Agency Information Collection Activities; Submission for Office of Management and Budget Review; Comment Request; Infectious Disease Issues in Xenotransplantation, 63768-63772 [E6-18203]
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Federal Register / Vol. 71, No. 210 / Tuesday, October 31, 2006 / Notices
TABLE 2.—ESTIMATED ANNUAL RECORDKEEPING BURDEN1—Continued
No. of
Recordkeepers
21 CFR Section
812.140 Nonsignificant
Annual Frequency
of Recordkeeping
600
Total Annual
Records
1
Hours per
Recordkeeper
600
6
Total
are no capital costs or operating and maintenance costs associated with this collection of information.
Dated: October 24, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6–18200 Filed 10–30–06; 8:45 am]
BILLING CODE 4160–01–S
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. 2006N–0239]
Agency Information Collection
Activities; Submission for Office of
Management and Budget Review;
Comment Request; Infectious Disease
Issues in Xenotransplantation
AGENCY:
Food and Drug Administration,
HHS.
Notice.
SUMMARY: The Food and Drug
Administration (FDA) is announcing
that a proposed collection of
information has been submitted to the
Office of Management and Budget
(OMB) for review and clearance under
the Paperwork Reduction Act of 1995.
DATES: Fax written comments on the
collection of information by November
30, 2006.
ADDRESSES: To ensure that comments on
the information collection are received,
OMB recommends that written
comments be faxed to the Office of
Information and Regulatory Affairs,
OMB, Attn: FDA Desk Officer, FAX:
202–395–6974.
FOR FURTHER INFORMATION CONTACT:
Jonna Capezzuto, Office of the Chief
Information Officer (HFA–250), Food
and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857, 301–827–
4659.
In
compliance with 44 U.S.C. 3507, FDA
has submitted the following proposed
collection of information to OMB for
review and clearance.
SUPPLEMENTARY INFORMATION:
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3,600
11,050
1 There
ACTION:
Total Hours
Infectious Disease Issues in
Xenotransplantation—(OMB Control
Number 0910–0456)—Extension
The statutory authority to collect this
information is provided under sections
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351 and 361 of the Public Health
Service (PHS) act (42 U.S.C. 262 and
264) and the provisions of the Federal
Food, Drug, and Cosmetic Act that
apply to drugs (21 U.S.C. 301 et seq.).
The PHS guideline recommends
procedures to diminish the risk of
transmission of infectious agents to the
xenotransplantation product recipient
and the general public. The PHS
guideline is intended to address public
health issues raised by
xenotransplantation, through
identification of general principles of
prevention and control of infectious
diseases associated with
xenotransplantation that may pose a
hazard to the public health. The
collection of information described in
this guideline is intended to provide
general guidance to sponsors in the
following ways: (1) The development of
xenotransplantation clinical protocols,
(2) the preparation of submissions to
FDA, and (3) the conduct of
xenotransplantation clinical trials. Also,
the collection of information will help
ensure that the sponsor maintains
important information in a crossreferenced system that links the relevant
records of the xenotransplantation
product recipient, xenotransplantation
product, source animal(s), animal
procurement center, and significant
nosocomial exposures. The PHS
guideline describes an occupational
health service program for the
protection of health care workers
involved in xenotransplantation
procedures, caring for
xenotransplantation product recipients,
and performing associated laboratory
testing. The guideline also describes a
public health need for a national
xenotransplantation database, which is
currently under development by PHS.
The PHS guideline is intended to
protect the public health and to help
ensure the safety of using
xenotransplantation products in
humans by preventing the introduction,
transmission, and spread of infectious
diseases associated with
xenotransplantation.
The PHS guideline also recommends
that certain specimens and records be
maintained for 50 years beyond the date
of the xenotransplantation. These
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include the following information, as
recommended by the specific PHS
guideline sections: (1) Records linking
each xenotransplantation product
recipient with relevant health records of
the source animal, herd, or colony, and
the specific organ, tissue, or cell type
included in or used in the manufacture
of the product (3.2.7.1); (2) aliquots of
serum samples from randomly selected
animal and specific disease
investigations (3.4.3.1); (3) source
animal biological specimens designated
for PHS use (3.7.1); animal health
records (3.7.2), including necropsy
results (3.6.4); and (4) recipients’
biological specimens (4.1.2). The
retention period is intended to assist
health care practitioners and officials in
surveillance and in tracking the source
of an infection, disease, or illness that
might emerge in the recipient, the
source animal, or the animal herd or
colony after a xenotransplantation.
The recommendation for maintaining
records for 50 years is based on clinical
experience with several human viruses
that have presented problems in human
to human transplantation and are
therefore thought to share certain
characteristics with viruses that may
pose potential risks in
xenotransplantation. These
characteristics include long latency
periods and the ability to establish
persistent infections. Several also share
the possibility of transmission among
individuals through intimate contact
with human body fluids. Human
immunodeficiency virus (HIV) and
Human T-lymphotropic virus are
human retroviruses. Retroviruses
contain ribonucleic acid (RNA) that is
reverse-transcribed into
deoxyribonucleic acid (DNA) using an
enzyme provided by the virus and the
human cell machinery. That viral DNA
can then be integrated into the human
cellular DNA. Both viruses establish
persistent infections and have long
latency periods before the onset of
disease, 10 years and 40 to 60 years,
respectively. The human hepatitis
viruses are not retroviruses, but several
share with HIV the characteristic that
they can be transmitted through body
fluids, can establish persistent
infections, and have long latency
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periods, e.g., approximately 30 years for
Hepatitis C.
In addition, the PHS guideline
recommends that a record system be
developed that allows easy, accurate,
and rapid linkage of information among
the specimen archive, the recipient’s
medical records, and the records of the
source animal for 50 years. The
development of such a record system is
a one-time burden. Such a system is
intended to cross-reference and locate
relevant records of recipients, products,
source animals, animal procurement
centers, and nosocomial exposures.
Respondents to this collection of
information are the sponsors of clinical
studies of investigational
xenotransplantation products under
investigational new drug applications
(INDs) and xenotransplantation product
procurement centers, referred to as
source animal facilities. There are an
estimated 12 respondents who are
sponsors of INDs that include protocols
for xenotransplantation in humans.
Other respondents for this collection of
information are an estimated 18 source
animal facilities that provide source
xenotransplantation product material to
sponsors for use in human
xenotransplantation procedures. These
18 source animal facilities keep medical
records of the herds/colonies as well as
the medical records of the individual
source animal(s). The total annual
reporting and recordkeeping burden is
estimated to be approximately 156
hours. The burden estimates are based
on FDA’s records of
xenotransplantation-related INDs and
estimates of time required to complete
the various reporting and recordkeeping
tasks described in the guideline. FDA
does not expect the level of clinical
studies using xenotransplantation to
increase significantly in the next few
years.
FDA is requesting an extension of
OMB approval for the following
reporting and recordkeeping
recommendations in the PHS guideline:
TABLE 1.—REPORTING
RECOMMENDATIONS
PHS
Guideline
Section
TABLE 2.—RECORDKEEPING
RECOMMENDATIONS—Continued
PHS
Guideline
Section
Description
Description
3.6.4
Document complete necropsy
results on source animals
(50-year record retention)
Link xenotransplantation product recipients to individual
source animal records and
archived biologic specimens
4.2.3.2
Record base-line sera of
xenotransplantation health
care workers and specific
nosocomial exposure
4.2.3.3
and
4.3.2
Keep a log of health care workers’ significant nosocomial
exposure(s)
4.3.1
Document each xenotransplant
procedure
5.2
Sponsor to make linked
records described in section
3.2.7 available for review
Add summary of individual
source animal record to permanent medical record of the
xenotransplantation product
recipient
3.7
3.5.4
Document absence of infectious agent in
xenotransplantation product if
its presence elsewhere in
source animal does not preclude using it
3.5.4
Include increased infectious
risk in informed consent if
source animal quarantine period of 3 weeks is shortened
Justify shortening a source animal’s quarantine period of 3
weeks prior to
xenotransplantation product
procurement
Document location and nature
of archived PHS specimens
in health care records of
xenotransplantation product
recipient and source animal
Standard operating procedures
(SOPs) of source animal facility should be available to
review bodies
3.5.1
Document full necropsy investigations including evaluation
for infectious etiologies
3.5.2
Notify sponsor or FDA of new
archive site when the source
animal facility or sponsor
ceases operations
3.4
3.4.3.2
3.5.1
3.2.7.2
3.5.5
Source animal facility to notify
clinical center when infectious agent is identified in
source animal or herd after
xenotransplantation product
procurement
TABLE 2.—RECORDKEEPING
RECOMMENDATIONS
PHS
Guideline
Section
3.2.7
Description
Establish records linking each
xenotransplantation product
recipient with relevant
records
4.3
Sponsor to maintain cross-referenced system that links all
relevant records (recipient,
product, source animal, animal procurement center, and
nosocomial exposures)
3.4.2
Document results of monitoring
program used to detect introduction of infectious agents
which may not be apparent
clinically
FDA estimates the burden for this
collection of information as follows:
TABLE 3.—ESTIMATED ANNUAL REPORTING BURDEN1
PHS Guideline Section
No. of
Respondents
3.2.7.22
Annual Frequency
per Response
1
Total Annual
Responses
Hours per
Response
Total Hours
1
1
0.5
0.5
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3.43
12
0.33
4
0.08
0.32
3.5.14
12
0.08
(0–1) 1
0.25
0.25
3.5.45
12
1
12
0.5
6.0
3.5.54
18
0.06
(0–1) 1
0.2
0.2
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TABLE 3.—ESTIMATED ANNUAL REPORTING BURDEN1—Continued
PHS Guideline Section
No. of
Respondents
Annual Frequency
per Response
Total Annual
Responses
Hours per
Response
Total
Total Hours
7.27
1There
are no capital costs or operating and maintenance costs associated with this collection of information.
2No animal facility or sponsor has ceased operations in the last 3 years, however, we are using 1 respondent for estimation purposes.
3FDA’s records indicate that an average of 4 INDs are expected to be submitted per year.
4To our knowledge, has not occurred in the past 3 years and is expected to continue to be a rare occurrence.
5Based on an estimate of 36 patients treated over a 3 year period, the average number of xenotransplantation product recipients per year is
estimated to be 12.
TABLE 4.—ESTIMATED ANNUAL RECORDKEEPING BURDEN1
PHS Guideline Section
No. of
Recordkeepers
3.2.72
Annual Frequency
per Recordkeeping
Total Annual
Records
Hours per
Record
Total Hours
16
16
1
1
1
4.33
12
1
12
0.83
3.4.24
12
11
132
0.25
33
3.4.3.25
18
4
72
0.3
21.6
3.5.16
12
0.08
(0–1) 1
0.5
0.5
3.5.26
12
0.08
(0–1) 1
0.25
0.25
3.5.4
12
1
12
0.17
2.04
3.6.47
12
2
24
0.25
6
3.77
18
1.33
24
0.08
1.92
4.2.3.28
12
300
0.17
4.2.3.26
25
9.96
51
12
0.08
(0–1) 1
0.17
0.17
12
0.08
(0–1) 1
0.17
0.17
4.3.1
12
1
12
0.25
3
5.29
12
3
36
0.08
2.88
4.2.3.3 and
4.3.26
Total
148.49
1There
are no capital costs or operating and maintenance costs associated with this collection of information.
1-time burden for new respondents to set up a recordkeeping system linking all relevant records. FDA estimates 1 new sponsor annually.
estimates there is minimal recordkeeping burden associated with maintaining the record system.
4Monitoring for sentinel animals (subset representative of herd) plus all source animals. There are approximately 6 sentinel animals per herd x
1 herd per facility x 18 facilities = 108 sentinel animals. There are approximately 24 source animals per year (see footnote 7 of this table); 108 +
24 = 132 monitoring records to document.
5Necropsy for animal deaths of unknown cause estimated to be approximately 4 per herd per year x 1 herd per facility x 18 facilities = 72.
6Has not occurred in the past 3 years and is expected to continue to be a rare occurrence.
7On average 2 source animals are used for preparing xenotransplantation product material for one recipient. The average number of source
animals is 2 source animals per recipient x 12 recipients annually = 24 source animals per year (see footnote 5 of table 3 of this document).
8FDA estimates there are approximately 12 clinical centers doing xenotransplantation procedures x approximately 25 health care workers involved per center = 300 health care workers.
924 source animal records + 12 recipient records = 36 total records.
2A
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3FDA
Because of the potential risk for crossspecies transmission of pathogenic
persistent virus, the guideline
recommends that health records be
retained for 50 years. Since these
records are medical records, the
retention of such records for up to 50
years is not information subject to the
PRA (5 CFR 1320.3(h)(5)). Also, because
of the limited number of clinical studies
with small patient populations, the
number of records is expected to be
insignificant at this time.
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Information collections in this
guideline not included in tables 1
through 4 can be found under existing
regulations and approved under the
OMB control numbers as follows: (1)
‘‘Current Good Manufacturing Practice
for Finished Pharmaceuticals,’’ 21 CFR
211.1 through 211.208, approved
through September 30, 2008, under
OMB control number 0910–0139; (2)
‘‘Investigational New Drug
Application,’’ 21 CFR 312.1 through
312.160, approved through May 31,
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2009, under OMB control number 0910–
0014; and (3) information included in a
license application, 21 CFR 601.2,
approved through September 30, 2008,
under OMB control number 0910–0338.
(Although it is possible that a
xenotransplantation product may not be
regulated as a biological product (e.g., it
may be regulated as a medical device),
FDA believes, based on its knowledge
and experience with
xenotransplantation, that any
xenotransplantation product subject to
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FDA regulation within the next 3 years
will most likely be regulated as a
biological product.) However, FDA
recognized that some of the information
collections go beyond approved
collections; assessments for these
burdens are included in tables 1 through
4.
In table 5 of this document, FDA
identifies those information collection
activities that are already encompassed
by existing regulations or are consistent
with voluntary standards that reflect
industry’s usual and customary business
practice.
TABLE 5.—COLLECTION OF INFORMATION REQUIRED BY CURRENT REGULATIONS AND STANDARDS
PHS
Guideline
Section
21 CFR Section (Unless
Otherwise Stated)
Description of Collection of Information Activity
Document off-site collaborations
2.5
Sponsor ensure counseling patient, family, and contacts
3.1.1 and
3.1.6
Document well-characterized health history and lineage of source animals
3.1.8
Registration with and import permit from the Centers for Disease Control and Prevention
3.2.2
Document collaboration with accredited microbiology labs
3.2.3
Procedures to ensure the humane care of animals
3.2.4
Procedures consistent for accreditation by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC International) and consistent with the National Research
Council’s (NRC’s) guide
AAALAC international
rules of accreditation2
and NRC guide3
3.2.5,
3.4,
and
3.4.1
Herd health maintenance and surveillance to be documented, available, and in accordance with documented procedures; record standard veterinary care
211.100 and 211.122
3.2.6
Animal facility SOPs
3.3.3
Validate assay methods
3.6.1
Procurement and processing of xenografts using documented aseptic conditions
3.6.2
Develop, implement, and enforce SOPs for procurement and screening processes
3.6.4
Communicate to FDA animal necropsy findings pertinent to health of recipient
3.7.1
PHS specimens to be linked to health records; provide to FDA justification for types of tissues, cells,
and plasma, and quantities of plasma and leukocytes collected
312.23(a)(6)
4.1.1
Surveillance of xenotransplant recipient; sponsor ensures documentation of surveillance program lifelong (justify > 2 years (yrs.)); investigator case histories (2 yrs. after investigation is discontinued)
312.23(a)(6)(iii)(f) and
(g), and 312.62(b) and
(c)
4.1.2
Sponsor to justify amount and type of reserve samples
4.1.2.2
System for prompt retrieval of PHS specimens and linkage to medical records (recipient and source
animal)
4.1.2.3
Notify FDA of a clinical episode potentially representing a xenogeneic infection
312.32
4.2.2.1
Document collaborations (transfer of obligation)
312.52
4.2.3.1
Develop educational materials (sponsor provides investigators with information needed to conduct investigation properly)
312.50
4.3
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2.2.1
312.52
Sponsor to keep records of receipt, shipment, and disposition of investigative drug; investigator to keep
records of case histories
312.62(c)
312.23(a)(7)(a) and
211.84
42 CFR 71.53
312.52
9 CFR parts 1, 2, and 3
and PHS Policy1
PHS Policy1
211.160(a)
211.100 and 211.122
211.84(d) and
211.122(c)
312.32(c)
211.122
312.57(a)
312.57 and 312.62(b)
1The ‘‘Public Health Service Policy on Humane Care and Use of Laboratory Animals’’ (https://www.grants.nih.gov/grants/olaw/references/
phspol.htm).
2AAALAC international rules of accreditation (https://www.aaalac.org/accreditation/rules.cfm). (FDA has verified the Web site address, but is not
responsible for subsequent changes to the Web site address after this document publishes in the Federal Register.)
2AAALAC international rules of accreditation (https://www.aaalac.org/accreditation/rules.cfm). (FDA has verified the Web site address, but is not
responsible for subsequent changes to the Web site address after this document publishes in the Federal Register.)
3NRC’s ‘‘Guide for the Care and Use of Laboratory Animals’’ (1996).
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In the Federal Register of June 22,
2006 (71 FR 35911), FDA published a
60-day notice requesting public
comment on the information collection
provisions. No comments were received.
Dated: October 24, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6–18203 Filed 10–30–06; 8:45 am]
BILLING CODE 4160–01–S
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. 2006N–0421]
Agency Information Collection
Activities; Proposed Collection;
Comment Request; Biological
Products: Reporting of Biological
Product Deviations in Manufacturing;
Forms FDA 3486 and 3486A
AGENCY:
Food and Drug Administration,
HHS.
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ACTION:
Notice.
SUMMARY: The Food and Drug
Administration (FDA) is announcing an
opportunity for public comment on the
proposed collection of certain
information by the agency. Under the
Paperwork Reduction Act of 1995 (the
PRA), Federal agencies are required to
publish notice in the Federal Register
concerning each proposed collection of
information, including each proposed
extension of an existing collection of
information, and to allow 60 days for
public comment in response to the
notice. This notice solicits comments on
the information collection requirements
relating to the reporting of biological
product deviations in manufacturing,
and Forms FDA 3486 and 3486A.
DATES: Submit written or electronic
comments on the collection of
information by January 2, 2007.
ADDRESSES: Submit electronic
comments on the collection of
information to: https://www.fda.gov/
dockets/ecomments. Submit written
comments on the collection of
information to the Division of Dockets
Management (HFA–305), Food and Drug
Administration, 5630 Fishers Lane, rm.
1061, Rockville, MD 20852. All
comments should be identified with the
docket number found in brackets in the
heading of this document.
FOR FURTHER INFORMATION CONTACT:
Jonna Capezzuto, Office of the Chief
Information Officer (HFA–250), Food
and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857, 301–827–
4659.
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Under the
PRA (44 U.S.C. 3501–3520), Federal
agencies must obtain approval from the
Office of Management and Budget
(OMB) for each collection of
information they conduct or sponsor.
‘‘Collection of information’’ is defined
in 44 U.S.C. 3502(3) and 5 CFR
1320.3(c) and includes agency requests
or requirements that members of the
public submit reports, keep records, or
provide information to a third party.
Section 3506(c)(2)(A) of the PRA (44
U.S.C. 3506(c)(2)(A)) requires Federal
agencies to provide a 60-day notice in
the Federal Register concerning each
proposed collection of information,
including each proposed extension of an
existing collection of information,
before submitting the collection to OMB
for approval. To comply with this
requirement, FDA is publishing notice
of the proposed collection of
information set forth in this document.
With respect to the following
collection of information, FDA invites
comments on these topics: (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.
SUPPLEMENTARY INFORMATION:
Biological Products: Reporting of
Biological Product Deviations in
Manufacturing; Forms FDA 3486 and
3486A (OMB Control Number 0910–
0458)—Extension
Under section 351 of the Public
Health Service Act (42 U.S.C. 262), all
biological products, including human
blood and blood components, offered
for sale in interstate commerce must be
licensed and meet standards designed to
ensure the continued safety, purity, and
potency of such products. In addition,
the Federal Food, Drug, and Cosmetic
Act (the act) (21 U.S.C. 351) provides
that drugs and devices (including
human blood and blood components)
are adulterated if they do not conform
with Current Good Manufacturing
Practice (CGMP) assuring that they meet
the requirements of the act. All
establishments manufacturing biological
products including human blood and
blood components must comply with
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the applicable CGMP regulations (parts
211, 606, and 820 (21 CFR parts 211,
606, and 820)). Transfusion services are
required under 42 CFR 493.1271 to
comply with 21 CFR parts 606 and 640
as they pertain to the performance of
manufacturing activities. FDA regards
biological product deviation (BPD)
reporting to be an essential tool in its
directive to protect public health by
establishing and maintaining
surveillance programs that provide
timely and useful information.
Section 600.14 requires the
manufacturer who holds the biological
product license, for other than human
blood and blood components, and who
had control over the product when the
deviation occurred, to report to the
Center for Biologics Evaluation and
Research (CBER) or to the Center for
Drugs Evaluation and Research (CDER)
as soon as possible but not to exceed 45
calendar days after acquiring
information reasonably suggesting that a
reportable event has occurred. Section
606.171 requires a licensed
manufacturer of human blood and blood
components, including Source Plasma;
an unlicensed registered blood
establishment; or a transfusion service
who had control over the product when
the deviation occurred, to report to
CBER as soon as possible but not to
exceed 45 calendar days after acquiring
information reasonably suggesting that a
reportable event has occurred. The BPD
reporting under 21 CFR 1271.350(b) for
human cells, tissues, and cellular and
tissue-based products is approved under
OMB control number 0910–0559
(expires November 30, 2007). Form FDA
3486 is used to submit BPDs under
these regulations.
Respondents to this collection of
information are the licensed
manufacturers of biological products
other than human blood and blood
components, licensed manufacturers of
blood and blood components including
Source Plasma, unlicensed registered
blood establishments, and transfusion
services. Based on information from
FDA’s database, there are an estimated
147 licensed manufacturers of biological
products other than human blood and
blood components, 194 licensed
manufacturers of human blood and
blood components, including Source
Plasma, and 1,230 unlicensed registered
blood establishments. Based on the
Center for Medicare and Medicaid
Services records, there are an estimated
4,980 transfusion services. The number
of licensed manufacturers and total
annual responses under § 600.14
include the estimates for both CBER and
CDER. The number of total annual
responses is based on the number of
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]]>Agencies
[Federal Register Volume 71, Number 210 (Tuesday, October 31, 2006)]
[Notices]
[Pages 63768-63772]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E6-18203]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 2006N-0239]
Agency Information Collection Activities; Submission for Office
of Management and Budget Review; Comment Request; Infectious Disease
Issues in Xenotransplantation
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing that a
proposed collection of information has been submitted to the Office of
Management and Budget (OMB) for review and clearance under the
Paperwork Reduction Act of 1995.
DATES: Fax written comments on the collection of information by
November 30, 2006.
ADDRESSES: To ensure that comments on the information collection are
received, OMB recommends that written comments be faxed to the Office
of Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer,
FAX: 202-395-6974.
FOR FURTHER INFORMATION CONTACT: Jonna Capezzuto, Office of the Chief
Information Officer (HFA-250), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-4659.
SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has
submitted the following proposed collection of information to OMB for
review and clearance.
Infectious Disease Issues in Xenotransplantation--(OMB Control Number
0910-0456)--Extension
The statutory authority to collect this information is provided
under sections 351 and 361 of the Public Health Service (PHS) act (42
U.S.C. 262 and 264) and the provisions of the Federal Food, Drug, and
Cosmetic Act that apply to drugs (21 U.S.C. 301 et seq.). The PHS
guideline recommends procedures to diminish the risk of transmission of
infectious agents to the xenotransplantation product recipient and the
general public. The PHS guideline is intended to address public health
issues raised by xenotransplantation, through identification of general
principles of prevention and control of infectious diseases associated
with xenotransplantation that may pose a hazard to the public health.
The collection of information described in this guideline is intended
to provide general guidance to sponsors in the following ways: (1) The
development of xenotransplantation clinical protocols, (2) the
preparation of submissions to FDA, and (3) the conduct of
xenotransplantation clinical trials. Also, the collection of
information will help ensure that the sponsor maintains important
information in a cross-referenced system that links the relevant
records of the xenotransplantation product recipient,
xenotransplantation product, source animal(s), animal procurement
center, and significant nosocomial exposures. The PHS guideline
describes an occupational health service program for the protection of
health care workers involved in xenotransplantation procedures, caring
for xenotransplantation product recipients, and performing associated
laboratory testing. The guideline also describes a public health need
for a national xenotransplantation database, which is currently under
development by PHS. The PHS guideline is intended to protect the public
health and to help ensure the safety of using xenotransplantation
products in humans by preventing the introduction, transmission, and
spread of infectious diseases associated with xenotransplantation.
The PHS guideline also recommends that certain specimens and
records be maintained for 50 years beyond the date of the
xenotransplantation. These include the following information, as
recommended by the specific PHS guideline sections: (1) Records linking
each xenotransplantation product recipient with relevant health records
of the source animal, herd, or colony, and the specific organ, tissue,
or cell type included in or used in the manufacture of the product
(3.2.7.1); (2) aliquots of serum samples from randomly selected animal
and specific disease investigations (3.4.3.1); (3) source animal
biological specimens designated for PHS use (3.7.1); animal health
records (3.7.2), including necropsy results (3.6.4); and (4)
recipients' biological specimens (4.1.2). The retention period is
intended to assist health care practitioners and officials in
surveillance and in tracking the source of an infection, disease, or
illness that might emerge in the recipient, the source animal, or the
animal herd or colony after a xenotransplantation.
The recommendation for maintaining records for 50 years is based on
clinical experience with several human viruses that have presented
problems in human to human transplantation and are therefore thought to
share certain characteristics with viruses that may pose potential
risks in xenotransplantation. These characteristics include long
latency periods and the ability to establish persistent infections.
Several also share the possibility of transmission among individuals
through intimate contact with human body fluids. Human immunodeficiency
virus (HIV) and Human T-lymphotropic virus are human retroviruses.
Retroviruses contain ribonucleic acid (RNA) that is reverse-transcribed
into deoxyribonucleic acid (DNA) using an enzyme provided by the virus
and the human cell machinery. That viral DNA can then be integrated
into the human cellular DNA. Both viruses establish persistent
infections and have long latency periods before the onset of disease,
10 years and 40 to 60 years, respectively. The human hepatitis viruses
are not retroviruses, but several share with HIV the characteristic
that they can be transmitted through body fluids, can establish
persistent infections, and have long latency
[[Page 63769]]
periods, e.g., approximately 30 years for Hepatitis C.
In addition, the PHS guideline recommends that a record system be
developed that allows easy, accurate, and rapid linkage of information
among the specimen archive, the recipient's medical records, and the
records of the source animal for 50 years. The development of such a
record system is a one-time burden. Such a system is intended to cross-
reference and locate relevant records of recipients, products, source
animals, animal procurement centers, and nosocomial exposures.
Respondents to this collection of information are the sponsors of
clinical studies of investigational xenotransplantation products under
investigational new drug applications (INDs) and xenotransplantation
product procurement centers, referred to as source animal facilities.
There are an estimated 12 respondents who are sponsors of INDs that
include protocols for xenotransplantation in humans. Other respondents
for this collection of information are an estimated 18 source animal
facilities that provide source xenotransplantation product material to
sponsors for use in human xenotransplantation procedures. These 18
source animal facilities keep medical records of the herds/colonies as
well as the medical records of the individual source animal(s). The
total annual reporting and recordkeeping burden is estimated to be
approximately 156 hours. The burden estimates are based on FDA's
records of xenotransplantation-related INDs and estimates of time
required to complete the various reporting and recordkeeping tasks
described in the guideline. FDA does not expect the level of clinical
studies using xenotransplantation to increase significantly in the next
few years.
FDA is requesting an extension of OMB approval for the following
reporting and recordkeeping recommendations in the PHS guideline:
Table 1.--Reporting Recommendations
------------------------------------------------------------------------
PHS Guideline Section Description
------------------------------------------------------------------------
3.2.7.2 Notify sponsor or FDA of new archive site
when the source animal facility or sponsor
ceases operations
------------------------------------------------------------------------
3.4 Standard operating procedures (SOPs) of
source animal facility should be available
to review bodies
------------------------------------------------------------------------
3.5.1 Include increased infectious risk in
informed consent if source animal
quarantine period of 3 weeks is shortened
------------------------------------------------------------------------
3.5.4 Sponsor to make linked records described in
section 3.2.7 available for review
------------------------------------------------------------------------
3.5.5 Source animal facility to notify clinical
center when infectious agent is identified
in source animal or herd after
xenotransplantation product procurement
------------------------------------------------------------------------
Table 2.--Recordkeeping Recommendations
------------------------------------------------------------------------
PHS Guideline Section Description
------------------------------------------------------------------------
3.2.7 Establish records linking each
xenotransplantation product recipient with
relevant records
------------------------------------------------------------------------
4.3 Sponsor to maintain cross-referenced system
that links all relevant records (recipient,
product, source animal, animal procurement
center, and nosocomial exposures)
------------------------------------------------------------------------
3.4.2 Document results of monitoring program used
to detect introduction of infectious agents
which may not be apparent clinically
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3.4.3.2 Document full necropsy investigations
including evaluation for infectious
etiologies
------------------------------------------------------------------------
3.5.1 Justify shortening a source animal's
quarantine period of 3 weeks prior to
xenotransplantation product procurement
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3.5.2 Document absence of infectious agent in
xenotransplantation product if its presence
elsewhere in source animal does not
preclude using it
------------------------------------------------------------------------
3.5.4 Add summary of individual source animal
record to permanent medical record of the
xenotransplantation product recipient
------------------------------------------------------------------------
3.6.4 Document complete necropsy results on source
animals (50-year record retention)
------------------------------------------------------------------------
3.7 Link xenotransplantation product recipients
to individual source animal records and
archived biologic specimens
------------------------------------------------------------------------
4.2.3.2 Record base-line sera of xenotransplantation
health care workers and specific nosocomial
exposure
------------------------------------------------------------------------
4.2.3.3 and 4.3.2 Keep a log of health care workers'
significant nosocomial exposure(s)
------------------------------------------------------------------------
4.3.1 Document each xenotransplant procedure
------------------------------------------------------------------------
5.2 Document location and nature of archived PHS
specimens in health care records of
xenotransplantation product recipient and
source animal
------------------------------------------------------------------------
FDA estimates the burden for this collection of information as
follows:
Table 3.--Estimated Annual Reporting Burden\1\
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No. of Annual Frequency per Total Annual Hours per
PHS Guideline Section Respondents Response Responses Response Total Hours
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3.2.7.2\2\ 1 1 1 0.5 0.5
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3.4\3\ 12 0.33 4 0.08 0.32
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3.5.1\4\ 12 0.08 (0-1) 1 0.25 0.25
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3.5.4\5\ 12 1 12 0.5 6.0
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3.5.5\4\ 18 0.06 (0-1) 1 0.2 0.2
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[[Page 63770]]
Total 7.27
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\1\There are no capital costs or operating and maintenance costs associated with this collection of information.
\2\No animal facility or sponsor has ceased operations in the last 3 years, however, we are using 1 respondent for estimation purposes.
\3\FDA's records indicate that an average of 4 INDs are expected to be submitted per year.
\4\To our knowledge, has not occurred in the past 3 years and is expected to continue to be a rare occurrence.
\5\Based on an estimate of 36 patients treated over a 3 year period, the average number of xenotransplantation product recipients per year is estimated
to be 12.
Table 4.--Estimated Annual Recordkeeping Burden\1\
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No. of Annual Frequency per Total Annual
PHS Guideline Section Recordkeepers Recordkeeping Records Hours per Record Total Hours
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3.2.7\2\ 1 1 1 16 16
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4.3\3\ 12 1 12 0.83 9.96
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3.4.2\4\ 12 11 132 0.25 33
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3.4.3.2\5\ 18 4 72 0.3 21.6
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3.5.1\6\ 12 0.08 (0-1) 1 0.5 0.5
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3.5.2\6\ 12 0.08 (0-1) 1 0.25 0.25
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3.5.4 12 1 12 0.17 2.04
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3.6.4\7\ 12 2 24 0.25 6
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3.7\7\ 18 1.33 24 0.08 1.92
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4.2.3.2\8\ 12 25 300 0.17 51
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4.2.3.2\6\ 12 0.08 (0-1) 1 0.17 0.17
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4.2.3.3 and 4.3.2\6\ 12 0.08 (0-1) 1 0.17 0.17
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4.3.1 12 1 12 0.25 3
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5.2\9\ 12 3 36 0.08 2.88
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Total 148.49
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\1\There are no capital costs or operating and maintenance costs associated with this collection of information.
\2\A 1-time burden for new respondents to set up a recordkeeping system linking all relevant records. FDA estimates 1 new sponsor annually.
\3\FDA estimates there is minimal recordkeeping burden associated with maintaining the record system.
\4\Monitoring for sentinel animals (subset representative of herd) plus all source animals. There are approximately 6 sentinel animals per herd x 1 herd
per facility x 18 facilities = 108 sentinel animals. There are approximately 24 source animals per year (see footnote 7 of this table); 108 + 24 = 132
monitoring records to document.
\5\Necropsy for animal deaths of unknown cause estimated to be approximately 4 per herd per year x 1 herd per facility x 18 facilities = 72.
\6\Has not occurred in the past 3 years and is expected to continue to be a rare occurrence.
\7\On average 2 source animals are used for preparing xenotransplantation product material for one recipient. The average number of source animals is 2
source animals per recipient x 12 recipients annually = 24 source animals per year (see footnote 5 of table 3 of this document).
\8\FDA estimates there are approximately 12 clinical centers doing xenotransplantation procedures x approximately 25 health care workers involved per
center = 300 health care workers.
\9\24 source animal records + 12 recipient records = 36 total records.
Because of the potential risk for cross-species transmission of
pathogenic persistent virus, the guideline recommends that health
records be retained for 50 years. Since these records are medical
records, the retention of such records for up to 50 years is not
information subject to the PRA (5 CFR 1320.3(h)(5)). Also, because of
the limited number of clinical studies with small patient populations,
the number of records is expected to be insignificant at this time.
Information collections in this guideline not included in tables 1
through 4 can be found under existing regulations and approved under
the OMB control numbers as follows: (1) ``Current Good Manufacturing
Practice for Finished Pharmaceuticals,'' 21 CFR 211.1 through 211.208,
approved through September 30, 2008, under OMB control number 0910-
0139; (2) ``Investigational New Drug Application,'' 21 CFR 312.1
through 312.160, approved through May 31, 2009, under OMB control
number 0910-0014; and (3) information included in a license
application, 21 CFR 601.2, approved through September 30, 2008, under
OMB control number 0910-0338. (Although it is possible that a
xenotransplantation product may not be regulated as a biological
product (e.g., it may be regulated as a medical device), FDA believes,
based on its knowledge and experience with xenotransplantation, that
any xenotransplantation product subject to
[[Page 63771]]
FDA regulation within the next 3 years will most likely be regulated as
a biological product.) However, FDA recognized that some of the
information collections go beyond approved collections; assessments for
these burdens are included in tables 1 through 4.
In table 5 of this document, FDA identifies those information
collection activities that are already encompassed by existing
regulations or are consistent with voluntary standards that reflect
industry's usual and customary business practice.
Table 5.--Collection of Information Required by Current Regulations and
Standards
------------------------------------------------------------------------
Description of
PHS Guideline Section Collection of 21 CFR Section (Unless
Information Activity Otherwise Stated)
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2.2.1 Document off-site 312.52
collaborations
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2.5 Sponsor ensure 312.62(c)
counseling patient,
family, and contacts
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3.1.1 and 3.1.6 Document well- 312.23(a)(7)(a) and
characterized health 211.84
history and lineage of
source animals
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3.1.8 Registration with and 42 CFR 71.53
import permit from the
Centers for Disease
Control and Prevention
------------------------------------------------------------------------
3.2.2 Document collaboration 312.52
with accredited
microbiology labs
------------------------------------------------------------------------
3.2.3 Procedures to ensure 9 CFR parts 1, 2, and 3
the humane care of and PHS Policy\1\
animals
------------------------------------------------------------------------
3.2.4 Procedures consistent AAALAC international
for accreditation by rules of
the Association for accreditation\2\ and
Assessment and NRC guide\3\
Accreditation of
Laboratory Animal Care
International (AAALAC
International) and
consistent with the
National Research
Council's (NRC's)
guide
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3.2.5, 3.4, and 3.4.1 Herd health maintenance 211.100 and 211.122
and surveillance to be
documented, available,
and in accordance with
documented procedures;
record standard
veterinary care
------------------------------------------------------------------------
3.2.6 Animal facility SOPs PHS Policy\1\
------------------------------------------------------------------------
3.3.3 Validate assay methods 211.160(a)
------------------------------------------------------------------------
3.6.1 Procurement and 211.100 and 211.122
processing of
xenografts using
documented aseptic
conditions
------------------------------------------------------------------------
3.6.2 Develop, implement, and 211.84(d) and
enforce SOPs for 211.122(c)
procurement and
screening processes
------------------------------------------------------------------------
3.6.4 Communicate to FDA 312.32(c)
animal necropsy
findings pertinent to
health of recipient
------------------------------------------------------------------------
3.7.1 PHS specimens to be 312.23(a)(6)
linked to health
records; provide to
FDA justification for
types of tissues,
cells, and plasma, and
quantities of plasma
and leukocytes
collected
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4.1.1 Surveillance of 312.23(a)(6)(iii)(f)
xenotransplant and (g), and 312.62(b)
recipient; sponsor and (c)
ensures documentation
of surveillance
program lifelong
(justify > 2 years
(yrs.)); investigator
case histories (2 yrs.
after investigation is
discontinued)
------------------------------------------------------------------------
4.1.2 Sponsor to justify 211.122
amount and type of
reserve samples
------------------------------------------------------------------------
4.1.2.2 System for prompt 312.57(a)
retrieval of PHS
specimens and linkage
to medical records
(recipient and source
animal)
------------------------------------------------------------------------
4.1.2.3 Notify FDA of a 312.32
clinical episode
potentially
representing a
xenogeneic infection
------------------------------------------------------------------------
4.2.2.1 Document collaborations 312.52
(transfer of
obligation)
------------------------------------------------------------------------
4.2.3.1 Develop educational 312.50
materials (sponsor
provides investigators
with information
needed to conduct
investigation
properly)
------------------------------------------------------------------------
4.3 Sponsor to keep records 312.57 and 312.62(b)
of receipt, shipment,
and disposition of
investigative drug;
investigator to keep
records of case
histories
------------------------------------------------------------------------
\1\The ``Public Health Service Policy on Humane Care and Use of
Laboratory Animals'' (https://www.grants.nih.gov/grants/olaw/references/
phspol.htm).
\2\AAALAC international rules of accreditation (https://www.aaalac.org/
accreditation/rules.cfm). (FDA has verified the Web site address, but
is not responsible for subsequent changes to the Web site address
after this document publishes in the Federal Register.)
\3\NRC's ``Guide for the Care and Use of Laboratory Animals'' (1996).
[[Page 63772]]
In the Federal Register of June 22, 2006 (71 FR 35911), FDA
published a 60-day notice requesting public comment on the information
collection provisions. No comments were received.
Dated: October 24, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6-18203 Filed 10-30-06; 8:45 am]
BILLING CODE 4160-01-S
