NIMH THERAPEUTIC EFFECTIVENESS PROTOCOL DEVELOPMENT PROGRAM

Release Date:  June 23, 1999 (see replacement PAR-03-078)

PA NUMBER:  PAR-99-119

National Institute of Mental Health

Application Receipt Dates:  October 1, February 1, and June 1

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

PURPOSE

The National Institute of Mental Health (NIMH) seeks to promote development of
highly informative effectiveness trials that evaluate treatments for mental
disorders.  This program announcement (PA) is directed toward the development
of infrastructure and resources for investigation of effectiveness of
therapeutic interventions through support of protocol design.  This PA has
been developed in response to a recommendation of the Clinical Treatment and
Services Research Workgroup of the National Advisory Mental Health Council. 
This program will support effectiveness trial development that will lead to
large-scale studies focusing on diseases and populations of major public
health significance that are consistent with the mission of the NIMH.  This is
part of a series of four program announcements making up a broad scale public
health oriented intervention research.  The other three program announcements
are INTERVENTIONS INFRASTRUCTURE PROGRAM (PAR-99-064), NIMH POSTDOCTORAL
RESEARCH TRAINING IN INTERVENTION TRIALS, (PA-99-072), and PILOT EFFECTIVENESS
TRIALS FOR MENTAL DISORDERS (PAR-99-118).

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, NIMH THERAPEUTIC
EFFECTIVENESS PROTOCOL DEVELOPMENT PROGRAM, is related to the priority area of
mental health and mental disorders.  Potential applicants may obtain a copy of
"Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic, for-profit and non-profit 
organizations, public and private, such as universities, colleges, hospitals,
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.

MECHANISM OF SUPPORT

The mechanism of support will be the Exploratory/Developmental Planning Grant
(R21) of the National Institutes of Health, which will provide up to a maximum
of $125,000 in direct cost per year for up to three years. Applicable
Facilities and Administrative (formerly known as indirect costs) will be
applied.  The award is not renewable.  Responsibility for the planning,
direction, and execution of the proposed project will be solely that of the
applicant.

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
http://www.nih.gov/grants/funding/modular/modular.htm

RESEARCH OBJECTIVES

The NIMH strongly encourages innovative public health-oriented research
designed to evaluate the effectiveness of therapeutics directed at mental
disorders.  This program has been established in order to facilitate the major
investment of effort and planning required for development of large-scale
effectiveness trials.  The overall goal of this announcement is the
improvement of practice directed toward treatment of mental disorders in
nonselected representative populations of patients in a broad range of
specialty and general health care settings.

The NIMH hopes to accelerate the widespread application of efficacious
treatments through the adoption of a public health model of intervention
research.  In a public health model, exclusion criteria are minimal (based
primarily on concerns for safety).  Rather than being criteria for exclusion,
age, gender, and comorbidity should become important factors that assure
sample representativeness and clinical generalizability.  Outcomes should be
broadly construed, to include performance, relationships (family,
interpersonal etc.), function, disability, quality of life, morbidity,
mortality, institutionalization, and health care resource use.  Settings
should be widely selected from a full range of academic and nonacademic
institutions, specialty and primary care, public and private facilities. 
Projected sample sizes should be sufficiently large to assure adequate power.

In order to facilitate development of research that achieves these goals, this
program will make support available for the establishment of multi-site
collaborations, communication between investigators, standardization of
research instruments, training research personnel, power analysis, database
construction, and patient recruitment efforts.  Each of these activities
should be directed toward the planning and design of a large-scale
effectiveness protocol.  The expected product will be a well-designed and
scientifically sound protocol complete with detailed operating manuals for
specified multi-center randomized effectiveness trials.

This program is not intended to support the gathering of pilot data.  A
separate Program Announcement has been developed for this purpose (PILOT
EFFECTIVENESS TRIALS FOR MENTAL DISORDERS).  It is assumed that prior to
submission for funding, investigators will have access to necessary
preclinical information, preliminary data on efficacy, and adequate
characterization of target patient populations.  Funding is not renewable and
it is expected that the proposed effectiveness trials will be funded through
other mechanisms.  These mechanisms would include R01s and other Federal
funding mechanisms.  In addition, support from industry through cooperative
agreements and other mechanisms is possible.  The ultimate goal of this
program will be the development of sound and complete research protocols that
will support further investigation.

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 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23,
No. 11, March 18, 1994 available on the web at the following URL address: 
http://www.nih.gov/grants/guide/1994/94.03.18/notice-nih-guideline008.html

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under that the age of
21) must be included in all human subjects 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 human subjects should read the
NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: http://www.nih.gov/grants/guide/notice-files/not98-024.html

APPLICATION PROCEDURES

Applicants are strongly encouraged to contact the program staff listed under
INQUIRIES with any questions regarding their proposed project and the goals of
this PA.

The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants.  The standard application deadlines as indicated in
the application kit should be followed.  Application kits are available at
most institutional offices of sponsored research and 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: [email protected].  Applications are also available on the World
Wide Web at: http://www.nih.gov/grants/forms.htm

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 $125,000 per year.  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 $125,000) 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 http://www.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:
http://www.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.

Applications not conforming to these guidelines will be considered
unresponsive to this PA and will be returned without further review.

The title and number of the program announcement must be typed in Section 2 on
the face page of the application.

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  20892-7710
BETHESDA, MD  20817 (for courier/overnight mail service)

Two additional copies must be sent or delivered to:

Henry J. Haigler, Ph.D
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6154 MSC 9608
Bethesda, MD 20892-9608

REVIEW CONSIDERATIONS

Applications will be evaluated for scientific and technical merit by an
appropriate scientific review group convened by NIMH in accordance with the
standard NIH peer review procedures.  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 appropriate national
advisory council or board.

Review Criteria:

All applications will be reviewed using the criteria below:

(1) Significance.  Does this study address a clinical problem of sufficient
public health significance?  If the aims of the multi-center effectiveness
trial planned under this award are achieved, will current clinical treatments
be significantly improved?  The background and significance section of the
application must discuss the rationale for further development of a large
multi-center effectiveness trial.

(2) Approach.  Are the conceptual framework, design, methods, and analyses
adequately developed and appropriate for the objectives of effectiveness trial
design?  The following methodological issues should be addressed:

Appropriateness of stated statistical hypotheses;
Selection of valid and clinically meaningful outcome measure(s);
Inclusion and exclusion criteria;
Ethical and safety issues;
Quality control and integrity of data;
Necessity for randomization and use of placebo or appropriate comparator drug;
Specific methods to be used for data management and analysis;
Population and demographics of the study subjects;
Potential for ancillary studies exploring basic and clinical research
questions.

(3) Innovation.  Does the project employ novel concepts or methods?  Does the
project extend or significantly add to existing clinical knowledge?

(4) Investigator. Is the investigator appropriately trained and well suited to
carry out this work?  Is the work proposed appropriate for the experience
level of the principal investigator?

(5) Environment.  Does the scientific environment in which the work will be
done contribute to the probability of success?  Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements?  Is there evidence of institutional
support?

(6) Appropriateness of the proposed budget and duration in relation to the
proposed research;

(7) Adequacy of plans to include genders, children and adolescents, and
minorities and their subgroups as appropriate for the scientific goals of the
research, or justification for their exclusion.  Plans for the recruitment and
retention of subjects will also be evaluated.

The initial review group will also examine the provisions for the protection
of human and animal subjects, the safety of the research environment, and
conformance with the NIH guidelines for Inclusion of Women, Children and
Adolescents and Minorities as Subjects in Clinical Research.

AWARD CRITERIA

Applications will compete for available funds with all other recommended
applications.  The following will be considered in making funding decisions:

Quality of the proposed project as determined by peer review, availability of
funds, and program priority.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or questions
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Herbert W. Harris, M.D., Ph.D. (adult and geriatric)
National Institute of Mental Health
6001 Executive Blvd, Room 7160 MSC 9635
Bethesda, MD  20892-9635
Telephone:  (301) 443-9125
FAX:  (301) 594-6784
Email: [email protected]

Benedetto Vitiello, M.D. (child and adolescent)
National Institute of Mental Health
6001 Executive Blvd, Room 7160 MSC 9635
Bethesda, MD  20892-9635
Phone: (301) 443-4283
Fax: (301) 443-4045
Email:  [email protected]

Direct inquiries regarding fiscal matters to:

Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
6001 Executive Blvd, Room 6115 MSC 9605
Bethesda, MD  20892-9605
Telephone: (301) 443-2805
FAX:  (301) 443-6885
Email:  [email protected]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.242.  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.  Awards will be administered under NIH Grants Policy
Statement (effective 10/1/98).

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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