[Federal Register Volume 83, Number 186 (Tuesday, September 25, 2018)]
[Notices]
[Pages 48441-48445]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-20764]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2012-N-0559]


Agency Information Collection Activities; Proposed Collection; 
Comment Request; Public Health Service Guideline on Infectious Disease 
Issues in Xenotransplantation

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
an opportunity for public comment on the proposed collection of certain 
information by the Agency. Under the Paperwork Reduction Act of 1995 
(PRA), Federal Agencies are required to publish notice in the Federal 
Register concerning each proposed collection of information, including 
each proposed extension of an existing collection of information, and 
to allow 60 days for public comment in response to this notice. This 
notice solicits comments on the collection of information contained in 
the Public Health Service (PHS) guideline entitled ``PHS Guideline on 
Infectious Disease Issues in Xenotransplantation'' dated January 19, 
2001.

DATES: Submit either electronic or written comments on the collection 
of information by November 26, 2018.

ADDRESSES: You may submit comments as follows. Please note that late, 
untimely filed comments will not be considered. Electronic comments 
must be submitted on or before November 26, 2018. The https://www.regulations.gov electronic filing system will accept comments until 
midnight Eastern Time at the end of November 26, 2018. Comments 
received by mail/hand delivery/courier (for written/paper submissions) 
will be considered timely if they are postmarked or the delivery 
service acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2012-N-0559 for ``PHS Guideline on Infectious Disease Issues in 
Xenotransplantation.'' Received comments, those filed in a timely 
manner (see ADDRESSES), will be placed in the docket and, except for 
those submitted as ``Confidential Submissions,'' publicly viewable at 
https://www.regulations.gov or at the Dockets Management Staff between 
9 a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.

[[Page 48442]]


FOR FURTHER INFORMATION CONTACT: Ila S. Mizrachi, Office of Operations, 
Food and Drug Administration, Three White Flint North, 10A-12M, 11601 
Landsdown St., North Bethesda, MD 20852, 301-796-7726, 
[email protected].

SUPPLEMENTARY INFORMATION: Under the PRA (44 U.S.C. 3501-3520), Federal 
Agencies must obtain approval from the Office of Management and Budget 
(OMB) for each collection of information they conduct or sponsor. 
``Collection of information'' is defined in 44 U.S.C. 3502(3) and 5 CFR 
1320.3(c) and includes Agency requests or requirements that members of 
the public submit reports, keep records, or provide information to a 
third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A)) 
requires Federal Agencies to provide a 60-day notice in the Federal 
Register concerning each proposed collection of information, including 
each proposed extension of an existing collection of information, 
before submitting the collection to OMB for approval. To comply with 
this requirement, FDA is publishing notice of the proposed collection 
of information set forth in this document.
    With respect to the following collection of information, FDA 
invites comments on these topics: (1) Whether the proposed collection 
of information is necessary for the proper performance of FDA's 
functions, including whether the information will have practical 
utility; (2) the accuracy of FDA's estimate of the burden of the 
proposed collection of information, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information to be collected; and (4) ways 
to minimize the burden of the collection of information on respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.

PHS 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 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.). 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

[[Page 48443]]

xenotransplantation-related INDs and estimates of time required to 
complete the various reporting, recordkeeping, and third-party 
disclosure tasks described in the PHS guideline.
    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.
------------------------------------------------------------------------


                 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    Total hours
                                    respondents     respondent       responses     per response
----------------------------------------------------------------------------------------------------------------
3.2.7.2 \2\.....................               1               1               1            0.50             0.5
                                                                                    (30 minutes)
----------------------------------------------------------------------------------------------------------------
\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            2.25
                                                                                    (45 minutes)
3.4.2 \4\.......................               3           10.67              32            0.25               8
                                                                                    (15 minutes)

[[Page 48444]]

 
3.4.3.2 \5\.....................               3            2.67               8            0.25               2
                                                                                    (15 minutes)
3.5.1 \6\.......................               3            0.33               1            0.50             0.5
                                                                                    (30 minutes)
3.5.2 \6\.......................               3            0.33               1            0.25            0.25
                                                                                    (15 minutes)
3.5.4...........................               3               1               3            0.17            0.51
                                                                                    (10 minutes)
3.6.4 \7\.......................               3            2.67               8            0.25               2
                                                                                    (15 minutes)
3.7 \7\.........................               4               2               8            0.08            0.64
                                                                                     (5 minutes)
4.2.3.2 \8\.....................               5              25             125            0.17           21.25
                                                                                    (10 minutes)
4.2.3.2 \6\.....................               5            0.20               1            0.17            0.17
                                                                                    (10 minutes)
4.2.3.3 and 4.3.2 \6\...........               5            0.20               1            0.17            0.17
                                                                                    (10 minutes)
4.3.1...........................               3               1               3            0.25            0.75
                                                                                    (15 minutes)
5.2 \9\.........................               3               4              12            0.08            0.96
                                                                                     (5 minutes)
                                 -------------------------------------------------------------------------------
    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                        Average
      PHS guideline section          Number of      disclosures    Total annual     burden per      Total hours
                                    respondents   per respondent    disclosures     disclosure
----------------------------------------------------------------------------------------------------------------
3.2.7.2 \2\.....................               1               1               1            0.50             0.5
                                                                                    (30 minutes)
3.4 \3\.........................               4            0.25               1            0.08            0.08
                                                                                     (5 minutes)
3.5.1 \4\.......................               4            0.25               1            0.25            0.25
                                                                                    (15 minutes)
3.5.4 \5\.......................               4               1               4            0.50               2
                                                                                    (30 minutes)
3.5.5 \4\.......................               4            0.25               1            0.25            0.25
                                                                                    (15 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

[[Page 48445]]

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
------------------------------------------------------------------------
                                Description of          21 CFR section
 PHS  guideline  section         collection of        (unless 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) and
                            characterized health      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 collaboration    312.52.
                            with accredited
                            microbiology labs.
3.2.3....................  Procedures to ensure the  9 CFR parts 1, 2,
                            humane care of animals.   and 3 and PHS
                                                      Policy \1\.
3.2.4....................  Procedures consistent     AAALAC
                            for accreditation by      International
                            the Association for       Rules of
                            Assessment and            Accreditation \2\
                            Accreditation of          and NRC Guide \3\.
                            Laboratory Animal 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 maintenance   211.100 and
                            and surveillance to be    211.122.
                            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, and   211.84(d) 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)(f
                            xenotransplant            ) and (g), and
                            recipient; sponsor        312.62(b) and (c).
                            ensures 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 clinical  312.32.
                            episode potentially
                            representing a
                            xenogeneic infection.
4.2.2.1..................  Document collaborations   312.52.
                            (transfer of
                            obligation).
4.2.3.1..................  Develop educational       312.50.
                            materials (sponsor
                            provides investigators
                            with information needed
                            to conduct
                            investigation properly).
4.3......................  Sponsor to keep records   312.57 and
                            of receipt, shipment,     312.62(b).
                            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: September 19, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-20764 Filed 9-24-18; 8:45 am]
 BILLING CODE 4164-01-P


