NIDCR CLINICAL TRIAL PLANNING GRANT

Release Date:  August 23, 1999 (see replacement PAR-03-042)

PA NUMBER:  PAR-99-157

National Institute of Dental and Craniofacial Research

THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.

PURPOSE

The National Institute of Dental and Craniofacial Research (NIDCR) is committed
to identifying effective preventive, diagnostic and treatment approaches to
craniofacial, oral and dental diseases and disorders that will improve health by
supporting well-executed clinical trials.  Clinical trials in one of the
following five scientific areas are encouraged and sought: Inherited Craniofacial
Diseases and Injury; Infectious Diseases; Neoplastic Diseases of the Head and
Neck; Chronic Disabling Diseases including pain conditions, temporomandibular
joint diseases, autoimmune diseases, and bone diseases; and Biomimetics, Tissue
Engineering and Biomaterials. The National Cancer Institute also has an active
interest in clinical trials related to head and neck neoplasms and may also fund
planning grants in this area.  The NIDCR is also interested in supporting
clinical trials aimed at evaluating interventions that can have their effect on
other systemic conditions (e.g., preterm low birthweight babies, cardiovascular
disease) through prevention, diagnosis or treatment of craniofacial, oral or
dental conditions (e.g., oral infections) and promotion of craniofacial, oral and
dental health. Before proceeding to a full-scale randomized clinical trial,
significant planning is often required.  The NIDCR Clinical Trial Planning Grant
allows for early peer review of the rationale and design of clinical trials of
interventions aimed at preventing or treating diseases and provides support for
the development of a detailed clinical trial research plan, including a complete
field-tested manual of operations and procedures.  Since many of the
craniofacial, oral and dental diseases and disorders for which clinical
interventions are designed to occur in scattered populations, the planning grant
can also be useful in supporting the development of clinical trial research
networks to develop multi-center clinical trials.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This PA, NIDCR Clinical Trial Planning
Grant, addresses the priority area of craniofacial, oral and dental health and
related objectives.  Potential applicants may obtain a copy of "Healthy People
2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No.
017-001-00473-1) through the Superintendent of Documents, Government Printing
Office, Washington, DC 20402-9325 (telephone 202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals, and
laboratories, units of State and local governments, and eligible agencies of the
Federal government.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.  All multi-
center trials must include a coordinating center.

MECHANISM OF SUPPORT

The mechanism of support will be the Developmental Planning Grant (R21).  For a
single-center trial the Institute will provide up to $250,000 in total costs
(direct costs plus facilities and administrative costs) for a single year. For
multi-center trials, each enrollment center and the coordinating center may apply
separately for a grant or the coordinating center may apply on behalf of each
enrollment center.  In either case, the total costs for each enrollment center
may not exceed $175,000 or $250,000 for the coordinating center. The award may
not be renewed.

Specific application instructions have been modified to reflect "MODULAR GRANT"
and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and
detailed instructions and information on Modular Grant applications can be found
at https://grants.nih.gov/grants/funding/modular/modular.htm

RESEARCH OBJECTIVES

Dental and craniofacial diseases and disorders are among the most common health
problems affecting the people of the United States and around the world. The
burden imposed by a variety of dental and craniofacial diseases and disorders
range from birth defects such as cleft lip and palate, which occurs in every 1
in 525 to 714 live births, to injuries to the head and face, resulting in nearly
20 million emergency room visits per year, to devastating head and neck cancers,
accounting for 8000 deaths and over 30,000 new cases per year.  The treatment of
over 1.2 million cancer patients each year can lead to painful mouth ulcers,
mucositis, rampant dental caries, fungal infections, impaired taste and loss of
function of the salivary glands.  Oral infections still remain common in our
populations.  Dental caries is experienced by 45% of school children and 94% of
adults have experienced this infection at some point in life.  Periodontal
infections occur in 90% of individuals older than 13 years and may be associated
with other systemic diseases or conditions such as diabetes, cardiovascular
disease, respiratory infections, and pre-term/low birth weight babies. Orofacial
pain is likely to have been experienced by over 20% of adults in the past six
months, is a major component of temporomandibular joint diseases (TMD) for at
least 6% of adults, and is a major component of Bell's palsy, trigeminal
neuralgia and fibromyalgia.  Salivary gland dysfunction in the form of Sjogren's
syndrome affects between 1 and 4 million Americans while over 30,000 individuals
who have cystic fibrosis are also at higher risk for concomitant salivary gland
dysfunction. Further, over 500 prescription drugs have xerostomic (dry mouth)
side effects, increasing the risk for both bacterial and fungal oral infections
as well as other oral conditions.  Oral candidiasis is commonly found in HIV-
infected patients.

The objective of the NIDCR Clinical Trial Planning Grant is to address
preliminary design and methodological issues for specific clinical trials used
to evaluate interventions for the treatment or prevention of craniofacial, oral
and dental diseases and disorders as well as the promotion of craniofacial, oral
and dental health.  The NIDCR Clinical Trial Planning Grant provides support for
activities relating to the development of specific elements which will be
essential to conducting a successful full-scale clinical trial, particularly
multi-center trials.  These elements can include adequate plans for recruitment
of patients, experimental design and protocols, data management, analytical
techniques, facilities, administrative procedures, and collaborative
arrangements.  Detailed information regarding the rationale of the clinical
trial, based on adequate, preclinical science and preliminary clinical research
(e.g., meta-analysis and/or literature review), must be developed prior to
submission and included in the application for a Clinical Trial Planning Grant
and will not be supported through this initiative. Further, the purpose of the
planning grant is not to obtain preliminary data or to conduct studies to support
the rationale for the clinical trial. These activities are supported through
other grant mechanisms including the NIDCR Clinical Trial Pilot Grant.  The
expected product of the planning grant is a detailed clinical trial research plan
including a complete field-tested manual of operations and procedures.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and their
subpopulations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the research.  This
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 20, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No.
11, March 28, 1994.

INCLUSION OF CHILDREN IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subject research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them.  This
policy applies to all initial (Type 1) applications submitted for receipt dates
after October 1, 1998.

All investigators proposing research involving children as subjects should read
the "NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN
RESEARCH INVOLVING HUMAN SUBJECTS," which were published in the NIH Guide for
Grants and Contracts, Vol. 27, No. 8, March 6, 1998.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted at the standard application deadlines as indicated in
the application kit.  Applications kits are available at most institutional
offices of sponsored research and may be obtained from the Division of Extramural
Outreach and Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email:
GrantsInfo@nih.gov.  The title and number of the program announcement must be
typed in Section 2 on the face page of the application. As with most applications
to NIH, the research plan is limited to 25 pages. All information for review of
the NIDCR Clinical Trial Planning Grant application must be included in the body
of the application; appendices will not be considered during the review for this
mechanism.

The completed original application and three legible copies must be sent or
delivered to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892
BETHESDA, MD  20817 (for express/courier service)

In order to facilitate the review of applications assigned to the NIDCR, the
applicant must, at the same time, mail or deliver two copies of the application
to:

Dr. H. George Hausch
Division of Extramural Research
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-38D - MSC 6402
Bethesda, MD  20892-6402

The modular grant concept establishes specific modules in which direct costs may
be requested as well as a maximum level for requested budgets.  Only limited
budgetary information is required under this approach.  The just-in-time concept
allows applicants to submit certain information only when there is a possibility
for an award. It is anticipated that these changes will reduce the administrative
burden for the applicants, reviewers and Institute staff.  The research grant
application form PHS 398 (rev. 4/98) is to be used in applying for these grants,
with the modifications noted below.

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up to
a total direct cost request of $250,000 per year. (Applications that request more
than $250,000 direct costs in any year must follow the traditional PHS 398
application instructions.) The total direct costs must be requested in accordance
with the program guidelines and the modifications made to the standard PHS 398
application instructions described below:

PHS 398

o  FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total
Direct plus Facilities and Administrative  (F&A) costs] for the initial budget
period Items 8a and 8b should be completed indicating the Direct and Total Costs
for the entire proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4
of the PHS 398. It is not required and will not be accepted with the application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398. It is not required and
will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative
page. (See https://grants.nih.gov/grants/funding/modular/modular.htm for sample
pages.) At the top of the page, enter the total direct costs requested for each
year.  This is not a Form page.

o  Under Personnel, list key project personnel, including their names, percent
of effort, and roles on the project.  No individual salary information should be
provided.  However, the applicant should use the NIH appropriation language
salary cap and the NIH policy for graduate student compensation in developing the
budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct plus
facilities and administrative) for each year, each rounded to the nearest $1,000. 
List the individuals/organizations with whom consortium or contractual
arrangements have been made, the percent effort of key personnel, and the role
on the project.  Indicate whether the collaborating institution is foreign or
domestic.  The total cost for a consortium/contractual arrangement is included
in the overall requested modular direct cost amount.  Include the Letter of
Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the
number of modules requested.

o  BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual's qualifications for a specific
role in the proposed project, as well as to evaluate the overall qualifications
of the research team.  A biographical sketch is required for all key personnel,
following the instructions below.  No more than three pages may be used for each
person.  A sample biographical sketch may be viewed at:
https://grants.nih.gov/grants/funding/modular/modular.htm

- Complete the educational block at the top of the form page; - List position(s)
and any honors;
- Provide information, including overall goals and responsibilities, on research
projects ongoing or completed during the last three years. - List selected peer-
reviewed publications, with full citations;

o  CHECKLIST - This page should be completed and submitted with the application. 
If the F&A rate agreement has been established, indicate the type of agreement
and the date.  All appropriate exclusions must be applied in the calculation of
the F&A costs for the initial budget period and all future budget years.

o  The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information is
necessary following the initial review.

REVIEW CONSIDERATIONS

Applications will be reviewed evaluated for scientific and technical merit by an
appropriate peer review group convened by the NIDCR in accordance with the review
criteria stated below.  As part of the initial merit review all applications will
receive a written critique and undergo a process in which only those applications
deemed to have the highest scientific merit, generally the top half of
applications under review, will be discussed, assigned a priority score, and
receive a second level review by the National Advisory Dental and Craniofacial
Research Council.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In the
written review, comments on the following aspects of the application will be made
in order to judge the likelihood that the proposed research will have a
substantial impact on the pursuit of these goals.  Each of these criteria will
be addressed and considered in the assignment of the overall score, weighting
them as appropriate for each application.  Note that the application does not
need to be strong in all categories to be judged likely to have major scientific
impact and thus deserve a high priority score.  For example, an investigator may
propose to carry out important work that by its nature is not innovative but is
essential to move a field forward.

(1) Rationale.  The background and significance of the application must address
the rationale for a future, full-scale, randomized clinical trial (RCT)
including:
- reasons for selection of intervention and mode of delivery including specific
details such as dose or a particular procedure;
- the biological mechanisms and clinical data that support conducting an RCT; -
information adequate to determine the significance and need to perform an RCT;
- compelling need to proceed with an RCT as soon as possible; - impact on health
care;
- competitive therapies - including both clinical and economic advantages and
disadvantages of each;
- ethical issues surrounding an RCT and the disease under study; and - a clear
statement of the question that an RCT would address.

(2) Study Design.  The application for a planning grant will include a full
description of the proposed experimental design of the future RCT.  While the
criteria listed below apply to all clinical trials, specific issues of particular
relevance to multi-center trials such as standardization/quality control of and
adherence to the clinical protocol and data collection or distribution, the use
of a coordinating center is required: - translation of the clinical question into
a statistical hypothesis; - sample size and duration of the RCT;
- endpoint(s) and data to be collected including relevance to the clinical and
statistical hypothesis being tested;
- randomization, masking (if appropriate), and inclusion/exclusion criteria; -
strengths and weaknesses of the proposed methods and possible alternatives;
ancillary therapies;
- plans to standardize and track adherence to the clinical protocol in each
center; and
- methods for standardization of procedures for data management and quality
control.

(3) Plans to Address Patient Recruitment/Retention. The application must address
the following items:
- availability of the requisite eligible patient pool;
- availability of children, women and minority individuals as trial participants
and specific recruitment and retention plans for their inclusion; and
- plans for recruitment outreach and, as appropriate, follow-up procedures to
ensure collection of data at stated intervals.

(4) Investigators. The application must include a clear statement of the
leadership and proposed organization of the RCT, including: - identification of
a principal investigator, and for multi-center trials, a core of potential center
investigators and staffing for a coordinating center; - professional training and
experience of the RCT organizers in such areas as the clinical problem under
study, administration of complex projects, and study design;
- inclusion of statisticians, data managers and study coordinators; - procedures
and plans for adding or dropping centers;
- for multi-center trials, the proposed organizational structure of the trial
particularly as related to the organizational relationships among the enrollment
centers and between the coordinating center and the enrollment centers; and
- essential committee structure appropriate to the complexity of the trial (e.g.,
Planning, Steering, Executive committees).

AWARD CRITERIA

Applications will compete for available funds with all other recommended
applications.  Quality of the proposed project as determined by peer review,
availability of funds, and program priority will be considered in making funding
decisions.

INQUIRIES

Inquiries are encouraged early in the development of the application.  The
opportunity to clarify any issues or questions from potential applicants is
welcome.

Direct inquiries regarding programmatic issues to:

Dr. Maryann Redford
Division of Extramural Research
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-24B, MSC 6402
Bethesda, MD 20892-6402
Telephone:  (301) 594-5588
FAX:  (301) 480-8318
Email: Maryann.Redford@nih.gov

Direct inquiries regarding fiscal matters to:

Mr. Martin R. Rubinstein
Division of Extramural Research
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-44A, MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800
Email:  Martin.Rubinstein@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.121.  Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241
and 285) and administered under PHS grants policies and Federal Regulations 42
CFR 52 and 45 CFR Part 74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant and contract recipients to provide a smoke-
free workplace and promote the non-use of all tobacco products.  In addition,
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American people.

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