[Federal Register Volume 77, Number 209 (Monday, October 29, 2012)]
[Notices]
[Pages 65560-65564]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2012-26494]


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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.

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

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 (the PRA).

DATES: Fax written comments on the collection of information by 
November 28, 2012.

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: Ila S. Mizrachi, Office of Information 
Management, Food and Drug Administration, 1350 Piccard Dr., PI50-400B, 
Rockville, MD 20850, 301-796-7726, [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 Public Health Service (PHS) Act (42 
U.S.C. 262 and 264) and the provisions of the Federal Food, Drug, and 
Cosmetic Act that apply to drugs (21 U.S.C. 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

[[Page 65561]]

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 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 two 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 that 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 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.

[[Page 65562]]

 
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 sponsor
                                when infectious agent is identified in
                                source animal or herd after
                                xenotransplantation product procurement.
------------------------------------------------------------------------

    In the Federal Register of June 14, 2012 (77 FR 35683), 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 not responsive to the comment request on the four 
specified aspects of the collection of information and did not provide 
any data or explanation that would support a change regarding the 
information collection requirements.
    FDA estimates the burden for this collection of information as 
follows:

                                 Table 4--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                    No. of
     PHS Guideline section          No. of       responses per   Total annual    Average burden     Total hours
                                  respondents     respondent       responses      per response
----------------------------------------------------------------------------------------------------------------
3.2.7.2 \2\...................               1               1               1  0.50 (30                    0.50
                                                                                 minutes).
----------------------------------------------------------------------------------------------------------------
\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\
----------------------------------------------------------------------------------------------------------------
                                                    No. of                       Average burden
     PHS Guideline section          No. of        records per    Total annual          per          Total hours
                                 recordkeepers   recordkeeper       records       recordkeeping
----------------------------------------------------------------------------------------------------------------
3.2.7 \2\.....................               1               1               1  16..............              16
4.3 \3\.......................               2               1               2  0.75 (45                    1.50
                                                                                 minutes).
3.4.2 \4\.....................               2              16              32  0.25 (15                       8
                                                                                 minutes).
3.4.3.2 \5\...................               2               4               8  0.25 (15                       2
                                                                                 minutes).
3.5.1 \6\.....................               2            0.50               1  0.50 (30                    0.50
                                                                                 minutes).
3.5.2 \6\.....................               2            0.50               1  0.25 (15                    0.25
                                                                                 minutes).
3.5.4.........................               2               1               2  0.17 (10                    0.34
                                                                                 minutes).
3.6.4 \7\.....................               2               4               8  0.25 (15                       2
                                                                                 minutes).
3.7 \7\.......................               4               2             8.0  0.08 (5 minutes)            0.64
4.2.3.2 \8\...................               2              25              50  0.17 (10                    8.50
                                                                                 minutes).
4.2.3.2 \6\...................               2            0.50               1  0.17 (10                    0.17
                                                                                 minutes).
4.2.3.3 and 4.3.2 \6\.........               2            0.50               1  0.17 (10                    0.17
                                                                                 minutes).
4.3.1.........................               2               1               2  0.25 (15                    0.50
                                                                                 minutes).
5.2 \9\.......................               2               6              12  0.08 (5 minutes)            0.96
                                                                                                 ---------------
    Total.....................  ..............  ..............  ..............  ................           41.53
----------------------------------------------------------------------------------------------------------------
\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 overage 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 3 of this document.)
\8\ FDA estimate there re approximately 2 clinical centers doing xenotransplantation procedure x approximately
  25 health care workers involved per center = 50 health care workers.
\9\ Eight source animal records + 4 recipient records = 12 total records.


[[Page 65563]]


                           Table 6--Estimated Annual Third-Party Disclosure Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                    No. of
     PHS Guideline section          No. of        disclosures    Total annual    Average burden     Total hours
                                  respondents   per respondent    disclosures    per disclosure
----------------------------------------------------------------------------------------------------------------
3.2.7.2 \2\...................               1            1                  1  0.50 (30                    0.50
                                                                                 minutes).
3.4 \3\.......................               4            0.50               2  0.08 (5 minutes)            0.16
3.5.1 \4\.....................               4            0.25               1  0.25 (15                    0.25
                                                                                 minutes).
3.5.4 \5\.....................               4            1                  4  0.50 (30                    2
                                                                                 minutes).
3.5.5 \4\.....................               4            0.25               1  0.25 (15                    0.25
                                                                                 minutes).
                                                                                                 ---------------
    Total.....................  ..............  ..............  ..............  ................            3.16
----------------------------------------------------------------------------------------------------------------
\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 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
  produce recipients per year is estimated to be 4.

    Because of the potential risk for cross-species transmission of 
pathogenic persistent virus, the guideline recommends that health 
records be retained for 50 years. Since these records are medical 
records, the retention of such records for up to 50 years is not 
information subject to the PRA (5 CFR 1320.3(h)(5)). Also, because of 
the limited number of clinical studies with small patient populations, 
the number of records is expected to be insignificant at this time.
    Information collections in this guideline not included in tables 1 
through 6 can be found under existing regulations and approved under 
the OMB control numbers as follows: (1) ``Current Good Manufacturing 
Practice for Finished Pharmaceuticals,'' 21 CFR 211.1 through 211.208, 
approved under OMB control number 0910-0139; (2) ``Investigational New 
Drug Application,'' 21 CFR 312.1 through 312.160, approved under OMB 
control number 0910-0014; and; (3) information included in a biologics 
license application, 21 CFR 601.2, approved under OMB control number 
0910-0338. (Although it is possible that a xenotransplantation product 
may not be regulated as a biological product (e.g., it may be regulated 
as a medical device), FDA believes, based on its knowledge and 
experience with xenotransplantation, that any xenotransplantation 
product subject to FDA regulation within the next 3 years will most 
likely be regulated as a biological product.) However, FDA recognized 
that some of the information collections go beyond approved 
collections; assessments for these burdens are included in tables 1 
through 6.
    In table 7 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
----------------------------------------------------------------------------------------------------------------
                                        Description of collection of information      21 CFR Section (unless
         PHS Guideline section                          activity                         otherwise stated)
----------------------------------------------------------------------------------------------------------------
2.2.1.................................  Document offsite collaborations.........  312.52
2.5...................................  Sponsor ensures counseling patient +      312.62(c)
                                         family + contacts..
3.1.1 and 3.1.6.......................  Document well-characterized health        312.23(a)(7)(a) and 211.84
                                         history and lineage of source animals.
3.1.8.................................  Registration with and import permit from  42 CFR 71.53
                                         the Centers for Disease Control and
                                         Prevention.
3.2.2.................................  Document collaboration with accredited    312.52
                                         microbiology labs..
3.2.3.................................  Procedures to ensure the humane care of   9 CFR parts 1, 2, and 3 and
                                         animals..                                 PHS Policy \1\
3.2.4.................................  Procedures consistent for accreditation   AAALAC International Rules of
                                         by the Association for Assessment and     Accreditation \2\ and NRC
                                         Accreditation of Laboratory Animal Care   Guide \3\
                                         International (AAALAC International)
                                         and consistent with the National
                                         Research Council's (NRC) Guide.
3.2.5, 3.4, and 3.4.1.................  Herd health maintenance and surveillance  211.100 and 211.122
                                         to be documented, available, and in
                                         accordance with documented procedures;
                                         record standard veterinary care.
3.2.6.................................  Animal facility SOPs....................  PHS Policy \1\
3.3.3.................................  Validate assay methods..................  211.160(a)
3.6.1.................................  Procurement and processing of xenografts  211.100 and 211.122
                                         using documented aseptic conditions.
3.6.2.................................  Develop, implement, and enforce SOPs for  211.84(d) and 211.122(c)
                                         procurement and screening processes.
3.6.4.................................  Communicate to FDA animal necropsy        312.32(c)
                                         findings pertinent to health of
                                         recipient.
3.7.1.................................  PHS specimens to be linked to health      312.23(a)(6)
                                         records; provide to FDA justification
                                         for types of tissues, cells, and
                                         plasma, and quantities of plasma and
                                         leukocytes collected.
4.1.1.................................  Surveillance of xenotransplant            312.23(a)(6)(iii)(f) and (g),
                                         recipient; sponsor ensures                and 312.62(b) and (c)
                                         documentation of surveillance program
                                         life-long (justify >2 years);
                                         investigator case histories (2 years
                                         after investigation is discontinued).

[[Page 65564]]

 
4.1.2.................................  Sponsor to justify amount and type of     211.122
                                         reserve samples..
4.1.2.2...............................  System for prompt retrieval of PHS        312.57(a)
                                         specimens and linkage to medical
                                         records (recipient and source animal).
4.1.2.3...............................  Notify FDA of a clinical episode          312.32
                                         potentially representing a xenogeneic
                                         infection.
4.2.2.1...............................  Document collaborations (transfer of      312.52
                                         obligation)..
4.2.3.1...............................  Develop educational materials (sponsor    312.50
                                         provides investigators with information
                                         needed to conduct investigation
                                         properly)..
4.3...................................  Sponsor to keep records of receipt,       312.57 and 312.62(b)
                                         shipment, and disposition of
                                         investigative drug; investigator to
                                         keep records of case histories.
----------------------------------------------------------------------------------------------------------------
\1\ The ``Public Health Service Policy on Humane Care and Use of Laboratory Animals'' (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: October 22, 2012.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2012-26494 Filed 10-26-12; 8:45 am]
BILLING CODE 4160-01-P