[Federal Register Volume 62, Number 145 (Tuesday, July 29, 1997)]
[Rules and Regulations]
[Pages 40429-40447]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-19819]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 16 and 1270
[Docket No. 93N-0453]
RIN 0910-AA40
Human Tissue Intended for Transplantation
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
to require certain infectious disease testing, donor screening, and
recordkeeping to help prevent the transmission of the human
immunodeficiency virus (HIV), and hepatitis viruses through human
tissue used in transplantation. In response to comments received, FDA
has clarified and modified many of the provisions of the interim rule
on human tissue intended for transplantation which was published in the
Federal Register of December 14, 1993. The final rule requires
facilities engaged in the recovery, screening, testing, processing,
storing, or distributing of human tissues to ensure that specified
minimum required medical screening and infectious disease testing has
been performed and that records documenting such screening and testing
for each human tissue are available for inspection by FDA. The
regulations also contain provisions for the inspection of such
facilities and for retaining, recalling, or destroying human tissue for
which appropriate documentation is not available.
DATES: The regulation is effective January 26, 1998. This effective
date is applicable to all human tissue intended for transplantation
procured on or after this date. Written comments on the information
collection requirements should be submitted by September 29, 1997.
ADDRESSES: Submit written comments on the information collection
requirements to the Dockets Management Branch (HFA-305), Food and Drug
Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. All
comments should be identified with the docket number found in brackets
in the heading of this document.
FOR FURTHER INFORMATION CONTACT: Paula S. McKeever, Center for
Biologics Evaluation and Research (HFM-630), Food and Drug
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448, 301-594-3074.
SUPPLEMENTARY INFORMATION:
I. Introduction
A. Background
In the Federal Register of December 14, 1993 (58 FR 65514), FDA
issued an interim rule on human tissue intended for transplantation
(hereinafter referred to as the interim rule). These regulations became
effective upon the date of publication in the Federal Register and
required human tissue in storage as of that date to be in compliance.
The interim rule was issued because of evidence indicating an immediate
need to protect the public health from the transmission of HIV
infection and hepatitis infection through transplantation of human
tissue from known donors infected with or at risk for these diseases.
The movement towards regulating human tissue was accelerated by a
hearing on appropriate oversight for human tissue banking chaired by
Senator (then Representative) Wyden before the Subcommittee on
Regulation, Business Opportunities and Technology of the Committee on
Small Business held on October 15, 1993. At the hearing,
representatives of persons involved in human tissue banking advocated
that legislation setting forth regulatory requirements for human tissue
banking be passed. There was testimony that human tissues from foreign
sources were being offered for sale in the United States with little
documentation as to the source of the human tissue, the cause of death,
the medical conditions of the donor, or the results of donor screening
and testing. This raised significant concerns about the safety and
quality of some of the human tissue available for transplantation. As a
result of a number of similar allegations, the agency initiated
inquiries into the possibility that human tissues intended for
transplantation were being supplied without appropriate infectious
disease testing and medical screening. In a relatively brief period of
time, the agency was able to confirm the availability for importation
and distribution to the United States of
[[Page 40430]]
human tissue that did not follow adequate screening and testing
standards to prevent transmission of infectious disease.
In the early 1990's, prior to the above-mentioned reports of the
distribution of imported human tissue not following adequate screening
and testing standards, the Centers for Disease Control and Prevention
(CDC) reported that HIV had been transmitted through transplantation of
human tissue. Based in part on the CDC report, the Assistant Secretary
for Health convened a Public Health Service Work Group to evaluate the
need for and type of Federal oversight that should be developed for
human tissue. In its report on July 18, 1991, the Work Group
recommended Federal development and publication of standards or
guidance on donor screening, testing, recordkeeping and tracking
procedures to reduce the risk of transmission of infectious disease.
The Work Group recommended that Federal agencies, including FDA,
proceed with pending regulations as ``expeditiously as possible.'' The
Work Group charged FDA to ``continue to assert its jurisdiction over
tissues on a product-by-product basis to ensure adequate oversight.''
The Work Group noted that investigation into the needed level of
mandatory oversight for human tissue transplantation, apart from organ
and bone marrow transplantation, should take place and recommended that
FDA evaluate this issue. Subsequently, FDA issued the interim rule.
Since the interim rule was issued, FDA has issued 15 orders for
retention, recall, and destruction of violative human tissue. In March
1995, following receipt of an order for retention, recall, and
destruction that caused shipments of a firm's processed allografts to
be held, a processor of human tissue filed a complaint in Federal
District Court challenging FDA's interim rule and the application of
internal guidance on the interim rule issued to field investigators.
The court issued the plaintiff preliminary injunctive relief by
enjoining FDA from detaining particular shipments of the plaintiff's
tissue. The plaintiff and FDA subsequently entered into an agreement
settling their dispute, and the plaintiff's complaint was dismissed.
After FDA issued the interim rule, FDA held three separate
workshops to promote continuous dialogue between FDA and the human
tissue industry. The first workshop, which FDA announced in the Federal
Register of June 10, 1994 (59 FR 29950), was entitled ``Public Workshop
on Human Tissue Intended for Transplantation'' and was held on June 20,
1994 (hereinafter referred to as the June 1994 workshop). An objective
of the workshop was to give industry the opportunity to discuss
practical concerns relating to the implementation of the interim rule.
It was the intention of FDA to review and consider the discussion of
these topics in the development of any future rulemaking. The comment
period on the interim rule closed March 14, 1994, but was reopened
until August 20, 1994, to allow interested persons additional time to
submit comments on both the interim rule and the workshop.
In the Federal Register of February 17, 1995 (60 FR 9335), FDA
announced that the Blood Products Advisory Committee, scheduled to meet
on March 23 and 24, 1995, would participate in a workshop entitled
``Human Tissue Intended for Transplantation and Human Reproductive
Tissue: Donor Screening and Infectious Disease Testing'' (hereinafter
referred to as the March 1995 workshop). The topics discussed at the
workshop were: (1) Recommendations for donor screening and infectious
disease testing for human tissue intended for transplantation, (2)
draft discussion points for screening and testing donors of human
reproductive tissue, and (3) a draft registration form. FDA made the
``Draft Discussion Points for Screening and Testing Donors of Human
Tissue Intended for Transplantation and Human Reproductive Tissue,''
and the draft establishment registration form available before and at
the meeting.
In the Federal Register of May 24, 1995 (60 FR 27406), FDA
announced a third workshop on human tissue. This workshop, entitled
``Human Tissue for Transplantation and Human Reproductive Tissue:
Scientific and Regulatory Issues and Perspectives'', was held on June
20 and 21, 1995 (hereinafter referred to as the June 1995 workshop).
The purpose of this workshop was to provide an opportunity for
continued discussion of the regulation of human tissue for
transplantation. The workshop consisted of plenary and breakout
sessions that focused on the following topics: (1) Donor screening, (2)
infectious disease testing and inactivation methods, (3) voluntary
standards, (4) assessment of industry practices related to tracking,
(5) interactions with organ procurement organizations and procurement
coordination practices, and (6) State regulatory approaches and
industry practices. FDA offered a draft discussion document concerning
the screening and testing of donors of human tissue intended for
transplantation in advance and at the workshop. The availability of the
draft document was announced in the Federal Register of June 20, 1995
(60 FR 32128). FDA requested that comments on the draft document be
sent to the Dockets Management Branch by July 20, 1995, for
consideration in the drafting of a guidance document.
In response to industry requests for clearer guidance on donor
screening and in an effort to consolidate and disseminate
recommendations on the screening of donors for signs and symptoms of
infectious disease, FDA has prepared a document entitled ``Guidance for
Screening and Testing of Donors of Human Tissue Intended for
Transplantation,'' the availability of which is announced elsewhere in
this issue of the Federal Register. This guidance was prepared taking
into account the issues addressed in the draft document distributed at
the workshop and comments received.
The final rule takes into account comments submitted to the Dockets
Management Branch, and discussions and information obtained through
public participation in the three workshops. The agency is taking this
action to provide clarification of the interim rule and to finalize its
provisions.
B. Scientific and Legal Justification
The use of HIV antibody testing on donors of human tissue makes the
human tissue inventory safer. However, it does not eliminate the
``window'' period between the time of infection and the presence of
detectable levels of antibodies to HIV. Therefore, as an added safety
measure FDA requires screening for behavioral and high risk information
in addition to testing for infection with the virus so that the safest
product will be made available. Like the HIV virus, evidence of
hepatitis B and hepatitis C is determined by screening and testing
human tissue donors. Since HIV and hepatitis viruses are transmitted by
parenteral and sexual modes, exclusion of potentially infected
donations by both screening and testing the human tissue donor has been
found to be reliable and widely accepted. These viruses may be
transmitted by a wide range of human tissue including solid organs,
musculoskeletal and integumentary tissue, and body fluids (e.g., semen
and breast milk).
FDA is issuing these regulatory requirements under the legal
authority of section 361 of the Public Health Service Act (the PHS Act,
42 U.S.C. 264). This section authorizes the Secretary of the Department
of Health and Human Services (the Secretary), to make and enforce such
regulations as
[[Page 40431]]
judged necessary to prevent the introduction, transmission, or spread
of communicable diseases from foreign countries into the States or from
State to State. Intrastate transactions may be regulated under
authority of this provision, as appropriate (see State of Louisiana v.
Mathews, 427 F. Supp. 174 (E. D. La. 1977)). Section 361 of the PHS Act
also provides for such inspection and destruction of articles found to
be so infected or contaminated as to be sources of dangerous infection
to humans, and other measures, as may be deemed by the Secretary to be
necessary. Section 361 of the PHS Act has been invoked by FDA to
regulate various activities or articles. For example, FDA has invoked
this authority to regulate conveyance sanitation, the source and use of
potable water, and milk pasteurization. The agency has also acted under
section 361 of the PHS Act to prevent the transmission of communicable
disease through shellfish, turtles, certain birds, and bristle brushes
(see 21 CFR parts 1240 and 1250). FDA has also relied in part on
section 361 of the PHS Act in issuing requirements to protect the blood
supply.
Authority for the enforcement of section 361 of the PHS Act is
provided for in part under section 368 of the PHS Act (42 U.S.C. 271).
Under section 368(a), any person who violates a regulation prescribed
under section 361 of the PHS Act may be punished by imprisonment for up
to 1 year (42 U.S.C. 271(a)). 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
(18 U.S.C. 3559 and 3571(c)). In addition, Federal District Courts have
jurisdiction to enjoin individuals and organizations from violating
regulations implementing section 361 of the PHS Act.
II. Highlights of the Final Rule
The final rule provides clarification of certain provisions of the
interim rule and responds to the comments and concerns expressed. In
response to comments received on the interim rule, definitions have
been added or modified for the following terms: Blood component,
colloid, contract services, crystalloid, donor medical history
interview, establishment, importer of record, legislative consent,
person, physical assessment, plasma dilution, reconstituted blood,
relevant medical records, responsible person, and summary of records.
The final rule further elaborates on the requirements for: (1) Criteria
for using an algorithm when determining plasma dilution, (2) documents
to be included in the summary of records, (3) responsibility for
maintaining the records used in determining the suitability of the
tissue for transplantation, (4) the relevant medical records for
corneal tissue recovered under legislative consent, and (5) the
shipment of tissue. The rule also describes the steps to be followed
when human tissue is offered for import.
Due to the renumbering of many of the sections in the rule the
following chart is being provided for comparison:
Table 1.--Comparison Chart of Final and Interim Rules
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Final Rule (section) Interim Rule (section) Nature of Change
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Subpart A--General Provisions
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Scope Additional exemptions added.
1270.1(a)(b)(c)(d) 1270.1(a)(b)
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Definitions Definitions added for:
1270.3(a)-(x) 1270.3(a)-(i) (b) blood component,
(c) colloid,
(d) contract services,
(e) crystalloid,
(h) donor medical history interview,
(i) establishment,
(k) importer of record,
(l) legislative consent,
(m) person,
(n) physical assessment,
(o) plasma dilution,
(r) reconstituted blood,
(t) relevant medical records,
(u) responsible person,
(w) summary of records.
1270.5 through 1270.20 Removed.
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Subpart B--Donor Screening and
Testing
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Human Tissue Intended for Renumbered. Clarification of (e)
Transplantation 1270.5(a)-(f) summary of records, addition of (b)
1270.21(a)-(h) testing of neonate donor (g)
standards for corneal retrieval,
and (h) plasma dilution.
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Subpart C--Procedures and Records
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Written Procedures Renumbered. Original paragraph (c)
1270.31(a)-(e) 1270.7(a)-(c) is now paragraph (e), new
paragraphs (c) and (d) require
written procedures for designating
and identifying quarantined tissue
and for preventing contamination or
cross-contamination of tissue
during processing.
[[Page 40432]]
Records, General Requirements Renumbered. Paragraphs (c) and (d)
1270.33(a)-(h) 1270.9(a)-(e) contain requirements for shipment
of human tissue prior to and after
a determination of suitability for
transplantation is made. Original
paragraphs (c),(d), and (e) are now
paragraphs(f),(g), and (h),
respectively. Paragraph (f) is
amended to clarify who is
responsible for record retention.
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Specific Records Renumbered. Original paragraphs (b)
1270.35(a)-(d) 1270.11(a)-(c) and (c) are now paragraphs (d) and
(b) respectively. New paragraph (c)
was added to require documentation
of receipt and distribution of
human tissue.
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Subpart D--Inspection of Tissue
Establishments
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Inspection Renumbered.
1270.41(a)-(e) 1270.13(a)-(e)
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1270.42(a)-(b) none Added steps to be followed when
human tissue is offered for import.
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1270.43(a)-(e) 1270.15(a)-(e) Renumbered.
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III. Comments on the Interim Rule and FDA Responses
FDA received 73 comments on the interim rule. Many comments
supported FDA's effort to prevent transmission of disease through
transplantation and the positive effect the interim rule had on
nationwide standardization. Other comments, primarily from
representatives and supporters of eye banks, objected to the interim
rule. The comments stated that implementation of the rule temporarily
halted transplantation operations of human tissue and argued that the
industry should be allowed to continue regulating itself because of its
excellent record in preventing the transmission of disease.
In general, the comments requested clarification and modification
of selected sections of the interim rule, presented data supporting the
suggested changes, and described burdens that particular sections would
impose, e.g., the effect on cornea recovery by the requirement for a
next of kin interview in States or territories with medical examiner
laws, the retrospective review of tissue in storage for compliance,
cadaveric specimen testing, and the import/export of human tissue from
countries without certified laboratories under the Clinical
Laboratories Improvement Amendments of 1988 (CLIA).
A. General Comments
1. One comment stated that the public health was threatened by the
interim rule in that it contributed to an existing backlog demand for
processed human tissue.
FDA recognizes that there may have been some temporary shortages of
a few types of human tissue due to a small amount of human tissue in
storage not being in compliance with the interim rule, but is not aware
of instances where the public health was affected adversely. FDA took
voluntary industry standards and State requirements into account in
issuing the rule to lessen the impact of the implementation of the
interim rule.
2. One comment stated that organ transplantation should be included
in the scope of the interim rule and inquired as to why it was not
covered.
The National Organ Transplant Act of 1984 provides for Federal
oversight of the human organ transplantation system. The Health
Resources Services Administration (HRSA) within the Department of
Health and Human Services (DHHS) currently administers programs related
to human organ transplantation. Human organs are specifically excluded
from the interim rule and the final rule (new Sec. 1270.3(j)(4))
because they are already regulated under existing Federal oversight
programs and FDA does not believe that additional oversight by FDA is
needed at this time.
3. Twenty-six comments maintained that eye banks adhere to strict
internal standards, have an excellent track record with few documented
disease transmission cases, and should not be regulated by the
government.
The agency acknowledges that the trade associations for eye banks,
the American Association of Tissue Banks (AATB) and the Eye Banks
Association of America (EBAA) are recognized to have strict internal
standards and that the eye banks have a reputation for conscientious
adherence to those standards. The agency notes, however, that although
corneas may have a degree of protection due to avascularity, they can,
like other tissues, carry viruses and transmit communicable diseases.
Therefore, FDA believes that corneas should be subject to the same
regulatory oversight as other tissues. The agency would also note that
the regulation will impose little or no burden for eye banks that are
in compliance with the voluntary AATB and EBAA standards because these
standards are substantially similar to the requirements of the
regulation.
4. Two comments supported required testing by CLIA-certified
laboratories.
Under provisions of the 1988 Amendments to the Clinical
Laboratories Improvement Act of 1967 (CLIA '88), laboratories engaged
in testing specimens in interstate commerce must meet the requirements
of section 353 of the Public Health Service Act (42 U.S.C. 263a) in
order to be licensed or remain licensed for testing in interstate
commerce. CLIA applies to laboratories, including physicians' office
laboratories, that test human specimens. Under CLIA '88,
[[Page 40433]]
such laboratories are subject to regulations designed to ensure the
quality and reliability of medical tests they perform. Therefore, the
requirement that all infectious disease testing be performed by CLIA-
certified laboratories, helps ensure standardized testing on all donors
of human tissue intended for transplantation.
5. One comment inquired if contract processing is permitted under
the interim rule.
FDA realizes that not all human tissue establishments have the
facilities to perform all manufacturing steps. It may be more cost
effective for establishments to contract out some testing and
processing procedures. There is no prohibition in the interim rule or
final rule concerning such contract services. Therefore, contract
services have been added to the definitions in Sec. 1270.3 (21 CFR
1270.3). FDA has revised Sec. 1270.41(a) (21 CFR 1270.41(a)) to clarify
that such contract services are subject to inspections conducted by
authorized representatives of FDA.
6. Two comments urged the expedited publication of the draft
guidance document Draft USPHS Guidelines for Preventing Transmission of
Human Immunodeficiency Virus Through Transplantation of Human Tissue
and Organs, that provides specific questions for use in donor
behavioral and high risk information screening.
At the time of publication of the interim rule, the final version
of the guidance document had not been made available. The Public Health
Service (PHS) published the final guideline on May 20, 1994, in the
Morbidity and Mortality Weekly Report (MMWR 1994:43, 1-17). FDA
considered these guidelines and previous PHS guidelines in the
preparation of the final rule and the guidance document that is being
announced as available by FDA elsewhere in this issue of the Federal
Register. The guidance document provides recommendations on appropriate
questions, clinical evidence, and physical evidence for use in donor
screening.
7. Two comments were made on alternative methods of preventing
transmission of HIV-1, HIV-2, hepatitis B, and hepatitis C viruses. One
comment asked that the rule provide for a waiver process based on
alternative methods of viral inactivation. One of the comments added
that claims of processes that result in viral inactivation or sterility
should be investigated for scientific accuracy prior to exemption from
any portion of these rules.
Presently, FDA is unaware of any alternative method of viral
inactivation that FDA believes warrants omission of HIV and hepatitis
testing. Therefore, FDA does not believe that such a change is
warranted at this time. FDA is interested in public comment on this
issue and will consider whether to include in future rulemaking a
process for the agency to grant waivers from any regulation under part
1270 (21 CFR part 1270).
8. Two comments recommended that an expert advisory committee, to
include transplant surgeons as members, be established as soon as
possible to review and make recommendations for future rulemaking.
Since the time the interim rule was published, FDA has requested
the Blood Products Advisory Committee (BPAC) to review data and make
recommendations regarding human tissue for transplantation in addition
to blood products. The agency recognizes the positive contribution of
experienced professionals in providing FDA with assistance on
regulatory issues and believes that the BPAC can serve in an advisory
role on human tissue intended for transplantation.
On July 13, 1995, a report by the Institute of Medicine (IOM)
entitled ``HIV and the Blood Supply: An Analysis in Crisis
Decisionmaking'' was released. The Secretary directed this
investigation in response to concerns voiced by the hemophilia
community concerning events leading to the transmission of HIV to
individuals with hemophilia from contaminated blood products. FDA has
made certain changes to BPAC consistent with recommendations in the
report. In particular, FDA has reformulated the membership of BPAC to
limit industry-affiliated representation to a single, nonvoting
representative. Additionally, FDA has revised the BPAC charter to
expand the possibility for consumer representation.
B. Comments on Specific Provisions in the Interim Rule
FDA has revised the interim rule as a result of comments submitted
to the docket. In addition, FDA on its own initiative is making changes
to clarify the requirements of the rule and its application to the
tissue industry. The term ``banked'' has been deleted from the phrase
``banked human tissue intended for transplantation'' wherever it
appears in the regulations because FDA believes the term ``banked'' is
unnecessary with respect to human tissues covered by this final rule
1. Scope (Sec. 1270.1)
Section 1270.1 defines the scope of the regulations governing human
tissue intended for transplantation to include human tissue and
establishments or persons engaged in the recovery, processing, storage,
or distribution of human tissue. FDA has revised Sec. 1270.1 by
explicitly stating that screening and testing activities are subject to
regulation. The final rule also clarifies that at this time the
regulations do not apply to human tissue intended for autologous use.
FDA is, however, currently conducting a review of human tissues that
includes autologous use and is considering proposing additional
regulations in this area.
9. One comment asked that practitioners in transplant
establishments who only store human tissue for transplant in their own
facilities be relieved from compliance with the provisions of the rule.
FDA recognizes that there are instances where human tissue is
received and stored temporarily in a hospital or other clinical
facility pending scheduled surgery within the same facility. FDA agrees
that hospitals or other clinical facilities that only receive and store
human tissue for transplantation within the same facility should not be
covered by the rule and thus FDA has added this provision in
Sec. 1270.1(d) of the final rule. Those hospitals or clinical
facilities that participate in the recovery, screening, testing,
processing, or distribution of human tissue in addition to storage for
transplantation are covered by the rule.
2. Definitions (Sec. 1270.3)
Section 1270.3 defines various terms used in the regulations. In
the final rule FDA has clarified, revised and simplified the
definitions. For clarity, FDA has added the terms ``shipment,'' and
``exportation'' to the definition of ``distribution'' (Sec. 1270.3(f)
of the final rule). The definition of ``processing'' (Sec. 1270.3(p) of
the final rule) has been revised by deleting the word ``potency'' and
by adding that processing includes ``the inactivation or removal of
adventitious agents.'' The phrase ``human tissue that has not yet been
characterized as suitable for transplantation'' has been added to
clarify the definition of ``quarantine'' (Sec. 1270.3(q) of the final
rule). The definition of ``storage'' (Sec. 1270.3(v) of the final rule)
has been simplified by deleting any reference to the facility holding
the tissue. The term ``native vasculature'' has been replaced by the
term ``original blood vessels'' in the definition of ``vascularized''
(Sec. 1270.3(x) of the final rule).
10. One comment suggested that the rule apply to normal human cells
such
[[Page 40434]]
as hepatocytes that can be transplanted with little or no manipulation.
The agency declines to accept the comment's suggestion. The rule
covers human tissue such as bone, ligament, tendons, fascia, cartilage,
corneas, and skin. Hepatocytes and other cellular based therapies are
regulated by FDA as biological products. (See description in
``Application of Current Statutory Authorities to Human Somatic Cell
Therapy Products and Gene Therapy Products'' (58 FR 53248).)
11. One comment asked for definition of the following terms: (1)
Blood component, (2) colloid or volume expander, (3) crystalloid, (4)
hemodilution, and (5) pretransfusion specimen.
FDA agrees that some additional definitions should be included and
is amending Sec. 1270.3 to include definitions for ``blood component,''
``colloid'' (volume expander), ``contract services,'' ``crystalloid,''
``donor medical history interview,'' ``establishment,'' ``importer of
record,'' ``legislative consent,'' ``person,'' ``physical assessment,''
``plasma dilution'' (to replace ``hemodilution''), ``relevant medical
records,'' ``reconstituted blood,'' ``responsible person,'' and
``summary of records.'' FDA believes that the term ``pretransfusion
specimen'' is self explanatory, therefore, a definition has not been
added.
12. One comment requested that the definition of ``vascularized''
that appears in Sec. 1270.3(c) of the interim rule be clarified.
FDA agrees that the definition of vascularized should be clarified
and has revised the definition.
13. Two comments requested a revision to the definition of human
tissue to specifically exclude human organs and those human tissues
that have been chemically or biophysically altered, such as heart
valves.
The definition of human tissue found in Sec. 1270.3(b) of the
interim rule (Sec. 1270.3(j) of the final rule) contains a specific
exclusion for vascularized organs (kidney, liver, heart, lung,
pancreas, or other vascularized human organs). Allograft heart valves,
dura mater allografts, epikeratophakia lenticules, preserved umbilical
cord vein grafts, and various skin and bone products that have been
chemically or biophysically altered are currently regulated as devices
under the authority of the Medical Device Amendments of 1976 (Pub. L.
94-295) and are therefore excluded from this definition of human
tissue. However, FDA is considering the regulation under part 1270 of
human heart valve allografts and certain other tissues now regulated as
devices. To allow all interested persons to comment on this regulatory
change, FDA intends to provide notice and request for comment on such
regulation in the Federal Register at a future date. Human tissues that
are processed in ways to only reduce infectivity or preserve human
tissue integrity are regulated under part 1270.
3. Donor Testing (Sec. 1270.21)
Section 1270.5 of the interim rule specifies the requirements for
testing donor blood specimens for evidence of communicable viruses,
i.e., HIV-1, HIV-2, hepatitis B, and hepatitis C. It requires that
these tests be done using FDA licensed test kits approved for such use
by FDA and performed in a laboratory certified under CLIA. In the final
rule, FDA has deleted the terms ``blood'' and ``serological'' and the
name of the communicable virus has been listed in place of a specific
marker test. This change has been made to allow for future advancement
in science and technology which could cause a change in the appropriate
test methodology. Section 1270.5(e) of the interim rule has been split
into Sec. 1270.21(f) and (g) of the final rule, in part to clarify the
revised requirements for corneal tissue retrieval.
14. One comment inquired if human tissue would be considered
suitable for transplantation if a repeatedly reactive screening test
for any of the viral marker tests was negative by confirmatory testing.
Some comments have encouraged FDA to allow the use of tissue for which
blood specimens tested repeatedly reactive for hepatitis B surface
antigen (HBsAg), if the results of confirmatory neutralization testing
do not confirm the results of the screening.
FDA does not concur with this suggestion. With current tests, early
HIV, hepatitis B virus, and hepatitis C virus infections can be missed
by the respective confirmatory test due to differences in the
sensitivity of the tests, albeit at a low frequency. The agency is
clarifying in the final rule, that suitability of human tissue shall be
determined by the results of screening tests for the required viral
markers. The rule requires that the donor be free of evidence of HIV,
hepatitis B, and hepatitis C. A repeatedly reactive screening test for
any of the viral markers indicates that the donor may have been exposed
to and infected with the particular virus. Any indication of the
possibility of infection must be taken into consideration when
determining the suitability of the human tissue. The use of screening
tests in determining the suitability of the donor of human tissue
intended for transplantation is clarified in Sec. 1270.21(a) of the
final rule which specifically identifies ``screening * * *'' as the
required test. Therefore, tissue that is repeatedly reactive is not
suitable for use even if confirmatory tests are negative. In addition,
if the tissue establishment becomes aware of indeterminate, repeatedly
reactive, or positive test results relative to HIV or hepatitis, even
if the tests are not specifically required by the final rule, then the
tissue is considered not suitable for transplantation.
15. Seven comments questioned the validity of certain viral marker
tests using cadaveric blood specimens. Concern was expressed over the
inadequate data that exists on the testing of cadaveric blood specimens
using FDA licensed screening kits for viral markers and guidance was
requested in determining the suitability of the donor.
FDA is aware of the need to clarify the appropriateness of using
cadaveric specimens, i.e., a blood specimen taken from a donor whose
heartbeat has ceased, with the currently licensed test kits. Generally,
the concern is that test results based on testing of cadaveric blood
specimens that exhibit some degree of hemolysis and/or lipemia may not
be accurate. FDA is working with manufacturers towards validation of
assays for cadaveric specimen use. Screening tests that have been
approved for testing cadaveric blood are to be used, once FDA approval
has been given and the labeling of the test kit has been modified to
specifically indicate the use of cadaveric blood specimens.
16. One comment dealt with a letter issued by CBER on December 28,
1993, to the tissue industry (hereinafter referred to as the December
1993 letter). This letter, which was intended to provide clarification
to the industry regarding HIV-2 testing, contained the statement, ``as
long as the tissue was tested by the best available test methods at the
time, and the newly available test methodology was adopted in a timely
manner, the tissue continues to be suitable for transplant.'' The
comment said this statement may be misleading because it could be
interpreted to include other newly licensed tests in addition to tests
for HIV-2.
Because the December 1993 letter addresses HIV-2 testing only, FDA
does not believe the statement cited by the comment could be easily
misinterpreted as referring to tests for other infectious agents.
17. Three comments requested further explanation of the approval
requirements for laboratories doing screening tests on donor specimens.
Specifically requested, was clarification
[[Page 40435]]
of the term ``registered and certified under CLIA'' and recognition, by
the Health Care Finance Administration (HCFA), of accreditation by an
acceptable alternative inspection organization.
Shortly after publication of the interim rule, FDA provided
guidance regarding Sec. 1270.5(b) in the December 1993 letter.
Laboratories have the option of coming under the jurisdiction of HCFA
directly, or indirectly by way of accreditation by a private
accreditation organization approved by HCFA for ``deemed status,'' or
by being located in a State approved for exemption under CLIA. In the
December 1993 letter, FDA recognized that many laboratories had been
registered but not yet certified under CLIA, because: (1) They had not
yet been surveyed (inspected) by HCFA or one of its agents; (2) they
had been surveyed but had not yet received their certificate of
compliance; or (3) the accrediting organization performing the survey
had applied for but had not yet received approval by HCFA for ``deemed
status'' under the 1988 amendments. During this transition period, FDA
stated that its preliminary interpretation was that a laboratory was
suitable for performing the testing required by the interim rule
provided: (1) The laboratory had an active and current history of being
surveyed by HCFA or one of its agents, by a private accrediting
organization, or an organization whose approval by HCFA was pending;
(2) the laboratory was in good standing with HCFA, and if applicable,
FDA, in that there was no regulatory action either pending or in effect
that would limit the laboratory's ability to perform the types of tests
that are required in the interim rule; and (3) the laboratory was
registered with HCFA at that time. Since the publication of the interim
rule, HCFA has completed the first survey of registered laboratories.
All laboratories that have met the inspection criteria have been issued
certification under CLIA. Thus, laboratories must now be certified
under CLIA.
18. One comment on Sec. 1270.5(a) (Sec. 1270.21(a) of the final
rule) urged that tests such as those run on lymph node tissue or
vitreous humor be considered in the absence of an appropriate blood
specimen.
In Sec. 1270.21 of the final rule, FDA has deleted the
identification of blood as the source of specimen required for
infectious disease testing, recognizing advances in technology and the
possibility of future approval of viral marker testing (used in
determining donor suitability) that may utilize alternative specimen
sources. At this time, blood is the only specimen approved for use with
FDA licensed viral marker tests to determine donor suitability.
19. One comment on Sec. 1270.5(b) (Sec. 1270.21(c) of the final
rule) asserted that the rule discriminates against importers of human
tissue because they are unable to comply with the requirement for
testing by a CLIA certified laboratory.
During a congressional hearing held on October 15, 1993, testimony
was given with respect to an increase of unsuitable human tissue
derived from foreign sources being offered for sale in the United
States by individuals unwilling to declare the actual source of the
human tissue, to provide documentation as to the cause of death, the
medical records of the donor, the results of donor screening and
testing, or to furnish specimens of donor serum for testing. Human
tissue imported from outside the United States must meet the same
standards of donor screening, testing, and tissue recovery applied to
all domestic human tissue because of the potential for the transmission
of communicable diseases. When the interim rule was published on
December 14, 1993, there were no CLIA certified testing laboratories in
foreign countries. Although these facilities were unavailable at the
time, foreign establishments were not prohibited from using domestic
CLIA certified laboratories for performing the required testing. Any
laboratory, foreign or domestic, may apply for certification under
CLIA. The proficiency of the laboratory performing the required testing
is a key element in assuring the safety of human tissue. Inspection and
regulation under CLIA helps to ensure that the laboratory is proficient
and competent to perform the required tests accurately. Therefore,
FDA's requirements are not intended to discriminate against foreign
importers, but are an attempt to help ensure that foreign human tissue
meets the same standards as human tissue procured in the United States
for transplantation.
4. Plasma Dilution
20. Under section 1270.5(d) (Sec. 1270.21(h) of the final rule),
human tissue from donors whose blood specimen may be diluted
sufficiently to affect infectious disease test results is unsuitable
unless the specimen is assessed for acceptability using an established
procedure to calculate dilution (algorithm). One comment suggested
revising the term ``hemodilution'' to ``plasma dilution'' to accurately
describe the dilutional component because it is the infused plasma or
fluid which dilutes the donor's plasma or serum used for testing, not
the red cell volume.
FDA agrees with the comment and is amending Sec. 1270.5(d)(1)
Sec. 1270.21(h)(2) in the final rule) to use the term ``plasma
dilution.''
21. Two comments on Sec. 1270.5(d) (Sec. 1270.21(h) of the final
rule) proposed revisions to include specific factors for consideration
in determining the suitability of human tissue when the possibility of
plasma dilution exists. The comments noted that FDA did not address
generally accepted criteria for making the determination of plasma
dilution.
FDA recognizes that the interim rule did not address different
factors such as amount of blood loss, renal output versus input of
fluids, time of sampling in relation to transfusion/infusion, and
volume transfused/infused in determining plasma dilution. Section
1270.21(h) of the final rule is revised to recognize that an algorithm
may be used to ensure that there has not been plasma dilution
sufficient to affect test results. Plasma dilution is further discussed
in comment 25 of this document. FDA also notes that factors regarding
the selection of an appropriate algorithm for determining plasma
dilution are discussed in the Guidance for Screening and Testing of
Donors of Human Tissue Intended for Transplantation. The notice of
availability of this guidance document may be found elsewhere in this
issue of the Federal Register.
22. One comment on Sec. 1270.5(d)(1) (Sec. 1270.21(g)(2)(i) of the
final rule) inquired if a pretransfusion/infusion specimen was
sufficient for testing or whether a posttransfusion/infusion specimen
should also be tested.
A posttransfusion/infusion specimen is not necessary when an
adequate pretransfusion/infusion specimen is available. If a
pretransfusion/infusion specimen is unavailable for testing, then for
the tissue to be assessed for suitability, a posttransfusion specimen
must be assessed for plasma dilution using an algorithm prior to
testing.
23. Five comments on Sec. 1270.5(d)(1) (Sec. 1270.21(g)(2) of the
final rule) discussed the difficulty in obtaining pretransfusion/
infusion specimens because many potential donors arrive at the
emergency room in the process of being transfused with blood or infused
with fluids, thus eliminating the possibility of obtaining a
pretransfusion/infusion specimen.
The agency realizes a pretransfusion/infusion specimen is not
always available. In those cases where the specimen is unavailable, an
algorithm to determine if plasma dilution may affect
[[Page 40436]]
test results should be applied to determine donor suitability. The
establishment's standard operating procedures (SOP's) should outline
this algorithm and the measures for determining donor suitability.
24. Two comments requested clarification of specific circumstances
when plasma dilution should be considered and what specific tests would
be affected by plasma dilution.
When a pretransfusion/infusion specimen is unavailable, FDA
believes the following criteria should be considered in evaluating the
need for using an algorithm to determine if plasma dilution is
sufficient to affect infectious disease test results: (1) Blood loss is
known or suspected to have occurred; (2) the tissue donor was
transfused or infused and an adequate pretransfusion/infusion specimen
is not available for infectious disease testing; (3) if preceding the
collection of the donor specimen in adult donors, more than 2,000
milliliters (mL) of: whole blood, reconstituted blood, red blood cells,
and/or colloids have been administered within the previous 48 hours
and/or; crystalloids have been administered within the previous one
hour; or any combination of these has occurred; and (4) in any donor 12
years of age or less, any transfusion/infusion has occurred. Once this
information is reviewed and the determination is made that the 2,000 mL
is exceeded or the donor is 12 years of age or less, the tissue is
considered unsuitable until an algorithm defined in the tissue
establishment's SOP's is used to assess whether the dilution affected
the test results.
25. Fourteen comments on Sec. 1270.5(d)(2) (Sec. 1270.21(h)(2)(ii)
of the final rule) requested clarification and guidance on specific
aspects of an acceptable algorithm in evaluating plasma dilution. One
comment stated that, in the absence of science, further rulemaking
should not include an arbitrary cutoff. In particular, the comments
asked FDA to elaborate on: (1) Who is responsible for determining the
parameters of the algorithm; (2) the type of blood, blood components,
and fluids to be included or excluded; (3) the time period that is to
be taken into consideration and the basis on which it is calculated;
(4) the unit of measurement to be used; (5) the maximum volume allowed;
and (6) the consideration given to output versus input.
FDA is not prescribing who may prepare the algorithm. It may be
prepared by any responsible person with adequate training and
understanding of the principles of plasma dilution. FDA discusses the
criteria for using an algorithm to determine plasma dilution in comment
24 of this document, and is providing additional information on a
suitable algorithm in the Guidance for Screening and Testing Donors of
Human Tissue Intended for Transplantation announced elsewhere in this
issue of the Federal Register. The information in the guidance document
is based on available scientific evidence and was the focus of the
workshop held in June 1995.
The discussion of an algorithm for determining plasma dilution in
the guidance document is based on the calculation of blood volume and
plasma volume in relation to the donor's body mass. Where blood loss
has occurred or is suspected, and a pretransfusion/infusion donor
specimen is not available,Sec. 1270.21(h) provides for use of an
algorithm when the transfusion/infusion of more than 2,000 mL of whole
blood, reconstituted blood, red blood cells, and/or colloids in the
previous 48 hours and/or crystalloids within the previous one hour, or
any combination, has occurred in the stated time periods prior to the
collection of the specimen. The time periods recommended by the
algorithm are based on the safety record of voluntary standards in the
tissue industry employing such a time period and on a 50 percent volume
dilution of blood or plasma. Transfused/infused products have been
broken into categories for the purpose of calculating the volumes
transfused/infused. They are blood, colloid, crystalloid, and a
combination of these categories.
FDA believes and has included in the regulations at Sec. 1270.21(h)
that if the following conditions are exceeded in a circumstance of
blood loss and replacement in an adult, or transfusion/infusion in a
child 12 years of age or less, the tissue shall be determined not
suitable for transplantation. The agency currently believes that
transfusion/infusion of greater than one blood volume in the case of
blood replacement or greater than one plasma volume in the case of
colloid and crystalloid infusion, could make infectious disease testing
results unreliable due to plasma dilution.
Table 2.--Blood and Plasma Volume Calculation
------------------------------------------------------------------------
Product(s) Hours prior to Calculated\1\
Category infused included in specimen volume
category collection administered
------------------------------------------------------------------------
Blood Blood unit Within 48 hours > one blood
labeled as volume
``Whole Blood,''
Blood unit
labeled as ``Red
Blood Cells,''
Reconstituted
blood\2\
------------------------------------------------------------------------
Colloid Plasma, Within 48 hours > one plasma
platelets, volume
albumin,
hetastarch,
dextran
------------------------------------------------------------------------
Crystalloid Saline, dextrose Within 1 hour > one plasma
in water, volume
Ringer's
lactate, other
balanced
electrolyte
solutions
------------------------------------------------------------------------
Blood and See all of the Within 48 hours > one blood
colloids above and within 1 volume (or if
and/or hour the calculated
crystalloids volume for
colloids only,
within 48 hours
of collection
and/or
crystalloids
within 1 hour
of collection
is > one plasma
volume)
------------------------------------------------------------------------
Colloids See above for Within 48 hours > one plasma
and colloid and and within 1 volume
crystalloids crystalloid hour
------------------------------------------------------------------------
\1\ Recommended methods for blood and plasma volume calculations may be
found in the ``Guidance for Screening and Testing of Donors of Human
Tissue Intended for Transplantation.''
[[Page 40437]]
\2\ Reconstituted blood means the extracorporeal resuspension of a blood
unit labeled as ``Red Blood Cells'' by the addition of colloids and/or
crystalloids to produce a hematocrit in the normal range.
5. Screening
26. Section 1270.5(e) (Sec. 1270.21(f) of the final rule) requires
that in order to determine the suitability of human tissue for
transplantation, the identity of the donor shall be ascertained and the
relevant medical records shall be reviewed to assure freedom from risk
factors for and clinical evidence of hepatitis B, hepatitis C, and HIV
infection. One comment requested that the medical history include all
available medical, coroner, and autopsy records, both written and those
communicated orally by health care practitioners.
FDA agrees that oral communications specific to the donor's
relevant medical history could affect donor suitability and should be
documented because they are an integral part of the donor testing and
screening process. This information should be recorded by a responsible
person and should serve as an adjunct to other available information
and records required by new Sec. 1270.21. FDA has included a definition
for ``relevant medical records'' in Sec. 1270.3(t) which is consistent
with the comment.
27. Twenty comments on Sec. 1270.5(e) (Sec. 1270.21(f) and (g) of
the final rule) expressed concern that the requirement for a donor
medical history interview (formerly the Next-of-Kin interview in the
interim rule) as part of the relevant medical records, would make it
more difficult to procure corneas under legislative consent (formerly
Medical Examiner Law in the interim rule and defined in Sec. 1270.3(h)
of the final rule). The comments suggested that the donor medical
history interview for corneas procured under legislative consent be
waived. One comment proposed using the ``all available information''
standard in determining suitability of corneas for transplantation. In
an opposing viewpoint, six comments disagreed with a waiver of donor
medical history interviews for corneas procured under legislative
consent. The latter stated that corneas procured as a result of
legislative consent do not meet industry standards and diminish the
ability of transplant professionals to effectively promote the
altruistic benefits of donation. These comments endorsed regulation of
corneas because corneal tissue does transmit disease and should be
regulated as strictly as other tissue.
After reviewing the numerous comments on the interim rule and the
discussions at the workshops, FDA acknowledges the need for flexibility
in the procurement of corneal tissue under legislative consent. Where
corneas are procured under legislative consent, FDA has modified the
regulations in the final rule to accept as sufficient a physical
assessment of the donor in the absence of a donor medical history
interview for behavioral and high risk information. Even though corneas
may have a degree of protection due to avascularity, FDA notes that it
is possible that viruses may be present in donor corneal tissue.
Therefore, the agency believes that this modification underscores the
importance of additional information gathering in determining the
suitability of a donor. Negative viral marker test results for HIV and
hepatitis, and review of other available information in addition to the
physical assessment, will continue to be a requirement. However, if
additional tissue other than cornea is recovered from the same donor,
then a donor medical history interview is required. Based on the
recommendation of the PHS ``Guidelines for Preventing Transmission of
Human Immunodeficiency Virus Through Transplantation of Human Tissue
and Organs'', (MMWR, May 20, 1994) FDA is requiring under new
Sec. 1270.21(g) documentation in the summary of records that corneal
tissue was procured under legislative consent so that the transplant
surgeon will be aware that: (1) A donor medical history interview was
not obtained, (2) a physical assessment of the donor for evidence of
high risk behavioral signs of HIV and hepatitis infection had been
made, and (3) the tissue was determined to be suitable in the absence
of the donor medical history interview.
28. One comment on Sec. 1270.5(f) (Sec. 1270.21(e) of the final
rule) stated that the requirement that a full set of records physically
accompany each of the approximately 300,000 allografts distributed
annually in the United States was superfluous as well as unduly
burdensome and expensive.
FDA believes that the comment has misinterpreted the meaning of
Sec. 1270.5(f). Human tissue that is determined to be suitable for
transplantation per Sec. 1270.9(b) (Sec. 1270.21(e) of the final rule)
must be accompanied by copies of original records, indicating that all
infectious disease testing and screening under Sec. 1270.5
(Sec. 1270.21 of the final rule) has been completed, reviewed by the
responsible person, and found to be negative. The agency has routinely
accepted completed summaries of such records as long as the summary
contains the identity of the testing laboratory, the listing and
interpretation of all required infectious disease tests, a listing of
the documents reviewed as part of the relevant medical records, and the
name of the person or establishment determining the suitability of the
human tissue for transplantation.
After review, FDA finds the recordkeeping requirements of the rule
no more burdensome or potentially costly than the standards established
by the American Association of Tissue Banks or the Eye Bank Association
of America which require labeling and package inserts to accompany a
shipment of human tissue.
6. Written Procedures (Sec. 1270.31)
Section 1270.7 (Sec. 1270.31 of the final rule) sets forth the
requirements for written procedures for infectious disease testing, and
obtaining, reviewing, and assessing the relevant medical records of the
donor.
The agency has added Sec. 1270.31(c) and (d) requiring written
procedures for the designation and identification of quarantined
tissue, and for the prevention of contamination or cross-contamination
of tissues during processing. Because HIV and hepatitis screening and
testing of the donor may be incomplete at the time of processing, and
to maintain the separation of suitable tissue from that not yet
determined to be suitable or tissue that has been determined to be
unsuitable for transplantation (which is the intent of the concept of
``quarantine'' as it is used in the final rule), FDA is requiring that
these written procedures be prepared and followed. FDA is also
requiring that the written procedures for preventing the contamination
or cross-contamination by tissues during processing be validated. These
requirements will facilitate the timely processing of tissue when
necessary (e.g., skin and cornea) while maintaining quarantine and
continuing current good practices performed by industry in daily
processing.
29. Two comments asked for a clearer statement that the written
procedures and records requirement of Secs. 1270.7(a) and 1270.9(a) are
the responsibility of the laboratory where the tests are run.
FDA has amended the requirements of Sec. 1270.9 (Sec. 1270.33 of
the final rule) to state that the person or establishment making the
determination regarding the suitability of human tissue is responsible
for retaining all testing and screening records used in making the
[[Page 40438]]
determination of suitability for transplantation. FDA believes that the
person (as defined in Sec. 1270.3(m) of the final rule) or
establishment (as defined in Sec. 1270.3(i) of the final rule) that has
made the determination of suitability should have and retain the
testing and screening records used in making the determination. The
individual records must also be retained by the establishment
performing the work being recorded. For human tissue that is determined
to be suitable, the person or establishment receiving the human tissue
should receive a summary of records (as described in Sec. 1270.1(w))
used in determining the suitability of the donor. The summary should
identify the responsible person, in addition to the person or
establishment that made the determination that the human tissue is
suitable for transplantation in accordance with Sec. 1270.21(e). Other
than having the summary, FDA does not expect the transplant institution
to receive complete documentation regarding the suitability of the
donor. If FDA has questions regarding donor suitability, the person or
establishment that made the determination of donor suitability will
ordinarily be contacted. That person or establishment is responsible
for having all records used in making the determination. With respect
to testing records, the testing laboratory should retain records of the
test results and the interpretation of the test results. Copies of the
interpretation of the test results should also be provided to, and
retained by, the person or establishment making the final determination
of donor suitability.
30. Three comments on Sec. 1270.7(c) (Sec. 1270.31 of the final
rule) requested clarification on which organization's SOP would be
acceptable and suggested that the agency require each facility to have
its own SOP that includes processing, storage, and final disposition of
human tissue.
The regulations require each facility to prepare and follow written
procedures for testing and screening of human tissue. In Sec. 1270.31
of the final rule, written procedures are required for all significant
steps involved in the infectious disease testing process which shall
conform to the manufacturers' instructions for use contained in the
package inserts, and for all significant steps in obtaining, reviewing,
and assessing for completeness the relevant medical records of the
donor. Any deviation from the establishment's written procedures shall
be recorded and justified. FDA investigators review an establishment's
written procedures during an inspection, to evaluate whether the SOP's
are consistent with the regulations, and to determine that the
establishment is following the procedures documented in the SOP's. A
detailed and complete SOP ensures uniformity and consistency for each
procedure performed. Each establishment may develop its own written
procedures or adopt those in a manual prepared by another organization,
as long as the procedures satisfy the requirements set out in the
regulations. Because each establishment differs, an establishment using
procedures developed by another establishment or organization should
evaluate those procedures to determine whether they are adequate or
need to be revised by that establishment. The responsibility for
ensuring adequacy of procedures and compliance rests with the
individual establishment regardless of the source of its procedures.
7. Records, general requirements (Sec. 1270.33) and Specific records
(Sec. 1270.35)
Sections 1270.9 and 1270.11 of the interim rule (Secs. 1270.33 and
1270.35, respectively of the final rule) set forth the general and
specific requirements for the maintenance of records. Under
Sec. 1270.33(c), all human tissue that is to be processed or shipped
prior to the determination of donor suitability must be under
quarantine, accompanied by records identifying the donor, and
identifying the tissue as not determined to be suitable for
transplantation. All human tissue found suitable for transplantation
must be accompanied by a complete summary of records, or copies of the
original records, documenting that all infectious disease testing and
screening has been completed, reviewed by the responsible person, and
identified as determined to be suitable for transplantation. The
summary of records also lists all the available records used in
determining the suitability of the donor so that the originals of these
records can be accessed, if necessary. These records include the donor
medical history interview, the relationship of the person interviewed
to the donor, the physical assessment of the donor, autopsy or coroner
records, hospital records, police records, and any other available
record used to document the suitability of the donor. If only corneal
tissue was procured under legislative consent in the absence of a donor
medical history interview, the accompanying summary of records shall
document that: (1) A donor medical history interview was not obtained;
(2) a physical assessment of the donor for evidence of high risk
behavior and signs of HIV and hepatitis infection had been made; and
(3) the tissue was determined to be suitable in the absence of the
donor medical history interview. Under Sec. 1270.9(c) (Sec. 1270.33(f)
of the final rule) the person or establishment making the determination
regarding the suitability of human tissue is responsible for retaining
the completed records and making them available to FDA upon their
request. #
Section 1270.35(c) of the final rule has been added to complete the
accounting of the inventory between determination of suitability
(Sec. 1270.35(a) and (b)) and the final disposition of the human tissue
(Sec. 1270.35(d)), e.g., the destruction of unsuitable tissue,
nonclinical research use, or distributed for transplantation. The
interim rule required the documentation of the records used in
determining the suitability of the human tissue, and the destruction or
disposition of unsuitable human tissue. The final rule requires in
Sec. 1270.35(c) documentation of the receipt and/or distribution of
human tissue.
31. One comment recommended that the facility that made the final
determination of donor suitability and retrieved the human tissue be
required to maintain the medical history and testing records for each
donor.
Retrieval and determination of donor suitability are often done by
separate facilities, therefore, FDA has modified the language in
Sec. 1270.9(c) (Sec. 1270.33(f) of the final rule) to require the
maintenance of records under Sec. 1270.5 (Sec. 1270.21 of the final
rule), including all testing and screening records, by the person or
establishment making the determination regarding the suitability of
human tissue. Persons or establishments performing operations that
would generate documentation that has a bearing on a donor's
suitability would retain that documentation and make it available
during an FDA authorized inspection.
32. Two comments urged FDA to continue to require record retention
for 10 years or until the expiration date of the human tissue, which
could be longer than 10 years, but in any event no less than 10 years.
FDA agrees with the comments and has modified Sec. 1270.33(h) to
require the retention of records for a period that extends at least 10
years beyond the date of transplantation, if known, distribution,
disposition, or expiration of any dating period related to the human
tissue, whichever is latest.
33. One comment stated that the definition for required exclusions
due to the presence of risk behaviors for certain diseases should be at
all times consonant with the recommendations of
[[Page 40439]]
the CDC and the human tissue bank professions.
FDA has developed guidance on behavioral and high risk information,
taking both the CDC's recommendations and those of the human tissue
bank professions into account. At the June 1995 workshop, FDA
distributed a draft document, which was also made available to the
general public, discussing screening and testing issues.
Representatives from CDC participated in all three workshops and FDA
has based its recommendations for testing and screening on the PHS
guidelines published in the Morbidity and Mortality Weekly Reports of
April 1991, and May 1994 and public comment submitted in response to
the workshop.
In conjunction with this rule, FDA is issuing a guidance document
concerning the screening and testing of donors of human tissue intended
for transplantation. FDA developed this document taking into account
the recommendations of PHS, the Medical Standards of the Eye Bank
Association of America, the American Association of Tissue Banks and
comments from other interested persons.
8. Inspections (Sec. 1270.41)
Section 1270.13 (Sec. 1270.41 of the final rule) addresses the
inspectional process. Establishments covered by the regulations include
those establishments that recover, screen, test, process, store, or
distribute human tissue and include those establishments performing
such activities under contract. In large part, inspections of tissue
establishments are conducted in the same manner as inspections of firms
dealing in other FDA regulated commodities. FDA is presently assessing
its inspectional procedures and the extent to which the agency can work
with other qualified organizations to make best use of limited
resources.
FDA investigators cover several major areas during an inspection.
All facilities are subject to examination, including any facility
contracted by the primary facility such as testing laboratories,
contract sterilizers, or off-site storage facilities. The investigators
may examine any human tissue at the firm to observe, for example,
whether it is appropriately quarantined, identified, and stored. The
inspections generally will focus on a review of required records.
Employees may be interviewed regarding their performance of regulated
activities. At the end of the inspection, if possible violations of the
regulations are found, the FDA investigator will issue to the
responsible person at the establishment a list of ``Inspectional
Observations'' (Form FDA-483), describing the observations of the
investigator that represent an observed or potential problem with the
facility or tissue. After the report of the investigator is reviewed,
FDA may issue additional correspondence to the establishment describing
the violations to the regulations and requesting appropriate followup
action.
FDA intends to continue to inspect regulated establishments, both
foreign and domestic, when deemed necessary by the agency to ensure
that human tissue is screened and tested to reduce risk of HIV,
hepatitis B, or hepatitis C. Frequency of inspection after an initial
inspection may depend on the extent of any violations found and will be
at the agency's discretion.
34. One comment on Sec. 1270.13 (Sec. 1270.41 of the final rule)
asserted that the provision which allows investigators to question
personnel of the establishment as the investigator deems necessary is
inappropriate under the governing case law. The comment cited Donovan
v. Dewey, 452 U.S. 594 (1981); Stark v. Wickard, 321 U.S. 559 (1944),
and Ernst v. Hochfelder, 425 U.S. 185 (1976) to support this assertion.
FDA disagrees with the interpretation of these three cases in the
context of the governing statutory authority, the PHS Act. Section 361
of the PHS Act authorizes the Secretary to issue and enforce
regulations to control communicable diseases, and it provides for such
inspection and destruction of articles found to be so infected or
contaminated as to be sources of dangerous infection to human beings,
and other measures, that may be necessary. These other measures include
the use of routine inspections and the questioning of personnel during
such inspections. The FDA inspector may question the firm's personnel
to determine if the staff is familiar with and following the firm's
written SOP's.
35. One comment on Sec. 1270.13(e) (redesignated as Sec. 1270.41(e)
of the final rule) asked FDA to clarify whether the FDA investigator or
a human tissue bank official is responsible for ensuring that records
to be copied are suitably expurgated. The comment also asked for
guidance on the scope and meaning of ``suitably.''
FDA has revised Sec. 1270.41(e) of the final rule to clarify that
FDA will follow its existing procedures regarding disclosure of
documents. Under these procedures, FDA takes necessary precautions to
protect the privacy of names of tissue donors or recipients prior to
public disclosure. These procedures are set forth in 21 CFR part 20.
See e.g., 21 CFR 20.63. FDA recognizes the sensitive nature of the
information that would identify a human tissue donor or recipient. FDA
may copy records containing identification of the donors or recipients
if such records are needed for example, to document the distribution of
potentially infectious human tissue.
9. Human Tissue Offered For Import (Sec. 1270.42)
Because some human tissue used for transplantation in the United
States is obtained from foreign sources or is processed in foreign
facilities and because of requests for clarification of requirements
for such tissue, FDA has added Sec. 1270.42 to clarify the
administrative steps for the importation of tissue into the United
States. Human tissue that has been recovered from sources outside the
United States can enter the country, and tissue that has been recovered
from sources in the United States that has been sent outside the United
States for processing can reenter the country consistent with the
provisions of Secs. 1270.33 and 1270.42. For tissue imported prior to
the determination of donor suitability, the tissue must be accompanied
by records assuring identification of the donor and indicating that the
tissue has not been determined to be suitable for transplantation. For
tissue determined to be suitable for transplantation, the tissue is to
be accompanied by a summary of records, or copies of the original
records, indicating that all infectious disease testing and screening
under Sec. 1270.21 has been completed, reviewed by the responsible
person, and found to be negative. Tissue that has been determined to be
suitable for transplantation must also be identified. As with other
imports, the importer of record (as defined in Sec. 1270.3(k) of the
final rule) for human tissue must notify the District Director of FDA
having jurisdiction over the port of entry when the articles are
offered for import. The tissue must be held in quarantine until and
unless the article is released by FDA. Human tissue that is offered for
import and is found to be in violation of part 1270, is subject to
recall and destruction in accordance with Sec. 1270.43 of the final
rule.
10. Retention, Recall, and Destruction of Human Tissue (Sec. 1270.43)
Section 1270.15 of the interim rule (Sec. 1270.43 of the final
rule) describes the procedures for the retention, recall, and
destruction of human tissue upon a finding that the human tissue may be
in violation of the regulations.
36. One comment on Sec. 1270.15 (Sec. 1270.43 of the final rule)
requested that the rule be clarified to state that
[[Page 40440]]
when a part 16 (21 CFR part 16) hearing has been requested, human
tissues need not be destroyed until the hearing is held.
FDA has clarified Sec. 1270.43(e) to state that any possible
destruction of human tissue would be held in abeyance pending
resolution of the hearing request. Under the provisions of
Sec. 16.24(d), the Commissioner of Food and Drugs (the Commissioner)
may take action pending a hearing that is necessary to protect the
public health. FDA is, however, sensitive to the potential economic
consequences that would result from the immediate destruction of
potentially violative human tissue. Any human tissue listed in such an
order must be held in quarantine and cannot be released prior to the
resolution of a hearing request and receipt of written notice from FDA.
If destruction is warranted, the destruction of the human tissue is to
be conducted under the supervision of a designated FDA official.
37. One comment asked that FDA clarify the ``may be in violation''
language in the recall and destruction part of the rule, particularly
with respect to what triggers the finding of a violation.
The procedures for retention, recall, and destruction in
Sec. 1270.43 will be used only when the agency deems it necessary to
ensure the suitability of human tissue for transplantation. FDA intends
to invoke Sec. 1270.43 of the final rule when there is evidence of a
violation related to tissue suitability, such as the source of the
human tissue, the adequacy of the testing or screening of the human
tissue, the completeness of the records accompanying the human tissue,
the adequacy of donor selection, and/or the attention given to the
possibility that the donor was at a high risk for HIV or hepatitis.
C. Comments on Legal Issues
38. Five comments objected to the immediate effective date of the
interim rule and questioned why such a measure was taken. Four comments
objected to the required retrospective application of the interim rule,
in that it applied to human tissue in storage upon the effective date,
which may have been collected and tested before the effective date of
the interim rule.
The Administrative Procedure Act (the APA) (5 U.S.C. 551 et. seq.)
governs the issuance of rules by executive agencies. The APA's
requirement of notice and comment prior to the implementation of a rule
may be dispensed with when the agency for ``good cause'' finds that the
procedures are ``impracticable, unnecessary, or contrary to the public
interest.'' (See 5 U.S.C. 553(b)(B).)
In the preamble to the interim rule (58 FR 65514 at 65518), FDA
described its good cause for proceeding directly to an interim rule.
Specifically, the agency stated that the Commissioner found that the
use of prior notice and comment rulemaking was ``contrary to the public
interest'' because of the ``unnecessary risk of transmission of HIV
infection and hepatitis infection from shipment and transplantation of
human tissues derived from inadequately tested or screened donors.''
During an investigation prior to the promulgation of the interim rule,
FDA investigators learned of the availability, importation, and
distribution of musculoskeletal tissue materials that had not been
adequately screened or tested for HIV, hepatitis B, and hepatitis C.
This investigation illustrated the need for swift action to reduce the
risk to the public health. Because of the public health risk posed by
the inadequately tested or screened tissues, FDA applied the
regulations not only to tissues screened after the effective date but
also to human tissue remaining in storage for transplantation.
As previously stated, FDA provided opportunities for public comment
following the promulgation of the interim rule and has considered those
comments and the agency's experience in developing the final rule.
The final rule will have an effective date of 180 days after the
date of publication and will apply to human tissue intended for
transplantation procured on or after the effective date. For tissue
procured prior to the effective date of the final rule, the interim
rule applies.
39. One comment urged Federal preemption of State and local
regulations on donor suitability, testing and labeling of human
tissues.
FDA declines to take such a measure because the agency is not aware
of any compelling reason that State regulatory authorities should be
preempted at this time. The rule provides the minimum criteria
necessary to help ensure tissue safety, and States are free to add
additional requirements that they believe are warranted.
D. Comments on Economic Issues
40. Two comments on the economic impact in the preamble to the
interim rule stated that the rule would result in an increase in the
human tissue processing fee that the recipient must pay. In addition,
one of the two comments stated that the number of human tissue
transplants mentioned by the agency may be inaccurate and human tissue
banking activities generate $59 million rather than $100 million per
year.
FDA has considered the data provided in these comments in
finalizing the regulations. The comments did not, however, provide the
agency with figures that would illustrate an increase in the human
tissue processing fee.
41. Three comments stated that the implementation of the
regulations will drive the cost of corneal transplant beyond the means
of the average person.
These comments did not provide data to support their contention.
FDA's intention is to make tissue that is available for transplantation
safer. The Eye Bank Association of America Statistical Report for 1994
does not support the premise that there has been any decrease in the
availability or transplantation of corneal tissue. Both the total
number of donations and the total number of transplants have increased
during 1994 under the Interim Rule. However, as discussed in comment
27, FDA acknowledges the need for flexibility and has modified the
requirement for corneas procured under legislative consent when there
is no medical history interview available.
E. Requests for Additional Regulations
42. Five comments asked FDA to regulate all human tissue banking
efforts including musculoskeletal, skin, eye, reproductive tissue,
blood vessel, bone marrow, heart valves, and hospital surgical bone
banks.
This rule does not apply to reproductive tissue, bone marrow, human
milk, and heart valves under part 1270. Heart valves are already
regulated by FDA as medical devices. HRSA administers the program for
the National Bone Marrow Donor Registry. As noted in comment No. 8, in
the near future, FDA is considering proposing additional regulations
governing the use of human tissue and is considering whether to expand
the scope of the rule to cover additional tissues.
43. Three comments stated that all tissue banks, despite their
type, should be federally registered and subject to inspection and
accreditation. One additional comment urged FDA to consider the use of
a nongovernmental organization as a private accrediting and/or
inspecting entity.
FDA declines to adopt the suggestions made by these comments as
they relate to registration and accreditation at this time, as they are
outside the scope of the rule, but is considering addressing
registration and accreditation in future rulemaking, at which time
comments will be solicited. Tissue facilities that are regulated under
the provisions of the
[[Page 40441]]
interim rule are subject to and will continue to be subject to Federal
inspection under the final rule.
44. One comment suggested that tissue banks should bank and hold
serum specimens from donors for 5 years beyond the expiration date of
the human tissue allograft for additional testing that may become
relevant to public health in the future.
The comment did not provide any demonstrable evidence that such a
practice is necessary for the protection of the public health. In the
absence of such evidence, FDA declines to add such a requirement.
Complete and careful donor screening and testing in accordance with the
provisions of the rule, as well as maintenance of records for the
period specified in Sec. 1270.33(h) should provide sufficient
information to investigate possible transmission of infectious disease.
FDA is willing to consider evidence that such a requirement is
warranted.
45. One comment urged a requirement that records show the
destination of all human tissue released for transplant.
FDA is requiring disposition records for human tissue (distribution
for transplantation, use for nonclinical research, or destruction) but
is not requiring tracking to the recipient at this time. FDA is
considering requirements for the tracking of human tissue for inclusion
in future rulemaking. FDA discussed the tracking of human tissue under
a Federal regulatory scheme with members of the industry at both the
March 1995 and June 1995 workshops described earlier. FDA notes that
currently the voluntary standards of the American Association of Tissue
Banks and the Eye Bank Association of America include the tracking of
human tissue from the donor to the recipient, transplanting surgeon or
institution.
46. Three comments requested FDA to consider developing
requirements for discussing donor medical history with the Next of Kin
or others who might sign the donation consent form.
FDA recognizes the requests for requiring a donor medical history
interview, and the need for guidance in conducting the donor medical
history interview for assurance that the donor did not participate in
high risk behavior for hepatitis and HIV infection. The donor medical
history interview is an integral part of the relevant medical records
and is defined as such in the final rule. FDA is announcing the
availability of ``Guidance for Screening and Testing of Donors of Human
Tissue Intended for Transplantation'' elsewhere in this Federal
Register to assist those facilities involved in determining the
suitability of a donor.
47. Two comments inquired about the mechanism used by FDA in
requiring new tests in the future and deleting obsolete tests, and
added that a careful evaluation and decision analysis should consider
the test's specificity, sensitivity, and positive utility.
It is the practice of FDA to thoroughly evaluate all data including
that accumulated by its scientists, by industry scientists, and by
academicians when considering the use of a test or deletion of a test
for communicable disease. When appropriate, FDA presents such data to
an advisory committee composed of specialists and requests their
recommendation. Therefore, FDA evaluates the need to add or delete a
test for communicable disease taking into account the available
scientific data and the effect of the test on the public health.
48. One comment inquired as to the suitability of an umbilical cord
blood specimen or the mother's blood specimen for viral marker testing
on newborn donors.
To date, none of the viral marker test kits address cord blood as
an adequate sample in the package insert. Cord blood may not be
acceptable for testing if contamination of the specimen with Wharton's
jelly occurs during collection. If an adequate cord blood specimen is
not available, then the mother's blood specimen will be considered
acceptable for testing. FDA has added Sec. 1270.21(b) to the final rule
to clarify that in the case of a neonate, the mother's specimen is
acceptable for testing.
F. Comments on New Regulatory Areas
49. Forty-four comments were also received that were beyond the
scope of this rulemaking. For example, five comments expressed concern
that FDA would require user fees to fund the regulation of human
tissue.
This final rule does not impose a user fee requirement for human
tissue. User fee authority to fund tissue banking regulation was
presented in legislation introduced by Representative Wyden in H.R.
3547 and Senator Simon in S. 1702 during the 1994 Congressional term.
Neither bill was passed.
50. One comment stated that it would be appropriate to include
recordkeeping and tracking requirements for hospitals and other
transplant facilities.
FDA at this time declines to incorporate tracking requirements in
this rule. Promulgation of tracking requirements would affect
transplant facilities currently not within the scope of the final rule,
unless they are involved in recovery, screening, testing, processing,
or distribution of human tissue. In this rulemaking, FDA is not
expanding the recordkeeping requirements beyond those in
Sec. 1270.35(c), or otherwise revising significantly its regulatory
program on human tissue at this time. The comments are being considered
as FDA reviews the possibility of further developing its regulatory
program and may be the subject of future rulemaking.
IV. Analysis of Impacts
FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).
Executive Order 12866 directs agencies to assess all costs and benefits
of available regulatory alternatives and, when regulation is necessary,
to select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this final rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. The agency has also
determined that this rule is a significant regulatory action under
paragraph (f)(4) of the Executive Order because it raises novel policy
issues.
The Regulatory Flexibility Act requires agencies to prepare a
Regulatory Flexibility Analysis for each rule unless the agency
certifies that the rule will not have a significant economic impact on
a substantial number of small entities. As explained below, the agency
certifies that this rule will not have a significant impact on a
substantial number of small entities.
A. The Need For the Regulation
The purpose of the final rule is to provide clarification of the
interim rule, revise the rule in response to public comments, and
finalize its provisions. The interim rule was promulgated as an
emergency measure to protect the public safety against human tissue
that had incomplete or no documentation ascertaining its freedom from
communicable diseases. This risk was clearly demonstrated by evidence
of human tissue from foreign sources that had been offered for sale in
the United States with little documentation of appropriate screening
and testing. The final rule takes into account comments submitted to
the Dockets Management Branch, and discussions and information obtained
through public participation in three workshops held following the
promulgation of the interim rule. The objective of the final rule is to
impose minimal requirements for testing and screening of human
[[Page 40442]]
tissue donors, while making all human tissue, imported and domestic,
safe for transplant needs.
B. A Description of Requirements
The interim rule requires all facilities to ensure that specified
minimum required medical screening and infectious disease testing has
been performed and that records documenting such screening and testing
for each human tissue are available for inspection by FDA. The final
rule clarifies and modifies requirements in the interim rule and adds
three additional requirements, which are currently voluntary industry
standards: written procedures for the designation and identification of
quarantined tissue (Sec. 1270.31(c)); written and validated procedures
for the prevention of contamination or cross-contamination of tissues
during processing (Sec. 1270.31(d)); and documentation of receipt and/
or distribution of human tissue determined to be suitable for
transplantation until it is distributed to the transplanting facility
(section 1270.35(c)).
C. The Type and Number of Firms Affected
The rule will affect any establishment or person engaged in the
recovery, screening, testing, processing, storage or distribution of
human tissues. Because of their small size, tissue specialty, and/or
interrelationship with other tissue establishments, most tissue
establishments do not perform all of these activities. Thus, the effect
of this rule will vary depending on the number and type of functions
performed. Because tissue establishments are not currently required to
register with FDA, the agency does not have a precise count of the
number of establishments that will be affected by this rule. EBAA
reports 110 member eye banks. Also, an FDA/HRSA sponsored survey
projected that in 1994, about 67 tissue banks procured musculoskeletal
tissue from cadaveric donors. (Jeffrey Prottas, (1995) ``A Study of the
Tissue Procurement and Distribution System of the United States'').
This survey also projected an additional 120 surgical bone banks,
entities which typically involved one or more surgeons who save and
freeze for later use bone obtained during routine surgical procedures.
There also may exist an unknown number of uncounted skin banks.
(Neither of these latter two groups--surgical bone and skin banks--are
believed to account for substantial volume of tissue.) All together,
therefore, FDA estimates that the rule may affect a total of about 400
establishments. Since the majority of these establishments employ fewer
than 15 employees, the Small Business Administration would define
almost all as small entities.
D. Nature of Impact
FDA finds that the final rule will have little adverse impact on
the tissue industry. When issuing the interim rule, FDA took voluntary
industry standards and State requirements into account to minimize the
impact on the supply of tissue available for transplantation and to
reduce the economic burden to industry. In its preamble to the interim
regulation (58 FR 65519), FDA determined that the only economic impact
of the rule would be related to the recordkeeping burdens, ``because
the cost of testing for infectious disease and the cost of screening
donors has already been assumed by the tissue banking industry and this
interim rule imposes no additional burdens.'' The agency has received
no new industry comment that would alter its conclusion that donor
testing and screening are universally accepted practice for the
industry.
The eye bank sector, however, has questioned the need for the
potential burden associated with certain aspects of the interim donor
screening requirements. Several comments suggested that the agency
exempt corneas from regulations due to an adequate safety record and
adequate internal standards (Comment 3). Some asked that the agency
exempt these operations from the requirement for a donor medical
history interview as part of the relevant medical record, if the
document was not available; stating that this requirement makes it more
difficult to procure corneas under legislative consent (Comment 27).
FDA has given great consideration to the impact that such changes
would have on both the tissue establishments and the public health. The
agency believes that all human tissues have the potential to transmit
communicable diseases and that every reasonable effort should be made
to prevent disease transmission, while ensuring the continued
availability of safe human tissue. Keeping these elements in focus, FDA
decided to regulate all human tissue under the same standards
(protecting the public health by preventing disease transmission),
while permitting the procurement of corneas under legislative consent
when a donor medical history interview is not available. Thus, the
final FDA rule allows greater flexibility in the procurement of corneal
tissue under legislative consent, while minimizing any potential
regulatory burden.
Similarly, the new requirements of the final rule, (e.g., preparing
two standard operating procedures and increased documentation for
receipt and/or distribution of human tissue) will not add significantly
to operating costs. The final requirements are part of industry
voluntary standards and therefore, are currently in place in most
tissue banks. The 60 tissue banks and 110 eye banks that are currently
members of the AATB and the EBAA, respectively, are likely to account
for the great majority of tissue transactions. For those few
establishments that do not have or must modify their existing written
procedures, FDA estimates that they will require a one-time expenditure
of approximately 7 hours for each of four required written SOP's.
Furthermore, since the smaller tissue banks would be unlikely to
process tissue (the Prottas survey projects that only 28 percent of the
67 musculoskeletal banks process tissue), the smaller tissue banks will
need to prepare only three written procedures.
Likewise, the new requirements for documenting the distribution and
receipt of human tissue will impose few costs. Prottas found that 95
percent of the surveyed musculoskeletal banks could track tissue to
recipient institutions. These banks presumably already identify and
document their products. Although the smallest tissue banks may need to
expand this effort, the associated cost would be mitigated by the
smaller number of transactions at such establishments.
In sum, the final rule sets minimal requirements to prevent the
transmission of communicable diseases from human tissue used for
transplantation. The vast majority of tissue establishments were
voluntarily complying with most of the requirements of the interim rule
before it was issued, and are voluntarily complying with the new
requirements in this final rule. As described in Section V of this
document, some entities may need to prepare or modify existing
documentation procedures, but FDA believes that very few will need to
alter actual operations. At almost no establishment would additional
reporting and recordkeeping activities take over 20 hours of time
annually for a nurse, physician assistant, or certified technician. As
a result, FDA expects that very few entities will incur significant
costs due to this rule. FDA therefore certifies that this rule will not
have a significant impact on a substantial number of small entities.
[[Page 40443]]
V. Paperwork Reduction Act of 1995
Although the December 14, 1993, interim rule (58 FR 65514) provided
a 90-day comment period under the Paperwork Reduction Act of 1980, and
this final rule responds to the comments received, FDA is providing an
additional opportunity for public comment under the Paperwork Reduction
Act of 1995, which was enacted after the expiration of the comment
period and applies to this final rule. Therefore, FDA now invites
comments on: (1) Whether the proposed collection of information is
necessary for the proper performance of FDA's functions, including
whether the information will have practical utility; (2) the accuracy
of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including through the use of
automated collection techniques, when appropriate, and other forms of
information technology. Individuals and organizations may submit
comments on the information collection provisions of this final rule by
September 29, 1997. Comments should be directed to the Dockets
Management Branch (address above).
At the close of the 60-day comment period, FDA will review the
comments received, revise the information collection provisions as
necessary, and submit these provisions to OMB for review and approval.
FDA will publish a notice in the Federal Register when the information
collection provisions are submitted to OMB, and an opportunity for
public comment to OMB will be provided at that time. Prior to the
effective date of this final rule, FDA will publish a notice in the
Federal Register of OMB's decision to approve, modify, or disapprove
the information collection provisions. An agency may not conduct or
sponsor, and a person is not required to respond to, a collection of
information unless it displays a currently valid OMB control number.
This final rule contains information collection requirements which
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995. The title, description, and
respondents of the information collections are shown below with an
estimate of the annual recordkeeping and periodic reporting burden.
Title: Human Tissue Intended for Transplantation: 21 CFR part 1270.
Description: FDA is issuing final regulations to prevent the
transmission of HIV, hepatitis B, and hepatitis C through the use of
human tissue for transplantation. The final regulations closely
parallel those contained in the interim rule on human tissue intended
for transplantation. Both the interim and final rule provide for
inspection by FDA of persons and tissue establishments engaged in the
recovery, screening, testing, processing, storage, or distribution of
human tissue. These facilities are required to meet standards intended
to ensure appropriate screening and testing of human tissue donors and
ensure that records are kept documenting that the appropriate screening
and testing have been completed.
Description of Respondents: Businesses or other for-profit;
nonprofit institutions; small businesses or organizations.
There are approximately 60 tissue establishments with 300 employees
that are members of the American Association of Tissue Banks. There are
an additional 600 individual members of which 50 percent are performing
a tissue banking activity. The Eye Bank Association of America's
membership consists of 120 eye banks of which 110 are in the
continental United States.
With the rare exceptions noted in the preamble, FDA believes that
all respondents perform donor testing and screening for HIV and
hepatitis and these regulations add no additional requirements. New
Sec. 1270.31(c) and (d) require written procedures for the designation
and identification of quarantined tissue and to prevent the
contamination or cross-contamination of tissue during processing.
Section 1270.35(c) requires documentation of the distribution and
receipt of human tissue, completing the accounting of tissue between
determination of suitability, and the destruction or disposition of the
tissue.
When the interim rule was promulgated, accredited members of the
American Association of Tissue Banks and the Eye Bank Association of
America were already in compliance with the regulations by adhering to
the standards established by these organizations. The requirements
added to the Final Rule will not impose additional burden since the
members will be complying with the current organizations' standards
which are comparable to the requirements in the final rule. To account
for persons or establishments that may not be a member of an industry
organization and, for whom therefore, the extent of compliance with the
requirements of the final rule is unknown, FDA will be using 1 percent
as an estimation of the information collection burden on the tissue
industry.
Industry estimates that in 1994 there were 350,000 bone
transplants, 42,000 corneal transplants, 5,000 patellar tendon
transplants, and the transplantation of 5,000 square feet of skin.
There are approximately 300 persons and 170 tissue banks currently
operating in the United States affected by the regulations.
Table 3.--Estimated Annual Recordkeeping Burden
----------------------------------------------------------------------------------------------------------------
Annual
21 CFR Section No. of Frequency per Total Annual Hours per Total Hours
Recordkeepers Recordkeeping Records Recordkeeper
----------------------------------------------------------------------------------------------------------------
1270.31(a) and 1270.31(b) and
1270.31(c) and 1270.31(d) 11 4 44 28 308
1270.35(a) and 1270.35(b) 11 420 4,620 290 3,190
1270.35(c) 11 2,893 31,823 4,782 52,602
1270.35(d) 11 17 187 17 187
Total 56,287
----------------------------------------------------------------------------------------------------------------
VI. Environmental Impact
The agency has determined under 21 CFR 25.24(a)(8) that this action
is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.
[[Page 40444]]
List of Subjects
21 CFR Part 16
Administrative practice and procedure.
21 CFR Part 1270
Communicable diseases, HIV/AIDS, Reporting and recordkeeping
requirements.
Therefore, under the Public Health Service Act, and under authority
delegated to the Commissioner of Food and Drugs, 21 CFR parts 16 and
1270 are amended as follows:
PART 16--REGULATORY HEARING BEFORE THE FOOD AND DRUG ADMINISTRATION
1. The authority citation for 21 CFR part 16 continues to read as
follows:
Authority: Secs. 201-903 of the Federal Food, Drug, and Cosmetic
Act (21 U.S.C. 321-394); 21 U.S.C. 41-50, 141-149, 467f, 679, 821,
1034; secs. 2, 351, 361 of the Public Health Service Act (42 U.S.C.
201, 262, 264); secs. 2-12 of the Fair Packaging and Labeling Act
(15 U.S.C. 1451-1461); 28 U.S.C. 2112.
2. Section 16.1 is amended in paragraph (b)(2) by revising the
entry for ``Sec. 1270.15(e) * * *'' to read as follows:
Sec. 16.1 Scope.
* * * * *
(b) * * *
(2) * * *
Sec. 1270.15(e), relating to the retention, recall, and destruction of
human tissue.
3. Part 1270 is revised to read as follows:
PART 1270--HUMAN TISSUE INTENDED FOR TRANSPLANTATION
Subpart A--General Provisions
Sec.
1270.1 Scope.
1270.3 Definitions.
Subpart B--Donor Screening and Testing
1270.21 Determination of donor suitability for human tissue
intended for transplantation.
Subpart C--Procedures and Records
1270.31 Written procedures.
1270.33 Records, general requirements.
1270.35 Specific records.
Subpart D--Inspection of Tissue Establishments
1270.41 Inspections.
1270.42 Human tissue offered for import.
1270.43 Retention, recall, and destruction of human tissue.
Authority: Secs. 215, 311, 361, 368 of the Public Health
Service Act (42 U.S.C. 216, 243, 264, 271).
Subpart A--General Provisions
Sec. 1270.1 Scope.
(a) The regulations in this part apply to human tissue and to
establishments or persons engaged in the recovery, screening, testing,
processing, storage, or distribution of human tissue.
(b) Regulations in this chapter as they apply to drugs, biologics,
devices, or other FDA-regulated commodities do not apply to human
tissue, except as specified in this part.
(c) Regulations in this chapter do not apply to autologous human
tissue.
(d) Regulations in this chapter do not apply to hospitals or other
clinical facilities that receive and store human tissue only for
transplantation within the same facility.
Sec. 1270.3 Definitions.
(a) Act for the purpose of this part means the Public Health
Service Act, section 361 (42 U.S.C. 264).
(b) Blood component means any part of a single-donor unit of blood
separated by physical or mechanical means.
(c) Colloid means a protein or polysaccharide solution that can be
used to increase or maintain osmotic (oncotic) pressure in the
intravascular compartment such as albumin, dextran, hetastarch; or
certain blood components, such as plasma and platelets.
(d) Contract services are those functions pertaining to the
recovery, screening, testing, processing, storage, or distribution of
human tissue that another establishment agrees to perform for a tissue
establishment.
(e) Crystalloid means a balanced salt and/or glucose solution used
for electrolyte replacement or to increase intravascular volume such as
saline, Ringer's lactate solution, or 5 percent dextrose in water.
(f) Distribution includes any transfer or shipment of human tissue
(including importation or exportation), whether or not such transfer or
shipment is entirely intrastate and whether or not possession of the
tissue is taken.
(g) Donor means a human being, living or dead, who is the source of
tissue for transplantation.
(h) Donor medical history interview means a documented dialogue
with an individual or individuals who would be knowledgeable of the
donor's relevant medical history and social behavior; such as the donor
if living, the next of kin, the nearest available relative, a member of
the donor's household, other individual with an affinity relationship,
and/or the primary treating physician. The relevant social history
includes questions to elicit whether or not the donor met certain
descriptions or engaged in certain activities or behaviors considered
to place such an individual at increased risk for HIV and hepatitis.
(i) Establishment means any facility under one management including
all locations, that engages in the recovery, screening, testing,
processing, storage, or distribution of human tissue intended for
transplantation.
(j) Human tissue means any tissue derived from a human body, which:
(1) Is intended for transplantation to another human for the
diagnosis, cure, mitigation, treatment, or prevention of any condition
or disease;
(2) Is recovered, processed, stored, or distributed by methods that
do not change tissue function or characteristics;
(3) Is not currently regulated as a human drug, biological product,
or medical device;
(4) Excludes kidney, liver, heart, lung, pancreas, or any other
vascularized human organ; and
(5) Excludes semen or other reproductive tissue, human milk, and
bone marrow.
(k) Importer of record means the person, establishment or their
representative responsible for making entry of imported goods in
accordance with all laws affecting such importation.
(l) Legislative consent means relating to any of the laws of the
various States that allow the medical examiner or coroner to procure
corneal tissue in the absence of consent of the donor's next-of-kin.
(m) Person includes an individual, partnership, corporation,
association, or other legal entity.
(n) Physical assessment means a limited autopsy or recent
antemortem or postmortem physical examination of the donor to assess
for any signs of HIV and hepatitis infection or signs suggestive of any
risk factor for such infections.
(o) Plasma dilution means a decrease in the concentration of the
donor's plasma proteins and circulating antigens or antibodies
resulting from the transfusion of blood or blood components and/or
infusion of fluids.
(p) Processing means any activity performed on tissue, other than
tissue recovery, including preparation, preservation for storage, and/
or removal from storage to assure the quality and/or sterility of human
tissue. Processing includes steps to inactivate and remove adventitious
agents.
(q) Quarantine means the identification of human tissue as not
suitable for transplantation, including human tissue that has not yet
been characterized as being suitable for
[[Page 40445]]
transplantation. Quarantine includes the storage of such tissue in an
area clearly identified for such use, or other procedures, such as
automated designation, for prevention of release of such tissue for
transplantation.
(r) Reconstituted blood means the extracorporeal resuspension of a
blood unit labeled as ``Red Blood Cells'' by the addition of colloids
and/or crystalloids to produce a hematocrit in the normal range.
(s) Recovery means the obtaining from a donor of tissue that is
intended for use in human transplantation.
(t) Relevant medical records means a collection of documents
including a donor medical history interview, a physical assessment of
the donor, laboratory test results, medical records, existing coroner
and autopsy reports, or information obtained from any source or records
which may pertain to donor suitability regarding high risk behaviors,
clinical signs and symptoms for HIV and hepatitis, and treatments
related to medical conditions suggestive of such risk.
(u) Responsible person means a person who is authorized to perform
designated functions for which he or she is trained and qualified.
(v) Storage means holding tissue.
(w) Summary of records means a condensed version of the required
testing and screening records that contains the identity of the testing
laboratory, the listing and interpretation of all required infectious
disease tests, and a listing of the documents reviewed as part of the
relevant medical records, and the name of the person or establishment
determining the suitability of the human tissue for transplantation.
(x) Vascularized means containing the original blood vessels which
are intended to carry blood after transplantation.
Subpart B--Donor Screening and Testing
Sec. 1270.21 Determination of donor suitability for human tissue
intended for transplantation.
(a) Donor specimens shall be tested for the following communicable
viruses, using Food and Drug Administration (FDA) licensed donor
screening tests in accordance with manufacturers' instructions:
(1) Human immunodeficiency virus, Type 1 (e.g., FDA licensed
screening test for anti-HIV-1);
(2) Human immunodeficiency virus, Type 2 (e.g., FDA licensed
screening test for anti-HIV-2);
(3) Hepatitis B (e.g., FDA licensed screening test for HBsAg); and
(4) Hepatitis C (e.g., FDA licensed screening test for anti-HCV).
(b) In the case of a neonate, the mother's specimen is acceptable
for testing.
(c) Such infectious disease testing shall be performed by a
laboratory certified under the Clinical Laboratories Improvement
Amendments of 1988 (CLIA).
(d) Human tissue shall be accompanied by records indicating that
the donor's specimen has been tested and found negative using FDA
licensed screening tests for HIV-1, HIV-2, hepatitis B, and hepatitis
C. FDA licensed screening tests labeled for cadaveric specimens must be
used when available.
(e) Human tissue for transplantation shall be accompanied by a
summary of records or copies of the original records of the donor's
relevant medical records as defined in Sec. 1270.3(t) which documents
freedom from risk factors for and clinical evidence of hepatitis B,
hepatitis C, or HIV infection. There shall be a responsible person
designated and identified in the original record and summary of records
as having made the determination that the human tissue is suitable for
transplantation.
(f) Determination by the responsible person that a donor of human
tissue intended for transplantation is suitable shall include
ascertainment of the donor's identity, and accurately recorded relevant
medical records (as defined in Sec. 1270.3(t)) which documents freedom
from risk factors for and clinical evidence of hepatitis B, hepatitis
C, and HIV infection.
(g) For corneal tissue procured under legislative consent where a
donor medical history screening interview has not occurred, a physical
assessment of the donor is required and other available information
shall be reviewed. The corneal tissue shall be accompanied by the
summary of records documenting that the corneal tissue was determined
to be suitable for transplantation in the absence of the donor medical
history interview. Corneal tissue procured under legislative consent
shall be documented as such in the summary of records.
(h) Human tissue shall be determined to be not suitable for
transplantation if from:
(1) A donor whose specimen has tested repeatedly reactive on a
screening test for HIV, hepatitis B, or hepatitis C;
(2) A donor where blood loss is known or suspected to have occurred
and transfusion/infusion of more than 2,000 milliliters (mL) of blood
(i.e., whole blood, reconstituted blood, or red blood cells), or
colloids within 48 hours; or more than 2,000 mL of crystalloids within
1 hour; or any combination thereof prior to the collection of a blood
specimen from the tissue donor for testing, unless:
(i) A pretransfusion or preinfusion blood specimen from the tissue
donor is available for infectious disease testing; or
(ii) An algorithm is utilized that evaluates the volumes
administered in the 48 hours prior to collecting the blood specimen
from the tissue donor to ensure that there has not been plasma dilution
sufficient to affect test results; or
(3) A donor who is 12 years of age or less and has been transfused
or infused at all, unless:
(i) A pretransfusion or preinfusion blood specimen from the tissue
donor is available for infectious disease testing; or
(ii) An algorithm is utilized that evaluates the volumes
administered in the 48 hours prior to collecting the blood specimen
from the tissue donor to ensure that there has not been plasma dilution
sufficient to affect test results.
Subpart C--Procedures and Records
Sec. 1270.31 Written procedures.
(a) There shall be written procedures prepared and followed for all
significant steps in the infectious disease testing process under
Sec. 1270.21 which shall conform to the manufacturers' instructions for
use contained in the package inserts for the required tests. These
procedures shall be readily available to the personnel in the area
where the procedures are performed unless impractical. Any deviation
from the written procedures shall be recorded and justified.
(b) There shall be written procedures prepared and followed for all
significant steps for obtaining, reviewing, and assessing the relevant
medical records of the donor as provided in Sec. 1270.21. Such
procedures shall be readily available to personnel who may perform the
procedures. Any deviation from the written procedures shall be recorded
and justified.
(c) There shall be written procedures prepared and followed for
designating and identifying quarantined tissue.
(d) There shall be written procedures prepared, validated, and
followed for prevention of infectious disease contamination or cross-
contamination by tissue during processing.
(e) In conformity with this section, any facility may use current
standard written procedures such as those in a technical manual
prepared by another organization, provided the procedures
[[Page 40446]]
are consistent with and at least as stringent as the requirements of
this part.
Sec. 1270.33 Records, general requirements.
(a) Records shall be maintained concurrently with the performance
of each significant step required in this part in the performance of
infectious disease screening and testing of donors of human tissue. All
records shall be accurate, indelible, and legible. The records shall
identify the person performing the work, the dates of the various
entries, and shall be as detailed as necessary to provide a complete
history of the work performed and to relate the records to the
particular tissue involved.
(b) All human tissue shall be quarantined until the following
criteria for donor suitability are satisfied:
(1) All infectious disease testing under Sec. 1270.21 has been
completed, reviewed by the responsible person, and found to be
negative; or
(2) Donor screening has been completed, reviewed by the responsible
person, and determined to assure freedom from risk factors for and
clinical evidence of HIV infection, hepatitis B, and hepatitis C.
(c) All human tissue processed or shipped prior to determination of
donor suitability must be under quarantine, accompanied by records
assuring identification of the donor and indicating that the tissue has
not been determined to be suitable for transplantation.
(d) All human tissue determined to be suitable for transplantation
must be accompanied by a summary of records, or copies of such original
records, documenting that all infectious disease testing and screening
under Sec. 1270.21 has been completed, reviewed by the responsible
person, and found to be negative, and that the tissue has been
determined to be suitable for transplantation.
(e) Human tissue shall be quarantined until the tissue is either
determined to be suitable for transplantation or appropriate
disposition is accomplished.
(f) All persons or establishments that generate records used in
determining the suitability of the donor shall retain such records and
make them available for authorized inspection or upon request by FDA.
The person(s) or establishment(s) making the determination regarding
the suitability of the donor shall retain all records, or true copies
of such records required under Sec. 1270.21, including all testing and
screening records, and shall make them available for authorized
inspection or upon request from FDA. Records that can be retrieved from
another location by electronic means meet the requirements of this
paragraph.
(g) Records required under this part may be retained
electronically, or as original paper records, or as true copies such as
photocopies, microfiche, or microfilm, in which case suitable reader
and photocopying equipment shall be readily available.
(h) Records shall be retained at least 10 years beyond the date of
transplantation if known, distribution, disposition, or expiration, of
the tissue, whichever is latest.
Sec. 1270.35 Specific records.
Records shall be maintained that include, but are not limited to:
(a) Documentation of results and interpretation of all required
infectious disease tests;
(b) Information on the identity and relevant medical records of the
donor, as required by Sec. 1270.21(e) in English or, if in another
language translated to English and accompanied by a statement of
authenticity by the translator which specifically identifies the
translated document;
(c) Documentation of the receipt and/or distribution of human
tissue; and
(d) Documentation of the destruction or other disposition of human
tissue.
Subpart D--Inspection of Tissue Establishments
Sec. 1270.41 Inspections.
(a) An establishment covered by these regulations in this part,
including any location performing contract services, shall permit an
authorized inspector of the Food and Drug Administration (FDA) to make
at any reasonable time and in a reasonable manner such inspection of
the establishment, its facilities, equipment, processes, products, and
records as may be necessary to determine compliance with the provisions
of this part. Such inspections may be made with or without notice and
will ordinarily be made during regular business hours.
(b) The frequency of inspection will be at the agency's discretion.
(c) The inspector shall call upon a responsible person of the
establishment and may question the personnel of the establishment as
the inspector deems necessary.
(d) The inspector may review and copy any records required to be
kept pursuant to part 1270.
(e) The public disclosure of records containing the name or other
positive identification of donors or recipients of human tissue will be
handled in accordance with FDA's procedures on disclosure of
information as set forth in 21 CFR part 20 of this chapter.
Sec. 1270.42 Human tissue offered for import.
(a) When human tissue is offered for entry, the importer of record
must notify the director of the district of the Food and Drug
Administration having jurisdiction over the port of entry through which
the tissue is imported or offered for import, or such officer of the
district as the director may designate to act in his or her behalf in
administering and enforcing this part.
(b) Human tissue offered for import must be quarantined until the
human tissue is released by FDA.
Sec. 1270.43 Retention, recall, and destruction of human tissue.
(a) Upon a finding that human tissue may be in violation of the
regulations in this part, an authorized Food and Drug Administration
(FDA) representative may:
(1) Serve upon the person who distributed the tissue a written
order that the tissue be recalled and/or destroyed, as appropriate, and
upon persons in possession of the tissue that the tissue shall be
retained until it is recalled by the distributor, destroyed, or
disposed of as agreed by FDA, or the safety of the tissue is confirmed;
and/or
(2) Take possession of and/or destroy the violative tissue.
(b) The written order will ordinarily provide that the human tissue
be recalled and/or destroyed within 5 working days from the date of
receipt of the order and will state with particularity the facts that
justify the order.
(c) After receipt of an order under this part, the person in
possession of the human tissue shall not distribute or dispose of the
tissue in any manner except to recall and/or destroy the tissue
consistent with the provisions of the order, under the supervision of
an authorized official of FDA.
(d) In lieu of paragraphs (b) and (c) of this section, other
arrangements for assuring the proper disposition of the tissue may be
agreed upon by the person receiving the written order and an authorized
official of FDA. Such arrangements may include providing FDA with
records or other written information that adequately assure that the
tissue has been recovered, screened, tested, processed, stored, and
distributed in conformance with part 1270.
(e) Within 5 working days of receipt of a written order for
retention, recall, and/or destruction of tissue (or within 5 working
days of the agency's possession
[[Page 40447]]
of such tissue), the recipient of the written order or prior possessor
of such tissue shall request a hearing on the matter in accordance with
part 16 of this chapter. The order for destruction will be held in
abeyance pending resolution of the hearing request.
Dated: July 7, 1997.
Michael A. Friedman,
Lead Deputy Commissioner for the Food and Drug Administration.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 97-19819 Filed 7-28-97; 8:45 am]
BILLING CODE 4160-01-F
