[Federal Register: August 27, 2002 (Volume 67, Number 166)]
[Notices]
[Page 55020-55024]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr27au02-60]
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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 (Catalog of Federal
Domestic Assistance No. 93.103)
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing changes
to its Office of Orphan Products Development (OPD) grant program for
fiscal year (FY) 2003. This announcement supercedes the previous
announcement of this program, which was published in the Federal
Register on August 27, 2001.
DATES: The application receipt dates are October 16, 2002, and April 2,
2003.
ADDRESSES: Application requests and completed applications should be
submitted to Maura Stephanos, Grants Management Specialist, Grants
Management Staff, Division of Contracts and Procurement Management
(HFA-520), Food and Drug Administration, 5600 Fishers Lane, Rockville,
MD 20857, 301-827-7183, FAX 301-827-7101, e-mail: mstepha1@oc.fda.gov.
Applications that are hand-carried or commercially delivered should be
addressed to 5630 Fishers Lane, rm. 2129, Rockville, MD 20857.
Applications may also be obtained from the OPD on the Internet at
http://www.fda.gov/orphan or at http://grants.nih.gov/grants/funding/
phs398/phs398.html. Note: Do not send applications to the Center for
Scientific Research (CSR), National Institutes of Health (NIH).
FOR FURTHER INFORMATION CONTACT:
Regarding the administrative and financial management issues of
this notice: Maura Stephanos (see ADDRESSES).
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, FAX 301-827-0017, e-mail: dlewis@oc.fda.gov.
SUPPLEMENTARY INFORMATION: 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 acceptable;
however, these must also be conducted under an IND or IDE to support a
change in labeling. The study protocol proposed in the grant
application must be under an active IND or IDE (not on clinical hold)
to qualify the application for scientific and technical review. (See
Program Review Criteria for important information about the IND/IDE
status of products to be studied under these grants.)
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 section 301 of the Federal Food, Drug, and Cosmetic Act
(the act) (21 U.S.C. 331 et seq.) or under section 351 of the Public
Health Service Act (the PHS Act) (42 U.S.C. 262).
FDA will support the clinical studies covered by this notice under
the authority of section 301 of the PHS Act. 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.
[[Page 55021]]
PHS's 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.
FDA is committed to achieving the health promotion and disease
prevention objectives of ``Healthy People 2010,'' a national effort
designed to reduce morbidity and mortality and to improve quality of
life. Applicants may obtain a paper copy of the ``Healthy People 2010''
objectives, vols. I and II, for $70 ($87.50 foreign) S/N 017-000-00550-
9, by writing to the Superintendent of Documents, P.O. Box 371954,
Pittsburgh, PA 15250-7954. Telephone orders can be placed to 202-512-
2250. The document is also available in CD-ROM format, S/N 017-001-
00549-5 for $19 ($23.50 foreign) as well as on the Internet at http://
health.gov/healthypeople/. Internet viewers should proceed to
``Publications.''
I. Program Research Goals
OPD was created to identify and promote the development of orphan
products. Orphan products are 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 people a year.
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 market 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. All
funded studies are subject to the requirements of the act and
regulations issued under it.
II. Award Amounts
FDA is announcing the expected availability of FY 2003 funds for
awarding grants to support clinical studies on the safety and
effectiveness of products (drugs, biologics, and devices) for rare
diseases or conditions (that is, with a prevalence, not incidence, of
fewer than 200,000 people in the United States).
Of the estimated FY 2003 funding ($13.3 million), approximately
$9.3 million will fund noncompeting continuation awards, and
approximately $4 million will fund 12 to 15 new awards. In the first
part of the funding cycle, approximately $1 million will be awarded to
successful applications received by the October 16, 2002, due date
(with the award starting after March 1, 2003). All applications
recommended for approval that are not funded in the first part of the
cycle will remain in competition for the second part of the funding
cycle with applications received by the April 2, 2003, due date. The
expected start date for these awards will be September 30, 2003.
Applications submitted for the first due date may be withdrawn and
resubmitted for the second due date.
Any phase (1, 2, or 3) 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 also eligible for up to
$300,000 in direct costs a year, plus applicable indirect costs, for up
to 3 years. Study proposals for the smaller grants ($150,000) may be
for phase 1, 2, or 3 clinical trials. Study proposals 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 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 product labeling.
Budgets for all years of requested support may not exceed the $150,000
or $300,000 direct cost limit, whichever is applicable.
III. 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 are
advised 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 the ultimate
responsibility for protecting human subjects under the award. The
awardee institution is also responsible for ensuring that all
collaborating performance site institutions engaged in the research
hold an approved assurance prior to their initiation of the research.
No awardee or performance site institution may spend funds on human
subject research or enroll subjects without the approved and applicable
assurance(s) on file with OHRP.
Applicants must also provide certification of Institutional Review
Board (IRB) review and approval for every site taking part in the
study. This documentation need not be on file with the FDA Grants
Management Office prior to the award, but must be on file before
research can begin at a site.
Applicants should review the section on human subjects in the
application instructions entitled ``I. Preparing Your Application,
Section C. Specific Instructions, Item 4, Human Subjects'' for further
information.
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. Key personnel include all principal investigators,
co-investigators, and performance site investigators responsible for
the design and conduct of the study. Within 30 days of award, the
principal investigator should provide a letter which includes the names
of the key personnel, the title of
[[Page 55022]]
the human subjects protection 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. Neither
DHHS, FDA, or OPD prescribe or endorse any specific education programs.
Many institutions have already 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, 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 (even if such a form
is in a draft version). 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. The applicant is
referred to DHHS regulations at 45 CFR 46.116 and 21 CFR 50.25 for
details regarding the (required) elements of informed consent.
IV. 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. 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.
V. 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 the 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 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
The 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 1 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 availability of Federal funds to support
the projects. Resources for this program are limited. Therefore, if two
applications propose duplicative or similar studies, FDA may support
only the study with the better score. Funds may be requested in the
budget to travel to FDA for meetings with OPD or reviewing division
staff about the progress of product development.
Before an award will be made, the 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 regulatory compliance,
no award will be made. Documentation of IRB approvals for all
performance sites must be on file with the FDA Grants Management Office
before research can begin at that site. This grant program does not
require the applicant to match or share in the project costs if an
award is made.
VI. Review Procedures and Criteria
A. Review Procedures
FDA's grants management and program staff will review all
applications sent in response to this notice. To be responsive, an
application must: (1) Be received by the specified due date; (2) be
submitted in accordance with sections V.B ``Eligibility,'' VII
``Submission Requirements,'' and VIII.A ``Submission Instructions'' of
this notice; (3) not exceed the recommended funding amount stated in
section II ``Award Amounts'' of this document; (4) be in compliance
with the following section VI.B `` Program Review Criteria;'' and (5)
bear the original signatures of both the principal investigator and the
Institution's/Organization's Authorized Official. Applications found to
be nonresponsive
[[Page 55023]]
will be returned to the applicant without further consideration
(unreviewed). Applicants are strongly encouraged to contact FDA to
resolve any questions about criteria before submitting their
application. Please 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 ADDRESSES).
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 phase of the review to
determine whether the proposed study will provide acceptable data that
could 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.
B. Program Review Criteria
Program review 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.
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 study protocol proposed in the grant application must be
under an active IND or IDE (not on clinical hold) to qualify the
application for scientific and technical review. Additional IND/IDE
information is described below:
The proposed clinical protocol should be submitted to the
FDA IND/IDE reviewing division a minimum of 30 days before the grant
application deadline.
The number assigned to the IND/IDE that includes the
proposed study should appear on the face page of the application with
the title of the project. The date the subject protocol was submitted
to FDA for the IND/IDE review should also be provided.
Protocols that would otherwise be eligible for an
exemption from the IND regulations must be conducted under an active
IND to be eligible for funding under this FDA grant program.
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 name of
the principal investigator identified in the application and the study
protocol must have been submitted to the IND/IDE.
Studies of already approved products, evaluating new
orphan indications, are also subject to these IND/IDE requirements.
Only medical foods that do not need premarket approval are
exempt 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 notice. 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 (even
if they are in a draft version).
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 instructions.
C. Scientific/Technical Review Criteria
The ad hoc expert panel will review the application based 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 including
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.
A score will be assigned based on the above scientific/technical
review criteria. The review panel may advise the program staff about
the appropriateness of the proposal to the goals of the OPD grant
program described in the section I ``Program Research Goals'' of this
document.
VII. 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 PHS 5161-1 (Rev.
7/00) for State and local governments, with three copies of the
appendices should be submitted to Maura Stephanos (see ADDRESSES).
State and local governments may use the PHS 398 (Rev. 5/01) application
form in lieu of the PHS 5161-1. The application receipt dates are
October 16, 2002, and April 2, 2003. The only material will be accepted
after the receipt date is evidence of final IRB approval. The mailing
package and item 2 of the application face page should be labeled,
``Response to RFA-FDA-OPD-2003.'' 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 notice 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 as part of the
application.
VIII. 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.
Private metered postmarks shall
[[Page 55024]]
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 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.) Please do not
send applications to the CSR at 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.
Applications must be submitted via mail or hand delivered as stated
above. FDA is unable to receive applications electronically.
B. Format for Application
Submission of the application must be on Grant Application Form PHS
398 (Rev. 5/01). Applications from State and local governments may be
sent on Form PHS 5161-1 (Rev. 7/00) or 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. The face page of the application should reflect
the request for applications number RFA-FDA-OPD-2003. 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. FDA does not adhere to the page limits or the type size and line
spacing requirements imposed by NIH on its applications.
Applicants have the option of omitting from the application copies
(not the original) specific salary rates or amounts for individuals
specified in the application budget and Social Security numbers if
otherwise required for individuals. The copies may include summary
salary information.
Data and information included in the application will generally not
be publicly available prior to the funding of the application. Data and
information included in the application, if identified by the applicant
as trade secret or confidential commercial information, will be given
confidential treatment to the extent permitted by the Freedom of
Information Act (5 U.S.C. 552(b)(4)) and FDA's implementing regulations
(including inter alia 21 CFR 20.61) even after funding has been
granted. Information collection requirements requested on Form PHS 398
(Rev. 5/01) have been sent by the PHS to the Office of Management and
Budget (OMB) and have been approved and assigned OMB control number
0925-0001. The requirements requested on Form PHS 5161-1 (Rev. 7/00)
were approved and assigned OMB control number 0348-0043.
Applicants 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.
Dated: August 21, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-21736 Filed 8-26-02; 8:45 am]
BILLING CODE 4160-01-S