[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.

[[Page 37141]]

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