Notice2022-08737
Agency Information Collection Activities; Submission for Office of Management and Budget Review; Comment Request; Public Health Service Guideline on Infectious Disease Issues in Xenotransplantation
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Published
April 25, 2022
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
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.
Full Text
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<title>Federal Register, Volume 87 Issue 79 (Monday, April 25, 2022)</title>
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[Federal Register Volume 87, Number 79 (Monday, April 25, 2022)]
[Notices]
[Pages 24316-24320]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2022-08737]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2012-N-0559]
Agency Information Collection Activities; Submission for Office
of Management and Budget Review; Comment Request; Public Health Service
Guideline on Infectious Disease Issues in Xenotransplantation
AGENCY: Food and Drug Administration, Health and Human Services (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: Submit written comments (including recommendations) on the
collection of information by May 25, 2022.
ADDRESSES: To ensure that comments on the information collection are
received, OMB recommends that written comments be submitted to <a href="https://www.reginfo.gov/public/do/PRAMain">https://www.reginfo.gov/public/do/PRAMain</a>. Find this particular information
collection by selecting ``Currently under Review--Open for Public
Comments'' or by using the search function. The OMB control number for
this information collection is 0910-0456. Also include the FDA docket
number found in brackets in the heading of this document.
FOR FURTHER INFORMATION CONTACT: Rachel Showalter, Office of
Operations, Food and Drug Administration, Three White Flint North, 10A-
12M, 11601 Landsdown St., North Bethesda, MD 20852, 240-994-7399,
<a href="/cdn-cgi/l/email-protection#3c6c6e7d6f485d5a5a7c5a585d1254544f125b534a"><span class="__cf_email__" data-cfemail="b5e5e7f4e6c1d4d3d3f5d3d1d49bddddc69bd2dac3">[email protected]</span></a>.
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.
Public Health Service (PHS) Guideline on Infectious Disease Issues in
Xenotransplantation
OMB Control Number 0910-0456--Extension
This information collection helps support implementation of the
Department of Health and Human Services' ``PHS Guideline on Infectious
Disease Issues in Xenotransplantation'' dated January 19, 2001,
available at: <a href="https://www.fda.gov/media/73803/download">https://www.fda.gov/media/73803/download</a>. FDA is
authorized to collect this information under sections 351 and 361 of
the PHS Act (42 U.S.C. 262 and 264) and provisions of the Federal Food,
Drug, and Cosmetic Act that apply to drugs (21 U.S.C. 321 et seq.). The
guideline was developed by the PHS to identify general principles for
the prevention and control of infectious diseases associated with
xenotransplantation that may pose a risk to public health. The PHS
guideline recommends procedures to diminish the risk of transmission of
infectious agents to the xenotransplantation product recipient and to
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 on the following
topics: (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 also
describes an occupational health service program for the protection of
health care workers involved in xenotransplantation
[[Page 24317]]
procedures, caring for xenotransplantation product recipients, and
performing associated laboratory testing. 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: (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); (4) animal health
records (3.7.2), including necropsy results (3.6.4); and (5)
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, such as human
cytomegalovirus and BK polyoma virus, which 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 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 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 significant 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 three respondents who are sponsors of INDs that
include protocols for xenotransplantation in humans and five clinical
centers doing xenotransplantation procedures. Other respondents for
this collection of information are an estimated four source animal
facilities which provide source xenotransplantation product material to
sponsors for use in human xenotransplantation procedures. These four
source animal facilities keep medical records of the herds/colonies as
well as the medical records of the individual source animal(s). The
burden estimates are based on FDA's records of xenotransplantation-
related INDs and estimates of time required to complete the various
reporting, recordkeeping, and third-party disclosure tasks described in
the PHS guideline.
In the Federal Register of October 22, 2021 (86 FR 58666), FDA
published a 60-day notice requesting public comment on the proposed
collection of information. FDA received one comment letter, which
contained multiple comments, in response to the notice. Several
comments (recommendations for selection of xenograft recipients,
hospital personnel and care providers, and handling of donor and
recipient tissue) were not responsive to the four information
collection topics solicited in the 60-day notice and therefore will not
be addressed in this notice.
(Comment 1) One comment in the letter was supportive of expanded
collection and testing of blood samples from xenograft recipients,
their immediate family, close social/sexual contacts, as well as other
persons at risk of exposure to infection.
(Response) We agree with the utility of blood sampling and testing
to track the source of any long-term developing infections as a result
of xenotransplantation. We have considered the comment and have
determined that the comment does not present information that would
warrant substantive changes to the guideline at this time.
(Comment 2) One comment in the letter recommended shortening the
50-year retention period for frozen samples of serum, cells, and
tissues recommended by the PHS guideline. Among other reasons, the
comment argued that transplant recipients generally manifest either
donor-derived or opportunistic infections in the first-year post-
transplantation; malignancies and uncommon infections may manifest
later, but generally within 5-10 years; and patient survival post-organ
transplantation is generally less than 20 years. The comment concluded
that storage of samples beyond 20 years for initial studies should not
be necessary.
(Response) We have considered the comment and have determined that
the comment does not present information that would warrant substantive
changes to the guideline at this time.
(Comment 3) One comment in the letter stated that the sponsor of
the clinical trial or the hospital in which the trial is carried out
should be relieved of the responsibility to store their records and
samples. The comment argued that ongoing data and specimen collection,
as well as the maintenance of repositories represents a significant
burden on both sponsors and transplant programs with resultant
significant cost and hardship that could deter xenotransplant progress.
The comment concluded that storage of records and samples should be the
responsibility of a recognized government authority or institution or
an FDA-designated organization. The comment recommended the creation of
a central repository for both data and specimen collection run by, or
under contract with, the Federal government.
(Response) The comment did not provide any data that would support
a change to the burden estimate in the 60-day notice. Thus, FDA has not
changed the burden estimate in table 1 of this document. We have
considered the comment and have determined that the comment does not
present information that would warrant substantive changes to the
guideline at this time.
FDA is requesting an extension of OMB approval for the following
reporting, recordkeeping and third-party
[[Page 24318]]
disclosure recommendations in the PHS guideline:
Table 1--Reporting Recommendations
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PHS guideline section Description
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3.2.7.2...................... Notify sponsor or FDA of new archive site
when the source animal facility or
sponsor ceases operations.
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Table 2--Recordkeeping Recommendations
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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.
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.
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 baseline 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
specimens in health care records of
xenotransplantation product recipient
and source animal.
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Table 3--Disclosure 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.
------------------------------------------------------------------------
FDA estimates the burden of this collection of information as
follows:
Table 4--Estimated Annual Reporting Burden \1\
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Number of
PHS guideline section Number of responses per Total annual Average burden per response Total hours
respondents respondent responses
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3.2.7.2 \2\.......................... 1 1 1 0.5 (30 minutes)................. 0.5
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
\2\ FDA is using one animal facility or sponsor for estimation purposes.
Table 5--Estimated Annual Recordkeeping Burden \1\
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Number of Number of records Total annual
PHS guideline section recordkeepers per recordkeeper records Average burden per recordkeeping Total hours
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3.2.7 \2\.............................. 1 1 1 16................................. 16
4.3 \3\................................ 3 1 3 0.75 (45 minutes).................. 2.25
3.4.2 \4\.............................. 3 10.67 32 0.25 (15 minutes).................. 8
3.4.3.2 \5\............................ 3 2.67 8 0.25 (15 minutes).................. 2
3.5.1 \6\.............................. 3 0.33 1 0.5 (30 minutes)................... 0.50
3.5.2 \6\.............................. 3 0.33 1 0.25 (15 minutes).................. 0.25
3.5.4.................................. 3 1 3 0.17 (10 minutes).................. 0.51
3.6.4 \7\.............................. 3 2.67 8 0.25 (15 minutes).................. 2
3.7 \7\................................ 4 2 8 0.08 (5 minutes)................... 0.64
[[Page 24319]]
4.2.3.2 \8\............................ 5 25 125 0.17 (10 minutes).................. 21.25
4.2.3.2 \6\............................ 5 0.2 1 0.17 (10 minutes).................. 0.17
4.2.3.3 and 4.3.2 \6\.................. 5 0.2 1 0.17 (10 minutes).................. 0.17
4.3.1.................................. 3 1 3 0.25 (15 minutes).................. 0.75
5.2 \9\................................ 3 4 12 0.08 (5 minutes)................... 0.96
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Total.............................. ................. ................. ................. ................................... 55.45
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
\2\ A one-time burden for new respondents to set up a recordkeeping system linking all relevant records. FDA is using one new sponsor for estimation
purposes.
\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 4 facilities = 24 sentinel animals. There are approximately 8 source animals per year (see footnote 7 of this table); 24 + 8 = 32
monitoring records to document.
\5\ Necropsy for animal deaths of unknown cause estimated to be approximately 2 per herd per year x 1 herd per facility x 4 facilities = 8.
\6\ Has not occurred in the past 3 years and is expected to continue to be a rare occurrence.
\7\ On average two 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 4 recipients annually = 8 source animals per year. (See footnote 5 of table 6.)
\8\ FDA estimates there are 5 clinical centers doing xenotransplantation procedures x approximately 25 health care workers involved per center = 125
health care workers.
\9\ Eight source animal records + 4 recipient records = 12 total records.
Table 6--Estimated Annual Third-Party Disclosure Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of
PHS guideline section Number of disclosures per Total annual Average burden per disclosure Total hours
respondents respondent disclosures
--------------------------------------------------------------------------------------------------------------------------------------------------------
3.2.7.2 \2\............................ 1 1 1 0.5 (30 minutes)................... 0.5
3.4 \3\................................ 4 0.25 1 0.08 (5 minutes)................... 0.08
3.5.1 \4\.............................. 4 0.25 1 0.25 (15 minutes).................. 0.25
3.5.4 \5\.............................. 4 1 4 0.5 (30 minutes)................... 2
3.5.5 \4\.............................. 4 0.25 1 0.25 (15 minutes).................. 0.25
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Total.............................. ................. ................. ................. ................................... 3.08
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
\2\ FDA is using one animal facility or sponsor for estimation purposes.
\3\ FDA's records indicate that an average of one IND is 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 12 patients treated over a 3 year period, the average number of xenotransplantation product recipients per year is estimated
to be 4.
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 6 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 under OMB control number 0910-0139; (2) ``Investigational New
Drug Application,'' 21 CFR 312.1 through 312.160, approved under OMB
control number 0910-0014; and (3) information included in a biologics
license application, 21 CFR 601.2, approved 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 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 6.
In table 7, FDA identifies those collection of information
activities that are already encompassed by existing regulations or are
consistent with voluntary standards which reflect industry's usual and
customary business practice.
Table 7--Collection of Information Required by Current Regulations and Standards
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21 CFR section (unless
PHS guideline section Description otherwise stated)
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2.2.1................................. Document offsite collaborations......... 312.52.
2.5................................... Sponsor ensures counseling patient + 312.62(c).
family + contacts.
[[Page 24320]]
3.1.1 and 3.1.6....................... Document well-characterized health 312.23(a)(7)(a) and 211.84.
history and lineage of source animals..
3.1.8................................. Registration with and import permit from 42 CFR 71.53.
the Centers for Disease Control and
Prevention..
3.2.2................................. Document collaboration with accredited 312.52.
microbiology labs.
3.2.3................................. Procedures to ensure the humane care of 9 CFR parts 1, 2, and 3 and
animals. PHS Policy \1\.
3.2.4................................. Procedures consistent for accreditation AAALAC International Rules of
by the Association for Assessment and Accreditation \2\ and NRC
Accreditation of Laboratory Animal Care Guide \3\.
International (AAALAC International)
and consistent with the National
Research Council's (NRC) Guide.
3.2.5, 3.4, and 3.4.1................. Herd health maintenance and surveillance 211.100 and 211.122.
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 processing of xenografts 211.100 and 211.122.
using documented aseptic conditions.
3.6.2................................. Develop, implement, and enforce SOPs for 211.84(d) and 211.122(c).
procurement and screening processes.
3.6.4................................. Communicate to FDA animal necropsy 312.32(c).
findings pertinent to health of
recipient.
3.7.1................................. PHS specimens to be linked to health 312.23(a)(6).
records; provide to FDA justification
for types of tissues, cells, and
plasma, and quantities of plasma and
leukocytes collected.
4.1.1................................. Surveillance of xenotransplant 312.23(a)(6)(iii)(f) and (g),
recipient; sponsor ensures and 312.62(b) and (c).
documentation of surveillance program
life-long (justify >2 yrs.);
investigator case histories (2 yrs.
after investigation is discontinued).
4.1.2................................. Sponsor to justify amount and type of 211.122.
reserve samples.
4.1.2.2............................... System for prompt retrieval of PHS 312.57(a).
specimens and linkage to medical
records (recipient and source animal).
4.1.2.3............................... Notify FDA of a clinical episode 312.32.
potentially representing a xenogeneic
infection.
4.2.2.1............................... Document collaborations (transfer of 312.52.
obligation).
4.2.3.1............................... Develop educational materials (sponsor 312.50.
provides investigators with information
needed to conduct investigation
properly).
4.3................................... Sponsor to keep records of receipt, 312.57 and 312.62(b).
shipment, and disposition of
investigative drug; investigator to
keep records of case histories.
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\1\ The ``Public Health Service Policy on Humane Care and Use of Laboratory Animals'' (<a href="https://olaw.nih.gov/policies-laws/phs-policy.htm">https://olaw.nih.gov/policies-laws/phs-policy.htm</a>).
\2\ AAALAC International Rules of Accreditation (<a href="https://www.aaalac.org/accreditation-program/rules-of-accreditation/">https://www.aaalac.org/accreditation-program/rules-of-accreditation/</a> accreditation/).
\3\ The NRC's ``Guide for the Care and Use of Laboratory Animals.''
Based on a review of the information collection since our last
request for OMB approval, we have made no adjustments to our burden
estimate other than to adjust total burden hours by one hour, from 60
to 59 total burden hours, to address an inadvertent error in disclosure
burden in the previous submissions to OMB.
Dated: April 19, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-08737 Filed 4-22-22; 8:45 am]
BILLING CODE 4164-01-P
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