[Federal Register Volume 65, Number 202 (Wednesday, October 18, 2000)]
[Notices]
[Pages 62359-62363]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-26671]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 96M-0311]


Agency Information Collection Activities; Submission for OMB 
Review; Comment Request; Public Health Service (PHS) Guideline on 
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 the 
proposed collection of information listed below has been submitted to 
the Office of Management and Budget (OMB) for review and clearance 
under the Paperwork Reduction Act of 1995 (the PRA).

DATES: Submit written comments on the collection of information by 
November 17, 2000.

ADDRESSES: Submit written comments on the collection of information to 
the Office of Information and Regulatory Affairs, OMB, New Executive 
Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn: 
Wendy Taylor, Desk Officer for FDA.

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

SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has 
submitted the following proposed collection of information to OMB for 
review and clearance.

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 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 PHS guideline also 
describes public health needs for: (1) A pilot national xenotransplant 
data base, which is currently under development by PHS; (2) a central 
PHS biologic specimen archive; and (3) the Secretary's Advisory 
Committee on Xenotransplantation, which is being developed and 
implemented by the Department of Health and Human Services. 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

[[Page 62360]]

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 PHS 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 (HTLV) 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 343 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 PHS 
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 number 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.
    In the Federal Register of May 26, 2000 (65 FR 34196), FDA, on 
behalf of PHS, published a 60-day notice for public comment on the 
proposed collection of information provisions in the PHS guideline on 
infectious disease issues in xenotransplantation. FDA received four 
letters of comment in response to the notice. One of the letters did 
not provide any comments on the information collection provisions. PHS 
is responding below to those comments which address information 
collection issues. Other comments, not related to the proposed 
information collection provisions, will be considered by PHS in future 
revisions of the guideline.
    Two comments addressed the PHS guideline recommendation that 
records be retained for 50 years.
    (Comment 1) One comment stated that although the need for record 
retention is very important, the retention of records for 50 years 
would be an undue burden on a sponsor.
    (Comment 2) The other comment stated that, in view of rapidly 
changing technology that would require conversion of data whenever 
newer computer systems are acquired, the retention period would 
constitute an undue burden because of the difficulty of maintaining 
linked, computerized data throughout this period of time.
    The 50-year retention period is intended to assist health care 
practitioners and public health officials in infectious disease 
surveillance and in tracking the source of an infection, disease, or 
illness that might emerge in the xenotransplantation product recipient, 
the source animal, or the animal herd or colony following 
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 
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 of these human viruses can also be transmitted 
among individuals through intimate contact with human body fluids. For 
example, HIV and HTLV are human retroviruses that 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).
    As new computer data systems are developed, both software and 
hardware manufacturers typically provide for the transfer or conversion 
of existing data into a new system. With today's rapidly developing 
information technology, such transfers and conversions are usual and 
customary practice. It is the responsibility of the sponsor to ensure 
that all data are appropriately transferred to, and retrievable from, 
their new/updated computer systems. Because of the need for the long-
term monitoring of the health of xenotransplantation product recipients 
and source animals, a sponsor should ensure that these data remain 
compatible with the computerized data systems that will be used during 
the 50-year retention period.

[[Page 62361]]

    Two comments addressed the submission of information to a national 
xenotransplantation data base.
    (Comment 3) One comment stated that it would be redundant to 
maintain records for 50 years and submit the same information to the 
National Xenotransplantation Database (NXD).
    (Comment 4) The other comment stated that it would constitute an 
additional burden to submit information to the NXD for companies that 
already submit these data to FDA.
    The NXD is not operational, but rather is in a pilot phase at this 
time. In developing this data base, PHS will make an effort, whenever 
possible, to avoid the imposition of any redundant or excess paperwork 
requirements. The public will be offered an opportunity to comment on 
any information collection burdens associated with the NXD prior to 
implementation. Sponsors should, however, recognize that they should 
maintain information that goes beyond what may be proposed for 
submission to the NXD. Such information includes, for example, personal 
identifiers that would enable PHS to contact specific individuals in 
case of a public health emergency, information on recipient contacts 
and health care workers, detailed information on the 
xenotransplantation procedure, and detailed information on husbandry of 
the source animal. Finally, because sponsors will need to monitor 
patient health over time, retention of records that are more complete 
than data submitted to the NXD will be necessary.
    (Comment 5) One comment stated that under sections 3.4.1 and 
3.4.3.2, all incidents that affect herd or colony health that are 
recorded by a source animal facility should also be reported to FDA.
    PHS agrees that in some cases incidents affecting animal herd or 
colony health should be reported to FDA. For example, under 
Sec. 312.32(c)(1)(i)(B) (21 CFR 312.32(c)(1)(i)(B)), a sponsor must 
notify FDA and all participating investigators of ``[a]ny finding from 
laboratory animals that suggests a significant risk for human subjects 
* * *'' Thus, if a health event in the source herd or colony suggests 
that recipients of xenotransplantation products from the source animals 
in that herd/colony may be at significant risk, the health event must 
be reported to FDA. However, as with any herd of animals, many health 
events may occur, such as injuries and minor illnesses. These events 
should be assessed, as appropriate, to determine whether there are any 
health implications for the xenotransplantation product recipients. 
Primary responsibility for designing and monitoring the conduct of 
xenotransplantation clinical trial rests with the sponsor (e.g., 21 CFR 
312.23(a)(6)(iii)(d) and 312.50). As part of the sponsor's 
responsibility when filing an IND, procedures should be developed to 
identify incidents that negatively affect the health of the herd or 
colony. This information is relevant to the safety review of every 
xenotransplantation product application. Such information, as well as 
the procedures to collect the information, should be reported to FDA. 
PHS has revised the guideline in section 3 to note the requirements for 
developing such procedures and for submitting the procedures to FDA.
    (Comment 6) One comment stated that under section 2.5.7, clinical 
investigators should report to FDA any serious or unexplained illnesses 
of xenotransplantation product recipients that are reported to them.
    PHS agrees that serious or unexplained illnesses should be reported 
but they should be reported by the sponsor rather than by the clinical 
investigator. For example, under Sec. 312.32(c)(1)(i)(A), a sponsor 
must notify FDA and all participating investigators of any adverse 
experience associated with the use of an investigational product that 
is both serious and unexpected. The sponsor is in the best position to 
evaluate such events and determine the implications of the event for 
the safety of the xenotransplantation product and any potential impact 
such product may have on the clinical study.
    FDA is requesting OMB approval for the following reporting and 
recordkeeping recommendations in the PHS guideline, except as noted:

                   Table 1.--Reporting Recommendations
------------------------------------------------------------------------
   PHS Guideline
      Section                            Description
------------------------------------------------------------------------
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.
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.--Reporting Recommendations
------------------------------------------------------------------------
   PHS Guideline
      Section                            Description
------------------------------------------------------------------------
3.2.3\1\             Procedures to ensure the humane care of animals.
3.2.4\2\             Incorporate procedures consistent with
                      accreditation by the Association for Assessment
                      and Accreditation of Laboratory Animal Care
                      International (AAALAC International) and
                      consistent with the National Research Council's
                      (NRC's) Guide.
3.2.6\3\             Animal facility SOP's should be described.
3.2.7 and 4.3        Establish records linking each xenotransplantation
                      product recipient with relevant records, including
                      SOP's of animal procurement, facility herd health
                      surveillance, and lifelong health history of
                      source animal. Maintain cross-referenced system
                      that links all relevant records (recipient,
                      product, source animal, animal procurement center,
                      and significant 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                Document justification for 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.

[[Page 62362]]

 
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 baseline 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.
------------------------------------------------------------------------
\1\ These procedures are set forth in 9 CFR parts 1, 2, and 3 and the
  ``Public Health Service Policy on Humane Care and Use of Laboratory
  Animals'' (http://www.grants.nih.gov/grants/olaw/references/phspol.htm) and are considered usual and customary practice.
\2\ These procedures are set forth in the AAALAC International Rules of
  Accreditation (http://www.aaalac.org) and the NRC's ``Guide for the
  Care and Use of Laboratory Animals'' (1996) and are considered usual
  and customary practice.
\3\ These  procedures  are  set  forth  in  the  ``Public  Health  Servi
  ce  Policy  on  Humane  Care  and  Use  of  Laboratory  Animals''  (http://www.grants.nih.gov/grants/olaw/references/phspol.htm) and are
  considered usual and customary practice.

    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
----------------------------------------------------------------------------------------------------------------
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
----------------------------------------------------------------------------------------------------------------
\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
----------------------------------------------------------------------------------------------------------------
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
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
\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.)

[[Page 62363]]

 
\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, they are not considered ``information'' as that term is 
defined under 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 601.2, approved 
under OMB control number 0910-0427. (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 expects, 
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.)

                         Table 5.--Collections of Information Under Current Regulations
----------------------------------------------------------------------------------------------------------------
   PHS Guideline                                                                       21 CFR Section (unless
      Section              Description of Collection of Information Activity              otherwise stated)
----------------------------------------------------------------------------------------------------------------
2.2.1               Document offsite 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       312.23(a)(7)(iv)(a) and
                     source animals.                                                 211.84
3.1.8               Registration with and import permit from the Centers for        42 CFR 71.53
                     Disease Control and Prevention.
3.2.2               Document collaboration with accredited microbiology labs.       312.52
3.2.5, 3.4, and     Herd health maintenance and surveillance to be documented,      211.100 and 211.122
 3.4.1               available, and in accordance with documented procedures;
                     record standard veterinary care.
3.3.3               Validate assay methods.                                         211.160(a)
3.6.1               Procurement and processing of xenografts using documented       211.100 and 211.122
                     aseptic conditions.
3.6.2               Develop, implement, and enforce SOP's for procurement and       211.84(d) and 211.122(c)
                     screening processes.
3.6.4               Communicate to FDA animal necropsy findings pertinent to        312.32(c)
                     health of recipient.
3.7.1               PHS specimens to be linked to health records; provide to FDA    312.23(a)(6)
                     justification for types of tissues, cells, and plasma, and
                     quantities of plasma and leukocytes collected.
4.1.1               Surveillance of xenotransplant recipient; sponsor ensures       312.23(a)(6)(iii)(f) and
                     documentation of surveillance program life-long (justify > 2    (g), and 312.62(b) and (c)
                     yrs.); investigator case histories (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 linkage to     312.57(a)
                     medical records (recipient and source animal).
4.1.2.3             Notify FDA of a clinical episode potentially representing a     312.32
                     xenogeneic infection.
4.2.2.1             Document collaborations (transfer of obligation).               312.52
4.2.3.1             Develop educational materials (sponsor provides investigators   312.50
                     with information needed to conduct investigation properly).
4.3                 Sponsor to keep records of receipt, shipment, and disposition   312.57 and 312.62(b)
                     of investigative drug; investigator to keep records of case
                     histories.
----------------------------------------------------------------------------------------------------------------


    Dated: October 10, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-26671 Filed 10-17-00; 8:45 am]
BILLING CODE 4160-01-F