[Federal Register: August 27, 2001 (Volume 66, Number 166)]
[Notices]
[Page 45048-45053]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr27au01-74]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
Clinical Studies of Safety and Effectiveness of Orphan Products;
Availability of Grants; Request for Applications
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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[[Page 45049]]
SUMMARY: The Food and Drug Administration (FDA) is announcing changes
to its Orphan Products Development (OPD) grant program for fiscal year
(FY) 2002. This announcement supersedes the previous announcement of
this program, which was published in the Federal Register of August 8,
2000.
DATES: The application receipt dates are October 17, 2001, and March 5,
2002.
ADDRESSES: Application forms are available from, and completed
applications should be sent to: Maura Stephanos, Grants Management
Specialist, Division of Contracts and Procurement Management (HFA-522),
Food and Drug Administration, 5600 Fishers Lane, rm. 2129, Rockville,
MD 20857, 301-827-7183, mstepha1@oc.fda.gov. Applications may also be
obtained at OPD on the Internet at http://www.fda.gov/orphan. (Note:
completed applications that are hand-carried or commercially delivered
should be addressed to 5630 Fishers Lane, rm. 2129, Rockville, MD
20857.)
FOR FURTHER INFORMATION CONTACT:
Regarding the administrative and financial management issues of
this notice: Maura Stephanos (address and telephone number cited
above).
Regarding the programmatic issues of this notice: Debra Y. Lewis,
Office of Orphan Products Development (HF-35), Food and Drug
Administration, 5600 Fishers Lane, rm. 15A-08, Rockville, MD 20857,
301-827-3666, dlewis@oc.fda.gov.
SUPPLEMENTARY INFORMATION: FDA is announcing the expected availability
of FY 2002 funds for awarding grants to support clinical trials on the
safety and effectiveness of products for a rare disease or condition
(that is, one with a prevalence, not incidence, of fewer than 200,000
people in the United States). Depending on FY 2002 funding, $12.5
million should be available, of which approximately $8.5 million will
be for noncompeting continuation awards. This will leave $4 million for
funding 12 to 15 new applications. The first part of the funding cycle
will award about $1 million to successful applications received on the
October 17, 2001 due date. These awards would start after March 1,
2002. All approved applications not funded in the first part of the
funding cycle will remain in competition for the second part of the
funding cycle. The expected start date for these applications will be
September 30, 2002. Applications submitted for the first due date may
be withdrawn and resubmitted for the second due date.
Any phase clinical trial is eligible for up to $150,000 in direct
costs a year, plus applicable indirect costs, for up to 3 years. Phase
2 and 3 clinical trials are eligible for up to $300,000 in direct costs
a year, plus applicable indirect costs, for up to 3 years.
FDA will support the clinical studies covered by this notice under
the authority of section 301 of the Public Health Service Act (the PHS
Act) (42 U.S.C. 241). FDA's research program is described in the
Catalog of Federal Domestic Assistance, No. 93.103. The Public Health
Service (PHS) strongly encourages all grant recipients to provide a
smoke-free workplace and to discourage the use of all tobacco products.
This is consistent with the PHS mission to protect and advance the
physical and mental health of the American people.
FDA is committed to achieving the health promotion and disease
prevention objectives of Healthy People 2010, a national activity to
reduce morbidity and mortality and to improve the quality of life.
Applicants may obtain a hard copy of the Healthy People 2010
objectives, Volumes I and II, Conference Edition (B0074) for $22 per
set, by writing to the Office of Disease Prevention and Health
Promotion (ODPHP) Communication Support Center, P.O. Box 37366,
Washington, DC 20013-7366. Each of the 28 chapters of Healthy People
2010 is priced at $2 per copy. Telephone orders can be placed to the
Center on 301-468-5690. The Center also sells the complete Conference
Edition in CD-ROM format (B0071) for $5. This publication is available
as well on the Internet at http://www.health.gov/healthypeople/.
Internet viewers should proceed to ``Publications.''
PHS policy is that applicants for PHS clinical research grants
should include minorities and women in study populations so research
findings can be of benefit to all people at risk of the disease,
disorder, or condition under study. Special emphasis should be placed
on the need for inclusion of minorities and women in studies of
diseases, disorders, and conditions that disproportionately affect
them. This policy applies to research subjects of all ages. If women or
minorities are excluded or poorly represented in clinical research, the
applicant should provide a clear and compelling rationale that shows
inclusion is inappropriate.
I. Program Research Goals
OPD was created to identify and promote the development of orphan
products. The OPD grant program defines orphan products as drugs,
biologics, medical devices, and foods for medical purposes that are
indicated for a rare disease or condition (that is, one with a
prevalence, not incidence, of fewer than 200,000 people in the United
States). Diagnostic tests and vaccines will qualify only if the U.S.
population of intended use is fewer than 200,000 a year.
One way to make orphan products available is to support clinical
research to find out whether the products are safe and effective. All
funded studies are subject to the requirements of the Federal Food,
Drug, and Cosmetic Act (the act) and regulations issued under it.
The goal of FDA's OPD grant program is the clinical development of
products for use in rare diseases or conditions where no current
therapy exists or where the product will improve the existing therapy.
FDA provides grants for clinical studies that will either result in or
substantially contribute to approval of these products. Applicants
should keep this goal in mind and must include an explanation in the
application's ``Background and Significance'' section of how their
proposed study will either help gain product approval or provide
essential data needed for product development. The applicant should
provide a summary of any meetings or discussions about the clinical
study that have occurred with FDA reviewing division staff as an
appendix to the application.
Except for medical foods that do not need premarket approval, FDA
will only consider awarding grants to support premarket clinical
studies to find out whether the products are safe and effective for
approval under the act (21 U.S.C. 301 et seq.) or under section 351 of
the PHS Act (42 U.S.C. 262). All studies of new drug and biological
products must be conducted under the FDA's investigational new drug
(IND) procedures and studies of medical devices must be conducted under
the investigational device exemption (IDE) procedures. Studies of
approved products to evaluate new orphan indications are also
acceptable; however, these also must be conducted under an IND or IDE
to support a change in labeling. (See section V.B of this document
(Program Review Criteria) for important requirements about IND/IDE
status of products to be studied under these grants.)
Studies proposed for the larger grants ($300,000) must be
continuing in phase 2 or phase 3 of investigation. Phase 2 trials
include controlled clinical studies conducted to evaluate the
effectiveness of the product for a particular indication in patients
with the disease or condition and to determine the common or short-term
side effects and risks associated with it. Phase 3 trials gather more
[[Page 45050]]
information about effectiveness and safety that is necessary to
evaluate the overall risk-benefit ratio of the product and to provide
an acceptable basis for physician labeling. Studies proposed for the
smaller grants ($150,000) may be phase 1, 2, or 3 trials. Budgets for
all years of requested support may not exceed the $300,000 or $150,000
direct cost limit, whichever is applicable.
Applications must propose a clinical trial of one therapy for one
indication. The applicant must provide supporting evidence that the
product to be studied is available to the applicant in the form and
quantity needed for the clinical trial. The applicant must also provide
supporting evidence that the patient population has been surveyed and
reasonable assurance that the necessary number of eligible patients is
available for the study. Funds may be requested in the budget to travel
to FDA for meetings with reviewing division staff about the progress of
product development.
II. Human Subject Protection and Informed Consent
A. Protection of Human Research Subjects
All institutions engaged in human subject research supported by the
Department of Health and Human Services (DHHS) must file an
``assurance'' of protection for human subjects with the Office for
Human Research Protection (OHRP) (45 CFR part 46). Applicants may wish
to visit the OHRP Internet site at http://ohrp.osophs.dhhs.gov for
guidance on human subjects issues. The requirement to file an assurance
includes both ``awardee'' and collaborating ``performance site''
institutions. Awardee institutions are automatically considered to be
engaged in human subject research whenever they receive a direct DHHS
award to support such research, even where all activities involving
human subjects are carried out by a subcontractor or collaborator. In
such cases, the awardee institution bears ultimate responsibility for
protecting human subjects under the award. The awardee is also
responsible for ensuring that all collaborating institutions engaged in
the research hold an approved assurance prior to their initiation of
the research. No awardee or performance site may spend funds on human
subject research or enroll subjects without the approved and applicable
assurance(s) on file with OHRP.
Existing assurances [multiple project assurances (MPAs),
cooperative project assurances (CPAs), and single project assurances
(SPAs)] will remain in effect through their current expiration date, or
December 31, 2003, whichever comes first. However, OHRP no longer
accepts changes to existing MPAs, CPAs, and SPAs. MPA, CPA, and SPA
institutions should file a new Federalwide assurance with OHRP if
changes are necessary. Applicants must provide certification of
Institutional Review Board (IRB) review and approval for every site
taking part in the study. However, this documentation need not be on
file with the grants management officer, FDA prior to the award.
Applicants should review the section on human subjects in the
application kit entitled ``Section C. Specific Instructions--Forms,
Item 4, Human Subjects'' (pp. 7 and 8 of the application kit), for IRB
review requirements.
B. Key Personnel Human Subject Protection Education
The awardee institution should ensure that all key personnel
receive appropriate training in their human subject protection
responsibilities. Within 30 days of award, the principal investigator
should provide a letter describing the human subjects protection
training for each individual identified as ``key personnel'' in the
proposed research. Key personnel include all principal investigators,
co-investigators, and performance site investigators responsible for
the design and conduct of the study. The description of training should
be submitted in a letter that includes the names of the key personnel
the title of the education program completed by each named personnel,
and a one-sentence description of the program. This letter should be
signed by the principal investigator and co-signed by an institution
official and sent to the Grants Management Office. OPD does not
prescribe or endorse any specific education programs. Many institutions
already have developed educational programs on the protection of
research subjects and have made participation in such programs a
requirement for their investigators. Other sources of appropriate
instruction might include the online tutorials offered by the Office of
Human Subjects Research, National Institutes of Health (NIH) at http://
ohsr.od.nih.gov/ and by OHRP at http://ohrp.osophs.dhhs.gov/
educmat.htm. Also, the University of Rochester has made available its
training program for individual investigators. Their manual can be
obtained through Centerwatch, Inc., at http://www.centerwatch.com.
C. Informed Consent
Consent forms, assent forms, and any other information given to a
subject, should be sent with the grant application. Information given
to the subject or his or her representative must be in language the
subject or representative can understand. No informed consent, whether
verbal or written, may include any language through which the subject
or representative waives any of the subject's legal rights, or by which
the subject or representative releases or appears to release the
investigator, the sponsor, or the institution or its agent from
liability. If a study involves both adults and children, separate
consent forms should be provided for the adults and the parents or
guardians of the children.
D. Elements of Informed Consent
The elements of informed consent are stated in the DHHS regulations
at 45 CFR 46.116 and 21 CFR 50.25 as follows:
1. Basic Elements of Informed Consent
In seeking informed consent, the following information shall be
provided to each subject.
(a) A statement that the study involves research, an explanation of
the purposes of the research and the expected duration of the subject's
participation, a description of the procedures to be followed, and
identification of any procedures that are experimental.
(b) A description of any reasonably foreseeable risks or
discomforts to the subject.
(c) A description of any benefits to the subject or to others that
may reasonably be expected from the research.
(d) A discussion of proper alternative procedures or courses of
treatment, if any, that might be helpful to the subject.
(e) A statement that describes the extent, if any, to which
confidentiality of records identifying the subject will be maintained,
and that notes the possibility that FDA may inspect the records.
(f) For research involving more than slight risk, an explanation of
whether any compensation and any medical treatments are available if
injury occurs and, if so, what they consist of or where further
information may be gained.
(g) An explanation of whom to contact for answers to relevant
questions about the research and research subject's rights, and whom to
contact if the subject is injured by the research.
(h) A statement that participation is voluntary, that refusal to
take part will
[[Page 45051]]
involve no penalty or loss of benefits to which the subject is
otherwise entitled, and that the subject may stop participation at any
time without penalty or loss of benefits to which the subject is
otherwise entitled.
2. Other Elements of Informed Consent
When suitable, one or more of the following elements of information
shall also be provided to each subject.
(a) A statement that the particular treatment or procedure may
involve risks to the subject (or the embryo or fetus, if the subject is
or may become pregnant) that are unforeseeable.
(b) Anticipated circumstances under which the investigator, without
regard to the subject's consent, may stop the subject's participation.
(c) Any costs to the subject that may result from participation in
the research.
(d) The consequences of a subject's decision to withdraw from the
research and procedures for orderly ending of participation by the
subject.
(e) A statement that significant new findings developed during the
research that may affect the subject's willingness to continue
participation will be provided to the subject.
(f) The estimated number of subjects involved in the study.
The informed consent requirements do not intend to preempt any
applicable Federal, State, or local laws that require other information
to be disclosed for informed consent to be legally effective. Nothing
in the notice intends to limit the authority of a physician to provide
emergency medical care as permitted under applicable Federal, State, or
local law.
III. Reporting Requirements
The original and two copies of the annual Financial Status Report
(FSR) (SF-269) must be sent to FDA's grants management officer within
90 days of the budget period end date of the grant. Failure to file the
FSR in a timely fashion will be grounds for suspension or termination
of the grant. For continuing grants, an annual program progress report
is also required. The noncompeting continuation application (PHS 2590)
will be considered the annual program progress report. Also, all new
and continuing grants must comply with all regulatory requirements
necessary to keep active status of their IND/IDE. This includes, but is
not limited to, submission of an annual report to the proper regulatory
review division within FDA. Failure to meet regulatory requirements
will be grounds for suspension or termination of the grant.
The program project officer will monitor grantees quarterly and
will prepare written reports. The monitoring may be in the form of
telephone conversations or e-mail between the project officer/grants
management specialist and the principal investigator. Periodic site
visits with officials of the grantee organization may also occur. The
results of these reports will be recorded in the official grant file
and may be available to the grantee on request consistent with FDA
disclosure regulations. Also, the grantee organization must comply with
all special terms and conditions, which state that future funding of
the study will depend on recommendations from the OPD project officer.
The scope of the recommendations will confirm that: (1) There has been
acceptable progress toward enrollment, based on specific circumstances
of the study; (2) there is an adequate supply of the product/device;
and (3) there is continued compliance with all FDA regulatory
requirements for the trial.
The grantee must file a final program progress report, FSR and
invention statement within 90 days after the end date of the project
period as noted on the notice of grant award.
IV. Mechanism of Support
A. Award Instrument
Support will be in the form of a grant. All awards will be subject
to all policies and requirements that govern the research grant
programs of PHS, including the provisions of 42 CFR part 52 and 45 CFR
parts 74 and 92. The regulations issued under Executive Order 12372 do
not apply to this program. The NIH's modular grant program does not
apply to this FDA grant program. All grant awards are subject to
applicable requirements for clinical investigations imposed by sections
505, 512, and 515 of the act (21 U.S.C. 355, 360b, and 360e), section
351 of the PHS Act (42 U.S.C. 262), and regulations issued under any of
these sections.
B. Eligibility
These grants are available to any foreign or domestic, public or
private nonprofit entity (including State and local units of
government) and any foreign or domestic, for-profit entity. For-profit
entities must commit to excluding fees or profit in their request for
support to receive grant awards. Organizations described in section
501(c)4 of the Internal Revenue Code of 1968 that lobby are not
eligible to receive grant awards.
C. Length of Support
The length of support will depend on the nature of the study. For
those studies with an expected duration of more than one year, a second
or third year of noncompetitive continuation of support will depend on:
(1) Performance during the preceding year; (2) Federal funds
availability; and (3) compliance with regulatory requirements of the
IND/IDE.
D. Funding Plan
The number of studies funded will depend on the quality of the
applications received and the Federal funds available to support the
projects. Before an award will be made, OPD will confirm the active
status of the protocol under the IND/IDE. If the protocol is under FDA
clinical hold for any reason, no award will be made. Also, if the IND/
IDE for the proposed study is not active and in complete regulatory
compliance, no award will be made. Documentation of IRB approvals for
all performance sites must be on file with the Grants Management
Office, FDA (address above), before research can begin at that site.
V. Review Procedure and Criteria
A. Review Method
Grants management and program staff will first review all
applications sent in response to this request for application (RFA). A
responsive application is defined as being in compliance with the
following program review criteria. Applications found to be
nonresponsive will be returned to the applicant without further
consideration.
B. Program Review Criteria
Applicants are strongly encouraged to contact FDA to resolve any
questions about criteria before submitting their application. Direct
all questions of a technical or scientific nature to the OPD program
staff and all questions of an administrative or financial nature to the
grants management staff. (See FOR FURTHER INFORMATION CONTACT section
of this document.) Applications considered nonresponsive will be
returned to the applicant unreviewed. Responsiveness criteria include
the following:
1. The application must propose a clinical trial intended to
provide safety and/or efficacy data of one therapy for one orphan
indication.
2. There must be an explanation in the ``Background and
Significance'' section of how the proposed study will either contribute
to product approval or provide essential data needed for product
development.
[[Page 45052]]
3. The prevalence, not incidence, of the population to be served by
the product must be fewer than 200,000 individuals in the United
States. The applicant should include, in the ``Background and
Significance'' section, a detailed explanation supplemented by
authoritative references in support of the prevalence figure.
Diagnostic tests and vaccines will qualify only if the population of
intended use is fewer than 200,000 individuals in the United States per
year.
4. The protocol proposed in the grant application must already be
under an active IND or IDE (not under review or on hold) before the
grant application deadline, as described below:
(a) The IND with the proposed clinical protocol must be submitted
to the FDA IND/IDE reviewing division a minimum of 30 days before the
grant application deadline. The IND/IDE must be in active status, in
compliance with all regulatory requirements and cannot have any type of
FDA clinical hold placed on it at the time the grant application is
submitted.
(b) The number assigned to the IND/IDE that includes the proposed
study must appear on the face page of the application with the title of
the project.
(c) The applicant should submit an IND/IDE verification with the
application. The verification includes the IND/IDE number, the date the
subject protocol was submitted to FDA for the IND/IDE review, the IND
serial number (if known), and a statement that the IND/IDE contains the
same protocol as proposed in the grant application and that this IND/
IDE is active (not under review or on hold).
(d) Protocols that would otherwise be eligible for an exemption
from the IND regulations must be conducted under an IND/IDE to be
eligible for funding under this FDA grant program.
(e) If the sponsor of the IND/IDE is other than the principal
investigator listed on the application, a letter from the sponsor
permitting access to the IND/IDE must be submitted. Both the principal
investigator named in the application and the study protocol must have
been submitted to the IND/IDE.
(f) Studies of already approved products, evaluating new orphan
indications, are also subject to these IND/IDE requirements.
(g) Only medical foods that do not need premarket approval are free
from these IND/IDE requirements.
5. The requested budget must be within the limits (either $150,000
in direct costs for each year for up to 3 years for any phase study, or
$300,000 in direct costs for each year for up to 3 years for phase 2 or
3 studies) as stated in this request for applications. Any application
received that requests support over the maximum amount allowable for
that particular study will be considered nonresponsive.
6. Proposed consent forms, assent forms, and any other information
given to a subject, should be included in the grant application.
7. Evidence that the product to be studied is available to the
applicant in the form and quantity needed for the clinical trial must
be included in the application. A current letter from the supplier as
an appendix will be acceptable.
8. Applicants must follow guidelines named in the PHS 398 (Rev. 5/
01) grant application kit.
Responsive applications will be reviewed and evaluated for
scientific and technical merit by an ad hoc panel of experts in the
subject field of the specific application. Consultation with the proper
FDA review division may also occur during this first review to
determine whether the proposed study will provide data that could
result in or contribute to product approval. Responsive applications
will be subject to a second review by a National Advisory Council for
concurrence with the recommendations made by the first-level reviewers,
and funding decisions will be made by the Commissioner of Food and
Drugs.
C. Scientific/Technical Review Criteria
The ad hoc expert panel will provide the first review. The
application will be judged on the following scientific and technical
merit criteria:
1. The soundness of the rationale for the proposed study.
2. The quality and appropriateness of the study design to include
the rationale for the statistical procedures.
3. The statistical justification for the number of patients chosen
for the study, based on the proposed outcome measures and the
appropriateness of the statistical procedures for analysis of the
results.
4. The adequacy of the evidence that the proposed number of
eligible subjects can be recruited in the requested timeframe.
5. The qualifications of the investigator and support staff, and
the resources available to them.
6. The adequacy of the justification for the request for financial
support.
7. The adequacy of plans for complying with regulations for
protection of human subjects.
8. The ability of the applicant to complete the proposed study
within its budget and within time limits stated in this RFA.
The priority score will be based on the scientific/technical review
criteria cited in section V.C of this document. Also, the reviewers may
advise the program staff about the appropriateness of the proposal to
the goals of the OPD grant program described in section I (Program
Research Goals) of this document.
D. Award Criteria
Resources for this program are limited. Therefore, should FDA
approve two or more applications that propose duplicative or similar
studies, FDA will support only the study with the best score.
VI. Submission Requirements
The original and two copies of the completed Grant Application Form
PHS 398 (Rev. 5/01) or the original and two copies of the PHS 5161-1
(Rev. 7/00) for State and local governments, with copies of the
appendices for each of the copies, should be delivered to Maura
Stephanos (address above). State and local governments may use the PHS
398 (Rev. 5/01) application form instead of the PHS 5161-1. The
application receipt dates are October 17, 2001, and March 5, 2002.
Other than evidence of final IRB approval, no material will be accepted
after the receipt date. The mailing package and item two of the
application face page should be labeled, ``Response to RFA-FDA-OPD-
2002.'' If an application for the same study was submitted in response
to a previous RFA but has not yet been funded, an application in
response to this RFA will be considered a request to withdraw the
previous application. Resubmissions are treated as new applications;
therefore, the applicant may wish to address the issues presented in
the summary statement from the previous review, and include a copy of
the summary statement itself.
VII. Method of Application
A. Submission Instructions
Applications will be accepted during normal working hours, from 8
a.m. to 4:30 p.m., Monday through Friday, by the established receipt
dates. Applications will be considered received on time if sent or
mailed by the receipt dates as shown by a legible U.S. Postal Service
dated postmark or a legible date receipt from a commercial carrier,
unless they arrive too late for orderly processing. Private metered
postmarks shall not be acceptable as proof of timely mailing.
Applications not received on time will not be considered for review and
will be returned to the applicant. (Applicants
[[Page 45053]]
should note the U.S. Postal Service does not uniformly provide dated
postmarks. Before relying on this method, applicants should check with
their local post office.) Do not send applications to the Center for
Scientific Research (CSR), NIH. Any application sent to NIH that is
then forwarded to FDA and received after the applicable due date will
be judged nonresponsive and returned to the applicant. Application
forms can be found on the Internet (address http://www.fda.gov/orphan).
However, as noted above, do not mail applications to NIH. Applicants
should know FDA does not adhere to the page limits or the type size and
line spacing requirements imposed by NIH on its applications.
B. Format for Application
Submission of the application must be on Grant Application Form PHS
398 (Rev. 5/01). All ``General Instructions'' and ``Specific
Instructions'' in the application kit should be followed except for the
receipt dates and the mailing label address. Do not send applications
to the CSR, NIH. Applications from State and local governments may be
sent on Form PHS 5161-1 (Rev. 7/00) or Form PHS 398 (Rev. 5/01). The
face page of the application should reflect the request for
applications number RFA-FDA-OPD-2002. The title of the proposed study
should include the name of the product and the disease/disorder to be
studied and the IND/IDE number. The format for all following pages of
the application should be single-spaced and single-sided. Data
information included in the application will generally not be publicly
available prior to the funding of the application. Data included in the
application may be entitled to confidential treatment as trade secret
or confidential commercial information within the meaning of the
Freedom of Information Act (5 U.S.C. 552(b)(4)) and FDA's implementing
regulations (21 CFR 20.61) even after funding has been granted. To
designate information that an applicant believes to be trade secret or
confidential commercial information that remains exempt from disclosure
after funding, sponsors should use the legend below. Information
collection requirements requested on Form PHS 398 (Rev. 5/01) has been
sent by the PHS to the Office of Management and Budget (OMB) and was
approved and assigned OMB control number 0925-0001.
C. Legend
Unless disclosure is required by the Freedom of Information Act as
amended (5 U.S.C. 552) as determined by the freedom of information
officials of DHHS or by a court, data contained in the portions of this
application which have been specifically identified by the applicant as
containing restricted information shall not be disclosed to the public
or used except for evaluation purposes.
Dated: August 21, 2001.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 01-21622 Filed 8-22-01; 2:46 pm]
BILLING CODE 4160-01-S