[Federal Register Volume 64, Number 131 (Friday, July 9, 1999)]
[Notices]
[Pages 37138-37142]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-17505]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
Pilot Training and Research Program; Demonstration Project;
Studies in Clinical Pharmacology and New Drug Review Technologies;
Availability of Cooperative Agreements; Request for Applications
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA), Center for Drug
Evaluation and Research (CDER) is announcing the anticipated
availability of funds for training and research cooperative agreements
for fiscal year (FY) 2000. This pilot program is a demonstration
project to evaluate the extent to which such a program can contribute
to an identifiable increase in the number of trained biomedical,
scientific personnel in clinical pharmacology. Research will be
conducted to study clinical pharmacology and biopharmaceutics issues
related to new drug development and review. If funds are appropriated
in FY 2000 for the program, FDA anticipates that approximately $3.0
million will be available. FDA anticipates making 4 to 10 cooperative
agreement awards to domestic medical schools at $300,000 to $750,000
per award per year (direct and indirect costs). Support for these
agreements may be for up to 3 years. The number of agreements funded
will depend on the quality of the applications received and the
availability of Federal funds to support the projects.
DATES: Submit applications by August 9, 1999. If the closing date falls
on a weekend, it will be extended to Monday; if the date falls on a
holiday, it will be extended to the following workday.
ADDRESSES: Application forms are available from, and completed
applications should only be submitted to: Rosemary Springer, Senior
Grants Management Specialist (HFA-520), Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857, 301-827-7182. Applications
hand-carried or commercially delivered should be addressed to 5630
Fishers Lane, rm. 2129, Rockville, MD 20852. Application forms can also
be found at ``http://www.nih.gov/grants/phs398/forms-toc.html''.
FOR FURTHER INFORMATION CONTACT:
Regarding the administrative and financial management aspects of
this notice: Rosemary Springer (address above).
Regarding the programmatic aspects of this notice: Shiew-Mei Huang,
Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug
Evaluation and Research (HFD-850), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-5690.
SUPPLEMENTARY INFORMATION: FDA, CDER is announcing the anticipated
availability of funds for FY 2000 for awarding cooperative agreements
to support post-doctoral training of clinical pharmacologists. The
training to be supported will be research studies related to new drug
development and review. FDA will support the studies covered by this
notice under Pub. L. 102-222. The law authorizes a pilot program for
training additional clinical pharmacologists. If funding is available,
FDA will award Demonstration Cooperative Agreements to evaluate the
extent to which such a program can contribute to increasing the number
of trained biomedical, scientific personnel in clinical pharmacology.
FDA's extramural program is described in the Catalog of Federal
Domestic Assistance, No. 93.948.
The Public Health Service (PHS) strongly encourages all award
recipients to provide a smoke-free work place 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. PHS urges applicants to submit work plans that address
[[Page 37139]]
specific objectives of ``Healthy People 2000.'' Potential applicants
may obtain a copy of Healthy People 2000 (Full Report, stock No. 017-
00100474-0) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325, 202-512-1800.
PHS Policy is that applicants for PHS clinical research grants are
required to include minorities and women in study populations so that
research findings can be of benefit to all persons at risk of the
disease, disorder or condition under study; special emphasis must be
placed on the need for inclusion of minorities and women in studies of
diseases, disorders, and conditions which disproportionately affect
them. This policy is intended to apply to males and females of all
ages. If women or minorities are excluded or inadequately represented
in clinical research, particularly in proposed population-based
studies, a clear and compelling rationale must be provided.
Some activities carried out by a recipient under this announcement
may be governed by Department of Health and Human Services' regulations
for the protection of human research subjects (45 CFR part 46). These
regulations require recipients to establish procedures for the
protection of subjects involved in any research activities. Prior to
funding and upon request of the Office for Protection from Research
Risks (OPRR), prospective recipients must have on file with OPRR an
assurance to comply with 45 CFR part 46. This assurance to comply is
called an Assurance document. It includes the Institutional Review
Board (IRB) designated for review and approval of procedures for
carrying out any research activities occurring in conjunction with this
award. If an applicable Assurance document for the applicant is not
already on file with OPRR, a formal request for the required Assurance
will be issued by OPRR at an appropriate point in the review process,
prior to award, and examples of required materials will be supplied at
that time. No applicant or performance site, without an approved and
applicable Assurance on file with OPRR, may spend funds on human
subject activities or accrue subjects. No performance site, even with
an OPRR-approved and applicable Assurance, may proceed without approval
by OPRR of an applicable Assurance for the recipients. Applicants may
wish to contact OPRR by facsimile 301-402-0527 to obtain preliminary
guidance on human subjects' issues. When contacting OPRR, applicants
should provide their institutional affiliation, geographic location,
and all available Requests for Application (RFA) citation information.
Applicants are advised that the section on human subjects on pages
7 and 8 in the application kit entitled ``Section C. Specific
Instructions--Forms, Item 4, Human Subjects,'' should be carefully
reviewed for the certification of Institutional Review Board (IRB)
approval requirements. Documentation of IRB approval for every
participating center is required to be on file with the Grants
Management Officer, FDA. The goal should be to include enough
information on the protection of human subjects in a sufficiently clear
fashion so reviewers will have adequate material to make a complete
review.
Consent and/or assent forms, and any additional information to be
given to a subject, should accompany the grant application. Information
that is given to the subject or the subject's representative must be in
language that the subject or his or her representative can understand.
No informed consent, whether oral or written, may include any language
through which the subject or the subject's representative is made to
waive 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 elements of informed consent are stated in the 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 which 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 which
may reasonably be expected from the research.
(d) A disclosure of appropriate alternative procedures or courses
of treatment, if any, that might be advantageous 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 minimal risk, an explanation
as to 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 obtained. Additional protections for children
involved as subjects in research are found in 45 CFR part 46, subpart
D.
(g) An explanation of whom to contact for answers to pertinent
questions about the research and research subject's rights, and whom to
contact in the event of research-related injury to the subject.
(h) A statement that participation is voluntary, that refusal to
participate will involve no penalty or loss of benefits to which the
subject is otherwise entitled, and that the subject may discontinue
participation at any time without penalty or loss of benefits to which
the subject is otherwise entitled.
2. Additional elements of informed consent.
When appropriate, 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) which are currently unforeseeable.
(b) Anticipated circumstances under which the subject's
participation may be terminated by the investigator without regard to
the subject's consent.
(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 termination of participation by the
subject.
(e) A statement that significant new findings developed during the
course of the research which may relate to the subject's willingness to
continue participation will be provided to the subject.
(f) The approximate number of subjects involved in the study.
Additional protections for children involved as subjects in
research are found in 45 CFR part 46, subpart D.
The informed consent requirements are not intended to preempt any
applicable Federal, State, or local laws which require additional
information to be disclosed for informed consent to be legally
effective.
Nothing in the notice is intended to limit the authority of a
physician to provide emergency medical care to the extent that a
physician is permitted to do so under applicable Federal, State, or
local law.
[[Page 37140]]
I. Background
There is currently a nationwide shortage of trained clinical
pharmacologists at a time when advances in molecular medicine have
provided an unparalleled opportunity to better understand
pharmacotherapeutics. This shortage limits the number of clinical
pharmacologists trained in the range of new technologies that are
driving the future directions of drug development and regulatory
science. Clinical pharmacologists have tremendous potential to
translate molecular insights and technology in a way that would promote
the public health, improve the quality and speed of the regulatory
review, and accelerate the development of new drugs in this country.
Pub. L. 102-222 authorizes a pilot project for a modern training
program to increase clinical pharmacology and mechanistic knowledge in
this country, and to help alleviate this shortage of trained biomedical
personnel. With this authority and appropriated funding, FDA will
establish a Demonstration Project to evaluate whether training and
research cooperative agreements can contribute to an increase in the
number of trained clinical pharmacologists. The public health role of
the FDA's CDER in this program relates directly to the safe and
effective use of prescription drugs. Several areas of clinical
pharmacology and biopharmaceutics research are related to the public
health by providing a bridge between bedside observations of clinical
outcome, and molecular insights and mechanistic knowledge. FDA seeks to
have research conducted in the clinical pharmacology training program
that will develop:
1. Understanding of the multiple enzyme isoforms responsible for
drug-drug interactions and the variations in risk associated with
different metabolic pathways;
2. The application of pharmacogenomics to characterize the
mechanisms of disease to target drug therapies to the causative events
and pathways of disease progression;
3. The development of molecularly based biological markers and
surrogate endpoints for clinical outcomes that can be linked to
systemic drug exposure to provide ways to assess early treatment
interventions and long term management of chronic diseases;
4. The application of sophisticated mechanistic-based exposure-
response models to design human clinical trials and simulate clinical
outcomes as a function of drug input and patient variables;
5. The development of an electronic bioinformatic database to
manage key metabolic and drug-drug interaction data that can provide
the core knowledge for an expert system intended to predict clinical
risks from in vitro and in vivo data; and
6. The biopharmaceutics and clinical pharmacology characterization
of complex drug substances including botanicals, herbs, and endogenous
proteins to offer the possibility that these agents can be used more
effectively and safely in the early treatment and long-term management
of diseases.
II. Research Goals and Objectives
The specific objective of this training and research program will
be to provide financial assistance to investigators who conduct
research as part of their clinical pharmacology training program. It is
of particular importance to the public health that this program advance
scientific knowledge of mechanisms of in vitro/in vivo metabolism/drug
interactions; characterization of individual exposure-response to
drugs; and the effect of age, gender, and race on drug disposition and
exposure-response relationships. Projects that fulfill any one or a
combination of the following specific objectives will be considered for
funding:
1. Mechanistic understanding of drug-drug, drug-food (e.g.,
grapefruit juice), and drug-non-prescription product interactions in
the general population;
2. Research to understand the mechanistic basis for individual
variability in pharmacokinetics and pharmacodynamics as a function of
intrinsic (gender, age) and extrinsic (co-administered drugs) factors:
application of pharmacogenomics, pharmacogenetics biological markers,
and surrogate endpoints to link exposure to clinical outcome;
3. Research to develop and evaluate biomarkers, and evaluate
noninvasive imaging as a way to assess safety and efficacy;
4. Computer modeling and clinical trial simulations: evaluation of
clinical study designs to confirm drug safety and efficacy; evaluation
of these techniques in the assessment of gender-, age-,
race-, and liver/kidney function-specific differences in drug response
and drug interactions;
5. Development of electronic databases to capture key metabolism/
drug interaction data and provide a linkage to an expert system to
assist new drug application reviews of pre-clinical and clinical drug
interaction data; and
6. Research to define the clinical pharmacology characteristics
(such as dose-exposure-response) of complex drug substances (such as
conjugated estrogens, botanical, and proteins), to assure proper use of
these substances; research to define the biopharmaceutic
characteristics of the active ingredients for these substances and
development of ways to establish the equivalency of these dosage forms
to establish standards for new and generic product approvals.
III. Reporting Requirements
A Program Progress Report and an annual Financial Status Report
(FSR) (SF-269) are required under 45 CFR 74.51 and 74.52. An original
FSR and two copies shall be submitted to FDA's Grants Management
Officer within 90 days of the budget expiration date of the cooperative
agreement. Failure to file the FSR (SF-269) on time will be grounds for
suspension or termination of the grant. Progress reports will be
required semiannually. The first report will be due 6 months after
award and the second report that will also serve as the annual report
will be due 90 days after the budget expiration date. CDER program
staff will advise the recipient of the suggested format for the Program
Progress Report at the appropriate time. A final FSR (SF-269) and
Program Progress Report must be submitted within 90 days after the
expiration of the project period as noted on the Notice of Grant Award.
Program monitoring of recipients will be conducted on an ongoing
basis and written reports will be reviewed and evaluated at least
semiannually by the Project Officer. Project monitoring may also be in
the form of telephone conversations between the Project Officer/Grants
Management Specialist and the Principal Investigator and/or a site
visit with appropriate officials of the recipient organization. The
results of these monitoring activities will be duly recorded in the
official file and may be available to the recipient upon request.
IV. Mechanism of Support
A. Award Instrument
Support for this program will be in the form of demonstration
cooperative agreements. These demonstration cooperative agreements will
be subject to all policies and requirements that govern the research
grant programs of the Public Health Service, as modified by this RFA,
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.
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B. Eligibility
These demonstration cooperative agreements are available to any
domestic public or private medical school. For-profit entities must
commit to excluding fees or profit in their request for support to
receive awards. Organizations described in section 501(c)(4) of the
Internal Revenue Code of 1968 that engage in lobbying are not eligible
to receive awards.
C. Length of Support
The length of support will be for up to three years. Funding beyond
the first year will be noncompetitive and will depend upon: (1)
Satisfactory performance during the preceding year; and (2) the
availability of Federal fiscal year appropriations.
V. Delineation of Substantive Involvement
Inherent in the cooperative agreement award is substantive
involvement by the awarding agency. Accordingly, FDA will have
substantive involvement in the programmatic activities of all the
projects funded under this RFA. Substantive involvement includes, but
is not limited to, the following:
1. FDA will appoint Project Officers who will actively monitor the
FDA supported program under each award and collaborate with award
recipients;
2. FDA will review experimental protocols describing study
objectives, study design, and data analysis methods prepared by Award
recipients;
3. FDA Project Officers and scientists will collaborate with the
recipient and have final approval on the experimental protocol;
4. FDA will collaborate on the interpretation of findings and may
incorporate information from studies in agency policy decisions
benefiting the public health;
5. FDA Project Officers will be eligible to participate as
coauthors on publications based on the research conducted.
VI. Review Procedure and Criteria
A. Review Method
Grants management and program staff will first review all
applications submitted in response to this RFA for responsiveness to
the RFA. If applications are found to be nonresponsive, they will be
returned to the applicant without further consideration.
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. Responsive applications will
also be subject to a second level of review by a National Advisory
Council for concurrence with the recommendations made by the first
level reviewers, and the final funding decisions will be made by the
Commissioner of FDA or designee.
B. Program Review Criteria
Applicants are strongly encouraged to contact FDA to resolve any
questions regarding criteria or administrative procedure prior to the
submission of their application. All questions of a technical or
scientific nature must be directed to the CDER contact and all
questions of an administrative or financial nature must be directed to
the Grants Management Office. (See the ``FOR FURTHER INFORMATION
CONTACT'' section at the beginning of this document.) Responsiveness
will be based on the following criteria:
1. Post-doctoral training and research studies should be proposed
on one or more of the six clinical pharmacology and biopharmaceutics
objectives listed in this notice under section II: Research Goals and
Objectives;
2. Whether the proposed study is within the budget and costs have
been adequately justified and fully documented;
3. Soundness of the rationale for the proposed study and
appropriateness of the study design to address the objectives of the
RFA;
4. Availability and adequacy of laboratory and associated clinical
pharmacology and biopharmaceutics resources;
5. Availability and adequacy of support services, e.g.,
biostatistics, computers, etc.; and
6. Research experience, training, and competence of the Principal
Investigator and support staff.
VII. Submission Requirements
Applications must contain one or more of the research objectives in
section II of this notice but may also contain other objectives not
specifically identified. However, each objective must be described and
budgeted independently. An overall budget incorporating all objectives
must be submitted as reflected on pages DD and EE of the Grant
Application Form PHS 398 (rev. 5/95).
Budget items normally allowed under Federal research programs will
be considered allowable under this program. In addition, stipend
support may be requested. Stipend levels may not exceed those which are
allowed under NIH regulations. Applicants may refer to the NIH web site
``http://www.nih.gov/grants/guide/notice.files/not98-161.html'' for
current stipend levels. PHS funds can be used for stipends paid only to
a U.S. citizen, a noncitizen national, or a person who has been
lawfully admitted to the U.S. for permanent residence at the time of
the application. Payback requirements are not applicable under this
program. PHS Expanded Authorities do not apply. Indirect costs
requested may not exceed 8 percent and will exclude equipment in the
base.
The original and five copies of the completed Grant Application
Form PHS 398 (Rev. 5/95) with copies of the appendices for each of the
copies, must be delivered to Rosemary Springer (address above). Submit
applications by August 9, 1999. If the closing date falls on a weekend,
it will be extended to Monday; if the date falls on a holiday, it will
be extended to the following workday. No supplemental or addendum
material will be accepted after the receipt date.
The outside of the mailing package and item 2 of the application
face page should be labeled, ``Response to RFA FDA CDER-CP-2000.''
VIII. Method of Application
A. Submission Instructions
Applications will be accepted during normal working hours, 8 a.m.
to 4:30 p.m., Monday through Friday, on or before the established
receipt date. Applications will be considered received on time if sent
or mailed on or before the receipt date as evidenced 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 should note
that 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), National Institutes of Health (NIH). Any application that is
sent to the NIH and therefore not received in time for orderly
processing, will be deemed unresponsive and returned to the applicant.
Instructions for completing the application forms can be found on the
NIH home page on the Internet (address ``http://www.nih.gov/grants/
phs398/phs398.html''; the forms can be found at ``http://www.nih.gov/
grants/phs398/forms_toc.html''). However, as noted above, applications
are not to be
[[Page 37142]]
mailed to the NIH. (Applicants are advised that FDA does not adhere to
the page limitations or the type size and line spacing requirements
imposed by the NIH on its applications). Applications must be submitted
via mail delivery as stated above. FDA is unable to receive
applications electronically. The Institutional National Research
Service Award requirements do not apply.
B. Format for Application
Submission of the application must be on Grant Application Form PHS
398 (Rev. 5/95). All ``General Instructions'' and ``Specific
Instructions'' in the application kit should be followed with the
exception of the receipt dates and the mailing label address. Do not
send applications to the CSR, NIH.
The face page of the application should reflect the request for
applications number RFA-FDA-CDER-CP-2000.
C. Confidentiality of Information
Data included in the application, if restricted with the legend
specified below, 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).
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 the Department of Health and Human Services or
by a court, data contained in the portions of this application which
have been specifically identified by page number, paragraph, etc., by
the applicant as containing restricted information shall not be used or
disclosed except for evaluation purposes.
IX. Paperwork Reduction Act of 1995
In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C.
3501-3520), the Office of Management and Budget (OMB) has assigned OMB
control number 0925-0001 to the collection of information regarding
grant applications in Form PHS 398. This approval expires February 28,
2001.
An agency may not conduct or sponsor, and a person is not required
to respond to, a collection of information unless it displays a
currently valid OMB control number.
Dated: July 2, 1999.
William K. Hubbard,
Senior Associate Commissioner for Policy, Planning and Legislation.
[FR Doc. 99-17505 Filed 7-6-99; 4:04 pm]
BILLING CODE 4160-01-F
