (b) Identification of HCT[sol]Ps in quarantine. You must clearly 
identify as quarantined an HCT[sol]P that is in quarantine pending 
completion of a donor-eligibility determination. The quarantined 
HCT[sol]P must be easily distinguishable from HCT[sol]Ps that are 
available for release and distribution.
    (c) Shipping of HCT[sol]Ps in quarantine. If you ship an HCT[sol]P 
before completion of the donor-eligibility determination, you must keep 
it in quarantine during shipment. The HCT[sol]P must be accompanied by 
records:
    (1) Identifying the donor (e.g., by a distinct identification code 
affixed to the HCT[sol]P container);
    (2) Stating that the donor-eligibility determination has not been 
completed; and
    (3) Stating that the product must not be implanted, transplanted, 
infused, or transferred until completion of the donor-eligibility 
determination, except under the terms of paragraph (d) of this section.
    (d) Use in cases of urgent medical need.
    (1) This subpart C does not prohibit the implantation, 
transplantation, infusion, or transfer of an HCT[sol]P from a donor for 
whom the donor-eligibility determination is not complete if there is a 
documented urgent medical need for the HCT[sol]P, as defined in Sec.  
1271.3(u).
    (2) If you make an HCT[sol]P available for use under the provisions 
of paragraph (d)(1) of this section, you must prominently label it 
``NOT EVALUATED FOR INFECTIOUS SUBSTANCES,'' and `` WARNING: Advise 
patient of communicable disease risks.'' The following information must 
accompany the HCT[sol]P:
    (i) The results of any donor screening required under Sec.  1271.75 
that has been completed;
    (ii) The results of any testing required under Sec.  1271.80 or 
1271.85 that has been completed; and
    (iii) A list of any screening or testing required under Sec.  
1271.75, 1271.80 or 1271.85 that has not yet been completed.
    (3) If you are the establishment that manufactured an HCT[sol]P 
used under the provisions of paragraph (d)(1) of this section, you must 
document that you notified the physician using the HCT[sol]P that the 
testing and screening were not complete.
    (4) In the case of an HCT[sol]P used for an urgent medical need 
under the provisions of paragraph (d)(1) of this section, you must 
complete the donor-eligibility determination during or after the use of 
the HCT[sol]P, and you must inform the physician of the results of the 
determination.


Sec.  1271.65  How do I store an HCT[sol]P from a donor determined to 
be ineligible, and what uses of the HCT[sol]P are not prohibited?

    (a) Storage. If you are the establishment that stores the 
HCT[sol]P, you must store or identify HCT[sol]Ps from donors who have 
been determined to be ineligible in a physically separate area clearly 
identified for such use, or follow other procedures, such as automated

[[Page 29832]]

designation, that are adequate to prevent improper release until 
destruction or other disposition of the HCT[sol]P in accordance with 
paragraph (b) or (c) of this section.
    (b) Limited uses of HCT[sol]P from ineligible donor.
    (1) An HCT[sol]P from a donor who has been determined to be 
ineligible, based on the results of required testing and/or screening, 
is not prohibited by subpart C of this part from use for implantation, 
transplantation, infusion, or transfer under the following 
circumstances:
    (i) The HCT[sol]P is for allogeneic use in a first-degree or 
second-degree blood relative;
    (ii) The HCT[sol]P consists of reproductive cells or tissue from a 
directed reproductive donor, as defined in Sec.  1271.3(l); or
    (iii) There is a documented urgent medical need as defined in Sec.  
1271.3(u).
    (2) You must prominently label an HCT[sol]P made available for use 
under the provisions of paragraph (b)(1) of this section with the 
Biohazard legend shown in Sec.  1271.3(h) with the statement ``WARNING: 
Advise patient of communicable disease risks,'' and, in the case of 
reactive test results, ``WARNING: Reactive test results for (name of 
disease agent or disease).'' The HCT[sol]P must be accompanied by the 
records required under Sec.  1271.55.
    (3) If you are the establishment that manufactured an HCT[sol]P 
used under the provisions of paragraph (b)(1) of this section, you must 
document that you notified the physician using the HCT[sol]P of the 
results of testing and screening.
    (c) Nonclinical use. You may make available for nonclinical 
purposes an HCT[sol]P from a donor who has been determined to be 
ineligible, based on the results of required testing and/or screening, 
provided that it is labeled:
    (1) ``For Nonclinical Use Only'' and
    (2) With the Biohazard legend shown in Sec.  1271.3(h).


Sec.  1271.75  How do I screen a donor?

    (a) All donors. Except as provided under Sec.  1271.90, if you are 
the establishment that performs donor screening, you must screen a 
donor of cells or tissue by reviewing the donor's relevant medical 
records for:
    (1) Risk factors for, and clinical evidence of, relevant 
communicable disease agents and diseases, including:
    (i) Human immunodeficiency virus;
    (ii) Hepatitis B virus;
    (iii) Hepatitis C virus;
    (iv) Human transmissible spongiform encephalopathy, including 
Creutzfeldt-Jakob disease;
    (v) Treponema pallidum; and
    (2) Communicable disease risks associated with xenotransplantation.
    (b) Donors of viable, leukocyte-rich cells or tissue. In addition 
to the relevant communicable disease agents and diseases for which 
screening is required under paragraph (a) of this section, and except 
as provided under Sec.  1271.90, you must screen the donor of viable, 
leukocyte-rich cells or tissue by reviewing the donor's relevant 
medical records for risk factors for and clinical evidence of relevant 
cell-associated communicable disease agents and diseases, including 
Human T-lymphotropic virus.
    (c) Donors of reproductive cells or tissue. In addition to the 
relevant communicable disease agents and diseases for which screening 
is required under paragraphs (a) and (b) of this section, as 
applicable, and except as provided under Sec.  1271.90, you must screen 
the donor of reproductive cells or tissue by reviewing the donor's 
relevant medical records for risk factors for and clinical evidence of 
infection due to relevant communicable diseases of the genitourinary 
tract. Such screening must include screening for the communicable 
disease agents listed in paragraphs (c)(1) and (c)(2) of this section. 
However, if the reproductive cells or tissues are recovered 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 screening for the communicable disease agents listed in 
paragraphs (c)(1) and (c)(2) of this section is not required. 
Communicable disease agents of the genitourinary tract for which you 
must screen include:
    (1) Chlamydia trachomatis; and
    (2) Neisseria gonorrhea.
    (d) Ineligible donors. You must determine ineligible a donor who is 
identified as having either of the following:
    (1) A risk factor for or clinical evidence of any of the relevant 
communicable disease agents or diseases for which screening is required 
under paragraphs (a)(1)(i), (b), or (c) of this section; or
    (2) Any communicable disease risk associated with 
xenotransplantation.
    (e) Abbreviated procedure for repeat donors. If you have performed 
a complete donor screening procedure on a living donor within the 
previous 6 months, you may use an abbreviated donor screening procedure 
on repeat donations. The abbreviated procedure must determine and 
document any changes in the donor's medical history since the previous 
donation that would make the donor ineligible, including relevant 
social behavior.


Sec.  1271.80  What are the general requirements for donor testing?

    (a) Testing for relevant communicable diseases is required. To 
adequately and appropriately reduce the risk of transmission of 
relevant communicable diseases, and except as provided under Sec.  
1271.90, if you are the establishment that performs donor testing, you 
must test a donor specimen for evidence of infection due to 
communicable disease agents in accordance with paragraph (c) of this 
section. You must test for those communicable disease agents specified 
in Sec.  1271.85. In the case of a donor 1 month of age or younger, you 
must test a specimen from the birth mother instead of a specimen from 
the donor.
    (b) Timing of specimen collection. You must collect the donor 
specimen at the time of recovery of cells or tissue from the donor. 
However, if collection at the time of recovery is not feasible, then 
you may collect the donor specimen up to 7 days before or after 
recovery or, for donors of peripheral blood stem/progenitor cells only, 
up to 30 days before recovery. In the case of a repeat semen donor from 
whom a specimen has already been collected and tested, and for whom 
retesting is required under Sec.  1271.85(d), you are not required to 
collect a donor specimen at the time of each donation.
    (c) Tests. You must test 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; 
however, until such time as appropriate FDA-licensed, approved, or 
cleared donor screening tests for Chlamydia trachomatis and for 
Neisseria gonorrhea are available, you must use FDA-licensed, approved, 
or cleared tests labeled for the detection of those organisms in an 
asymptomatic, low-prevalence population. You must use a test 
specifically labeled for cadaveric specimens instead of a more 
generally labeled test when applicable and when available. Required 
testing under this section must be performed by a laboratory that 
either is certified to perform such testing on human specimens under 
the Clinical Laboratory Improvement Amendments of 1988 (42 U.S.C. 263a) 
and 42 CFR part 493, or has met equivalent requirements as determined 
by the Centers for Medicare and Medicaid Services.
    (d) Ineligible donors. You must determine the following donors to 
be ineligible:
    (1) A donor whose specimen tests reactive on a screening test for a

[[Page 29833]]

communicable disease agent in accordance with Sec.  1271.85, except for 
a donor whose specimen tests reactive on a non-treponemal screening 
test for syphilis and negative on a specific treponemal confirmatory 
test;
    (2)(i) A donor in whom plasma dilution sufficient to affect the 
results of communicable disease testing is suspected, unless:
    (A) You test a specimen taken from the donor before transfusion or 
infusion and up to 7 days before recovery of cells or tissue; or
    (B) You use an appropriate algorithm designed to evaluate volumes 
administered in the 48 hours before specimen collection, and the 
algorithm shows that plasma dilution sufficient to affect the results 
of communicable disease testing has not occurred.
    (ii) Clinical situations in which you must suspect plasma dilution 
sufficient to affect the results of communicable disease testing 
include but are not limited to the following:
    (A) Blood loss is known or suspected in a donor over 12 years of 
age, and the donor has received a transfusion or infusion of any of the 
following, alone or in combination:
    (1) More than 2,000 milliliters (mL) of blood (e.g., whole blood, 
red blood cells) or colloids within 48 hours before death or specimen 
collection, whichever occurred earlier, or
    (2) More than 2,000 mL of crystalloids within 1 hour before death 
or specimen collection, whichever occurred earlier.
    (B) Regardless of the presence or absence of blood loss, the donor 
is 12 years of age or younger and has received a transfusion or 
infusion of any amount of any of the following, alone or in 
combination:
    (1) Blood (e.g., whole blood, red blood cells) or colloids within 
48 hours before death or specimen collection, whichever occurred 
earlier, or
    (2) Crystalloids within 1 hour before death or specimen collection, 
whichever occurred earlier.


Sec.  1271.85  What donor testing is required for different types of 
cells and tissues?

    (a) All donors. To adequately and appropriately reduce the risk of 
transmission of relevant communicable diseases, and except as provided 
under Sec.  1271.90, you must test a specimen from the donor of cells 
or tissue, whether viable or nonviable, for evidence of infection due 
to relevant communicable disease agents, including:
    (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) Donors of viable, leukocyte-rich cells or tissue. In addition 
to the relevant communicable disease agents for which testing is 
required under paragraph (a) of this section, and except as provided 
under Sec.  1271.90,
    (1) You must test a specimen from the donor of viable, leukocyte-
rich cells or tissue to adequately and appropriately reduce the risk of 
transmission of relevant cell-associated communicable diseases, 
including:
    (i) Human T-lymphotropic virus, type I; and
    (ii) Human T-lymphotropic virus, type II.
    (2) You must test a specimen from the donor of viable, leukocyte-
rich cells or tissue for evidence of infection due to cytomegalovirus 
(CMV), to adequately and appropriately reduce the risk of transmission. 
You must establish and maintain a standard operating procedure 
governing the release of an HCT[sol]P from a donor whose specimen tests 
reactive for CMV.
    (c) Donors of reproductive cells or tissue. In addition to the 
communicable disease agents for which testing is required under 
paragraphs (a) and (b) of this section, as applicable, and except as 
provided under Sec.  1271.90, you must test a specimen from the donor 
of reproductive cells or tissue to adequately and appropriately reduce 
the risk of transmission of relevant communicable disease agents of the 
genitourinary tract. Such testing must include testing for the 
communicable disease agents listed in paragraphs (c)(1) and (c)(2) of 
this section. However, if the reproductive cells or tissues are 
recovered 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 testing for the communicable disease 
agents listed in paragraphs (c)(1) and (c)(2) of this section is not 
required. Communicable disease agents of the genitourinary tract for 
which you must test include:
    (1) Chlamydia trachomatis; and
    (2) Neisseria gonorrhea.
    (d) Retesting anonymous semen donors. Except as provided under 
Sec.  1271.90 and except for directed reproductive donors as defined in 
Sec.  1271.3(l), at least 6 months after the date of donation of semen 
from anonymous donors, you must collect a new specimen from the donor 
and test it for evidence of infection due to the communicable disease 
agents for which testing is required under paragraphs (a), (b), and (c) 
of this section.
    (e) Dura mater. For donors of dura mater, you must perform an 
adequate assessment designed to detect evidence of transmissible 
spongiform encephalopathy.


Sec.  1271.90  Are there exceptions from the requirement of determining 
donor eligibility, and what labeling requirements apply?

    (a) Donor-eligibility determination not required. You are not 
required to make a donor-eligibility determination under Sec.  1271.50 
or to perform donor screening or testing under Sec. Sec.  1271.75, 
1271.80 and 1271.85 for:
    (1) Cells and tissues for autologous use; or
    (2) Reproductive cells or tissue donated by a sexually intimate 
partner of the recipient for reproductive use; or
    (3) Cryopreserved cells or tissue for reproductive use, originally 
exempt under paragraph (a)(1) or (a)(2) at the time of donation, that 
are subsequently intended for directed donation, provided that
    (i) Additional donations are unavailable, for example, due to the 
infertility or health of a donor of the cryopreserved reproductive 
cells or tissue; and
    (ii) Appropriate measures are taken to screen and test the donor(s) 
before transfer to the recipient.
    (b) Required labeling. You must prominently label an HCT[sol]P 
listed in paragraph (a) of this section:
    (1) ``FOR AUTOLOGOUS USE ONLY,'' if it is stored for autologous 
use;
    (2) ``NOT EVALUATED FOR INFECTIOUS SUBSTANCES'' and ``WARNING: 
Advise patient of communicable disease risks,'' unless you have 
performed all otherwise applicable screening and testing under 
Sec. Sec.  1271.75, 1271.80, and 1271.85; and
    (3) With the Biohazard legend shown in Sec.  1271.3(h), with the 
statement ``WARNING: Advise patient of communicable disease risks,'' 
and, in the case of reactive test results, ``WARNING: Reactive test 
results for (name of disease agent or disease)'' if the results of any 
screening or testing performed indicate:
    (i) The presence of relevant communicable disease agents and/or
    (ii) Risk factors for or clinical evidence of relevant communicable 
disease agents or diseases.


[[Page 29834]]


    Dated: March 10, 2004.
Lester M. Crawford,
Acting Commissioner for Food and Drugs.

    Dated: March 10, 2004.
Tommy G. Thompson,
Secretary of Health and Human Services.
[FR Doc. 04-11245 Filed 5-20-04; 8:45 am]
BILLING CODE 4160-01-S