[Federal Register Volume 81, Number 17 (Wednesday, January 27, 2016)]
[Notices]
[Pages 4628-4631]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-01638]


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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 
February 26, 2016.

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 [email protected]. 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: FDA PRA Staff, Office of Operations, 
Food and Drug Administration, 8455 Colesville Rd., COLE-14526, Silver 
Spring, MD 20993-0002, [email protected].

SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has 
submitted the following proposed collection of information to OMB for 
review and clearance.

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 
(section 3.2.7.1); (2) aliquots of serum samples from randomly selected 
animal and specific disease investigations (section 3.4.3.1); (3) 
source animal biological specimens designated for PHS use (section 
3.7.1); animal health records (section 3.7.2), including necropsy 
results (section 3.6.4); and (4) recipients' biological specimens 
(section 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

[[Page 4629]]

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

    In the Federal Register of October 5, 2015 (80 FR 60153), FDA 
published a 60-day notice requesting public comment on the proposed 
collection of information. FDA received one comment from the public. 
The comment was supportive of the extended recordkeeping requirements 
in case it would be necessary to track the source of any long-term 
developing infections as result of xenotransplantation.
    FDA estimates the burden for this collection of information as 
follows:

[[Page 4630]]



                                                     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  0.5 (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
          PHS guideline section               Number of      records per    Total annual         Average  burden per  recordkeeping         Total hours
                                            recordkeepers   recordkeeper       records
--------------------------------------------------------------------------------------------------------------------------------------------------------
3.2.7 \2\................................               1               1               1  16...........................................              16
4.3 \3\..................................               3               1               3  0.75 (45 minutes)............................            2.25
3.4.2 \4\................................               3           10.67              32  0.25 (15 minutes)............................               8
3.4.3.2 \5\..............................               3            2.67               8  0.25 (15 minutes)............................               2
3.5.1 \6\................................               3            0.33               1  0.50 (30 minutes)............................             0.5
3.5.2 \6\................................               3            0.33               1  0.25 (15 minutes)............................            0.25
3.5.4....................................               3               1               3  0.17 (10 minutes)............................            0.51
3.6.4 \7\................................               3            2.67               8  0.25 (15 minutes)............................               2
3.7 \7\..................................               4               2               8  0.08 (5 minutes).............................            0.64
4.2.3.2 \8\..............................               5              25             125  0.17 (10 minutes)............................           21.25
4.2.3.2 \6\..............................               5            0.20               1  0.17 (10 minutes)............................            0.17
4.2.3.3 and 4.3.2 \6\....................               5            0.20               1  0.17 (10 minutes)............................            0.17
4.3.1....................................               3               1               3  0.25 (15 minutes)............................            0.75
5.2 \9\..................................               3               4              12  0.08 (5 minutes).............................            0.96
                                          --------------------------------------------------------------------------------------------------------------
    Total................................  ..............  ..............  ..............  .............................................           55.45
--------------------------------------------------------------------------------------------------------------------------------------------------------
\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 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.)
\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
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                              Number of
                                              Number of      disclosures    Total annual
          PHS guideline section              respondents         per         disclosures          Average  burden per  disclosure           Total hours
                                                             respondent
--------------------------------------------------------------------------------------------------------------------------------------------------------
3.2.7.2 \2\..............................               1               1               1  0.5 (30 minutes).............................             0.5
3.4 \3\..................................               4            0.25               1  0.08 (5 minutes).............................            0.08
3.5.1 \4\................................               4            0.25               1  0.25 (15 minutes)............................            0.25
3.5.4 \5\................................               4               1               4  0.5 (30 minutes).............................               2
3.5.5 \4\................................               4            0.25               1  0.25 (15 minutes)............................            0.25
                                          --------------------------------------------------------------------------------------------------------------
    Total................................  ..............  ..............  ..............  .............................................            3.08
--------------------------------------------------------------------------------------------------------------------------------------------------------
\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 1 IND is expected to be submitted per year.
\4\ To our knowledge, has not occurred in the past 3 years and is expected to continue to be a rare occurrence.
\5\ Based on an estimate of 12 patients treated over a 3-year period, the average number of xenotransplantation product recipients per year is estimated
  to be 4.

    Because of the potential risk for cross-species transmission of 
pathogenic persistent virus, the guideline recommends that health 
records be retained for 50 years. Since these records are medical 
records, the retention of such records for up to 50 years is not 
information subject to the PRA (5 CFR 1320.3(h)(5)). Also, because of 
the limited number of clinical studies with small patient populations, 
the number of records is expected to be insignificant at this time.
    Information collections in this guideline not included in tables 1 
through 6 can be found under existing regulations and approved under 
the

[[Page 4631]]

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 collections 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 collection of      21 CFR section  (unless
              PHS guideline section                      information activity             otherwise stated)
----------------------------------------------------------------------------------------------------------------
2.2.1...........................................  Document offsite collaborations..  312.52.
2.5.............................................  Sponsor ensures counseling         312.62(c).
                                                   patient + family + contacts.
3.1.1 and 3.1.6.................................  Document well-characterized        312.23(a)(7)(a) and 211.84.
                                                   health history and lineage of
                                                   source animals.
3.1.8...........................................  Registration with and import       42 CFR 71.53.
                                                   permit from the Centers for
                                                   Disease Control and Prevention.
3.2.2...........................................  Document collaboration with        312.52.
                                                   accredited microbiology labs.
3.2.3...........................................  Procedures to ensure the humane    9 CFR parts 1, 2, and 3 and
                                                   care of animals.                   PHS Policy.\1\
3.2.4...........................................  Procedures consistent for          AAALAC International Rules
                                                   accreditation by the Association   of Accreditation \2\ and
                                                   for Assessment and Accreditation   NRC Guide.\3\
                                                   of 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 and        211.100 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 processing of      211.100 and 211.122.
                                                   xenografts using documented
                                                   aseptic conditions.
3.6.2...........................................  Develop, implement, and enforce    211.84(d) and 211.122(c).
                                                   SOPs for procurement and
                                                   screening processes.
3.6.4...........................................  Communicate to FDA animal          312.32(c).
                                                   necropsy findings pertinent to
                                                   health of recipient.
3.7.1...........................................  PHS specimens to be linked to      312.23(a)(6).
                                                   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 xenotransplant     312.23(a)(6)(iii)(f) and
                                                   recipient; sponsor ensures         (g), and 312.62(b) and
                                                   documentation of surveillance      (c).
                                                   program life-long (justify >2
                                                   yrs.); investigator case
                                                   histories (2 yrs. after
                                                   investigation is discontinued).
4.1.2...........................................  Sponsor to justify amount and      211.122.
                                                   type of reserve samples.
4.1.2.2.........................................  System for prompt retrieval of     312.57(a).
                                                   PHS specimens and linkage to
                                                   medical records (recipient and
                                                   source animal).
4.1.2.3.........................................  Notify FDA of a clinical episode   312.32.
                                                   potentially representing a
                                                   xenogeneic infection.
4.2.2.1.........................................  Document collaborations (transfer  312.52.
                                                   of obligation).
4.2.3.1.........................................  Develop educational materials      312.50.
                                                   (sponsor provides investigators
                                                   with information needed to
                                                   conduct investigation properly).
4.3.............................................  Sponsor to keep records of         312.57 and 312.62(b).
                                                   receipt, 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.''


    Dated: January 22, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-01638 Filed 1-26-16; 8:45 am]
BILLING CODE 4164-01-P