[Federal Register Volume 87, Number 79 (Monday, April 25, 2022)]
[Notices]
[Pages 24316-24320]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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 https://www.reginfo.gov/public/do/PRAMain. 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, 
[email protected].

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: https://www.fda.gov/media/73803/download. 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
------------------------------------------------------------------------
    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.
------------------------------------------------------------------------

    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
--------------------------------------------------------------------------------------------------------------------------------------------------------
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
--------------------------------------------------------------------------------------------------------------------------------------------------------
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
                                        ----------------------------------------------------------------------------------------------------------------
    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\
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                                                                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
                                        ----------------------------------------------------------------------------------------------------------------
    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.
----------------------------------------------------------------------------------------------------------------
\1\ The ``Public Health Service Policy on Humane Care and Use of Laboratory Animals'' (https://olaw.nih.gov/policies-laws/phs-policy.htm).
\2\ AAALAC International Rules of Accreditation (https://www.aaalac.org/accreditation-program/rules-of-accreditation/ 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