[Federal Register Volume 65, Number 103 (Friday, May 26, 2000)]
[Notices]
[Pages 34196-34200]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-13340]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 96M-0311]


Agency Information Collection Activities; Proposed Collection; 
Comment Request

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, 
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.''

DATES: Submit written comments on the collection of information by July 
25, 2002.

ADDRESSES: Submit written requests for single copies of the guideline 
entitled ``PHS Guideline on Infectious Disease Issues in 
Xenotransplantation'' to the Office of Communication, Training, and 
Manufacturers Assistance (HFM-40), Center for Biologics Evaluation and 
Research (CBER), Food and Drug Administration, 1401 Rockville Pike, 
Rockville, MD 20852-1448. Send one self-addressed adhesive label to 
assist that office in processing your requests. The document may also 
be obtained by mail by calling the CBER Voice Information System at 1-
800-835-4709 or 301-827-1800, or by fax by calling the FAX Information 
System at 1-888-CBER-FAX or 301-827-3844.
    Submit written comments on the collection of information to the 
Dockets Management Branch (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: Karen L. Nelson, Office of Information 
Resources Management (HFA-250), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-1482.

SUPPLEMENTARY INFORMATION:

I. Background

    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 request 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, 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.

PHS Guideline on Infectious Disease Issues in Xenotransplantation

    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.). This PHS guideline is revised based 
on public comment to a previous document entitled ``Draft Public Health 
Service (PHS) Guideline on Infectious Disease Issues in 
Xenotransplantation (August 1996),'' which published in the Federal 
Register of September 23, 1996 (61 FR 49919). 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

[[Page 34197]]

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 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 pilot national xenotransplant data base, 
which is currently under development by the PHS; (2) a central PHS 
biologic specimen archive; and (3) the Secretary's Advisory Committee 
on Xenotransplantation (SACX), which is being developed and implemented 
by the Department of Health and Human Services (DHHS). These public 
health programs and this PHS guideline are intended to protect the 
public health and help ensure the safety of using xenotransplantation 
products in humans by preventing the introduction, transmission, and 
spread of infectious diseases associated with xenotransplantation.
    Respondents to this collection of information are the sponsors of 
clinical studies of investigational xenotransplantation products under 
investigational new drug applications (IND's) and xenotransplantation 
product procurement centers, referred to as source animal facilities. 
Currently, there are 11 respondents who are sponsors of IND's, which 
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 PHS guideline proposes 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. Although the draft guideline discussed holding 
specimens and records indefinitely, comments described this 
recommendation as impractical and unfeasible.
    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. They 
contain ribonucleic acid that is reverse-transcribed into 
deoxyribonucleic acid (DNA) using an enzyme provided by the virus and 
the cell machinery. That DNA can then be integrated into the 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. If record systems are 
maintained in a computer data base, electronic backups should be kept 
in a secure office facility and backup on hard copy should be routinely 
performed (4.1.2.2). The development of such a record system would be a 
one-time burden. Such a system is intended to cross-reference and 
locate relevant records or recipients, source animals and facilities, 
and specimens of both the recipient and the source animal. Based on 
agency experience in establishing new, small volume, recordkeeping and 
tracking systems, we estimate approximately 16 hours would be necessary 
for each sponsor to set up the records system.
    The total annual reporting and recordkeeping burden is estimated to 
be approximately 327 hours. The burden estimates are based on FDA's 
records of xenotransplantation-related IND's and estimates of time 
required to create an appropriate record system and to complete the 
various reporting and recordkeeping tasks described in the guideline. A 
total of 22 IND's have been submitted since 1994 resulting in an 
average of 4 IND submissions per year. A total of 87 patients have been 
treated over a 3-year period indicating there are on average 29 
xenotransplantation product recipients per year. FDA does not expect 
the level of clinical studies using xenotransplantation to increase 
significantly in the next few years; therefore, the agency is using 
these historical figures in projecting burdens for the next 3 years.
    FDA is requesting OMB approval for the following reporting and 
recordkeeping recommendations in the PHS guideline:

                                       Table 1.--Reporting Recommendations
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 PHS Guideline Section                                         Description
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3.2.7.2                 Notify sponsor or FDA of new archive site when source animal facility or sponsor ceases
                         operations.
3.4                     Standard operating procedures (SOP's) 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.

[[Page 34198]]

 
3.5.5                   Source animal facility to notify clinical center when infectious agent is identified in
                         source animal or herd after xenotransplantation product procurement.
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                                     Table 2.--Recordkeeping Recommendations
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 PHS Guideline Section                                         Description
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3.2.7 and 4.3           Establish records linking each xenotransplantation product recipient with relevant
                         records. 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.
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    FDA estimates the burden for this collection of information as 
follows:

                                 Table 3.--Estimated Annual Reporting Burden\1\
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                                                      Annual
      PHS Guideline Section           No. of       Frequency per   Total Annual      Hours per      Total Hours
                                    Respondents      Response        Responses       Response
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3.2.7.2\2\                             18               0               0               0.5             0
3.2.7.2\2\                             11               0               0               0.5             0
3.4\3\                                 11               0.4             4               0.08            0.3
3.5.1\4\                               11               0.09            1               0.25            0.25
3.5.4\5\                               11               2.6            29               0.5            14.5
3.5.5\4\                               18               0.06            1               0.2             0.2
Total                                                                                                  15.25
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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 to date and none are expected to cease operation in the
  next several years.
\3\ FDA's records indicate that an average of four IND's have been and are expected to be submitted per year.
\4\ Has not occurred in the past 5 years and is expected to continue to be a rare occurrence.
\5\ Based on 87 patients treated over the last 3 years, the average number of xenotransplantation product
  recipients per year is estimated to be 29.


                               Table 4.--Estimated Annual Recordkeeping Burden\1\
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                                                      Annual
      PHS Guideline Section           No. of       Frequency per   Total Annual      Hours per      Total Hours
                                   Recordkeepers   Recordkeeping      Records      Recordkeeper
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3.2.7 and 4.3\2\                       11               1             N/A              16             172
3.4.2\3\                               11              15.1           166               3.77           41.5
3.4.3.2\4\                             18               4.0            72               1.32           23.8
3.5.1\5\                               11               0.09       (0-1)1               0.045           0.5
3.5.2\5\                               11               0.09       (0-1)1               0.023           0.25
3.5.4                                  11               2.6            29               0.45            4.9
3.6.4\6\                               11               5.3            58               1.32           14.5
3.7\6\                                 18               3.2            58               0.26            4.6
4.2.3.2\7\                             11              27.3           300               4.64           51
4.2.3.2\5\                             11               0.09       (0-1)1               0.015           0.17
4.2.3.3 and 4.3.2\5\                   11               0.09       (0-1)1               0.015           0.17
4.3.1                                  11               2.6            29               0.66            7.25
5.2\8\                                 11               7.9            87               0.63            6.96
Total                                                                                                 327.6
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

[[Page 34199]]

 
\2\ A one-time burden for setting up a recordkeeping system which rapidly links information regarding the
  specimen archive, the recipient's medical records, and source animals.
\3\ 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 58 source animals per year (see footnote 6 of this table); 108 + 58 = 166 monitoring records
  to document.
\4\ 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.
\5\ Has not occurred in the past 5 years and is expected to continue to be a rare occurrence.
\6\ 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 29 recipients annually = 58 source
  animals per year. (See footnote 5 of table 3 of this document.)
\7\ FDA estimates there are approximately 12 clinical centers doing xenotransplantation procedures x
  approximately 25 health care workers involved per center = 300 health care workers.
\8\ Fifty-eight source animal records + 29 recipient records = 87 total records.

    Because xenotransplantation is a relatively new area of medical 
science, potential problems and adverse effects are not well known. 
Because of the potential risk for cross-species transmission of 
infectious agents from source animals to patients, their close 
contacts, and the general public and the latency period of known human 
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 small and, therefore, the capital and 
operating costs are expected to be insignificant at this time.
    Many of the information collections described in this guideline are 
not new and can be found under existing regulations and, therefore, are 
not included in the hour burden estimates in tables 1 through 4 of this 
document. These information collections are included under the 
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 601.1 through 
601.3, approved under OMB control number 0910-0124. (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 practice.

                                    Table 5.--Collection of Information Required by Current Regulations and Standards
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                                                                                                                     21 CFR Section (unless otherwise
PHS Guideline  Section                      Description of Collection of Information Activity                                     stated)
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2.2.1                   Document off-site collaborations                                                          312.52
2.5                     Sponsor ensure counseling patient + family + contacts                                     312.62(c)
3.1.1 and 3.1.6         Document well-characterized health history and lineage of source animals                  312.23(a)(7)(a) and 211.84
3.1.8                   Registration with and import permit from the Centers for Disease Control and Prevention   42 CFR 71.53
3.2.2                   Document collaboration with accredited microbiology labs                                  312.52
3.2.3                   Procedures to ensure the humane care of animals                                           9 CFR parts 1, 2, and 3 and PHS
                                                                                                                   Policy\1\
3.2.4                   Procedures consistent for accreditation by the Association for Assessment and             AAALAC International Rules of
                         Accreditation of Laboratory Animal Care International (AAALAC International) and          Accreditation\2\ and NRC Guide\3\
                         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 documented, available, and in accordance   211.100 and 211.122
                         with documented procedures; record standard veterinary care
3.2.6                   Animal facility SOP's                                                                     PHS Policy\1\
3.3.3                   Validate assay methods                                                                    211.160(a)
3.6.1                   Procurement and processing of xenografts using documented aseptic conditions              211.100 and 211.122
3.6.2                   Develop, implement, and enforce SOP's for procurement and screening processes             211.84(d) and 211.122(c)
3.6.4                   Communicate to FDA animal necropsy findings pertinent to health of recipient              312.32(c)
3.7.1                   PHS specimens to be linked to health records; provide to FDA justification for types of   312.23(a)(6)
                         tissues, cells, and plasma, and quantities of plasma and leukocytes collected
4.1.1                   Surveillance of xenotransplant recipient; sponsor ensures documentation of surveillance   312.23(a)(6)(iii)(f) and (g), and
                         program life-long (justify >2 yrs.); investigator case histories (2 yrs. after            312.62(b) and (c)
                         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 linkage to medical records (recipient    312.57(a)
                         and source animal)
4.1.2.3                 Notify FDA of a clinical episode potentially representing a xenogeneic infection          312.32
4.2.2.1                 Document collaborations (transfer of obligation)                                          312.52
4.2.3.1                 Develop educational materials (sponsor provides investigators with information needed to  312.50
                         conduct investigation properly)

[[Page 34200]]

 
4.3                     Sponsor to keep records of receipt, shipment, and disposition of investigative drug;      312.57 and 312.62(b)
                         investigator to  keep records of case histories
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\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/html/rules.html).
\3\ The NRC's ``Guide for the Care and Use of Laboratory Animals'' (1996).

II. Electronic Access

    Persons with access to the Internet may obtain the guideline at 
http://www.fda.gov/cber/guidelines.htm.

    Dated: May 23, 2000.
William K. Hubbard,
Senior Associate Commissioner for Policy, Planning, and Legislation.
[FR Doc. 00-13340 Filed 5-25-00; 8:45 am]
BILLING CODE 4160-01-F