[Federal Register Volume 74, Number 221 (Wednesday, November 18, 2009)]
[Notices]
[Pages 59545-59549]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-27658]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2009-N-0291]


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 
December 18, 2009.

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, or e-mailed 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:  Liz Berbakos, Office of Information 
Management (HFA-710), Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, 301-796-3792, [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.

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 to sponsors general guidance on the 
following topics: (1) The development of xenotransplantation clinical 
protocols, (2) the preparation of submissions to FDA, and (3) the 
conduct of xenotransplantation clinical trials. Also, the collection of 
information will help ensure that the sponsor maintains important 
information in a cross-referenced system that links the relevant 
records of the xenotransplantation product recipient, 
xenotransplantation product, source animal(s), animal procurement 
center, and significant nosocomial exposures. The PHS guideline 
describes an occupational health service program for the protection of 
health care workers involved in xenotransplantation procedures, caring 
for xenotransplantation product recipients,

[[Page 59546]]

and performing associated laboratory testing. The guideline also 
describes a public health need for a national xenotransplantation 
database, which is currently under development by the 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: (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 
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.
    In the Federal Register of July 10, 2009 (74 FR 33260), FDA 
published a notice requesting public comment on the proposed collection 
of information. No comments were received.

                   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).
------------------------------------------------------------------------

[[Page 59547]]

 
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      Keep a log of health care workers' significant
 4.3.2            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 of this collection of information as 
follows:

                                 Table 3.--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
 PHS Guideline        No. of         Annual Frequency       Total Annual        Hours per
    Section        Respondents         per Response          Responses           Response         Total Hours
----------------------------------------------------------------------------------------------------------------
3.2.7.2\2\                      1                  1                     1               0.5                0.5
----------------------------------------------------------------------------------------------------------------
3.4\3\                         12                  0.17                  2               0.08               0.16
----------------------------------------------------------------------------------------------------------------
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                                                                                                       7.11
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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 for
  estimation purposes.
\3\ FDA's records indicate that an average of two INDs are expected to be submitted per year.
\4\ To our knowledge, has not occurred in the past 3 years and is expected to continue to be a rare occurrence.
\5\ Based on an estimate of 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\
----------------------------------------------------------------------------------------------------------------
 PHS Guideline        No. of         Annual Frequency       Total Annual
    Section       Recordkeepers      per Recordkeeping        Records       Hours per  Record     Total Hours
----------------------------------------------------------------------------------------------------------------
3.2.7\2\                        1                  1                     1              16                 16.0
----------------------------------------------------------------------------------------------------------------
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
----------------------------------------------------------------------------------------------------------------
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
----------------------------------------------------------------------------------------------------------------

[[Page 59548]]

 
3.5.4                          12                  1                    12               0.17               2.04
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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
----------------------------------------------------------------------------------------------------------------
4.2.3.2\6\                     12                  0.08            (0-1) 1               0.17               0.17
----------------------------------------------------------------------------------------------------------------
4.2.3.3 and                    12                  0.08            (0-1) 1               0.17               0.17
 4.3.2\6\
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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 one 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 two source animals are used for preparing xenotransplantation product material for one recipient.
  The average number of source animals is 2 source animals per recipient x 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\ Twenty-four 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. Because 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 of this document 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 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 4.
    In table 5 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 5.--Collection of Information Required by Current Regulations and Standards
----------------------------------------------------------------------------------------------------------------
                                                                                       21 CFR Section (unless
  PHS Guideline  Section       Description of Collection of Information Activity          otherwise stated)
----------------------------------------------------------------------------------------------------------------
2.2.1                       Document off-site collaborations                        312.52
----------------------------------------------------------------------------------------------------------------
2.5                         Sponsor ensures counseling patient + family + contacts  312.62(c)
----------------------------------------------------------------------------------------------------------------
3.1.1 and 3.1.6             Document well-characterized health history and lineage  312.23(a)(7)(a) and 211.84
                             of source animals
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3.1.8                       Registration with and import permit from the Centers    42 CFR 71.53
                             for Disease Control and Prevention
----------------------------------------------------------------------------------------------------------------
3.2.2                       Document collaboration with accredited microbiology     312.52
                             labs
----------------------------------------------------------------------------------------------------------------
3.2.3                       Procedures to ensure the humane care of animals         9 CFR parts 1, 2, and 3 and
                                                                                     PHS Policy\1\
----------------------------------------------------------------------------------------------------------------

[[Page 59549]]

 
3.2.4                       Procedures consistent for accreditation by the          AAALAC International Rules
                             Association for Assessment and Accreditation of         of Accreditation\2\ and NRC
                             Laboratory Animal Care International (AAALAC            Guide\3\
                             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 to be          211.100 and 211.122
                             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 using          211.100 and 211.122
                             documented aseptic conditions
----------------------------------------------------------------------------------------------------------------
3.6.2                       Develop, implement, and enforce SOP's for procurement   211.84(d) and 211.122(c)
                             and screening processes
----------------------------------------------------------------------------------------------------------------
3.6.4                       Communicate to FDA animal necropsy findings pertinent   312.32(c)
                             to health of recipient
----------------------------------------------------------------------------------------------------------------
3.7.1                       PHS specimens to be linked to health records; provide   312.23(a)(6)
                             to FDA justification for types of tissues, cells, and
                             plasma, and quantities of plasma and leukocytes
                             collected
----------------------------------------------------------------------------------------------------------------
4.1.1                       Surveillance of xenotransplant recipient; sponsor       312.23(a)(6)(iii)(f) and
                             ensures documentation of surveillance program life-     (a)(6)(iii)(g), and
                             long (justify >2 yrs.); investigator case histories     312.62(b) and (c)
                             (2 yrs. After investigation is discontinued)
----------------------------------------------------------------------------------------------------------------
4.1.2                       Sponsor to justify amount and type of reserve samples   211.122
----------------------------------------------------------------------------------------------------------------
4.1.2.2                     System for prompt retrieval of PHS specimens and        312.57(a)
                             linkage to medical records (recipient and source
                             animal)
----------------------------------------------------------------------------------------------------------------
4.1.2.3                     Notify FDA of a clinical episode potentially            312.32
                             representing a xenogeneic infection
----------------------------------------------------------------------------------------------------------------
4.2.2.1                     Document collaborations (transfer of obligation)        312.52
----------------------------------------------------------------------------------------------------------------
4.2.3.1                     Develop educational materials (sponsor provides         312.50
                             investigators with information needed to conduct
                             investigation properly)
----------------------------------------------------------------------------------------------------------------
4.3                         Sponsor to keep records of receipt, shipment, and       312.57 and 312.62(b)
                             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). (FDA has verified the Web site address, but is not responsible for
  subsequent changes to the Web site after this document publishes in the Federal Register.)
\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 after this
  document publishes in the Federal Register.)
\3\ The NRC's ``Guide for the Care and Use of Laboratory Animals'' (1996).


    Dated: November 12, 2009.
David Horowitz,
Assistant Commissioner for Policy.
[FR Doc. E9-27658 Filed 11-17-09; 8:45 am]
BILLING CODE 4160-01-S