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

July 29, 2025

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.

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<title>Federal Register, Volume 90 Issue 143 (Tuesday, July 29, 2025)</title>
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[Federal Register Volume 90, Number 143 (Tuesday, July 29, 2025)]
[Notices]
[Pages 35689-35693]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2025-14227]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2024-N-0383]

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, 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 August 28, 2025.

[[Page 35690]]

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: Domini Bean, Office of Operations,
Food and Drug Administration, Three White Flint North, 10A-12M, 11601
Landsdown St., North Bethesda, MD 20852, 301-796-5733,
<a href="/cdn-cgi/l/email-protection#09595b485a7d686f6f496f6d682761617a276e667f"><span class="__cf_email__" data-cfemail="421210031136232424022426236c2a2a316c252d34">[email&#160;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.

PHS Guideline on Infectious Disease Issues in Xenotransplantation

OMB Control Number 0910-0456--Extension

This information collection helps to support Agency regulations and
guidance. The statutory authority to collect this information is
provided under sections 351 and 361 of the Public Health Service Act
(PHS Act) (42 U.S.C. 262 and 264) and the provisions of the Federal
Food, Drug, and Cosmetic Act (FD&C Act) that apply to drugs (21 U.S.C.
321 et seq.). In the Federal Register of January 29, 2001 (66 FR 8120),
FDA announced the availability of the ``PHS Guideline on Infectious
Disease Issues in Xenotransplantation.'' The guideline, available from
our website at <a href="https://www.fda.gov/media/73803/download">https://www.fda.gov/media/73803/download</a> was developed
by the U.S. Public Health Service (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
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 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); 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 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 five respondents who are sponsors of seven 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 two
source animal facilities which provide source xenotransplantation
product material to sponsors for use in human xenotransplantation
procedures. These two source animal facilities keep medical records of
the herds/colonies as well as the medical records of the individual
source animal(s). There are an estimated three herds of approximately
six animals per herd. 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.

[[Page 35691]]

We are therefore requesting an extension of OMB approval for the
following reporting, recordkeeping, and third-party disclosure
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.
------------------------------------------------------------------------

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.
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.
------------------------------------------------------------------------

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.
------------------------------------------------------------------------

In the Federal Register of May 1, 2025 (90 FR 18669), we published
a 60-day notice soliciting public comment on the proposed collection of
information. One comment was submitted to the docket suggesting FDA
prohibit xenotransplantation, but proffered no alternative estimates
regarding our assessment of burden associated with the information
collection recommendations set forth in the PHS guideline. We have
therefore made no adjustment to our estimate of burden for the
information collection in response to the public comment, which is as
follows:

Table 4--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
Number of
PHS guideline section Number of responses per Total annual Average burden Total hours
respondents respondent responses per response
----------------------------------------------------------------------------------------------------------------
3.2.7.2 \2\.................... 1 1 1 0.50 (30 minutes) 0.50
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
\2\ FDA is using 1 animal facility or sponsor for estimation purposes.

Table 5--Estimated Annual Recordkeeping Burden\1\
----------------------------------------------------------------------------------------------------------------
Number of
PHS guideline section Number of records per Total annual Average burden Total hours
recordkeepers recordkeeper records per recordkeeping
----------------------------------------------------------------------------------------------------------------
3.2.7 \2\...................... 1 1 1 16............... 16
4.3 \3\........................ 5 1 5 0.75 (45 minutes) 3.75
3.4.2 \4\...................... 5 8.80 44 0.25 (15 minutes) 11
3.4.3.2 \5\.................... 5 2.40 12 0.25 (15 minutes) 3

[[Page 35692]]

3.5.1 \6\...................... 5 0.33 1 0.50 (30 minutes) 0.50
3.5.2 \6\...................... 5 0.33 1 0.25 (15 minutes) 0.25
3.5.4.......................... 5 1 5 0.17 (10 minutes) 0.85
3.6.4 \7\...................... 5 1.60 8 0.25 (15 minutes) 2
3.7 \7\........................ 4 2 8 0.08 (5 minutes). 0.64
4.2.3.2 \8\.................... 4 25 100 0.17 (10 minutes) 17.0
4.2.3.2 \6\.................... 4 0.20 1 0.17 (10 minutes) 0.17
4.2.3.3 and 4.3.2 \6\.......... 4 0.25 1 0.17 (10 minutes) 0.17
4.3.1.......................... 5 1.40 7 0.25 (15 minutes) 1.25
5.2 \9\........................ 5 2.40 12 0.08 (5 minutes). 0.96
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Total...................... ............... ............... ............ ................. 57.54
----------------------------------------------------------------------------------------------------------------
\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 1 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 3 herds per facility x 2 facilities = 36 sentinel animals. There
are approximately 8 source animals per year (see footnote 7 of this table); 36 + 8 = 44 monitoring records to
document.
\5\ Necropsy for animal deaths of unknown cause estimated to be approximately 2 per herd per year x 3 herds per
facility x 2 facilities = 12.
\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 4 recipients annually = 8 source
animals per year. (See footnote 5 of table 6 of this document.)
\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 Total hours
respondents respondent disclosures per disclosure
----------------------------------------------------------------------------------------------------------------
3.2.7.2 \2\................... 1 1 2 0.50 (30 minutes) 1.00
3.4 \3\....................... 2 0.50 1 0.08 (5 minutes). 0.08
3.5.1 \4\..................... 2 0.50 1 0.25 (15 minutes) 0.25
3.5.4 \5\.................... 2 2 4 0.50 (30 minutes) 2.00
3.5.5 \4\..................... 2 0.50 1 0.25 (15 minutes) 0.25
---------------------------------------------------------------------------------
Total..................... ............... ................ ............ ................. 3.58
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
\2\ FDA is using 1 animal facility or sponsor for estimation purposes.
\3\ FDA's records indicate that an average of 2 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 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 of this document, 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.

[[Page 35693]]

Table 7--Collection of Information Required by Current Regulations and
Standards
------------------------------------------------------------------------
21 CFR section
Description of (unless
PHS guideline section collection of otherwise
information activity stated)
------------------------------------------------------------------------
2.2.1.......................... Document off-site 312.52.
collaborations.
2.5............................ Sponsor ensures 312.62(c).
counseling patient +
family + contacts.
3.1.1 and 3.1.6................ Document well- 312.23(a)(7)(a)
characterized health and 211.84.
history and lineage
of source animals.
3.1.8.......................... Registration with and 42 CFR 71.53.
import permit from
the Centers for
Disease Control and
Prevention.
3.2.2.......................... Document 312.52.
collaboration with
accredited
microbiology labs.
3.2.3.......................... Procedures to ensure 9 CFR parts 1,
the humane care of 2, and 3 and
animals. PHS Policy.\1\
3.2.4.......................... Procedures consistent AAALAC
for accreditation by International
the Association for Rules of
Assessment and Accreditation
Accreditation of \2\ and NRC
Laboratory Animal Guide.\3\
Care International
(AAALAC
International) and
consistent with the
National Research
Council's (NRC)
Guide.
3.2.5, 3.4, and 3.4.1.......... Herd health 211.100 and
maintenance and 211.122.
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 211.160(a).
methods.
3.6.1.......................... Procurement and 211.100 and
processing of 211.122.
xenografts using
documented aseptic
conditions.
3.6.2.......................... Develop, implement, 211.84(d) and
and enforce SOP's 211.122(c).
for 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.
4.1.1.......................... Surveillance of 312.23(a)(6)(iii
xenotransplant )(f) and (g),
recipient; sponsor and 312.62(b)
ensures 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 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 312.52.
collaborations
(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 312.57 and
records of receipt, 312.62(b).
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'' (<a href="https://olaw.nih.gov/policies-laws/phs-policy.htm">https://olaw.nih.gov/policies-laws/phs-policy.htm</a>).
\2\ AALAC 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>).
\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 adjusted our burden estimate which
has resulted in a burden increase of 3.09 hours (new total of 62.12
hours) from our previous estimate of 59.03 hours. Change in the
increase in burden was the result of the change of the number of
recordkeepers due to the change in the number submission of IND's
sponsors and a change in the number of animal source facilities.

Dated: July 23, 2025.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2025-14227 Filed 7-28-25; 8:45 am]
BILLING CODE 4164-01-P

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