PILOT CLINICAL TRIAL GRANTS FOR PHARMACOLOGICAL INTERVENTIONS IN PEDIATRIC TBI

Release Date:  Spetember 5, 2000

RFA:  HD-00-024
 
National Institute of Child Health and Human Development
 (http://www.nichd.nih.gov)
National Institute of Neurological Disorders and Stroke
 (http://www.ninds.nih.gov)

Letter of Intent Receipt Date:  October 2, 2000
Application Receipt Date:       November 17, 2000

THIS RFA 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 RFA.

PURPOSE
 
The National Institute of Child Health and Human Development (NICHD) and the 
National Institute of Neurological Disorders and Stroke (NINDS) are committed 
to evaluate the efficacy of specific pharmacological interventions to improve 
outcomes in pediatric patients following Traumatic Brain Injury (TBI), by 
supporting well-executed clinical trials.  Before proceeding to a large 
clinical trial, pilot clinical studies are often required.  The NICHD and 
NINDS are interested in supporting pilot studies required to obtain necessary 
information to clearly establish the clinical basis for proceeding to a full-
scale trial.  The purpose of a Pilot Clinical Trial Grant for Pharmacological 
Interventions in Pediatric TBI is to obtain preliminary data and conduct 
studies to support the rationale for a subsequent full-scale clinical trial 
of pharmacological intervention.

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a PHS-
led national activity for setting priority areas.  This RFA is related to one 
or more priority areas. Potential applicants may obtain "Healthy People 2010" 
at: http://www.health.gov/healthypeople.

ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by domestic and foreign, 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

This RFA will use the National Institutes of Health (NIH) Individual 
Exploratory/ Developmental Research Grant (R21) award mechanism.  
Responsibility for the planning, direction, and execution of the proposed 
project will be solely that of the applicant.  The total project period for 
an application submitted in response to this RFA may not exceed two years.   
This RFA is a one-time solicitation.  The anticipated award date is July 1, 
2001.

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

FUNDS AVAILABLE

The NICHD and NINDS each intend to commit approximately $750,000 in total 
costs [direct plus Facilities and Administrative (F&A) costs] in FY 2001 to 
fund up to seven new grants in response to this RFA.  An applicant may 
request a project period of up to two years and a budget for direct costs of 
up to $150,000 per year.  Although this program is provided for in the 
financial plans of NICHD and NINDS, awards pursuant to this RFA are 
contingent upon the availability of funds and the receipt of a sufficient 
number of meritorious applications.

RESEARCH OBJECTIVES

Background
 
Over the past decade, many neuroprotective agents have been developed to 
improve the outcome in patients with acute cerebral disorders such as stroke, 
subarachnoid hemorrhage, and head injury.  A number of different classes of 
drugs (e.g., calcium channel blockers, glutamate antagonists, cholinesterase 
inhibitors) have been tested in head-injured adults across the stages of 
recovery.  Although there are data regarding the mechanism of action of such 
drugs in adults, little information exists on the safety or efficacy of 
pharmaceuticals in children.  Adjunctive pharmacological treatment has also 
been suggested to facilitate behavioral management during the rehabilitation 
process and to improve functional outcome.  While small case studies in 
adults suggest that some of these agents may be useful for improving 
attention and memory and, possibly, for enhancing plasticity, there is a 
dearth of information on appropriate dosages and effects of these agents in 
pediatric TBI patients.

Research Scope

The objective of the NICHD/NINDS Pilot Clinical Trial Grant is to promote 
clinical trials research to evaluate efficacy of pharmacological 
interventions for the physiological and behavioral sequelae of TBI in 
pediatric patients.  To meet this objective, the proposed pilot study must 
successfully incorporate creative and realistic solutions to difficult 
problems in clinical neurological research for the particular intervention 
being evaluated.

Research topics responsive to this RFA include, but are not limited to, the 
following:

o  Collection of preliminary data for establishing measures of efficacy and 
safety in children; 

o  Neuropsychological studies that target higher cognitive functions as 
possible outcome measures;

o  New statistical methods that approach such issues as change over time, 
assessment based on specific recovery curves of individual children, or 
psychosocial parameters before and after injury;

o  Studies to refine intervention strategies (dosage, duration, delivery 
system) for children across age ranges;

o  Development of new pharmacotherapies for children that consider age as a 
factor;

o  Development of paradigms to focus on age-specific biology, including 
toxicological risks within age groups;

o  Evaluation of interactions of pharmacological agents and behavioral 
treatments; 

o  Studies to define and refine target population among developmental stages 
in children;

o  Studies of the safety of drugs being tested/used in adult TBI;

o  Approaches to long-term assessment of behavioral change among various ages 
of older children injured within the first four years of postnatal life.

The application should directly address how the Pilot Grant will advance the 
design of a subsequent full-scale clinical trial.  The application also 
should address the intrinsic scientific value of the study to be conducted 
under the Pilot Grant, whether or not a full-scale trial is performed.

In preparing for the definitive clinical trial, a pilot study should address 
questions that are formulated to optimize the design of the eventual trial 
rather than address the clinical question with lower power.

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 sub-populations must be included in all NIH-supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are provided indicating 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 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated Guidelines are available at  
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:  The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to provide a description of plans 
to conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS 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 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,” published in the NIH Guide for Grants and 
Contracts, March 6, 1998, and available on the Internet at:  
http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

Investigators may also obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, Internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.
 
LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes a 
descriptive title of the proposed research, the name, address, and telephone 
number of the Principal Investigator, the identities of other key personnel 
and participating institutions, and the number and title of this RFA.  
Although a letter of intent is not required, is not binding, and does not 
enter into the review of a subsequent application, the information that it 
contains allows NICHD staff to estimate the potential review workload and 
plan the review.

The letter of intent is to be sent to Dr. Beth Ansel at the address listed 
under INQUIRIES, below, by October 2, 2000.

APPLICATION PROCEDURES 

The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants. These forms are available at most institutional 
offices of sponsored research, on the Internet at 
http://grants.nih.gov/grants/funding/phs398/phs398.html, and from the 
Division of Extramural Outreach and Information Resources, National 
Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-
7910, telephone 301-435-0714, E-mail:  grantsinfo@nih.gov. 

Application Instructions

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 NIH 
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.

For responses to this RFA, Modular Grant applications will request direct 
costs in $25,000 modules, up to a total direct cost request of $150,000 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:

o FACE PAGE:  Items 7a and 7b should be completed, indicating Direct Costs 
(in $25,000 increments up to a maximum of $150,000) 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://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 ALL 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 F & A) 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://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 telephone number of the 
individual to contact concerning fiscal and administrative issues if 
additional information is necessary following the initial review.

Submission Instructions  

The RFA label available in the PHS 398 (rev. 4/98) application form must be 
stapled to the bottom of the face page of the application and must display 
the RFA number HD-00-024.  A sample RFA label is available at 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.  Please note this 
is in the pdf format.  Failure to use this label could result in delayed 
processing of the application such that it may not reach the review committee 
in time for review.  In addition, the RFA title and number must be typed on 
line 2 of the face page of the application form and the YES box must be 
marked.

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed photocopies, in one package to:

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

At the time of submission, two additional copies of the application should 
also be sent to:

L. R. Stanford, Ph.D.
Director, Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5E03F, MSC 7510
Bethesda, MD 20892-7510
Bethesda, MD 20854 (for express/courier service)

Applications must be received by November 17, 2000.  If an application is 
received after that date, it will be returned to the applicant without 
review.  

The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed.  This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must 
include an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and for 
responsiveness by NICHD and NINDS.  Incomplete and/or non-responsive 
applications will be returned to the applicant without further consideration.

Applications that are complete and responsive to the RFA will be reviewed for 
scientific and technical merit by a review group convened by the Division of 
Scientific Review, NICHD.  As part of the initial merit review, all 
applications will receive a written critique and may undergo a process in 
which only those applications deemed to have the highest scientific merit 
will be discussed, assigned a priority score, and receive a second level 
review by the National Advisory Council of NICHD and/or NINDS. 

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 comments, reviewers will be asked to discuss the following 
aspects of the application 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 assigning 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) Significance:  Does this study address an important problem?  If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

(2) Approach:  Are the conceptual frameworks, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

(3) Innovation:  Does the project employ novel concepts, approaches or 
method?  Are the aims original and innovative?  Does the project challenge 
existing paradigms or develop new methodologies or technologies? 

(4) Investigator:  Is the investigator appropriately trained and well suited 
to carry out this work?  Is the work proposed appropriate to the experience 
level of the Principal Investigator and other researchers (if any)?

(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?

In addition to the above criteria, in accordance with NIH policy, 
applications also will be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects also will be 
evaluated.

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  The adequacy of the proposed protection for humans, animals, and the 
environment, to the extent they may be adversely affected by the project 
proposed in the application.

Schedule

Application Receipt Date:         November 17, 2000
Letter of Intent Receipt Date:    October 2, 2000
Peer Review Date:                 February/March 2001
Council Review:                   June 2001
Earliest Anticipated Start Date:  July 1, 2001

AWARD CRITERIA 

Funding decisions will be based on scientific and technical merit as 
determined by peer review, program balance and need, and the availability of 
funds.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or questions from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:

Beth M. Ansel, Ph.D., CCC-SLP
Director, Clinical Practices Research Program 
National Center for Medical Rehabilitation Research
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 2A03, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 402-2242
FAX:   (301) 402-0832
E-mail:  Beth_Ansel@nih.gov
 
Mary Ellen Cheung, Ph.D.
National Institute of Neurological Disorders and Stroke
Neuroscience Center
6001 Executive Boulevard, Room 2209, MSC 9525
Bethesda, MD  20892-9525
Rockville, MD  20852 (courier service)
Telephone:   (301) 496-1447
FAX:  (301) 480-1080
E-mail:  mm108w@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Mary Ellen Colvin
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17H, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-1304
FAX:  (301)  402-0915
E-mail:  ColvinM@mail.nih.gov

Ms. Rita Rollins-Hickey
Grants Management Branch
National Institute of Neurological Disorders and Stroke
Neuroscience Center
6001 Executive Boulevard, Room 3254, MSC 9525
Bethesda, MD  20892-9525
Telephone:  (301) 496-7488
E-mail:  rr46W@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos. 
93.929 and 93.853.  Awards are made under authorization of Sections 301 and 
405 of the Public Health Service Act as amended (42 USC 241 and 284) and 
administered under NIH grants policies and Federal Regulations 42 CFR 52 and 
45 CFR Parts 74 and 92.  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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