[Federal Register Volume 84, Number 84 (Wednesday, May 1, 2019)]
[Notices]
[Pages 18551-18555]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-08845]


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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, 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 May 31, 
2019.

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: 202-395-7285, or emailed to oira_submission@omb.eop.gov. All 
comments should be identified with the OMB control number 0910-0456. 
Also include the FDA docket number found in brackets in the heading of 
this document.

FOR FURTHER INFORMATION CONTACT: JonnaLynn Capezzuto, Office of 
Operations, Food and Drug Administration, Three White Flint North, 10A-
12M, 11601 Landsdown St., North Bethesda, MD 20852, 301-796-3794, 
PRAStaff@fda.hhs.gov.

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.

[[Page 18552]]

Public Health Service Guideline on 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. 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 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 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 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 September 25, 2018 (83 FR 48441), FDA 
published a 60-day notice requesting public comment on the proposed 
collection of information. No comments were received.
    FDA is 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.
------------------------------------------------------------------------


[[Page 18553]]


                 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 for this collection of information as 
follows:

                                                     Table 4--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                               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   0.50 (30 minutes)........................             0.5
--------------------------------------------------------------------------------------------------------------------------------------------------------
\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                     Average burden
     PHS guideline section         Number of      records per    Total annual          per          Total hours
                                 recordkeepers   recordkeeper       records       recordkeeping
----------------------------------------------------------------------------------------------------------------
3.2.7 \2\.....................               1               1               1  16..............              16
4.3 \3\.......................               3               1               3  0.75 (45                    2.25
                                                                                 minutes).
3.4.2 \4\.....................               3           10.67              32  0.25 (15                       8
                                                                                 minutes).
3.4.3.2 \5\...................               3            2.67               8  0.25 (15                       2
                                                                                 minutes).
3.5.1 \6\.....................               3            0.33               1  0.50 (30                     0.5
                                                                                 minutes).
3.5.2 \6\.....................               3            0.33               1  0.25 (15                    0.25
                                                                                 minutes).
3.5.4.........................               3               1               3  0.17 (10                    0.51
                                                                                 minutes).
3.6.4 \7\.....................               3            2.67               8  0.25 (15                       2
                                                                                 minutes).
3.7 \7\.......................               4               2               8  0.08 (5 minutes)            0.64
4.2.3.2 \8\...................               5              25             125  0.17 (10                   21.25
                                                                                 minutes).
4.2.3.2 \6\...................               5            0.20               1  0.17 (10                    0.17
                                                                                 minutes).
4.2.3.3 and 4.3.2 \6\.........               5            0.20               1  0.17 (10                    0.17
                                                                                 minutes).
4.3.1.........................               3               1               3  0.25 (15                    0.75
                                                                                 minutes).
5.2 \9\.......................               3               4              12  0.08 (5 minutes)            0.96
                               ---------------------------------------------------------------------------------

[[Page 18554]]

 
    Total.....................  ..............  ..............  ..............  ................           55.45
----------------------------------------------------------------------------------------------------------------
\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 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 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    Total annual    Average burden     Total hours
                                  respondents   per respondent    disclosures    per disclosure
----------------------------------------------------------------------------------------------------------------
3.2.7.2 \2\...................               1               1               1  0.50 (30                     0.5
                                                                                 minutes).
3.4 \3\.......................               4            0.25               1  0.08 (5 minutes)            0.08
3.5.1 \4\.....................               4            0.25               1  0.25 (15                    0.25
                                                                                 minutes).
3.5.4 \5\.....................               4               1               4  0.50 (30                       2
                                                                                 minutes).
3.5.5 \4\.....................               4            0.25               1  0.25 (15                    0.25
                                                                                 minutes).
                               ---------------------------------------------------------------------------------
    Total.....................  ..............  ..............  ..............  ................            3.08
----------------------------------------------------------------------------------------------------------------
\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 1 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, 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
------------------------------------------------------------------------
                                                         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.

[[Page 18555]]

 
3.2.2.........................  Document collaboration  312.52.
                                 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 methods  211.160(a).
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 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.
4.1.1.........................  Surveillance of         312.23(a)(6)(iii
                                 xenotransplant          )(f) and (g),
                                 recipient; sponsor      and 312.62(b)
                                 ensures documentation   and (c).
                                 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'' (https://www.grants.nih.gov/grants/olaw/references/phspol.htm).
\2\ AAALAC International Rules of Accreditation (https://www.aaalac.org/accreditation/rules.cfm).
\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.

    Dated: April 26, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-08845 Filed 4-30-19; 8:45 am]
 BILLING CODE 4164-01-P


