[Federal Register Volume 68, Number 132 (Thursday, July 10, 2003)]
[Notices]
[Pages 41153-41157]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-17407]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2003N-0269]


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 September 8, 2003.

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: JonnaLynn P. 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: (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.

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: (1) The development of 
xenotransplantation clinical protocols, (2) the preparation of 
submissions to FDA, and (3) the

[[Page 41154]]

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 public health needs 
for: (1) A national xenotransplantation database, which is currently 
under development by the PHS; (2) a central PHS biologic specimen 
archive, also under consideration; and (3) the Secretary's Advisory 
Committee on Xenotransplantation, which was developed and has been 
implemented by the Department of Health and Human Services (DHHS). 
These public health programs and the PHS guideline are 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. 
Currently, there are 12 respondents who are sponsors of INDs that 
include protocols for xenotransplantation in humans. Other respondents 
for this collection of information are 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.
------------------------------------------------------------------------


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

[[Page 41155]]

 
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'
4.3.2                         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\
------------------------------------------------------------------------
                                Annual
PHS Guideline      No. of      Frequency     Total    Hours per   Total
   Section      Respondents       per       Annual     Response   Hours
                               Response    Responses
------------------------------------------------------------------------
3.2.7.2\2\     18             0           0           0.5        0
------------------------------------------------------------------------
3.2.7.2\2\     2              1           2           0.5        1.0
------------------------------------------------------------------------
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                                                            7.77
------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs
  associated with this collection of information.
\2\No animal facility and 2 sponsors have ceased operations in the last
  3 years.
\3\FDA's records indicate that an average of 4 INDs are expected to be
  submitted per year.
\4\Has not occurred in the past 3 years and is expected to continue to
  be a rare occurrence.
\5\Based on 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\
----------------------------------------------------------------------------------------------------------------
                                                                      Total
 PHS Guideline            No. of            Annual Frequency per     Annual           Hours per          Total
    Section        [chyph]Recordkeepers     [chyph]Recordkeeping     Records     [chyph]Recordkeeper     Hours
----------------------------------------------------------------------------------------------------------------
3.2.7\2\         1                        1                        1           16                      16.0
----------------------------------------------------------------------------------------------------------------
4.3\3\           12                       1                        12          0.83                    9.96
----------------------------------------------------------------------------------------------------------------
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
----------------------------------------------------------------------------------------------------------------
3.5.4            12                       1                        12          0.17                    2.04
----------------------------------------------------------------------------------------------------------------
3.6.4\7\         12                       2                        24          0.25                    6.0
----------------------------------------------------------------------------------------------------------------

[[Page 41156]]

 
3.7\7\           18                       1.33                     24          0.08                    1.92
----------------------------------------------------------------------------------------------------------------
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          12                       0.08                     (0-1) 1     0.17                    0.17
and 4.3.2\6\
----------------------------------------------------------------------------------------------------------------
4.3.1            12                       1                        12          0.25                    3.0
----------------------------------------------------------------------------------------------------------------
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 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\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. 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 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
    21 CFR         Description of Collection of       (unless otherwise
   Section             Information Activity                stated)
------------------------------------------------------------------------
2.2.1          Document off-site collaborations      312.52
------------------------------------------------------------------------
2.5            Sponsor ensure counseling patient +   312.62(c)
                family + contacts
------------------------------------------------------------------------
3.1.1 and      Document well-characterized health    312.23(a)(7)(a) and
 3.1.6          history and lineage of source         211.84
                animals
------------------------------------------------------------------------
3.1.8          Registration with and import permit   42 CFR 71.53
                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 care  9 CFR parts 1, 2,
                of animals                            and 3 and PHS
                                                      Policy\1\
------------------------------------------------------------------------
3.2.4          Procedures consistent for             AAALAC
                accreditation by the Association      International
                for Assessment and Accreditation of   Rules of
                Laboratory Animal Care                Accreditation\2\
                International (AAALAC                 and NRC Guide\3\
                International) and consistent with
                the National Research Council's
                (NRC) Guide
------------------------------------------------------------------------

[[Page 41157]]

 
3.2.5, 3.4,    Herd health maintenance and           211.100 and 211.122
 and 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 SOPs  211.84(d) and
                for procurement and screening         211.122(c)
                processes
------------------------------------------------------------------------
3.6.4          Communicate to FDA animal necropsy    312.32(c)
                findings pertinent to health of
                recipient
------------------------------------------------------------------------
3.7.1          PHS specimens to be linked to health  312.23(a)(6)
                records; provide to FDA
                justification for types of tissues,
                cells, and plasma, and quantities
                of plasma and leukocytes collected
------------------------------------------------------------------------
4.1.1          Surveillance of xenotransplant        312.23(a)(6)(iii)(f
                recipient; sponsor ensures            ) and (g), and
                documentation of surveillance         312.62(b) and (c)
                program life-long (justify 2 yrs.); investigator case
                histories (2 yrs. after
                investigation is discontinued)
------------------------------------------------------------------------
4.1.2          Sponsor to justify amount and type    211.122
                of reserve samples
------------------------------------------------------------------------
4.1.2.2        System for prompt retrieval of PHS    312.57(a)
                specimens and linkage to medical
                records (recipient and source
                animal)
------------------------------------------------------------------------
4.1.2.3        Notify FDA of a clinical episode      312.32
                potentially representing a
                xenogeneic infection
------------------------------------------------------------------------
4.2.2.1        Document collaborations (transfer of  312.52
                obligation)
------------------------------------------------------------------------
4.2.3.1        Develop educational materials         312.50
                (sponsor provides investigators
                with information needed to conduct
                investigation properly)
------------------------------------------------------------------------
4.3            Sponsor to keep records of receipt,   312.57 and
                shipment, and disposition of          312.62(b)
                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).
  (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: July 2, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-17407 Filed 7-9-03; 8:45 am]
BILLING CODE 4160-01-S