[Federal Register Volume 71, Number 210 (Tuesday, October 31, 2006)]
[Notices]
[Pages 63768-63772]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E6-18203]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2006N-0239]


Agency Information Collection Activities; Submission for Office 
of Management and Budget Review; Comment Request; 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 
November 30, 2006.

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: 202-395-6974.

FOR FURTHER INFORMATION CONTACT: Jonna Capezzuto, Office of the Chief 
Information Officer (HFA-250), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-4659.

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.

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 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 to sponsors in the following ways: (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 guideline also describes a public health need 
for a national xenotransplantation database, which is currently under 
development by PHS. 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 the following information, as 
recommended by the specific PHS guideline sections: (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 (RNA) 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

[[Page 63769]]

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 12 respondents who are sponsors of INDs that 
include protocols for xenotransplantation in humans. Other respondents 
for this collection of information are an estimated 18 source animal 
facilities that provide source xenotransplantation product material to 
sponsors for use in human xenotransplantation procedures. These 18 
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 156 hours. The burden estimates are based on FDA's 
records of xenotransplantation-related INDs and estimates of time 
required to complete the various reporting and recordkeeping tasks 
described in the guideline. FDA does not expect the level of clinical 
studies using xenotransplantation to increase significantly in the next 
few years.
    FDA is requesting an extension of OMB approval for the following 
reporting and recordkeeping 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
------------------------------------------------------------------------
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
------------------------------------------------------------------------


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

    FDA estimates the burden for this collection of information as 
follows:

                                                     Table 3.--Estimated Annual Reporting Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                           No. of       Annual Frequency  per     Total Annual         Hours per
               PHS Guideline Section                    Respondents            Response            Responses           Response           Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
3.2.7.2\2\                                                           1                  1                      1               0.5                 0.5
--------------------------------------------------------------------------------------------------------------------------------------------------------
3.4\3\                                                              12                  0.33                   4               0.08                0.32
--------------------------------------------------------------------------------------------------------------------------------------------------------
3.5.1\4\                                                            12                  0.08             (0-1) 1               0.25                0.25
--------------------------------------------------------------------------------------------------------------------------------------------------------
3.5.4\5\                                                            12                  1                     12               0.5                 6.0
--------------------------------------------------------------------------------------------------------------------------------------------------------
3.5.5\4\                                                            18                  0.06             (0-1) 1               0.2                 0.2
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 63770]]

 
Total                                                                                                                                              7.27
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.
\2\No animal facility or sponsor has ceased operations in the last 3 years, however, we are using 1 respondent for estimation purposes.
\3\FDA's records indicate that an average of 4 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 36 patients treated over a 3 year period, the average number of xenotransplantation product recipients per year is estimated
  to be 12.


                                                   Table 4.--Estimated Annual Recordkeeping Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                           No. of       Annual Frequency  per     Total Annual
               PHS Guideline Section                   Recordkeepers        Recordkeeping           Records        Hours per  Record      Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
3.2.7\2\                                                             1                  1                      1              16                  16
--------------------------------------------------------------------------------------------------------------------------------------------------------
4.3\3\                                                              12                  1                     12               0.83                9.96
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3.4.2\4\                                                            12                 11                    132               0.25               33
--------------------------------------------------------------------------------------------------------------------------------------------------------
3.4.3.2\5\                                                          18                  4                     72               0.3                21.6
--------------------------------------------------------------------------------------------------------------------------------------------------------
3.5.1\6\                                                            12                  0.08             (0-1) 1               0.5                 0.5
--------------------------------------------------------------------------------------------------------------------------------------------------------
3.5.2\6\                                                            12                  0.08             (0-1) 1               0.25                0.25
--------------------------------------------------------------------------------------------------------------------------------------------------------
3.5.4                                                               12                  1                     12               0.17                2.04
--------------------------------------------------------------------------------------------------------------------------------------------------------
3.6.4\7\                                                            12                  2                     24               0.25                6
--------------------------------------------------------------------------------------------------------------------------------------------------------
3.7\7\                                                              18                  1.33                  24               0.08                1.92
--------------------------------------------------------------------------------------------------------------------------------------------------------
4.2.3.2\8\                                                          12                 25                    300               0.17               51
--------------------------------------------------------------------------------------------------------------------------------------------------------
4.2.3.2\6\                                                          12                  0.08             (0-1) 1               0.17                0.17
--------------------------------------------------------------------------------------------------------------------------------------------------------
4.2.3.3 and 4.3.2\6\                                                12                  0.08             (0-1) 1               0.17                0.17
--------------------------------------------------------------------------------------------------------------------------------------------------------
4.3.1                                                               12                  1                     12               0.25                3
--------------------------------------------------------------------------------------------------------------------------------------------------------
5.2\9\                                                              12                  3                     36               0.08                2.88
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                                                                                                            148.49
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.
\2\A 1-time burden for new respondents to set up a recordkeeping system linking all relevant records. FDA estimates 1 new sponsor annually.
\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 18 facilities = 108 sentinel animals. There are approximately 24 source animals per year (see footnote 7 of this table); 108 + 24 = 132
  monitoring records to document.
\5\Necropsy for animal deaths of unknown cause estimated to be approximately 4 per herd per year x 1 herd per facility x 18 facilities = 72.
\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 12 recipients annually = 24 source animals per year (see footnote 5 of table 3 of this document).
\8\FDA estimates there are approximately 12 clinical centers doing xenotransplantation procedures x approximately 25 health care workers involved per
  center = 300 health care workers.
\9\24 source animal records + 12 recipient records = 36 total records.

    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 4 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 through September 30, 2008, under OMB control number 0910-
0139; (2) ``Investigational New Drug Application,'' 21 CFR 312.1 
through 312.160, approved through May 31, 2009, under OMB control 
number 0910-0014; and (3) information included in a license 
application, 21 CFR 601.2, approved through September 30, 2008, 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

[[Page 63771]]

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 4.
    In table 5 of this document, FDA identifies those information 
collection activities that are already encompassed by existing 
regulations or are consistent with voluntary standards that reflect 
industry's usual and customary business practice.

 Table 5.--Collection of Information Required by Current Regulations and
                                Standards
------------------------------------------------------------------------
                             Description of
 PHS Guideline Section       Collection of        21 CFR Section (Unless
                          Information Activity      Otherwise Stated)
------------------------------------------------------------------------
2.2.1                   Document off-site                         312.52
                         collaborations
------------------------------------------------------------------------
2.5                     Sponsor ensure                         312.62(c)
                         counseling patient,
                         family, and contacts
------------------------------------------------------------------------
3.1.1 and 3.1.6         Document well-               312.23(a)(7)(a) and
                         characterized health                     211.84
                         history and lineage of
                         source animals
------------------------------------------------------------------------
3.1.8                   Registration with and               42 CFR 71.53
                         import permit from the
                         Centers for Disease
                         Control and Prevention
------------------------------------------------------------------------
3.2.2                   Document collaboration                    312.52
                         with accredited
                         microbiology labs
------------------------------------------------------------------------
3.2.3                   Procedures to ensure     9 CFR parts 1, 2, and 3
                         the humane care of            and PHS Policy\1\
                         animals
------------------------------------------------------------------------
3.2.4                   Procedures consistent       AAALAC international
                         for accreditation by                   rules of
                         the Association for        accreditation\2\ and
                         Assessment and                     NRC guide\3\
                         Accreditation of
                         Laboratory Animal Care
                         International (AAALAC
                         International) and
                         consistent with the
                         National Research
                         Council's (NRC's)
                         guide
------------------------------------------------------------------------
3.2.5, 3.4, and 3.4.1   Herd health maintenance      211.100 and 211.122
                         and surveillance to be
                         documented, available,
                         and in accordance with
                         documented procedures;
                         record standard
                         veterinary care
------------------------------------------------------------------------
3.2.6                   Animal facility SOPs               PHS Policy\1\
------------------------------------------------------------------------
3.3.3                   Validate assay methods                211.160(a)
------------------------------------------------------------------------
3.6.1                   Procurement and              211.100 and 211.122
                         processing of
                         xenografts using
                         documented aseptic
                         conditions
------------------------------------------------------------------------
3.6.2                   Develop, implement, and            211.84(d) and
                         enforce SOPs for                     211.122(c)
                         procurement and
                         screening processes
------------------------------------------------------------------------
3.6.4                   Communicate to FDA                     312.32(c)
                         animal necropsy
                         findings pertinent to
                         health of recipient
------------------------------------------------------------------------
3.7.1                   PHS specimens to be                 312.23(a)(6)
                         linked to health
                         records; provide to
                         FDA justification for
                         types of tissues,
                         cells, and plasma, and
                         quantities of plasma
                         and leukocytes
                         collected
------------------------------------------------------------------------
4.1.1                   Surveillance of             312.23(a)(6)(iii)(f)
                         xenotransplant           and (g), and 312.62(b)
                         recipient; sponsor                      and (c)
                         ensures documentation
                         of surveillance
                         program lifelong
                         (justify > 2 years
                         (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 collaborations                   312.52
                         (transfer of
                         obligation)
------------------------------------------------------------------------
4.2.3.1                 Develop educational                       312.50
                         materials (sponsor
                         provides investigators
                         with information
                         needed to conduct
                         investigation
                         properly)
------------------------------------------------------------------------
4.3                     Sponsor to keep records     312.57 and 312.62(b)
                         of 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). (FDA has verified the Web site address, but
  is not responsible for subsequent changes to the Web site address
  after this document publishes in the Federal Register.)
\3\NRC's ``Guide for the Care and Use of Laboratory Animals'' (1996).


[[Page 63772]]

    In the Federal Register of June 22, 2006 (71 FR 35911), FDA 
published a 60-day notice requesting public comment on the information 
collection provisions. No comments were received.

    Dated: October 24, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6-18203 Filed 10-30-06; 8:45 am]
BILLING CODE 4160-01-S