[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]
[[Page 29785]]
-----------------------------------------------------------------------
Part II
Department of Health and Human Services
-----------------------------------------------------------------------
Food and Drug Administration
-----------------------------------------------------------------------
21 CFR Parts 210, 211, 820, and 1271
Eligibility Determination for Donors of Human Cells, Tissues, and
Cellular and Tissue-Based Products; Final Rule and Notice
[[Page 29786]]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 210, 211, 820, and 1271
[Docket No. 1997N-0484S]
[RIN 0910-AB27]
Eligibility Determination for Donors of Human Cells, Tissues, and
Cellular and Tissue-Based Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is requiring human
cell, tissue, and cellular and tissue-based product (HCT[sol]P)
establishments to screen and test cell and tissue donors for risk
factors for, and clinical evidence of, relevant communicable disease
agents and diseases. The agency is amending the current good
manufacturing practice (CGMP) and quality system (QS) regulations that
apply to HCT[sol]Ps regulated as drugs, medical devices, and/or
biological products to clarify the role of the new donor-eligibility
regulations in relation to existing CGMP regulations. By preventing the
transmission of communicable disease by the wide spectrum of HCT[sol]Ps
that are marketed now or may be marketed in the future, the agency's
action will improve protection of the public health and increase public
confidence in new technologies.
DATES: This rule is effective May 25, 2005. This rule is applicable to
cells and tissues recovered on or after May 25, 2005.
FOR FURTHER INFORMATION CONTACT: Paula S. McKeever, Center for
Biologics Evaluation and Research (HFM-17), Food and Drug
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448, 301-827-6210.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Introduction
A. Background
B. Legal Authority
II. Highlights of the Final Rule
A. Plain Language
B. New Terminology and Definitions
C. Other Highlights
III. Comments on the Proposed Rule and FDA's Responses
A. General
B. Amendments to 21 CFR Parts 210, 211, and 820
C. Definitions (Sec. 1271.3)
D. Part 1271, Subpart C--Donor-Eligibility
E. Economic Impacts
IV. Analysis of Economic Impacts
A. Objectives and Basis of the Proposed Action
B. The Type and Number of Entities Affected
C. Nature of Impacts
D. Benefits of the Final Rule
E. Small Entity Impacts and Analysis of Alternatives
V. Environmental Impact
VI. Federalism Assessment
VII. The Paperwork Reduction Act of 1995
VIII. References
I. Introduction
This final rule is part of a comprehensive new system of regulation
for HCT[sol]Ps. The goal of the new approach is to improve protection
of the public health without imposing unnecessary restrictions on
research, development, or the availability of new products.
Consolidating the regulation of HCT[sol]Ps into one regulatory program
is expected to lead to increased consistency and greater efficiency.
Together, these planned improvements will increase the safety of
HCT[sol]Ps, and public confidence in their safety. We intend to make
the good tissue practice final rule, which has not yet published but
which FDA intends to issue soon, effective 1 year after publication of
this rule. Once both this rule and the good tissue practice regulations
are in effect, FDA's comprehensive regulatory framework will be
complete.
A. Background
In 1997, FDA proposed a new approach to the regulation of
HCT[sol]Ps (62 FR 9721, March 4, 1997). (The term ``HCT[sol]P'' is
defined at Sec. 1271.3(d) (21 CFR 1271.3(d).) To improve the
regulation of HCT[sol]Ps, we announced our intention to establish a
comprehensive regulatory program for HCT[sol]Ps, contained in part 1271
(21 CFR part 1271). In accordance with the tiered, risk-based approach
that we proposed, some HCT[sol]Ps would be regulated only under these
new regulations, while others would also be regulated as drugs,
devices, and/or biological products.
To implement the proposed approach, we issued three proposed rules:
Establishment Registration and Listing for Manufacturers
of Human Cellular and Tissue-Based Products (the registration proposed
rule) (63 FR 26744, May 14, 1998);
Suitability Determination for Donors of Human Cellular and
Tissue-Based Products (the donor-suitability proposed rule) (64 FR
52696, September 30, 1999); and
Current Good Tissue Practice for Manufacturers of Human
Cellular and Tissue-Based Products; Inspection and Enforcement (the
CGTP proposed rule) (66 FR 1508, January 8, 2001).
We published a final rule entitled ``Human Cells, Tissues, and
Cellular and Tissue-Based Products; Establishment Registration and
Listing,'' in the Federal Register on January 19, 2001 (the
registration final rule) (66 FR 5447). The registration final rule put
into place general provisions pertaining to the scope and applicability
of part 1271. These provisions are contained in subpart A of part 1271,
along with a section that contains definitions applicable to all of
part 1271 (Sec. 1271.3). The registration final rule requires cell and
tissue establishments to register with us and submit a list of their
HCT[sol]Ps; the procedures for registration and listing are contained
in subpart B of part 1271.
Some sections of the registration final rule became effective on
April 4, 2001. Under those provisions, we now receive registration and
listing information from establishments that engage in the recovery,
screening, testing, processing, storage, or distribution of human
tissue intended for transplantation (as described in Sec.
1271.3(d)(1)). The effective date for the remaining sections was
January 21, 2003, by which time we expected to have completed
rulemaking for all of part 1271 (66 FR 5447 at 5448). At that time, the
registration and listing requirements would have become effective for
all other HCT[sol]Ps (as described in Sec. 1271.3(d)(2)). However, we
recognized that unanticipated delays in completing the rulemaking for
the remainder of part 1271 could occur, and we noted that, should the
rulemaking proceedings be delayed past the 2-year timeframe, we would
consider whether to maintain the 2-year effective date for the
HCT[sol]Ps described in Sec. 1271.3(d)(2) or whether to extend that
date for some or all of these HCT[sol]Ps (66 FR 5447 at 5449). Since
the rulemaking proceedings were delayed past the original 2-year
effective date of January 21, 2003, we delayed the effective date of
Sec. 1271.3(d)(2) until January 21, 2004 (68 FR 2690, January 21,
2003). After the definition became final on January 21, 2004, we issued
an interim final rule excepting human dura mater and human heart valve
allografts from the scope of the definition of ``human cells, tissues,
or cellular or tissue-based products (HCT[sol]Ps)'' (69 FR 3823,
January 27, 2004). We took this action to assure that these products,
which were subject to the Federal Food, Drug, and Cosmetic Act (the
act) and therefore regulated under the current good
[[Page 29787]]
manufacturing practice regulations set out in the quality system
regulations in part 820 (21 CFR part 820), were not released from the
scope of those regulations before a more comprehensive regulatory
framework applicable to HCT[sol]Ps, including donor eligibility
requirements, good tissue practice regulations, and appropriate
enforcement provisions, is fully in place. When that comprehensive
framework is in place, we intend that human dura mater and human heart
valve allografts will be subject to it. We intend to revoke the interim
final rule at that time.
We are now making final the donor-suitability proposed rule that
was proposed on September 30, 1999. (For reasons discussed in comment
26 of this document, we refer in this final rule to donor
``eligibility'' rather than ``suitability.'') The comment period for
that proposed rule closed on December 29, 1999. On April 18, 2000, we
reopened the comment period for an additional 90 days. We took this
step in response to requests for an extension of the comment period as
well as to provide sufficient time for State officials to participate
in the rulemaking (65 FR 20774, April 18, 2000).
Because of their nature as derivatives of the human body,
HCT[sol]Ps pose a risk of transmitting communicable diseases. For this
reason, this final rule requires that most cell and tissue donors be
tested and screened for evidence of relevant communicable disease
infection. It also contains other related requirements (e.g., on
records, quarantine, storage, and labeling). These donor-eligibility
requirements, which locate in subpart C of part 1271, are part of the
core requirements applicable both to HCT[sol]Ps regulated solely under
these regulations and section 361 (the 361 HCT[sol]Ps) of the Public
Health Service Act (the PHS Act) and to those HCT[sol]Ps also subject
to regulation as drugs, devices, and/or biological products. As part of
this rulemaking, we are also amending the drug CGMP regulations and the
device QS regulations to clarify the role of the donor-eligibility
requirements in the manufacture of HCT[sol]Ps subject to regulation as
drugs, devices, and/or biological products.
Since the publication of the donor-suitability proposed rule, we
have continued to obtain current and accurate information on the risks
of communicable-disease transmission by HCT[sol]Ps and the most
appropriate testing and screening measures. To this end, we have met
with FDA's Transmissible Spongiform Encephalopathies Advisory Committee
(TSEAC) (January 18 to 19, 2001, and June 26 to 27, 2002); the Blood
Products Advisory Committee (BPAC) (December 13 to 14, 2001, and March
14 to 15, 2002); and the Centers for Disease Control and Prevention
(CDC) (June 26 to 27, 2000). We have placed information on these
meetings in the docket for this rulemaking.
We have used the information obtained at those meetings to develop
a draft guidance document on determining donor eligibility entitled
``Eligibility Determination for Donors of Human Cells, Tissues, and
Cellular and Tissue-Based Products'' (the donor-eligibility draft
guidance). Elsewhere in this issue of the Federal Register, we announce
the availability of that draft guidance, and solicit comments on its
contents. We have also developed draft guidance on screening for
Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease
(vCJD) entitled ``Guidance for Industry: Preventive Measures to Reduce
the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD)
and Variant Creutzfeldt-Jakob Disease (vCJD) by Human Cells, Tissues,
and Cellular and Tissue-Based Products (HCT[sol]Ps)'' (the CJD draft
guidance) (67 FR 42789, June 25, 2002). We intend to combine the donor-
eligibility draft guidance with the CJD draft guidance, and to issue a
single final guidance document.
B. Legal Authority
We are issuing these new regulations under the authority of section
361 of the PHS Act (42 U.S.C. 264). Under that section, by delegation
from the Surgeon General and the Secretary of Health and Human
Services, FDA may make and enforce regulations necessary to prevent the
introduction, transmission, or spread of communicable diseases between
the States or from foreign countries into the States. Intrastate
transactions affecting communicable disease transmission may also be
regulated under section 361 of the PHS Act. (See Louisiana v. Mathews,
427 F. supp. 174, 176 (E.D. La. 1977).)
It is especially important to recognize that HCT[sol]P
manufacturing inevitably has interstate effects. HCT[sol]Ps recovered
in one State may be sent to another for processing, then shipped for
use throughout the United States, or beyond. FDA has been involved in
many recalls where HCT[sol]Ps processed in a single establishment have
been distributed in many States.
Section 361 of the PHS Act authorizes FDA to issue regulations
necessary to prevent the introduction, transmission, or spread of
communicable diseases. Communicable diseases include, but are not
limited to, those transmitted by viruses, bacteria, fungi, parasites,
and transmissible spongiform encephalopathy agents.
Certain diseases are transmissible through the implantation,
transplantation, infusion, or transfer of HCT[sol]Ps derived from
donors infected with those diseases. To prevent the introduction,
transmission, or spread of such diseases, we consider it necessary to
take appropriate measures to prevent the use of cells or tissues from
infected donors. Thus, these regulations require that, before the use
of most HCT[sol]Ps, the cell or tissue donor must be determined to be
eligible to donate, based on the results of screening and testing for
relevant communicable diseases. In most cases, a donor who tests
reactive for a particular disease, or who possesses clinical evidence
of or risk factors for such a disease, would be considered ineligible,
and cells and tissues from that donor would not ordinarily be used.
In addition to regulations governing the testing and screening of
donors for relevant communicable disease and quarantine and storage of
HCT[sol]Ps, FDA has also determined that regulations requiring
establishments to maintain certain records related to HCT[sol]Ps and to
establish standard operating procedures are necessary to prevent the
introduction, transmission, or spread interstate of communicable
disease. A single donor may be the source of a large number of
HCT[sol]Ps. For example, it may be discovered, long after the donation
and transplantations have been completed, that a donor of HCT[sol]Ps
transplanted into a large number of recipients had a relevant
communicable disease. Although it might be too late to prevent the
recipients' infections, it would not be too late to for the recipient
to obtain treatment and take steps to avoid infecting others, such as
close family members. However, unless adequate records were maintained,
and maintained for the period of time throughout which infections may
be identified, it would be impossible to identify the recipients
potentially infected by the donor's HCTPs. This would be a critical
breakdown in the prevention of disease transmission. Accordingly, FDA
determined that the maintenance and retention of records are necessary
to prevent the interstate introduction, transmission, and spread of
communicable disease. Since some diseases, such as transmissible
spongiform encephalopathies (TSEs), appear to have a long latency
period, FDA has determined that a 10-year record retention period is
necessary.
Similarly, it is necessary for establishments to establish,
maintain,
[[Page 29788]]
and follow procedures related to the prevention of communicable
disease. The agency has determined that these provisions are necessary
to ensure that the important protections created by these regulations
are actually effected and are not simply empty promises. Only
manufacturing conducted in accordance with established procedures can
assure that HCT[sol]Ps meet the standards in these rules. If
standardized processes are not developed and used, mistakes,
inevitably, are made. Moreover, review of procedures can be critical to
determining the cause of a disease transmission. Without that analysis,
it would be impossible to prevent a future occurrence, with possibly
fatal consequences.
These regulations are intended to prevent the transmission of
communicable disease through the implantation, transplantation,
infusion, or transfer of HCT[sol]Ps. However, as noted in the
registration and donor-suitability proposed rules, all HCT[sol]Ps pose
some risk of carrying pathogens that could cause disease in health-care
personnel, other handlers of tissue, recipients, and family members or
other contacts of recipients (63 FR 26744 and 64 FR 52696 at 52698).
This broader concern for the spread of communicable disease is
reflected in certain labeling requirements in these regulations and in
the criteria for identifying a relevant communicable disease. We
recognize that regulations exist that are specifically designed to
protect employees who may come in contact with infectious materials
(see 29 CFR 1910.1030, 42 CFR 72.6, and 49 CFR 173.196), and we do not
consider these regulations to be in conflict with those other
regulations currently in effect. However, we have made an effort to be
consistent with the terminology used in these other regulations; e.g.,
``Infectious Substances'' and the Biohazard legend.
Under section 361 of the PHS Act, FDA is authorized to enforce the
regulations it issues to prevent the introduction, transmission, or
spread of communicable diseases interstate through such means as
inspection, disinfection, sanitation, destruction of animals or
articles found to be so infected or contaminated as to be sources of
dangerous infection in human beings, and other measures that may be
necessary. In addition, under section 368(a) of the PHS Act, any person
who violates a regulation prescribed under section 361 of the PHS Act
may be punished by imprisonment for up to 1 year. Individuals may also
be punished for violating such a regulation by a fine of up to $100,000
if death has not resulted from the violation or up to $250,000 if death
has resulted. For organizational defendants, fines range up to $200,000
and $500,000. Individuals and organizations also face possible
alternative fines based on the amount of gain or loss (18 U.S.C. 3559
and 3571(b) through (d)). Federal District Courts also have
jurisdiction to enjoin individuals and organizations from violating
regulations implementing section 361 of the PHS Act. (See Califano v.
Yamasaki, 442 U.S. 682, 704-05 (1979); United States v. Beatrice Foods
Co., 493 F.2d 1259, 1271-72 (8th Cir. 1974), cert. denied, 420 U.S. 961
(1975).) Under sections 501(a)(2)(B) and (h), and 520(f)(1) of the
Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 351(a)(2)(B)
and (h), and 21 U.S.C. 360j(f)(1)), drugs (including biological
products) and devices (including biological products) are subject to
CGMP requirements designed to ensure, among other things, product
safety (21 U.S.C. 351(a)(2)(B) and (h), and 21 U.S.C. 360j(f)(1)). The
authorities supporting the CGMP and QS regulations are also applicable
when the CGMP and QS regulations apply to an HCT[sol]P regulated as a
drug, biological product, or device. Currently, the CGMP and QS
regulations applicable to HCT[sol]Ps regulated as drugs or devices do
not delineate testing and screening procedures for communicable
diseases. (See parts 210, 211, and 820 (21 CFR parts 210, 211, and
820).) Nevertheless, we consider communicable-disease testing and
screening to be steps in the manufacturing process that are crucial to
the safety of such products. As a result, we are amending the existing
CGMP regulations for drugs in parts 210 and 211 and the QS regulations
for devices in part 820, which include CGMP requirements, to make clear
that the testing and screening provisions of part 1271 subpart C apply
to HCT[sol]Ps regulated as drugs, devices, and/or biological products.
Under Sec. 210.1(c), the manufacturer of an HCT[sol]P regulated as
a drug, including a biological product that is a drug under the act,
must comply with the donor-eligibility procedures in part 1271, subpart
C. Failure to follow the CGMP requirements, including the testing and
screening procedures in part 1271, would make the product adulterated
under the act. In issuing this regulation, FDA is relying on the drug
CGMP authorities (in particular, section 501(a)(2)(B) of the act (21
U.S.C. 351(a)(2)(B)), as well as section 361 of the PHS Act. Under
Sec. 820.1(a)(1), the manufacturer of an HCT[sol]P regulated as a
device, including a biological product that is a device under the act,
must comply with the same procedures.
Section 375 of the PHS Act provides for Federal oversight of the
nation's Organ Procurement and Transplantation Network, and section 379
of the PHS Act authorizes the National Bone Marrow Donor Registry (42
U.S.C. 274c and 274k). The Health Resources and Services Administration
(HRSA) currently administers both of these programs. Given HRSA
oversight in these areas, vascularized human organs (to include
vascularized subparts of human organs) and minimally manipulated bone
marrow (as defined in Sec. 1271.3(d)(2)) for unrelated allogeneic use
are specifically excluded from these final regulations.
II. Highlights of the Final Rule
This final rule requires establishments to make donor-eligibility
determinations for cell and tissue donors, based on donor screening and
testing for relevant communicable disease agents and diseases (Sec.
1271.45). The regulations cover how to screen and test donors
(Sec. Sec. 1271.75, 1271.80, and 1271.85), as well as how to make the
donor-eligibility determination (Sec. 1271.50). The term ``relevant
communicable disease agent or disease'' is defined at Sec. 1271.3(r).
The rule also contains related requirements pertaining to procedures
(Sec. 1271.47); records (Sec. 1271.55); quarantine (Sec. 1271.60);
and storage of HCT[sol]Ps from ineligible donors (Sec. 1271.65). Two
of these provisions describe situations where it is not prohibited to
use an HCT[sol]P from an ineligible donor or a donor who has not yet
been determined eligible (Sec. Sec. 1271.60 and 1271.65). Exceptions
from the requirement for making a donor-eligibility determination
appear in Sec. 1271.90.
The donor-eligibility draft guidance that may be found elsewhere in
this Federal Register is intended to assist establishments in complying
with the requirements of this final rule and contains details that are
not in the regulation. Although not binding, the draft guidance
presents the agency's current thinking on the topics covered. For
example, whereas the regulation requires an establishment to screen
donors for risk factors, the draft guidance specifies what we consider
those risk factors to be. Similarly, the draft guidance contains
recommendations on which tests to use to comply with the testing
requirements in Sec. Sec. 1271.80 and 1271.85. The draft guidance also
identifies several additional disease agents or diseases that we
believe meet the definition of relevant communicable disease agent or
[[Page 29789]]
disease. We welcome comments on the draft guidance. As scientific
knowledge is developed, new tests are introduced, and additional
relevant communicable disease agents and diseases are identified, we
intend to follow the good guidance practices set out in Sec. 10.115 to
modify the donor-eligibility guidance so that it remains current.
A. Plain Language
In the Federal Register of June 10, 1998 (63 FR 31885), the
Presidential Memorandum on Plain Language in Government Writing was
issued. The goal of the plain language initiative is to publish
government documents that are easier to understand.
In response to this initiative, we have written the donor-
eligibility regulation in plain language. We have taken the following
actions:
Written the regulation in question-and-answer format;
Reorganized some regulatory sections for greater clarity;
and
Followed other plain-language conventions, such as using
``must'' instead of ``shall.''
The resulting codified language is easier to read and understand
than the proposed regulation. These editorial changes are for clarity
only and do not change the substance of the requirements.
B. New Terminology and Definitions
In the registration final rule, we discussed our decision to
replace the term ``human cellular or tissue-based products'' with
``human cells, tissues, and cellular and tissue-based products''
(abbreviated HCT[sol]Ps) (66 FR 5447 at 5455). For consistency, we have
made the same change in this final rule.
In response to comments, we have changed the term ``donor
suitability'' to ``donor eligibility.''
In addition, we have made several changes to the definition of
``relevant communicable disease agent or disease'' with respect to
prevalence. We intend the new language to cover both intentional and
unintentional release of infectious agents.
We have also modified the definition of ``directed donor'' and
changed the term to ``directed reproductive donor.''
We have deleted the definitions of ``xenotransplantation'' and
``close contacts.''
C. Other Highlights
This final rule contains other changes from the proposed rule.
These changes are listed as follows:
Provisions in Sec. 1271.47, originally proposed in the
CGTP proposed rule, require that HCT[sol]P establishments establish and
maintain procedures for the steps they perform in determining donor
eligibility, including testing and screening;
The requirement for donor retesting 6 months after
donation now applies only to anonymous semen donors. In addition, you
do not have to obtain a specimen for testing at each donation from a
repeat anonymous donor, so long as you do not release the donation
unless the donor has been retested (at least 6 months post donation).
Directed donations of semen are excepted from the retesting
requirement;
Physical separation between HCT[sol]Ps from ineligible and
eligible donors is no longer required;
We have removed the requirement that a physician must
consent to the use of an HCT[sol]P from an ineligible donor;
You must screen all donors for Treponema pallidum and some
donors for Human T-lymphotropic virus (HTLV) (in addition to testing);
You must screen donors for ``communicable disease risks
associated with xenotransplantation.'' Under the proposed rule, receipt
of a xenotransplantation product would have made a donor ineligible
under all circumstances. Now, receipt of a xenotransplantation product
no longer overrides the special circumstances, listed in Sec.
1271.65(b)(1), under which use of an HCT[sol]P from an ineligible donor
is not prohibited;
We have modified the requirements applicable to testing
for Cytomegalovirus (CMV);
If the donor is one month of age or younger, you must test
a specimen from the birth mother;
The requirements on timing of specimen collection allow 7
days before or after recovery, or for donors of peripheral blood stem
progenitor cells only, up to 30 days before recovery, if specimen
collection at the time of recovery is not feasible; and
Required testing can be performed by a laboratory that has
met requirements equivalent to those imposed by the Clinical Laboratory
Improvement Amendments of 1988 (CLIA), as determined by the Centers for
Medicare and Medicaid Services (CMS).
III. Comments on the Proposed Rule and FDA's Responses
We received over 500 comments on the proposed rule.
Some comments raised issues relating to the general provisions in
subpart A of part 1271 or the registration and listing procedures in
subpart B, and we considered those comments in drafting the
registration final rule (66 FR 5447 at 5450, January 19, 2001). For
example, in that final rule we discussed comments on dispute resolution
(66 FR 5447 at 5451); homologous use (66 FR 5447 at 5458); the practice
of medicine (66 FR 5447 at 5452); minimal manipulation (66 FR 5447 at
5457); the definition of ``family-related allogeneic use'' (66 FR 5447
at 5454); the terms ``human cellular or tissue-based product'' and
``manufacture'' (66 FR 5447 at 5455 and 5456); the regulation of bone
allografts (66 FR 5447 at 5457); establishments not required to comply
with part 1271 (66 FR 5447 at 5460); and the frequency of updates (66
FR 5447 at 5460 and 5461). If we considered an issue in the
registration final rule, we are not reiterating our response here.
Several comments submitted to the docket for the CGTP proposed rule
raised issues that are appropriately addressed in this final rule. We
respond to those comments in comments 32, 48, 49, and 59, and in the
discussion of Sec. 1271.47 in section III.D.3 of this document.
We received two requests for an extension of the comment period. On
April 18, 2000, a document was published in the Federal Register
reopening the comment period for an additional 90 days (65 FR 20774).
A. General
(Comment 1) We received various comments expressing general
approval of the proposed rule. One comment applauded us for addressing
concerns of vital interest to the protection of the public health.
Another comment expressed continued support for our efforts to design a
comprehensive regulatory program for HCT[sol]Ps, and agreed that
screening and testing of donors constitutes a vital component of such a
program. Other comments supported our goal of preventing the
transmission of communicable diseases through donor screening and
testing. One comment supported requiring semen banks to comply with the
proposed screening and testing regulations.
We also received comments voicing general criticism of the proposed
rule and of our comprehensive regulatory approach to cells and tissues.
Some comments described the proposed rule as unnecessary or burdensome.
One comment asserted that the regulations were inconsistent with the
Congressionally supported ``least burdensome'' practice of regulation.
(Response) We acknowledge and appreciate the supportive comments.
This rule contains important requirements that will help prevent the
transmission of communicable diseases by HCT[sol]Ps. Moreover, it forms
a vital
[[Page 29790]]
component of the new tiered, risk-based regulatory program, which will
be superior to the patchwork of requirements that it replaces. As
discussed in greater detail in section IV of this document, this rule
is consistent with Executive Order 12866, which, in its eleventh
Principle of Regulation applicable to Federal rulemaking, requires FDA
to ``* * * tailor its regulations to impose the least burden on society
* * * consistent with obtaining the regulatory objectives.'' FDA has
designed this regulatory program to impose only appropriate, and
appropriately limited, burdens.
For example, the compliance expectations for a small medical
practice that provides artificial insemination are commensurate with
the communicable disease risks associated with its activities. If the
practice is limited to artificial insemination using either semen from
an anonymous or directed reproductive donor obtained from a semen bank
(Sec. 1271.15(d)), or semen recovered at the practice and immediately
used to inseminate the donor's sexually intimate partner (Sec.
1271.15(e)), then the risks are minimal and the practice is not
required to comply with part 1271. If the semen is not immediately
transferred to a donor's sexually intimate partner but instead is
stored (raising concerns about possible cross-contamination during
storage), the practice would not be eligible for the exception under
Sec. 1271.15(e) and would need to comply with the requirements in part
1271 subpart B (registration and listing) and in applicable sections of
subpart C (minimal standard operating procedures, minimal
recordkeeping, and specific labeling for stored reproductive cells or
tissue from sexually intimate partners if not screened or tested).
Additional risks are associated with the recovery of semen from an
anonymous or directed reproductive donor for artificial insemination;
practitioners who perform these services are not eligible for the
exception under Sec. 1271.15(d) and must comply with both subpart B
(registration and listing) and all of subpart C (donor screening and
testing, standard operating procedures, recordkeeping, and labeling) in
part 1271. FDA intends to provide further detailed guidance regarding
these risk-based approaches.
We have striven to establish regulations that provide public health
protection without imposing an undue burden on regulated industry. In
this sense, they are also entirely consistent with the requirement for
``least burdensome'' regulation of devices set out in section 205(a)
and (b) of the Food and Drug Administration Modernization Act of 1997.
(Comment 2) Several comments asked that provisions be made for
HCT[sol]Ps collected before the effective date of this regulation and
opposed retrospective application of the new regulations.
(Response) This regulation will apply to cells and tissues
recovered on or after the effective date of the regulation.
(Comment 3) One comment urged us to coordinate our donor screening
requirements with those of other countries.
(Response) We support the long-term goal of international
harmonization. In the process of developing this final rule, we have
reviewed standards from other countries and met with representatives
from the European Union, Australia, Japan, and other nations. The
requirements in place in other countries are diverse and rarely static,
reflecting the fact that other countries may have screening needs
different from those in the United States and different tests available
to them. The challenge of achieving consistency is underscored by the
European Commission's announcement of the need for a new directive on
human tissue, intended to replace the current myriad of 15 differing--
and sometimes nonexistent--national laws on the subject. On June 19,
2002, the Commission of European Communities put forth a ``Proposal for
a Directive of the European Parliament and of the Council on setting
standards of quality and safety for the donation, procurement, testing,
processing, storage, and distribution of human tissues and cells.''
Completion of this directive is expected to take several years. We
applaud this effort and will continue to follow developments in tissue
regulation throughout the world. However, at this time, our primary
goal is to put into place the basic safeguards set out in this rule, an
effort that may provide a starting point for further harmonization
efforts.
(Comment 4) Several comments stated that the rule would conflict
with the rule concerning privacy of health care information proposed by
the Department of Health and Human Services (HHS) on November 3, 1999.
The privacy rule was subsequently finalized on December 28, 2000 (65 FR
82462), and amended on August 14, 2002 (67 FR 53182).
(Response) The Department regulations on privacy of health care
information (the Privacy Rule) were codified at 45 CFR parts 160 and
164. The Privacy Rule does not include the procurement or banking of
organs, blood (including autologous), sperm, eyes or any other tissue
or human product within the definition of health care and the
establishments that perform such activities are not considered health
care providers when conducting these functions (65 FR 82462 at 82477,
December 28, 2000). In addition, the Privacy Rule authorizes health
care providers who are subject to the Privacy Rule to ``disclose
protected health information to organ procurement organizations or
other entities engaged in the procurement, banking or transplantation
of cadaveric organs, eyes, or tissue for the purpose of facilitating
organ, eye or tissue donation and transplantation'' (45 CFR
164.512(h)). The preamble to the Privacy Rule notes that, when an
individual has not previously authorized release of protected health
information, this provision of the Privacy Rule ``* * * is intended to
allow covered entities [those subject to the privacy rule] to initiate
contact with organ and tissue donation and transplantation
organizations to facilitate transplantation of cadaveric organs, eyes,
and tissues'' (65 FR 82464 at 82534). The Privacy Rule further
authorizes covered entities to disclose protected health information to
persons subject to the jurisdiction of FDA with respect to an FDA-
regulated product or activity for which that person has responsibility,
for the purpose of activities related to the quality, safety or
effectiveness of such FDA-regulated product or activity (45 CFR
164.512(b)(1)(iii)). Finally, we further note that in the event that
one of the previously mentioned provisions is not applicable, covered
entities may disclose protected health information pursuant to an
authorization from the individual or the individual's personal
representative (45 CFR 164.502(a)(1)(iv) and (g)(1), and 164.508). For
these reasons, we do not believe that the Privacy Rule conflicts with
this final rule.
However, FDA has considered the impact of this donor-eligibility
final rule on patient privacy. We have deleted the requirement that
relevant patient records accompany an HCT[sol]P, requiring instead a
summary of records. We made this change in response to concerns about
privacy.
(Comment 5) One comment stated that, in the proposed rule, FDA
improperly ``relied'' on provisions of the registration proposed rule.
Another comment objected to the rulemaking process, asserting that we
circumvented the usual departmental review process before publishing
the proposed rule.
(Response) We disagree with both comments. In the proposed rule,
the agency did not ``rely'' on the registration
[[Page 29791]]
proposed rule, but merely described another ongoing, related,
rulemaking. Moreover, we made clear that the provisions of the
registration proposed rule we referenced in the preamble to the donor-
suitability proposed rule were merely proposals. The agency received
comments related to those proposals in the donor suitability docket.
When we finalized those provisions in the registration final rule, we
considered comments received in the donor suitability docket, as well
as in the registration docket (66 FR 5447 at 5450). With respect to the
second comment, we disagree that we followed anything other than our
usual review process; however, we note that these procedures constitute
department practice and are not required by regulation by law or
regulation.
(Comment 6) One comment cited a potential conflict with the
regulation issued by CMS requiring hospitals to notify organ
procurement organizations (OPOs) upon patients' death or imminent death
(42 CFR 482.45). The comment pointed out that OPOs might, in some
instances, determine donor eligibility for tissue donors. The comment
asserted that FDA does not regulate OPOs and questioned who would be
accountable for compliance with FDA regulations.
(Response) We disagree that there is a conflict between the
regulations in part 1271 and CMS's regulation of OPOs; we also disagree
that OPOs are exempt from FDA regulations. The determination of donor
eligibility is a key function of an HCT[sol]P manufacturing
establishment. Therefore, although human organs are excluded from the
definition of HCT[sol]P, and thus not covered by the regulations in
part 1271, any OPO that performs any part of any HCT[sol]P
manufacturing function, is subject to the regulations in part 1271.
Such an OPO must register with the agency and comply with all
applicable regulations in part 1271; thus, an OPO that screens tissue
donors must do so in compliance with the regulations in part 1271 on
donor screening. If an OPO performs no tissue manufacturing functions,
it would not be subject to these regulations.
(Comment 7) One comment recommended that we set allowable limits
for additives to allograft tissues, such as glycerol.
(Response) We decline to set a specific limit on such additives in
these regulations. We point out, however, that one of the criteria in
Sec. 1271.10 for regulation of an HCT[sol]P solely under section 361
of the PHS Act and part 1271 is that the manufacture of the HCT[sol]P
does not involve the combination of the cell or tissue component with a
drug or a device, except for a sterilizing, preserving, or storage
agent, and then only if the addition of the agent does not raise new
clinical safety concerns with respect to the HCT[sol]P. Should an
additive raise new safety concerns or, as in the case of glycerol, be
for any purpose other than sterilizing, preserving, or storage, the
HCT[sol]P would be subject to regulation under the act and/or section
351 of the PHS Act, and FDA would consider allowable limits of chemical
additives in the context of the premarket review process.
(Comment 8) One comment asserted that tissue banks should audit
their domestic and international tissue recovery and distribution
intermediaries to assure accountability to the same standards that they
themselves uphold.
(Response) We agree that documentation of these audits would help
assure our goals of protecting the public health. Audits and other ways
of ensuring accountability are addressed in the CGTP proposed rule.
(Comment 9) One comment supported the establishment of a central
registry for tracking all reproductive tissue donors to locate donors
and recipients in an emergency.
(Response) We encourage interested parties to explore methods of
tracking donors, donations, and recipients, including the establishment
of such a central registry. However, we do not propose to require such
a registry at this time.
(Comment 10) One comment asked that the regulations clarify the
responsibilities of reproductive tissue banks and client depositors
with respect to length of storage of tissue and the right of a bank to
destroy tissue of noncompliant depositors.
(Response) The requested clarification is beyond the scope of these
regulations, which concern communicable disease transmission and not
provisions of agreements between HCT[sol]P establishments and
individual clients that are unrelated to communicable disease
transmission.
(Comment 11) One comment questioned why these regulations do not
address the use of cellular material other than from the patient in in-
vitro fertilization. Another comment supported restrictions on gene,
ooplasm, and nuclear transfer.
(Response) We recognize the comments' concerns and are addressing
these issues in contexts outside of this rulemaking.
B. Amendments to 21 CFR Parts 210, 211, and 820
We proposed amending Sec. Sec. 210.1 and 820.1 to require
manufacturers of HCT[sol]Ps regulated as drugs, medical devices, and/or
biological products to comply with the donor-eligibility procedures in
subpart C and the current good tissue practice (CGTP) procedures in
subpart D of part 1271. (We also proposed minor amendments, for
consistency, to Sec. Sec. 210.2 and 211.1.) The donor-eligibility and
CGTP procedures would be considered part of CGMP requirements for drugs
and the QS requirements for devices.
The proposed amendment to Sec. 210.1 stated that failure to comply
with the donor-eligibility, CGTP, or other CGMP regulations would
render adulterated, under section 501(a)(2)(B) of the act, an HCT[sol]P
regulated as a drug and/or biological product, and the HCT[sol]P, as
well as the person responsible for the failure to comply, would be
subject to regulatory action. The proposed amendments to Sec. 820.1
were comparable, stating in part that the failure to comply with any
applicable donor-eligibility, CGTP, or QS regulation would render a
device adulterated under section 501(h) of the act.
We received no comments on the proposed amendments.
We are finalizing the proposed modifications to Sec. Sec. 211.1(b)
and 820.1(a), which add a cross-reference to the regulations in part
1271. As finalized, Sec. 211.1(b) applies to HCT[sol]Ps that are also
regulated as drugs or biological products subject to the drug current
good manufacturing practice (CGMP) regulations in parts 210 and 211,
and Sec. 820.1(a) applies to HCT[sol]Ps that are also regulated as
devices subject to the QS regulations in part 820.
In response to a comment submitted on the CGTP proposed rule that
asserted that the ``impossible to comply'' language in proposed Sec.
1271.150(c) did not provide useful guidance, we have modified this
provision by replacing the ``impossible to comply'' language with more
specific wording referring to a conflict between applicable regulations
in different parts. In the event of a conflict between applicable
regulations in part 1271 and regulations in parts 210, 211, or 820, the
regulations specifically applicable to the product in question will
supersede the more general regulations. Because the ``impossible to
comply'' language is contained in related provisions in other parts we
have made the same change to these provisions to ensure consistency.
This new language is intended for
[[Page 29792]]
purposes of clarity. The ``impossible to comply'' language in our
current regulations was not the subject of complaints by regulated
establishments. With the revised language, FDA intends to continue to
interpret the standard reasonably and does not intend to impose
unreasonable burdens on establishments.
We note that the phrase ``impossible to comply'' has been used for
products other than HCT[sol]Ps since FDA first issued the device CGMP
regulations in 1978 (43 FR 31508, July 21, 1978). Two months later, FDA
used the phrase in the drug CGMP regulations (43 FR 45014, September
29, 1978). FDA explained in the preamble to the drug regulations that
``impossible to comply'' encompasses situations where regulations
contradict or conflict each other (43 FR 45014 at 45029).
The new language on a conflict between applicable regulations
replaces the phrase ``impossible to comply'' in Sec. Sec. 210.2(a),
211.1(b), 820.1(a), and 820.1(b). (Although a revision to Sec.
820.1(b) was not proposed, it is now necessary to revise that paragraph
for consistency with Sec. 820.1(a).) The new language pertains only to
conflicts that occur between applicable regulations in one part (e.g.,
part 211) and applicable regulations in another part (e.g., part 1271)
and not between regulations within one part (e.g., between two
regulations in part 211). FDA believes that, in the event of such a
conflict, the more specifically applicable regulation would be found in
part 1271.
We are also finalizing proposed Sec. 210.1(c), which would provide
that the failure to comply with any applicable provision in part 1271,
subparts C and D, would render a drug adulterated under section
501(a)(2)(B) of the act.
We have made minor revisions to the wording of the proposed
amendments to Sec. Sec. 210.1(c), 210.2, 211.1(b), and 820.1(a). These
changes include the addition of a reference to section 361 of the PHS
Act in Sec. Sec. 210.1(c) and 820.1(a). We have also clarified in
Sec. 210.1(c) that screening refers to donor screening and that
testing includes donor testing.
However, we are not finalizing proposed Sec. 820.1(c) in this
rule, which would have provided that the failure to comply with any
applicable provision in part 1271, subparts C and D, would render a
device adulterated under section 501(h) of the act. The act requires
FDA to follow special procedures when issuing regulations under the
device good manufacturing practice (GMP) authority; those procedures
are not applicable to regulations issued under the CGMP authority for
drugs. Before issuing regulations establishing requirements under
section 520(f) of the act, the act requires FDA to submit the proposed
regulations for review by an advisory committee meeting the criteria
established in section 520(f)(3). However, FDA's advisory committee for
device GMP regulations has not met since April 29, 1997, and only six
of the required nine seats are currently filled. Although the agency
believes it would be desirable to include a provision such as proposed
Sec. 820.1(c), we believe it is not absolutely necessary to the
regulatory scheme. When the device GMP advisory committee has been
fully reconstituted, FDA may consider submitting proposed Sec.
820.1(c) for its consideration. In the meantime, FDA intends to enforce
violations of part 1271, subparts C and D, under the enforcement
provisions contained in section 368 of the PHS act (42 U.S.C. 271), and
the general equitable powers of the Federal courts.
Finally, we note that the references to part 1271 in these sections
(Sec. Sec. 210.1, 210.2, 211.1, and 820.1) refer to ``applicable''
provisions of part 1271. In the event that the final CGTP rule provides
that any or all provisions in that rule are not being implemented for
certain HCT[sol]Ps, those CGTP provisions would not be ``applicable''
for those HCT[sol]Ps.
C. Definitions (Sec. 1271.3)
We have grouped all definitions pertinent to part 1271 in a single
definitions section (Sec. 1271.3), among the general provisions of
subpart A.
We received no comments on the proposed definitions of the
following terms, and those definitions appear in the final rule either
unchanged or with only minor changes for consistency in terminology
(i.e., references to HCT[sol]Ps): Biohazard legend (Sec. 1271.3(h)),
blood component (Sec. 1271.3(i)), donor (Sec. 1271.3(m)), plasma
dilution (Sec. 1271.3(p)), responsible person (Sec. 1271.3(t)), act
(Sec. 1271.3(v)); PHS Act (Sec. 1271.3(w)); and FDA (Sec.
1271.3(x)). For clarity, we have added the phrase ``of a cadaveric
donor'' to the term ``physical assessment,'' but have made no other
change to that definition (Sec. 1271.3(o)).
We received no comments on the proposed definitions of the terms
``embryo'' and ``gamete,'' but have deleted those definitions from this
final rule as unnecessary; ``gamete'' is not used in the codified
provisions and ``embryo'' is generally understood. We received no
comments on the term ``reconstituted blood,'' but have deleted the term
from the final rule because of its potential to cause confusion. We
have incorporated the substance of the proposed definition of ``summary
of records'' into Sec. 1271.55 and so have deleted the definition of
that term from the final rule. We received no comments on that
definition. We also received no comments on the proposed definition of
``quarantine,'' and it remains unchanged in this final rule (Sec.
1271.3(q)); however, comments on the quarantine provisions in Sec.
1271.60 are addressed in section III.D.6 of this document.
1. Colloid (Sec. 1271.3(j)) and Crystalloid (Sec. 1271.3(k))
Proposed Sec. 1271.3(k) defined ``colloid,'' and proposed Sec.
1271.3(l) defined ``crystalloid.'' Both are terms used in Sec. 1271.80
with respect to plasma dilution. Although we specifically requested
comments on the appropriateness of these definitions, no comments were
submitted.
For greater accuracy, we have made minor changes to the language of
each definition. The final rule contains a two-part definition of
``colloid'' in Sec. 1271.3(j). Under the first part, a colloid is a
protein or polysaccharide solution, such as albumin, dextran, or
hetastarch, that can be used to increase or maintain osmotic (oncotic)
pressure in the intravascular compartment. We have deleted the word
``certain'' from the second part of the definition, so that it now
reads: ``Blood components such as plasma and platelets.''
The final rule replaces the word ``balanced'' in the proposed
definition of crystalloid with ``isotonic,'' so that the definition now
refers to an isotonic salt and/or glucose solution used for electrolyte
replacement or to increase intravascular volume, such as saline
solution, Ringer's lactate solution, or 5 percent dextrose in water.
2. Directed Reproductive Donor (Sec. 1271.3(l))
The proposed rule contained a definition of ``directed donor,'' a
term used in proposed Sec. 1271.65(b) to describe a situation in which
the use of reproductive cells or tissue from an ineligible donor would
not be prohibited. In considering the comments on Sec. 1271.65(b),
discussed in greater detail in section III.C.5 of this document, we
concluded that, for clarity, we should limit the definition of
``directed donor'' to donors of reproductive cells and tissue and
change the term to ``directed reproductive donor.'' Because the term
``directed reproductive donor'' is used only in the context of the
donation of reproductive cells and tissue, these changes do not affect
the scope of the exception.
[[Page 29793]]
As proposed, a directed donation involved the designation of a
specific potential recipient. We have maintained this part of the
definition in the final rule.
(Comment 12) Our review of comments indicated that there was some
confusion about whether the designation of a specific recipient could
take place in the context of anonymous semen donation (i.e., a
situation in which the donor and recipient do not know each other).
(Response) We did not intend for the term ``directed donor'' to
refer to anonymous donations. Rather, our intention was to respect the
existence of relationships between people. To recognize existing
relationships between donors and recipients, we have added language to
the definition of ``directed reproductive donor'' to indicate that, in
a directed donation, the donor knows and is known by the recipient
before donation.
We have also clarified the definition by noting that directed
reproductive donors do not include sexually intimate donors, who are
excepted from screening and testing requirements under Sec. 1271.90.
This change is intended to make clear that, for the purpose of this
rule, there are three categories of reproductive donors, subject to
three different sets of requirements listed as follows: (1) The
anonymous donor, to whom all the donor-eligibility requirements apply;
(2) the directed reproductive donor, whose reproductive cells and
tissue may be used even if the donor is determined ineligible; and (3)
the sexually intimate partner, for whom testing and screening are not
required (discussed in section III.D.11 of this document).
(Comment 13) One comment requested that we define an additional
category of anonymous semen donor, the ``Identification Revealed
Donor.'' Under this kind of donation, the identity of an anonymous
semen donor may be revealed to the child and/or mother at some point
after birth. (We also received comments supporting this type of
arrangement.) The comment suggested a related change to proposed Sec.
1271.75 so that screening for risk factors for relevant communicable
diseases would not be required for donors whose identities may be
revealed later.
(Response) Donor identification is outside our jurisdiction and
unrelated to the purpose of this rule, which is to prevent the
transmission of communicable disease. For these reasons, this rule does
not address any agreements that might be entered into for revealing a
donor's identity at a future time.
We note that the suggested change to the screening requirement in
Sec. 1271.75 would exempt the anonymous donors described in the
comment from screening for risk factors for human immunodeficiency
virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), human
transmissible spongiform encephalopathy (TSE), including CJD and vCJD,
Treponema pallidum, HTLV, Chlamydia trachomatis, and Neisseria
gonorrhea. We cannot justify this exception on public health grounds.
Whether or not the identity of an anonymous donor may be revealed later
has no bearing on the appropriate screening and testing of that donor.
For the prevention of the transmission of communicable disease, the
same requirements should apply to all anonymous donors.
We have distinguished between directed reproductive donors and
anonymous donors to respect the existence of relationships between
people who know each other and have made a joint decision for the
recipient to conceive a child. In contrast to the directed reproductive
donor who has an existing relationship with the recipient, only the
potential for a future relationship exists for the anonymous donors
described in the comment. Under the identification-revealed donation
arrangement described in the comment, there is no relationship between
donor and recipient at the time of donation. The recipient does not
even know the name of the donor at the time of the donation, and may
never learn the donor's identity at all. For these reasons, we decline
to add a new definition for ``identification revealed donor.''
3. Donor Medical History Interview (Sec. 1271.3(n))
The donor medical history interview is one of the relevant medical
records that are reviewed in the donor screening process. We proposed
to define ``donor medical history interview'' as a documented dialog
with the donor, if living, or, if the donor is not living or is unable
to participate in the interview, with an individual knowledgeable about
the donor's medical history and relevant social behavior (proposed
Sec. 1271.3(o)). The proposed definition provided examples of possible
interviewees and described the questions to be asked about relevant
social behavior
(Comment 14) Several comments asserted that the proposed definition
of donor medical history interview implies that an in-person, face-to-
face interview would be required. One comment assumed that the
definition includes communications with friends and life partners.
(Response) A donor medical history interview means a ``documented
dialog.'' You may conduct such a dialog in person, by telephone, or
through written or other forms of communication that allow the exchange
of information between interviewer and interviewee. The interview
method should allow the interviewer to ask followup questions to
collect necessary information or to clarify responses. In the case of a
living donor, a face-to-face interview is generally the most effective
way to conduct a dialog.
We agree that the definition may include communications with
friends and life partners, if they are knowledgeable about the donor's
medical history and relevant social behavior.
We note that the definition of ``donor medical history interview''
is among the provisions of this final rule that we have redrafted for
clarity and plain language reasons. The meaning of the definition
remains unchanged.
4. Relevant Communicable Disease Agent or Disease (Sec. 1271.3(r))
Proposed Sec. 1271.3(y) contained a 2-part definition of
``relevant communicable disease or disease agent.'' The first part
listed those disease agents and diseases that are specifically
identified in Sec. Sec. 1271.75 and 1271.85 as relevant communicable
diseases for which screening and testing would be required. These are
as follows: HIV, types 1 and 2; HBV; HCV; TSE, including CJD and vCJD;
Treponema pallidum; HTLV, types I and II; CMV; Chlamydia trachomatis
and Neisseria gonorrhea. The proposed rule noted that in some
instances, FDA had identified a disease agent or disease as relevant
for a particular type of HCT[sol]P and that this distinction was
reflected in the proposed testing and screening requirements in
Sec. Sec. 1271.75 and 1271.85 (64 FR 52696 at 52701). For clarity, we
have reorganized the list of identified relevant communicable disease
agents and diseases in the first part of the definition (Sec.
1271.3(r)(1)) according to tissue type. Thus, for example, HIV, types 1
and 2, is listed as relevant for all cells and tissues; HTLV, types I
and II, is listed as a cell-associated disease agent or disease
relevant for viable, leukocyte-rich cells and tissues; and Chlamydia
trachomatis is listed as a disease agent or disease of the
genitourinary tract relevant for reproductive cells and tissues. This
is an organizational change and not substantive.
[[Page 29794]]
The second part of the proposed definition described criteria for
other communicable diseases or disease agents to be considered
``relevant.'' The proposed criteria related to prevalence, transmission
risk, significance of health risk, and the availability of appropriate
screening and/or testing methods. We have made changes to several
aspects of this part of the definition, discussed in comments 16
through 19 of this document.
``Relevant communicable disease agent or disease'' is defined in
the final rule at Sec. 1271.3(r)
(Comment 15) One comment stated that we had not sufficiently
demonstrated the need to expand agency oversight to include diseases in
addition to HIV and hepatitis. Another comment asserted that
transmission of CJD and syphilis (Treponema pallidum) via cornea
transplants is rare or nonexistent.
(Response) When we issued part 1270 as an interim rule in 1993,
among other reasons, we were acting swiftly to counter the transmission
of three serious disease agents, HIV, HBV, and HCV (64 FR 52696 at
52698). One reason for the inclusion of more diseases and disease
agents in the proposed rule and this final rule is that the new rules
cover more types of cells and tissues than were subject to part 1270.
These additional cells and tissues pose additional risks of
transmitting communicable disease. For example, we are now requiring
you to test donors of viable, leukocyte-rich tissue for HTLV and CMV;
this requirement did not previously exist, because part 1270 did not
cover such viable, leukocyte-rich HCT[sol]Ps as semen and hematopoietic
stem/progenitor cells. Similarly, we are now requiring that you test
donors of reproductive tissue for Neisseria gonorrhea and Chlamydia
trachomatis, a requirement that did not exist under part 1270, which
did not cover reproductive tissue.
We proposed to add TSE (including CJD and vCJD) and syphilis to the
list of disease agents and diseases for which donors of all types of
cells and tissues would be required to undergo screening and/or
testing, because these two diseases present significant health risks.
We disagree with the assertion that testing is unnecessary due to the
infrequency of transmission. With respect to CJD, there have been over
100 transmissions of CJD from dura mater worldwide (including 3 in the
United States) and 1 transmission from cornea (in addition to 2
possible transmissions), and the number of cases of vCJD is rising.
With respect to syphilis, several factors could be responsible for the
lack of reports of syphilis transmission via organs, tissues, or cells,
including the use of antibiotics during tissue processing and the
storage of tissues at low temperature. (Treponema pallidum does not
survive when stored at 4 [deg]C for more than 48 to 72 hours.) However,
these factors might not always be in place; i.e., antibiotics might not
be used, and fresh bone grafts might not be stored under time and
temperature conditions that would kill the organism, if present.
Because of the potential for transmission by cells and tissue,
including cornea, of both CJD and syphilis, we are maintaining the
screening and testing requirements in the final rule.
(Comment 16) Several comments asked about the procedure we would
use to identify additional relevant communicable disease agents and
diseases under the second part of the definition. Two comments asserted
that we should specify that procedure, and that, except in cases of
real urgency, the agency must afford interested parties prior notice
and an opportunity to comment before adding a new disease agent or
disease to the list. According to these comments, providing for such
input would provide the following results: (1) Reveal scientific
complexities otherwise unknown to FDA, (2) allow us to avoid imposing
an additional testing obligation where no test is available, and (3)
help avert the unnecessary destruction of tissues in inventory. Some
comments stated that tissue establishments would have a difficult time
identifying a new relevant communicable disease agent or disease under
the four factors set out in the proposed rule. In the absence of
guidance by the agency, establishments might feel forced to conduct
testing that was not supported by the risk, due to liability concerns.
(Response) We agree that public participation in these issues is
important. We intend to issue guidance in accordance with the good
guidance practices set out in Sec. 10.115 to advise you when, in the
agency's view, a new relevant communicable disease agent or disease
exists. Good guidance practices provide the public with an opportunity
to comment on guidance before its implementation, except when the
agency determines that prior public participation is not feasible or
appropriate (e.g., in a public health emergency). When FDA issues
guidance for immediate implementation, the public is invited to comment
after publication. In suitable situations, we will hold public meetings
or consult with advisory committees to help us identify communicable
disease agents or diseases for which donor screening and testing should
be performed.
We also believe that, by issuing guidance, the agency will assist
small tissue establishments, which may not be in a position to track
the prevalence of emerging diseases and disease agents in a timely
manner. Through guidance, FDA will perform an important communications
function and assist small tissue establishments in meeting their
regulatory obligations to test and screen for relevant communicable
diseases and disease agents.
Under the final rule, whether or not a disease or disease agent is
``relevant'' under the rule will still be measured by the factors set
out in Sec. 1271.3(r)(2)(i), (r)(2)(ii), and (r)(2)(iii), taken
together. We recognize that, due to a variety of circumstances, you may
not be aware of every instance when a disease or disease agent meets
these factors. We therefore intend to clarify the application of these
criteria in guidance. FDA's role in issuing guidance is to provide
notice that the definitional elements appear to be met. FDA's
notification will take the form of guidance and will not constitute a
rule. In an enforcement action involving testing and screening for a
new relevant communicable disease or disease agent, FDA's
identification in guidance of the disease or disease agent would not be
dispositive of the issue of whether it meets the factors set out in
Sec. 1271.3(r)(2)(i), (r)(2)(ii), and (r)(2)(iii). In such an action,
FDA would have to establish that the disease met those factors.
(Comment 17) One comment asserted that the application of
``relevant'' is subject to FDA's sole determination, which is further
complicated by FDA's interpretation of terms such as ``risk'' and
``appropriate screening.'' The comment asserted that these terms are
not sufficiently defined, and that relevant risk is broadly applied and
does not sufficiently address risk by specific tissue. Another comment
stated that ``relevant disease risk'' is overly broad and would subject
all tissue entities to unfair malpractice claims, leaving the system
vulnerable and subject to unnecessary costs. The comment further opined
that the mere hypothetical threat of a disease or agent would make it
eligible for required screening and testing.
(Response) The rule establishes factors that must be met before a
disease agent or disease is ``relevant'' under this rule. As explained
in comment 16 of this document, we intend to follow good guidance
practices to notify you that the agency believes additional relevant
communicable disease agents or
[[Page 29795]]
diseases exist. This will provide the opportunity for public
participation in the process.
We disagree with those comments that question the terms ``relevant
disease risk'' and ``relevant risk.'' These are not terms that we used
in the proposed definition of relevant communicable disease agent or
disease, and they do not appear in the final definition.
With respect to the comment on requiring testing and screening for
a disease that poses a ``mere hypothetical threat,'' screening and
testing would be required only when supported by a sound scientific
basis. Identifying a relevant communicable disease agent or disease
will entail an evaluation of the risk of the disease based on the
criteria in Sec. 1271.3(r)(2). Establishments would not be required to
determine independently which disease agents and diseases meet the
definition of ``relevant communicable disease agent or disease,'' and
could simply follow FDA guidance concerning communicable diseases or
disease agents newly identified as relevant. Establishments could also
participate in FDA's identification process, for example by commenting
on draft and final guidances. Such FDA guidances would identify disease
agents or diseases which, in the agency's view, meet the standards for
``relevant communicable disease or disease agent.'' Each guidance would
describe effective, and thus ``appropriate,'' screening practices, and
would list recommended tests, if there are available and effective
tests that have been licensed, approved, or cleared by FDA.
(Comment 18) One comment asserted that the term ``prevalent'' is
not sufficiently defined. Another comment asked at which point and by
whom a disease would be designated sufficiently prevalent among
potential donors.
(Response) We have made several changes to the definition of
``relevant communicable disease agent or disease'' with respect to
prevalence.
First, we have made the question of prevalence and/or incidence
part of the evaluation of the risk of transmissibility of a
communicable disease agent or disease. We have implemented this change
by dividing the question of risk of transmissibility into the following
two parts: (1) Is the disease or disease agent potentially
transmissible by an HCT[sol]P? and (2) does the disease or disease
agent have sufficient incidence and/or prevalence to affect the
potential donor population? This change is reflected in Sec.
1271.3(r)(2)(i). Both questions are important in considering whether to
require testing and/or screening for a communicable disease or disease
agent; grouping them will ensure that both factors are considered
together.
We believe that the factors set out in Sec. 1271.3(r)(2)(i),
(r)(2)(ii), and (r)(2)(iii) should be considered as a whole. This
approach is useful in explaining the concept of prevalence/incidence.
On the one hand, a highly prevalent but relatively harmless disease
agent might not be considered relevant. For example, some communicable
diseases (e.g., Ureaplasma urealyticum, a disease of the genitourinary
tract) are prevalent, but their pathogenicity to cell and tissue
recipients is of questionable clinical significance. For this reason,
we do not currently consider Ureaplasma urealyticum to be a relevant
communicable disease agent. On the other hand, testing or screening
might be required for a less prevalent but particularly virulent agent.
Examples of communicable diseases that are less prevalent, yet pose
extremely significant health risks, are TSE and HIV-2.
The second change we have made is to modify the proposed language
on prevalence so that it now refers to ``sufficient incidence and/or
prevalence to affect the potential donor population.'' Whereas
prevalence refers to the number of existing cases over a period of
time, incidence refers to the number of new cases. Both prevalence and
incidence are important indicators of the risk that a potential
HCT[sol]P donor could be infected with a particular disease or disease
agent, and that HCT[sol]Ps from that donor could transmit the disease.
The third change we have made is to identify an alternative to
prevalence. Under Sec. 1271.3(r)(2)(i)(B), a relevant communicable
disease or disease agent is one that ``* * * either (1) has sufficient
incidence and/or prevalence to affect the potential donor population,
or (2) may have been released accidentally or intentionally in a manner
that could place donors at risk of infection.''
We intend this new language to cover both intentional and
unintentional release of infectious agents. Although prevalence/
incidence remains an important consideration in determining whether a
communicable disease or disease agent should be considered relevant, we
recognize that when an infectious agent is released, whether by
accident or purposefully (e.g., to inflict harm), we may not
immediately have adequate information to assess the prevalence of the
disease or disease agent. In this instance, where we have information
about the release of an infectious agent, and the other prongs of the
definition are met, it is important for the agency to be able to
respond promptly by issuing guidance on testing and screening without
awaiting the accumulation of data on prevalence.
In response to the second comment, which asked at which point and
by whom would a disease be designated sufficiently prevalent among
potential donors, we discuss in comment 16 of this document, the
procedures we will follow to communicate the agency's conclusions
concerning when a disease or disease agent meets the definition of
relevant communicable disease or disease agent.
(Comment 19) One comment asked us to define ``significant'' health
risk. This comment asserted that the term is vague and subject to
misinterpretation.
(Response) In response to this comment, we have replaced the phrase
with more specific language in Sec. 1271.3(r)(2)(ii). The definition
now states that a relevant communicable disease agent or disease is one
that could be fatal or life-threatening, could result in permanent
impairment of a body function or permanent damage to body structure, or
could necessitate medical or surgical intervention to preclude
permanent impairment of body function or permanent damage to a body
structure. This more specific description is modeled on language used
in the agency's regulations on medical device reporting (see 21 CFR
803.3(bb)).
5. Relevant Medical Records (Sec. 1271.3(s))
Donor screening involves the review of relevant medical records for
risk factors for, and clinical evidence of, a relevant communicable
disease agents and diseases. Proposed Sec. 1271.3(v) would define
``relevant medical records'' as a collection of documents that includes
a current donor medical history interview and a current report of the
physical assessment of a cadaveric donor or the physical examination of
a living donor. The proposed definition listed additional records that
would be considered relevant medical records if they were available.
(Comment 20) One comment opposed including, in the definition of
``relevant medical records,'' a current report of a physical assessment
or examination. The comment asserted that these evaluations are of
minimal utility, particularly if the available exam was not performed
to look for evidence of specific disease, and suggested that the
requirement be moved to the ``if available'' part of the definition.
(Response) We disagree with this comment. There are clear physical
findings that could indicate that a donor either has a relevant
communicable
[[Page 29796]]
disease or exhibits signs of risk factors for such a disease. Examples
include jaundice, lymphadenopathy, or needle marks. The donor-
eligibility draft guidance that accompanies this final rule lists
physical findings that would suggest if a cadaveric or living donor
could have a relevant communicable disease and that should be looked
for in the physical assessment or examination.
(Comment 21) Five comments questioned the need for a physical
examination of a cord blood donor. Three of these recommended that the
requirement not apply to cord blood donors, but only to HCT[sol]Ps for
which the physical examination is relevant to the safety of the donor
or the HCT[sol]P. Two comments proposed requiring only a limited
physical examination.
(Response) We disagree with the suggestion that it is unnecessary
to conduct a physical examination of a cord blood donor. A physical
examination could reveal risk factors for or the presence of a relevant
communicable disease.
We note that the purpose of the physical examination is to assess
for signs of a relevant communicable disease and for signs suggestive
of any risk factor for a relevant communicable disease. The donor-
eligibility draft guidance announced elsewhere in this Federal Register
provides further information on physical evidence of relevant
communicable diseases that may be observed during the physical
examination of a living donor.
(Comment 22) One comment asserted that the scope of medical records
should be limited to information pertaining to relevant communicable
diseases. The comment expressed concern that a potentially significant
finding would be lost in the minutiae. The comment cited autopsy
results as an example of a record that does not add significant value
to the donor screening process, noting also that certain products need
to be released before coroner and autopsy reports are available.
(Response) We agree that the scope of medical records that you
review in donor screening is limited to information pertaining to
relevant communicable diseases. We disagree, however, with the
assertion that autopsy results do not provide significant information.
On the contrary, an autopsy can lead to the discovery of subclinical
evidence of relevant communicable diseases (e.g., liver disease may
indicate hepatitis). We understand that certain HCT[sol]Ps need to be
released before autopsy results are available (e.g., corneas). However,
autopsy results are an important component of a donor's relevant
medical records, and you must review them if they are available at the
time of the donor-eligibility determination.
(Comment 23) Other comments recommended that the definition of
``relevant medical records'' be limited to processing records, health
histories, and the infectious disease test results of the donor. These
comments expressed concern that the definition includes the donor's
medical records ``if available.'' This comment urged us to make the
summary of records the sole set of documents required to accompany the
product.
(Response) We agree that the summary of records should be the sole
set of documents required to accompany an HCT[sol]P, and we have
modified Sec. 1271.55, as discussed in greater detail in comment 29 of
this document. However, for the purposes of donor screening, we
continue to believe that a larger range of information should be
considered, including the donor's medical records, if available. For
that reason, we have not changed the list of documents that make up the
relevant medical records.
6. Urgent Medical Need (Sec. 1271.3(u))
Under proposed Sec. 1271.65(b) and (c), an HCT[sol]P from an
ineligible donor could be used in cases of urgent medical need. We
proposed to define ``urgent medical need'' as meaning that no
comparable HCT[sol]P is available and the recipient is likely to suffer
serious morbidity without the product.
(Comment 24) One comment requested that we add to the definition of
``urgent medical need'' the requirement that the risk of morbidity with
use of the product be considerably less than without the product.
(Response) We decline to make this change. We expect that doctors
will use their professional judgment to balance the risk of using an
HCT[sol]P against the risk of not using it.
We have, however, modified the definition of ``urgent medical
need'' to include the risk of death, in addition to the risk of serious
morbidity. The risk of death is clearly more urgent than the risk of
serious morbidity and should have been included in the proposed
definition.
7. Xenotransplantation Product Recipient and Intimate Contact of a
Xenotransplantation Product Recipient
Proposed Sec. 1271.75(a)(2) would require you to determine whether
a potential donor has received a xenotransplant (now called a
xenotransplantation product) or has been a close contact of such a
recipient. We proposed to define ``xenotransplantation'' and ``close
contact'' in proposed Sec. 1271.3(aa) and (bb).
(Comment 25) Several comments requested clarification of the
definitions of ``xenotransplantation'' and ``close contacts,''
including the meaning of ``live cells'' and ``ex vivo,'' two terms used
to define xenotransplantation. One comment preferred the term
``intimate contact'' to ``close contact.'' We were also asked to
provide examples of activities that could result in exchanges of bodily
fluids, a factor in the proposed definition of close contact.
(Response) The final rule does not contain definitions of
``xenotransplantation'' or ``close contact.'' These terms are relevant
to the determination under Sec. 1271.50, concerning whether the donor
presents communicable disease risks associated with
xenotransplantation. We now explain our current understanding of
``xenotransplantation,'' ``xenotransplantation product,''
``xenotransplantation product recipient,'' and ``intimate contact of a
xenotransplantation product recipient'' in the donor-eligibility draft
guidance announced elsewhere in this issue of the Federal Register.
The terminology used in the accompanying guidance, and the
definitions provided, are consistent with guidance on
xenotransplantation developed by the Public Health Service (PHS) and by
FDA (PHS Guideline on Infectious Disease Issues in Xenotransplantation;
Availability (66 FR 8120, January 29, 2001); Draft Guidance for
Industry: Precautionary Measures to Reduce the Possible Risk of
Transmission of Zoonoses by Blood and Blood Products from
Xenotransplantation Product Recipients and Their Intimate Contacts (67
FR 6266, February 11, 2002). In the accompanying guidance, we describe
``xenotransplantation'' as any procedure that involves the
transplantation, implantation, or infusion into a human recipient of
either of the following: (1) Live cells, tissue, or organs from a
nonhuman animal source; or (2) Human body fluids, cells, tissues, or
organs that have had ex vivo contact with live nonhuman animal cells,
tissues, or organs. By ``live cells'' we mean cells that have the
ability to metabolize or divide. By ``ex vivo'' we mean outside of an
individual's body.
We agree with the comment that the term ``intimate contact'' is
preferable to ``close contact,'' because it is more specific. The
donor-eligibility draft guidance describes ``intimate contact of a
xenotransplantation product recipient'' as a person who has engaged
[[Page 29797]]
in activities that could result in the intimate exchange of body fluids
with a xenotransplantation product recipient. Examples of intimate
contacts include, but are not limited to, sexual partners, household
members who share razors or toothbrushes, and health care workers or
laboratory personnel with repeated percutaneous, mucosal, or other
direct exposures. Mere sharing of domicile or casual contact, such as
hugging or kissing without the exchange of saliva, would not be
interpreted as intimate contact.
D. Part 1271, Subpart C--Donor Eligibility
Subpart C of part 1271 contains the donor-eligibility requirements
for HCT[sol]Ps, including donor screening and testing.
1. General
(Comment 26) We received comments urging the use of a term other
than ``unsuitable'' to describe a reproductive tissue donor with risk
factors for relevant communicable disease.
(Response) ``Suitability'' is a term with wide usage in tissue and
blood establishments. We understand, however, that when the term
``unsuitable'' is applied to a donor, it may take on an unintended
meaning. For that reason, we have decided to substitute the more
neutral terms ``donor eligibility,'' ``eligible donor,'' and
``ineligible donor'' throughout this final rule. Like the donor-
suitability determination in the proposed rule, the donor-eligibility
determination will be based on both screening and testing. A donor is
``ineligible'' if either screening or testing indicates the presence of
a communicable disease or risk factor for a communicable disease.
Throughout this rule, we refer to the ``donor-suitability proposed
rule,'' but in all other instances, even references to the provisions
of that rule, we now refer to ``donor eligibility.''
2. What Requirements Does This Subpart Contain? (Sec. 1271.45)
In this final rule, we have added Sec. 1271.45 (``What
requirements does this subpart contain?''). Section 1271.45(a) states
that subpart C sets out requirements for determining donor eligibility,
and points out that the requirements in subpart C are a component of
CGTP requirements.
Section 1271.45(b) requires a determination of eligibility, based
on donor screening and testing for relevant communicable disease agents
and diseases, for all donors of cells or tissue used in HCT[sol]Ps,
except as provided under Sec. 1271.90. Section 1271.45(b) also states
that, in the case of an embryo or of cells derived from an embryo, a
donor-eligibility determination is required for both the oocyte donor
and the semen donor. We have moved this requirement from proposed Sec.
1271.50(a). We have also extended the proposed requirement, which
referred only to embryos, to cells derived from an embryo. Although
this meaning was implicit in the proposed language, we have made this
change for greater clarity.
Section 1271.45(c) prohibits the implantation, transplantation,
infusion, or transfer of an HCT[sol]P unless the cell or tissue donor
has been determined to be eligible, except as provided under Sec. Sec.
1271.60(d), 1271.65(b), and 1271.90. This was originally proposed in
Sec. 1271.50(a).
Section 1271.45(d) states that, if you are an establishment that
performs any function described in subpart C, you must comply with the
requirements that are applicable to that function.
3. What Procedures Must I Establish and Maintain? (Sec. 1271.47)
In this final rule, we have added Sec. 1271.47 (``What procedures
must I establish and maintain?''). This reflects an organizational
change, but is not substantive. General requirements for establishing
and maintaining procedures were proposed as part of the GTP proposed
rule (Sec. 1271.180). These proposed requirements would apply to all
significant steps in the manufacture of HCT[sol]Ps, including donor
screening and testing. However, in finalizing the donor-eligibility
rule, we have decided that a separate provision on procedures specific
to the donor-eligibility requirements of subpart C is warranted. To
consolidate procedural requirements within the donor-eligibility
requirements, and to remind you that you must develop procedures for
testing and screening, we have added Sec. 1271.47. Final section Sec.
1271.47 is based on proposed Sec. 1271.180, but tailored to be
specific to donor-eligibility requirements. (In this final rule, we
sometimes refer to procedures as standard operating procedures (SOPs).)
For greater clarity and ease of reading, we have divided the
proposed language into paragraphs. Paragraph (a) of Sec. 1271.47
requires that you establish and maintain written procedures for all
steps that you perform in testing, screening, determining donor
eligibility, and complying with all other requirements in subpart C.
Paragraph (a) of Sec. 1271.47 incorporates an explanation of the
phrase ``establish and maintain.'' This definition was proposed in the
GTP proposed rule under Sec. 1271.3(ll); we received no comments on
the proposed definition. Paragraph (b) of Sec. 1271.47 requires that a
responsible person must review and approve all procedures before
implementation. Under paragraph (c) of Sec. 1271.47, written
procedures must be readily available to personnel. Paragraph (d) of
Sec. 1271.47 contains requirements relating to departures from
established procedures. Paragraph (e) of Sec. 1271.47 states that an
establishment may adopt current standard procedures, provided that
certain conditions are met.
Section 1271.47 reflects the following changes to proposed Sec.
1271.180, made in response to comments submitted to the GTP proposed
rule docket:
All steps. Proposed Sec. 1271.180 would require procedures for
``all significant steps'' that an establishment performs. One comment
asked for examples of what constitutes a ``significant step'' and asked
how it differs from ``any step.''
A ``significant'' step is not considered different from ``any or
all steps,'' as the latter term is used in the definition of
``manufacture'' in Sec. 1271.3(e). For this reason, we have removed
the word ``significant,'' and Sec. 1271.47(a) refers instead to ``all
steps.''
Periodic review. Proposed Sec. 1271.180 would require
establishments to review and, if necessary, revise all procedures at
least once in a 12-month period. One comment objected to the
specificity of this requirement, citing the more flexible requirements
in the CGMP and QS regulations.
We agree with this comment and note that the comparable
requirements in the CGMP and QS regulations (Sec. Sec. 211.100 and
820.40) do not require an annual review of procedures. For this reason,
we are deleting the proposed requirement, Sec. 1271.47 does not
contain a requirement for an annual review of procedures.
Departures from procedures. We have replaced the term ``deviation''
with ``departure'' in this final rule to prevent confusion with
HCT[sol]P deviation reporting in the CGTP proposed rule. Several
comments objected to the proposed requirement that departures from
procedures be authorized in advance, because departures are not
foreseeable and cannot be authorized before they occur. One comment
suggested requiring a justification for the departures to be recorded
at the time of the occurrence, and requiring approval of the departures
by a responsible person before release of the tissue.
We agree with these comments and have modified the requirement in
[[Page 29798]]
accordance with the suggestion. Section 1271.47(d) now requires an
establishment to record and justify any departure from a procedure
relevent to preventing risks of communicable disease transmission at
the time of its occurrence, rather than before. The provision further
states that the establishment must not make available for distribution
any HCT[sol]P from a donor whose eligibility is determined under such a
deviation unless a responsible person has determined that the departure
does not increase the risk of communicable disease transmission through
the use of the HCT[sol]P.
Archiving of obsolete procedures. Proposed Sec. 1271.180 would
require obsolete procedures to be archived for at least 10 years. One
comment suggested that a longer retention period of 10 years after
transplantation would be more appropriate and consistent with record
retention requirements in Sec. 1271.270 (which also appear in proposed
Sec. 1271.55).
We have deleted archiving obsolete procedures as a requirement, but
we recommend that establishments archive their obsolete procedures so
that they may reference at any time and as needed a specific procedure
used for manufacturing a specific HCT[sol]P that is still available for
use and in storage.
4. How Do I Determine Whether a Donor Is Eligible? (Sec. 1271.50)
Proposed Sec. 1271.50 sets out basic requirements with respect to
the donor-eligibility determination. Under proposed Sec. 1271.50(b),
the determination would be required to be performed by a responsible
person. Under proposed Sec. 1271.50(b), the responsible person would
determine a donor to be eligible if the following requirements are met:
(1) The results of donor screening indicated that the donor was free
from risk factors for, and clinical evidence of, infection due to
relevant communicable disease agents and diseases and is neither a
xenotransplant recipient nor a close contact of a xenotransplant
recipient, and (2) the results of donor testing for relevant
communicable disease agents are negative or nonreactive.
Final Sec. 1271.50 reflects changes in screening for
xenotransplantation made in Sec. 1271.75, discussed in comment 48 of
this document.
(Comment 27) Two comments supported the provision in proposed Sec.
1271.50 that required a determination of eligibility to be based on
both screening and testing. These comments further asserted that
requiring both screening and testing for all prospective donors would
assure that a prospective donor who is deemed unsuitable, and who is
covered by proposed Sec. 1271.65, nevertheless, would be subject to
mandatory testing.
(Response) We agree that you must base a donor-eligibility
determination on both screening and testing. If the screening shows the
presence of a risk factor, the donor becomes ineligible and there is no
reason to conduct the testing. Thus, we disagree that testing is
mandatory where screening indicates a risk factor for a relevant
communicable disease and use under Sec. 1271.65 is not sought. To
require testing in the case of a donor already determined ineligible
based on screening would impose an unnecessary expense.
If the screening does not reveal any risk factors, the testing
should be conducted to determine the donor's eligibility. We also agree
that, if donor screening indicates a risk factor, and you wish to use
the HCT[sol]P from the ineligible donor under the provisions of Sec.
1271.65(b), you must complete all required testing.
(Comment 28) One comment asked whether a person who has tested
positive for a treatable communicable disease could donate reproductive
tissue.
(Response) A living donor who tests positive for a relevant
communicable disease is ineligible to donate, but could become eligible
to donate reproductive tissue in the future after successful treatment
of the disease. In the donor-eligibility draft guidance, we make
recommendations concerning the length of time following treatment of
various communicable diseases after which a donor could become eligible
to donate.
5. What Records Must Accompany an HCT[sol]P After the Donor-Eligibility
Determination Is Complete? (Sec. 1271.55)
Proposed Sec. 1271.55(a) would require documentation of the donor-
eligibility determination to accompany the HCT[sol]P. This
documentation would include a copy of the donor's relevant medical
records, results of required testing, and the name and address of the
establishment that made the determination. Alternatively, the HCT[sol]P
could be accompanied by a summary of records (defined in proposed Sec.
1271.3(x)). In both instances, the donor's name must be deleted from
the documentation. Proposed Sec. 1271.55(b) would require that the
establishment that generated the records used in the eligibility
determination, and the establishment that made the determination,
maintain the records for 10 years and make them available for FDA
inspection.
(Comment 29) Several comments described as burdensome the
requirement in proposed Sec. 1271.55(a) that a copy of the donor's
relevant medical records accompany an HCT[sol]P. One comment questioned
the confidentiality of information in these records, even with the
donor's name redacted. Other comments urged us to require only that a
summary of records accompany an HCT[sol]P, to ensure patient privacy
and the appropriate use of a patient's medical records. Another comment
supported our decision to require deletion of the donor's name.
(Response) To increase confidentiality protections, we have removed
the provision in Sec. 1271.55 for relevant medical records to
accompany an HCT[sol]P. The regulation now requires only that the
summary of records accompany the HCT[sol]P. We note that this change
affects only the documentation that accompanies the HCT[sol]P; it does
not affect the requirement in Sec. 1271.75(a) to review relevant
medical records.
As redrafted, Sec. 1271.55(a) requires that, once a donor-
eligibility determination has been made, the HCT[sol]P must be
accompanied by: (1) A distinct identification code affixed to the
HCT[sol]P container, e.g., alphanumeric, that relates the HCT[sol]P to
the donor and to all records pertaining to the HCT[sol]P and, except in
the case of autologous or directed reproductive donations, does not
include an individual's name, social security number, or medical record
number; (2) a statement whether, based on the results of screening and
testing, the donor has been determined to be eligible or ineligible;
and (3) a summary of the records used to make the donor-eligibility
determination. We have specified that the distinct identification code
must be affixed to the HCT[sol]P container (rather than attached by a
tie-tag) because it is crucial that this information never become
separated from the HCT[sol]P. Instead of defining ``summary of
records'' in Sec. 1271.3, as proposed, we describe in Sec. 1271.55(b)
that the summary of records must contain the following components: (1)
A statement that the testing was performed by a laboratory certified to
perform such testing on human specimens under the Clinical Laboratory
Improvement Amendments of 1988 or that has met equivalent requirements
as determined by the Centers for Medicare and Medicaid Services; (2) a
listing and interpretation of the results of all communicable disease
tests performed; and (3) the name and address of the establishment that
made the donor-eligibility determination. We have
[[Page 29799]]
removed the requirement for a statement describing the types of
records, which may have been reviewed as part of the relevant medical
records, because it did not add useful information about the particular
HCT[sol]P. We note that the requirement to list and interpret all
communicable disease tests refers not just to those tests required
under this rule, but would also include any nonrequired communicable
disease tests that have been performed.
We have added one item to the list of information in the summary of
records, in the case of an HCT[sol]P from a donor, ineligible based on
screening, that is released under the provisions of Sec. 1271.65(b),
the summary of records must contain a statement noting the reason or
reasons for the determination of ineligibility. This information will
greatly assist practitioners in weighing the risks of using an
HCT[sol]P from an ineligible donor and in explaining risks to the
recipient.
The final regulation, at Sec. 1271.55(c), states that the records
that accompany the HCT[sol]P must not include the donor's name and
other personal information that might identify the donor.
(Comment 30) One comment asked whether separate records would be
required for all batches of HCT[sol]Ps made from a single cell bank.
(Response) If you make multiple batches from a single cell bank,
you may maintain a single set of donor-eligibility records for the cell
bank. However, each HCT[sol]P from that cell bank must be accompanied
by a copy of the summary of records.
(Comment 31) One comment asserted that it is important to permit a
tissue bank to qualify a donor as eligible and then to certify that
eligibility to the establishment that further processes the cells or
tissue without providing specific donor information. This comment also
asserted that a mechanism should provide traceability through use of a
donor number that can be used to trace the cells or tissue to the
tissue bank if necessary.
(Response) Under Sec. 1271.55, an HCT[sol]P must be accompanied by
a summary of records that indicates the conclusions of the donor-
eligibility determination and that does not contain information that
could identify the donor. We have added the requirement for a distinct
identification code, e.g., alphanumeric, that relates the HCT[sol]P to
the donor and to all records pertaining to the HCT[sol]P and, except in
the case of autologous or directed reproductive donation, does not
include an individual's name, social security number, or medical record
number. This requirement is consistent with the tracking requirements
of the CGTP proposed rule.
(Comment 32) One comment supported the requirement in proposed
Sec. 1271.55(b) that records regarding gamete donation be kept 10
years.
(Response) We appreciate this comment and have maintained the
requirement, in Sec. 1271.55(d), that donor-eligibility records must
be maintained for 10 years.
The record retention requirements in Sec. 1271.55(d) have been
reorganized and clarified. In several instances, we have modified the
requirements for consistency with the more general records requirements
of the GTP rule. For example, proposed Sec. 1271.55(b) would require
records to be retained: ``* * * at least 10 years after the date of
implantation, transplantation, infusion, or transfer of the product, or
if the date of implantation, transplantation, infusion, or transfer is
not known, then * * * at least 10 years after the date of the product's
distribution, disposition, or expiration, whichever is latest.'' Three
comments submitted to the GTP docket pointed out that similar language
in proposed Sec. 1271.270(e) is confusing.
Accordingly, we have revised the relevant language in proposed
Sec. 1271.55(b) by replacing the words ``implantation,
transplantation, infusion, or transfer'' with ``administration.''
Section 1271.55(d) now reads ``You must retain the records pertaining
to a particular HCT[sol]P at least 10 years after the date of its
administration, or if the date of administration is not known, then at
least 10 years after the date of the HCT[sol]P's distribution,
disposition, or expiration, whichever is latest.''
We have made several other changes to the record retention
requirements that both improve the language and also increase
consistency with the proposed GTP rule. Final Sec. 1271.55(d) requires
that all records must be accurate, indelible, and legible; this
language is consistent with the proposed GTP rule (proposed Sec.
1271.270(a)). Similarly, Sec. 1271.55(d) sets out a more specific list
of required documentation than appeared in the proposed rule; as in
proposed Sec. 1271.270(c), Sec. 1271.55(d) specifies that you must
maintain documentation of the results and interpretation of all testing
and screening for relevant communicable disease and disease agents; the
name and address of the testing laboratory or laboratories;
documentation of the donor-eligibility determination; the name of the
responsible person who made the determination; and the date of the
determination. (No comments were received on either of these issues.)
We have also incorporated into Sec. 1271.55(d) the requirement
that information on the identity and relevant medical records of the
donor must be in English, or, if in another language, must be
translated into English. We received two comments on the docket for the
GTP rule about the English language requirement in proposed Sec.
1271.270(c). One comment stated that the proposed language implied that
the original non-English record may be destroyed, and suggested
revising the regulation to indicate that the original may be in any
language and should be retained, but that a copy translated into
English should also be kept. Another comment asserted that we should
stipulate that the English translation requirement applies to products
distributed within the United States.
We disagree that the proposed regulation implies that an original
record that is not in English can be destroyed, and for this reason we
have added the codified language that the information on the identity
and relevant medical records of the donor must be retained. You must
maintain the original documentation, whether or not the documentation
is in English. These requirements apply to all HCT[sol]Ps that are
imported into the United States, for distribution within the United
States, and that are shipped under Sec. 1271.60(c) into the United
States for processing or other manufacture before distribution in
another country.
(Comment 33) One comment requested that we change proposed Sec.
1271.55(b) to require that any party involved in the collection,
processing, or transplantation of an HCT[sol]P be allowed access to the
donor's medical records.
(Response) The purpose of the language, as proposed, was to ensure
FDA's access to records supporting a donor-eligibility determination.
Because of concerns about maintaining the confidentiality of patient
information, we decline to expand the provision to require an
establishment to make medical records available to any party involved
in the collection, processing, or transplantation of the HCT[sol]P.
6. What Quarantine and Other Requirements Apply Before the Donor-
Eligibility Determination Is Complete? (Sec. 1271.60)
Proposed Sec. 1271.60 contained provisions for quarantine of
HCT[sol]Ps pending the donor-eligibility determination. Proposed Sec.
1271.60(a) stated that, ``* * * [f]or reproductive cells and tissues
that can reliably be
[[Page 29800]]
stored, quarantine shall last until completion of the testing required
under Sec. 1271.85(d).'' (In Sec. 1271.85(d), we proposed to require
retesting of the donor of such reproductive cells or tissue at least 6
months after the date of donation.)
(Comment 34) One comment supported the provision in Sec. 1271.60
that permits, under certain safeguards, shipping of material that is in
quarantine.
(Response) We have maintained this provision in the final rule.
(Comment 35) Many comments opposed any quarantine requirement for
embryos. These comments disputed the communicable disease risks
associated with embryos. They also cited increased costs from a
quarantine; decreased success rates through use of frozen embryos;
adverse effects on patients from a quarantine requirement; logistical
concerns associated with retesting; and other possible consequences of
a quarantine requirement, including loss of embryos.
Some comments asserted that current screening practices are
adequate. Others asserted that FDA was interfering with the practice of
medicine or criticized our approach as having a potentially negative
effect on the field of reproductive medicine. Many comments suggested
alternative approaches, such as optional quarantine, mandatory
insurance coverage for infertility, and creation of an embryo bank. One
comment described a clinically effective program using frozen embryos
that was instituted to help ensure patient confidentiality.
(Response) We also received comments opposed to quarantining
oocytes. Some comments distinguished between oocytes and semen based on
differences in communicable disease risk, cryopreservation success,
availability, cost, and other factors.
We have considered the many comments received on the retesting and
quarantine requirements and have decided to clarify our intentions with
respect to embryos and oocytes. In the preamble to the proposed rule,
we stated that reproductive cells and tissues that can reliably be
stored are those that maintain function and integrity during storage.
As examples, we listed spermatozoa and sperm progenitor cells (64 FR
52696 at 52706). Given technologies at the time, we did not assert that
embryos or oocytes could reliably be stored. Thus, we did not intend
the quarantine and retesting requirement to apply to embryos or
oocytes.
To clarify the provisions for quarantine and retesting of
reproductive HCT[sol]Ps, we have deleted the phrase ``reproductive
cells and tissue that can reliably be stored.'' The 6-month quarantine
requirement in Sec. 1271.60(a) and the retesting requirement in Sec.
1271.85(d) applies only to anonymous semen donors.
We disagree with comments that minimize the communicable disease
risks associated with reproductive cells and tissue. Among other
things, these comments assert that there have been no known
transmissions of disease by ova or embryos or that there is no
compelling evidence to indicate that human gametes or embryos are
capable of transmitting infectious disease
Each cell in the human body has receptors for viruses and bacteria
and is thus capable of transmitting communicable disease. Even
avascular tissue has been known to transmit disease (e.g., corneas have
transmitted HBV). Semen is known to have transmitted HBV and HIV.
Because embryos are a result of the combining of sperm and ova, they
have the potential of being contaminated by communicable disease agents
transmitted by the sperm. Moreover, bacterial contamination and
transmission of HCV has occurred in assisted reproduction procedures.
Two cases have been reported of women in France who were HCV antibody
negative, but seroconverted after undergoing assisted reproductive
technology (ART) procedures. The cause of transmission was theorized to
be cross-contamination by health care workers (Lesourd, F., et al.,
``Transmissions of Hepatitis C Virus During the Ancillary Procedures
for Assisted Conception,'' Human Reproduction, vol. 15, no. 5 pp. 1083-
1085, (2000)).
Because there is a risk that ova and embryos could transmit
disease, this risk should not be ignored. Given the lack of oversight
and reporting requirements to date, it is difficult to know whether
incidents of transmission of disease by ova or embryos have occurred.
(Comment 36) Many comments objected to the application of the
quarantine and retesting requirements to directed semen donations.
These comments pointed out that, under the proposed regulation, semen
from a directed donor would have to be quarantined for 6 months pending
retesting of the donor. Comments asserted that this would effectively
bar the use of fresh semen in directed donations. Some comments cited
problems with sperm cryopreservation and noted a higher conception rate
with fresh semen than with frozen semen. Other comments pointed out the
delay in conception that would result from quarantine. Some comments
asserted that the proposed provisions would encourage people to perform
inseminations without medical assistance and safety screening.
(Response) On December 14, 2001, we asked the BPAC whether,
compared with fresh semen, the use of cryopreserved semen for
artificial insemination reduces pregnancy rates per cycle. After a
presentation of data, the committee agreed that the practice of
cryopreserving semen for artificial insemination does reduce pregnancy
rates.
In light of the comments and the opinion of the BPAC, we have
reconsidered whether to require quarantine and retesting in directed
semen donation. The requirement to retest the donor was intended to
provide an important added measure of protection by addressing the
``window period'' between the time of infection and the presence of
detectable levels of antigens and/or antibodies to communicable
diseases and agents such as HIV. However, we recognize that semen from
different donors varies in its ability to withstand cryopreservation.
Because of the variability in whether a particular donor's sperm will
survive the freeze/thaw process, a requirement for quarantine could
defeat the intentions of the directed reproductive donor and intended
recipient who have made a joint decision for the recipient to conceive
a child. Accordingly, we have modified the regulation to except
directed semen donors from the 6-month retesting requirement in Sec.
1271.85(d). Because of this change, the requirement in Sec. 1271.60(a)
that semen be quarantined until the completion of retesting under Sec.
1271.85(a) no longer applies to directed semen donations.
7. How Do I Store an HCT[sol]P From a Donor Determined to Be
Ineligible, and What Uses of the HCT[sol]P Are Not Prohibited? (Sec.
1271.65)
Proposed Sec. 1271.65(a) would require HCT[sol]Ps from ineligible
donors to be kept in quarantine and physically separate from other
HCT[sol]Ps until destruction or other permissible disposition was
accomplished. Proposed Sec. 1271.65(b) described three situations in
which these regulations would not prohibit the use of an HCT[sol]P from
an ineligible donor, and additional requirements that would apply in
those instances. The three cases were as follows: (1) Family-related,
allogeneic use; (2) directed donation of reproductive cells or tissue;
and (3) urgent medical need. Under proposed Sec. 1271.65(c), the use
of an HCT[sol]P from a donor for whom the donor-eligibility
[[Page 29801]]
determination had not yet been completed would not have been prohibited
in cases of urgent medical need. (For organizational consistency, we
have moved that provision to Sec. 1271.60 of this final regulation,
which deals with HCT[sol]Ps pending the donor-eligibility
determination.) Finally, proposed Sec. 1271.65(d) would impose special
labeling requirements on HCT[sol]Ps used under Sec. 1271.65(b).
Proposed Sec. 1271.65(b)(4) would prohibit making available an
HCT[sol]P from a xenotransplantation product recipient or an intimate
contact of a xenotransplantation product recipient for use in the
special circumstances set out elsewhere in paragraph (b) (family-
related, allogeneic use; directed donation of reproductive cells or
tissue; and urgent medical need). Throughout this final rule, we have
adopted a more flexible approach to screening for xenotransplantation
than proposed. This new approach is intended to recognize that
different kinds of xenotransplantation may present different degrees of
risk and to provide us with the ability to respond appropriately to
these differences as the field of xenotransplantation develops. The
absolute prohibition in proposed paragraph (b)(4) is not consistent
with this new flexibility in approach, and so we have deleted it from
Sec. 1271.65.
(Comment 37) Several comments questioned how to comply with the
requirement that HCT[sol]Ps from ineligible donors be kept physically
separate from other HCT[sol]Ps. Some comments asserted that physical
separation would require additional refrigerator storage units,
presenting an unnecessary cost and space burden. These comments
questioned the benefit of physically separate storage, suggested that
quarantine alone should be sufficient, or requested that we delete the
physical separation requirement. One comment asked whether storing in
vapor phase nitrogen or encasing units in plastic bags is sufficient to
prevent cross-contamination.
(Response) We have revised Sec. 1271.65(a) to delete the
requirement for physical separation. Section 1271.65(a) now
incorporates language from the definition of quarantine; however, the
term ``quarantine'' is no longer used in paragraph (a), because we
believe it is more appropriately reserved for HCT[sol]Ps awaiting the
outcome of the donor-eligibility determination. Section 1271.65(a) now
requires you either to store or identify HCT[sol]Ps from ineligible
donors in a physically separate area clearly identified for such use or
to follow other procedures that prevent improper release, such as
automated designation, until destruction of the HCT[sol]P or other
disposition in accordance with Sec. 1271.65(b) or (c).
As revised, Sec. 1271.65(a) now provides establishments with
flexibility in achieving the goal of preventing the improper release of
HCT[sol]Ps from ineligible donors. You may choose to keep HCT[sol]Ps
from ineligible donors in a physically separate area clearly identified
for such use. Such physical separation may include storage on a
separate shelf in a refrigerator or freezer that also contains other
shelves storing HCT[sol]Ps in quarantine pending the donor-eligibility
determination and shelves storing HCT[sol]Ps from eligible donors. A
separate refrigerator or freezer may not be necessary.
Alternatively, Sec. 1271.65(a) allows you to use other procedures
that prevent improper release. Such procedures could include automated
designation to prevent improper release. For example, some
establishments label HCT[sol]Ps with bar codes and store the HCT[sol]Ps
in freezers that maintain a constant temperature. Moving the products
to a separate storage area would risk transient warming. Instead, the
HCT[sol]Ps remain in the original storage area and are tracked by a
validated computer system that maintains information on the results of
screening and testing. At the time of release of the HCT[sol]P, the
establishment activates the computer system to assure identification
and retrieval of the specific HCT[sol]P for the intended recipient.
This is an example of a system of automated designation that could
satisfy the requirements of Sec. 1271.65(a).
The provisions of the CGTP proposed rule would require you to
establish and maintain procedures for the control of storage areas to
prevent such problems as cross-contamination and improper release
(proposed Sec. 1271.260(a)).
As for the comment regarding vapor phase nitrogen and plastic bags,
limited scientific evidence exists to show the effectiveness of
measures such as overwrap bags or storage in the vapor phase of liquid
nitrogen to reduce the likelihood of cross-contamination. Such measures
could be used if sufficient evidence exists of their ability to
minimize the risk of cross-contamination.
(Comment 38) One comment urged us to delete the exception for
family-related, allogeneic use, arguing that the urgent medical need
exception would apply for both related and unrelated stem/progenitor
cell donors. Another comment supported the concept that hematopoietic
stem/progenitor cell donors who are related to the recipient should be
held to the same standards as unrelated donors with respect to
screening and testing for communicable disease.
(Response) Although we recognize that the urgent medical need
exception might apply in some instances of donations between family
members, we decline to make the change requested by the first comment.
Our intention in crafting the exception was to recognize that, in some
situations, a recipient and his or her physician might weigh the risks
of using an HCT[sol]P from an ineligible family member in the absence
of an urgent medical need, if such an action were in keeping with the
family's wishes; this exception, with its added safeguards, would allow
them to do so.
We agree with the second comment that the same screening and
testing requirements should apply to donors of hematopoietic stem/
progenitor cells who are related to the recipient as to unrelated
donors, and the final rule is consistent with this view. However, we
have chosen to defer to the family and physician the decision of
whether or not to use an HCT[sol]P from a related donor who has been
determined to be ineligible. For this reason, the regulations do not
prohibit such use.
We have rewritten proposed Sec. 1271.65(b)(1) to reflect changes
made in the registration final rule (66 FR 5447 at 5454). The proposed
exception for ``family-related, allogeneic use'' extended only to
first-degree blood relatives; as modified, the exception now extends to
``allogeneic use in a first-degree or second-degree blood relative.''
Our decision, expressed in the registration final rule, to broaden the
scope of related donors was based on several factors, which also apply
here. The likelihood of finding a donor with a haplotype identical to
that of the recipient is greater among blood-related individuals than
among unrelated individuals. In addition, for certain ethnic groups, it
is extremely difficult to find an appropriate unrelated donor. Finally,
registry outcome data for some hematologic malignancies suggest that
peripheral blood and bone marrow transplant recipients may have a
better survival rate when transplanted with hematopoietic stem/
progenitor cells from related donors (66 FR 5447 at 5454).
Parents, children, and siblings are considered first-degree
relatives. Aunts, uncles, nieces, nephews, first cousins, grandparents,
and grandchildren are second-degree relatives. Relations by adoption or
marriage are excluded from Sec. 1271.65(b)(1), because they are not in
the same genetic pool as blood relatives.
(Comment 39) We received comments on the proposed provision for
directed
[[Page 29802]]
donation of HCT[sol]Ps from ineligible donors. Elsewhere in this rule,
we respond to comments on the definition of directed reproductive donor
and on the applicability of retesting requirements to directed
donations of reproductive cells and tissues.
One comment on proposed Sec. 1271.65 praised the directed donor
provision as appropriate. This comment stated that the directed donor
provisions should also apply when a woman seeks a second child by the
same anonymous donor with known high-risk behavior.
(Response) We disagree that the directed reproductive donor
provisions of Sec. 1271.65(b) extend to anonymous donation. As
discussed in comment 13 of this document, the term ``directed
reproductive donor'' does not apply to anonymous donations, but to
situations where the donor knows, and is known by, the recipient.
Moreover, under this final rule, all potential anonymous semen donors
must be screened for risk factors for relevant communicable disease,
including high-risk behavior; potential donors with a high-risk
behavior will be determined ineligible.
(Comment 40) One comment expressed concern about allowing patients
and physicians to decide whether to use donated gametes from a directed
reproductive donor who is found to be ineligible. This comment asserted
that it is essential that patients be fully informed, and that written
contracts be signed indicating the possible risks to recipient and
baby, so that there is complete understanding for the risks involved.
(Response) It is essential that the patient who chooses to use a
directed donation from an ineligible donor be fully informed of the
risks involved. For any use under Sec. 1271.65(b)(1), the
establishment must notify the physician using the HCT[sol]P from the
ineligible donor of the results of testing and screening. Under Sec.
1271.65(b), the HCT[sol]P must be labeled prominently with the
Biohazard legend and must bear the statement ``WARNING: Advise patient
of communicable disease risks,'' and, in the case of reactive test
results, ``WARNING: Reactive test results for (name of disease agent or
disease).'' In the case of reproductive HCT[sol]Ps, this includes risk
to the baby. We have removed the proposed requirement for the
establishment to document that the physician agreed to explain the
communicable disease risks associated with the use of the HCT[sol]P to
the recipient or the recipient's legally authorized representative and
that the physician agreed to obtain from the recipient or the
recipient's legally authorized representative consent to use the
HCT[sol]P. We decline to require a written contract between physician
and patient. We know that physicians are under legal and ethical
restrictions, requiring them to discuss the risks of communicable
disease transmission stemming from the use of HCT[sol]Ps. We rely on
physicians to meet these obligations when obtaining consent to
procedures involving HCT[sol]Ps from patients and their legal
representatives.
(Comment 41) One comment on directed donations of reproductive
cells or tissue praised FDA for adding clarity to a process that has
created confusion for donors and patients. This comment endorsed the
procedures in proposed Sec. 1271.65(b), but objected to the proposed
requirement for physician consent. The comment asserted that the
patient has the right to make his or her own decisions about medical
treatment, that physician consent is unnecessary because of other
standards of physician conduct, and that some physicians may withhold
consent for invalid reasons.
(Response) In light of this comment, we have reconsidered the
necessity of requiring documentation of the physician's authorization
of the use of an HCT[sol]P from an ineligible donor in the directed
reproductive donor situation, as well as in cases of urgent medical
need or use in a first- or second-degree blood relative. Our decision
is not based on an evaluation of patients' rights, but on the
observation that, in each of these situations, a physician will be
closely involved in the decision to use the HCT[sol]P from the
ineligible donor. For this reason, no additional requirement to obtain
physician consent is necessary.
For the same reasons, we have also removed the requirement for
physician authorization from the provisions governing use of an
HCT[sol]P for urgent medical need before completion of the donor-
eligibility determination (Sec. 1271.60(d)).
(Comment 42) Several comments strongly supported the urgent medical
need provision in proposed Sec. 1271.65(b) and (c). Some comments
commended the structuring of the proposed regulations, noting that the
transplanting physician and the informed patient may deem appropriate a
tissue that is positive for infectious disease when comparing
alternatives, particularly in a matter of life or death or other
emergency medical situations. One comment asserted that the transplant
physician must be the ultimate authority for the use of tissues from
all donors and noted that the prevalence of CMV positivity in the
normal donor population will make this exception widely used.
(Response) We have maintained the provisions for urgent medical
need, although, as noted, the provisions governing use pending the
donor-eligibility determination have been moved to Sec. 1271.60. (To
ensure that the physician receives sufficient information about the
risks of the HCT[sol]P, Sec. 1271.60(d)(2) requires that an HCT[sol]P
from a donor for whom the eligibility determination is not complete be
accompanied by results of donor screening and testing that have been
completed, as well as a list of any screening or testing that has not
yet been completed.)
We also note that, under the final regulation, you are not required
to determine a donor ineligible on the basis of a reactive CMV test,
but under Sec. 1271.85(b)(2) you must establish and maintain an SOP
governing the release of an HCT[sol]P from a donor whose specimen tests
reactive for CMV. Thus, it will be unnecessary to invoke the urgent
medical need provisions to use an HCT[sol]P from a donor who has tested
positive for CMV. (See the discussion in comment 60 of this document.)
(Comment 43) One comment asserted that labeling tissue ``untested
for Biohazard'' might cause transportation issues, because commercial
carriers are reluctant to transport a container labeled ``Biohazard.''
The comment recommended that the proposed regulations clarify that the
tissue container, not necessarily the tissue tr