[Federal Register Volume 71, Number 120 (Thursday, June 22, 2006)]
[Notices]
[Pages 35911-35915]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E6-9816]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2006N-0239]


Agency Information Collection Activities; Proposed Collection; 
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 an 
opportunity for public comment on the proposed collection of certain 
information by the agency. Under the Paperwork Reduction Act of 1995 
(the PRA), Federal agencies are required to publish notice in the 
Federal Register concerning each proposed collection of information, 
including each proposed extension of an existing collection of 
information, and to allow 60 days for public comment in response to the 
notice. This notice solicits comments on the collection of information 
contained in the Public Health Service (PHS) guideline entitled ``PHS 
Guideline on Infectious Disease Issues in Xenotransplantation'' dated 
January 19, 2001.

DATES: Submit written or electronic comments on the collection of 
information by August 21, 2006.

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

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

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

[[Page 35912]]

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 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 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 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 which 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
------------------------------------------------------------------------


[[Page 35913]]


                 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\
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                                                           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
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                                                                                                               7.27
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\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\
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                                                           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                  16.0
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4.3\3\                                                              12                   1                    12                0.83                9.96
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3.4.2\4\                                                            12                  11                   132                0.25               33.0
--------------------------------------------------------------------------------------------------------------------------------------------------------
3.4.3.2\5\                                                          18                   4                    72                0.3                21.6
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3.5.1\6\                                                            12                   0.08            (0-1) 1                0.5                 0.5
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3.5.2\6\                                                            12                   0.08            (0-1) 1                0.25                0.25
--------------------------------------------------------------------------------------------------------------------------------------------------------
3.5.4                                                               12                   1                    12                0.17                2.04
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[[Page 35914]]

 
3.6.4\7\                                                            12                   2                    24                0.25                6.0
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3.7\7\                                                              18                   1.33                 24                0.08                1.92
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4.2.3.2\8\                                                          12                  25                   300                0.17               51.0
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4.2.3.2\6\                                                          12                   0.08            (0-1) 1                0.17                0.17
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4.2.3.3 and 4.3.2\6\                                                12                   0.08            (0-1) 1                0.17                0.17
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4.3.1                                                               12                   1                    12                0.25                3.0
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5.2\9\                                                              12                   3                    36                0.08                2.88
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Total                                                                                                                                             148.49
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\1\There are no capital costs or operating and maintenance costs associated with this collection of information.
\2\A one-time burden for new respondents to set up a recordkeeping system linking all relevant records. FDA 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 9/30/2008 under OMB control number 0910-0139; (2) 
``Investigational New Drug Application,'' 21 CFR 312.1 through 312.160, 
approved through 5/31/2009 under OMB control number 0910-0014; and (3) 
information included in a license application, 21 CFR 601.2, approved 
through 9/30/2008 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 
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 which reflect 
industry's usual and customary business practice.

 Table 5.--Collection of Information Required by Current Regulations and
                                Standards
------------------------------------------------------------------------
                                                       21 CFR Section
  PHS Guideline     Description of Collection of     (Unless Otherwise
     Section            Information Activity              Stated)
------------------------------------------------------------------------
2.2.1             Document off-site                312.52
                   collaborations
------------------------------------------------------------------------
2.5               Sponsor ensure counseling        312.62(c)
                   patient, family, and contacts
------------------------------------------------------------------------
3.1.1 and 3.1.6   Document well-characterized      312.23(a)(7)(a) and
                   health history and lineage of    211.84
                   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
                   care of animals                  3 and PHS Policy\1\
------------------------------------------------------------------------

[[Page 35915]]

 
3.2.4             Procedures consistent for        AAALAC international
                   accreditation by the             rules of
                   Association for Assessment and   accreditation\2\ and
                   Accreditation of Laboratory      NRC guide\3\
                   Animal Care International
                   (AAALAC International) and
                   consistent with the National
                   Research Council's (NRC's)
                   guide
------------------------------------------------------------------------
3.2.5, 3.4, and   Herd health maintenance and      211.100 and 211.122
 3.4.1             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
                   SOPs for procurement and         211.122(c)
                   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)
                   recipient; sponsor ensures       and (g), and
                   documentation of surveillance    312.62(b) and (c)
                   program lifelong (justify > 2
                   years (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         312.32
                   episode potentially
                   representing a xenogeneic
                   infection
------------------------------------------------------------------------
4.2.2.1           Document collaborations          312.52
                   (transfer of obligation)
------------------------------------------------------------------------
4.2.3.1           Develop educational 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). (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).


    Dated: June 15, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6-9816 Filed 6-21-06; 8:45 am]
BILLING CODE 4160-01-S