
[Federal Register Volume 77, Number 115 (Thursday, June 14, 2012)]
[Notices]
[Pages 35683-35687]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2012-14483]


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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.

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SUMMARY: The Food and Drug Administration (FDA) is announcing an 
opportunity for public comment on the proposed collection of certain 
information by the Agency. Under the Paperwork Reduction Act of 1995 
(the 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 August 13, 2012.

ADDRESSES: Submit electronic comments on the collection of information 
to http://www.regulations.gov. Submit written comments on the 
collection of information to the Division of Dockets Management (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. All comments should be identified with the docket 
number found in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT: Ila S. Mizrachi, Office of Information 
Management, Food and Drug Administration, 1350 Piccard Dr., Rockville, 
MD 20850, 301-796-7726, Ila.Mizrachi@fda.hhs.gov.

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: (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. 301 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

[[Page 35684]]

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 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 2 respondents who are sponsors of INDs that 
include protocols for xenotransplantation in humans. 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 
total annual reporting and recordkeeping burden is estimated to be 
approximately 45 hours. 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.
    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 base-line 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 PHS
                            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:

[[Page 35685]]



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


                                                   Table 5--Estimated Annual Recordkeeping Burden \1\
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                                         Number of     Number of records     Total annual
       PHS guideline section           recordkeepers    per recordkeeper       records           Average burden per  recordkeeping        Total hours
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3.2.7 \2\..........................                 1               1                   1    16......................................              16
4.3 \3\............................                 2               1                   2    0.75 (45 minutes).......................               1.50
3.4.2 \4\..........................                 2              16                  32    0.25 (15 minutes).......................               8
3.4.3.2 \5\........................                 2               4                   8    0.25 (15 minutes).......................               2
3.5.1 \6\..........................                 2               0.50                1    0.50 (30 minutes).......................               0.50
3.5.2 \6\..........................                 2               0.50                1    0.25 (15 minutes).......................               0.25
3.5.4..............................                 2               1                   2    0.17 (10 minutes).......................               0.34
3.6.4 \7\..........................                 2               4                   8    0.25 (15 minutes).......................               2
3.7 \7\............................                 4               2                   8.0  0.08 (5 minutes)........................               0.64
4.2.3.2 \8\........................                 2              25                  50    0.17 (10 minutes).......................               8.50
4.2.3.2 \6\........................                 2               0.50                1    0.17 (10 minutes).......................               0.17
4.2.3.3 and 4.3.2 \6\..............                 2               0.50                1    0.17 (10 minutes).......................               0.17
4.3.1..............................                 2               1                   2    0.25 (15 minutes).......................               0.50
5.2 \9\............................                 2               6                  12    0.08 (5 minutes)........................               0.96
                                    --------------------------------------------------------------------------------------------------------------------
    Total..........................  ................  .................  .................  ........................................              41.53
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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 of this document.)
\8\ FDA estimates there are approximately 2 clinical centers doing xenotransplantation procedures x approximately 25 health care workers involved per
  center = 50 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  0.50 (30 minutes).......................               0.50
3.4 \3\.............................                 4               0.50                 2  0.08 (5 minutes)........................               0.16
3.5.1 \4\...........................                 4               0.25                 1  0.25 (15 minutes).......................               0.25
3.5.4 \5\...........................                 4               1                    4  0.50 (30 minutes).......................               2
3.5.5 \4\...........................                 4               0.25                 1  0.25 (15 minutes).......................               0.25
                                     -------------------------------------------------------------------------------------------------------------------
    Total...........................  ................  .................  ................  ........................................               3.16
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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 two 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

[[Page 35686]]

312.160, approved under OMB control number 0910-0014; and; (3) 
information included in a biologics license application, 21 CFR 601.2, 
approved under OMB control number 0910-0338. (Although it is possible 
that a xenotransplantation product may not be regulated as a biological 
product (e.g., it may be regulated as a medical device), FDA believes, 
based on its knowledge and experience with xenotransplantation, that 
any xenotransplantation product subject to FDA regulation within the 
next 3 years will most likely be regulated as a biological product.) 
However, FDA recognized that some of the information collections go 
beyond approved collections; assessments for these burdens are included 
in tables 1 through 6.
    In table 7 of this document, FDA identifies those collection of 
information activities that are already encompassed by existing 
regulations or are consistent with voluntary standards which reflect 
industry's usual and customary business practice.

 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         and 211.84.
                                    health history and
                                    lineage of source
                                    animals.
3.1.8............................  Registration with     42 CFR 71.53.
                                    and import permit
                                    from the Centers
                                    for Disease Control
                                    and Prevention.
3.2.2............................  Document              312.52.
                                    collaboration with
                                    accredited
                                    microbiology labs.
3.2.3............................  Procedures to ensure  9 CFR parts 1,
                                    the humane care of    2, and 3 and
                                    animals.              PHS Policy.\1\
3.2.4............................  Procedures            AAALAC
                                    consistent for        International
                                    accreditation by      Rules of
                                    the Association for   Accreditation
                                    Assessment and        \2\ and NRC
                                    Accreditation of      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           211.100 and
                                    maintenance and       211.122.
                                    surveillance to be
                                    documented,
                                    available, and in
                                    accordance with
                                    documented
                                    procedures; record
                                    standard veterinary
                                    care.
3.2.6............................  Animal facility SOPs  PHS Policy.\1\
3.3.3............................  Validate assay        211.160(a).
                                    methods.
3.6.1............................  Procurement and       211.100 and
                                    processing of         211.122.
                                    xenografts using
                                    documented aseptic
                                    conditions.
3.6.2............................  Develop, implement,   211.84(d) and
                                    and enforce SOP's     211.122(c).
                                    for procurement and
                                    screening processes.
3.6.4............................  Communicate to FDA    312.32(c).
                                    animal necropsy
                                    findings pertinent
                                    to health of
                                    recipient.
3.7.1............................  PHS specimens to be   312.23(a)(6).
                                    linked to health
                                    records; provide to
                                    FDA justification
                                    for types of
                                    tissues, cells, and
                                    plasma, and
                                    quantities of
                                    plasma and
                                    leukocytes
                                    collected.
4.1.1............................  Surveillance of       312.23(a)(6)(ii
                                    xenotransplant        i)(f) and (g),
                                    recipient; sponsor    and 312.62(b)
                                    ensures               and (c).
                                    documentation of
                                    surveillance
                                    program life-long
                                    (justify >2 yrs.);
                                    investigator case
                                    histories (2 yrs.
                                    after investigation
                                    is discontinued).
4.1.2............................  Sponsor to justify    211.122.
                                    amount and type of
                                    reserve samples.
4.1.2.2..........................  System for prompt     312.57(a).
                                    retrieval of PHS
                                    specimens and
                                    linkage to medical
                                    records (recipient
                                    and source animal).
4.1.2.3..........................  Notify FDA of a       312.32.
                                    clinical episode
                                    potentially
                                    representing a
                                    xenogeneic
                                    infection.
4.2.2.1..........................  Document              312.52.
                                    collaborations
                                    (transfer of
                                    obligation).
4.2.3.1..........................  Develop educational   312.50.
                                    materials (sponsor
                                    provides
                                    investigators with
                                    information needed
                                    to conduct
                                    investigation
                                    properly).
4.3..............................  Sponsor to keep       312.57 and
                                    records of receipt,   312.62(b).
                                    shipment, and
                                    disposition of
                                    investigative drug;
                                    investigator to
                                    keep records of
                                    case histories.
------------------------------------------------------------------------
\1\ The ``Public Health Service Policy on Humane Care and Use of
  Laboratory Animals'' (http://www.grants.nih.gov/grants/olaw/references/phspol.htm).
\2\ AAALAC International Rules of Accreditation (http://www.aaalac.org/accreditation/rules.cfm).
\3\ The NRC's ``Guide for the Care and Use of Laboratory Animals.''



[[Page 35687]]

    Dated: June 8, 2012.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2012-14483 Filed 6-13-12; 8:45 am]
BILLING CODE 4160-01-P


