[Printable PDF]
[Federal Register: May 25, 2004 (Volume 69, Number 101)]
[Rules and Regulations]
[Page 29785-29834]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr25my04-11]
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Part II
Department of Health and Human Services
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Food and Drug Administration
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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
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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.
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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
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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,
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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
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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
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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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/tissue/min.htm.
Additional materials associated with the donor eligibility
rule are available on the Internet at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.thespermbankofca.org/services/fees.htm
).
6. The Sperm Bank of California (http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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