MODEL VALIDATION FOR ANTIEPILEPTOGENIC AND RESISTANT EPILEPSY THERAPIES

RELEASE DATE:  August 21, 2003
 
RFA Number:  RFA-NS-04-002
 
National Institutes of Neurological Disorders and Stroke (NINDS)
 (http://www.ninds.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER:  93.853
 
LETTER OF INTENT RECEIPT DATE:  October 21, 2003

APPLICATION RECEIPT DATE:   November 21, 2003

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA

The NINDS invites applications to validate animal models of 
pharmacoresistant epilepsy or intervention in the epileptogenic 
processes leading to chronic disease.  The goal of this grant program 
is to validate proposed models of pharmacoresistant epilepsy and/or 
antiepileptogenic models for use in drug discovery.  It will establish 
baseline data and introduce new methods for evaluating the therapeutic 
potential of novel compounds for the treatment of epilepsy. 

RESEARCH OBJECTIVES

Background

This solicitation is derived from a congressionally and community 
supported concept identified as one of the epilepsy benchmarks.  The 
concept was defined at the White House initiated Curing Epilepsy 
conference held in March 2000 and two follow-up NIH Workshops: Models 
for Epilepsy and Epileptogenesis held in March 2001 and Identification 
and Characterization of Animal Models of Human Therapy Resistance and 
Epileptogenesis held September 26-27, 2002.

This RFA is designed to validate selected screening paradigms for 
pharmacoresistant epilepsy or for intervention in the disease processes 
that lead to chronic epilepsy (antiepileptogenesis).  Due to the 
similarity expected in eliciting an epilepsy-like state (spontaneous 
recurrent seizures) either chemically or electrically induced models of 
status epilepticus are acceptable.  Proposals for the pharmacologic 
evaluation of drugs in resistant and/or epileptogenic models are being 
sought.  This activity will characterize the effects of standard 
anticonvulsants in representative models.  Results will be shared with 
the research community.  The outcome of this work will provide 
important data for future comparative assessments of new mechanisms 
related to disease processes.  Applicants may focus separately on 
either of the two areas of interest but are not restricted from 
submitting proposals for both. 
 
Areas of Interest

Validations of proposed models for either pharmacoresistance or 
antiepileptogenesis are to be tested.  Proposals addressing one or both 
of the issues are welcomed.  In both adult and pediatric patients, two 
populations appear to exist; a population that is therapy sensitive 
(responds to existing therapies) and one that is therapy resistant.  It 
has recently been reported that up to 35-40 percent of the 2.5 million 
Americans with seizures are resistant to existing therapies.  Yet, the 
basis for this resistance is not understood.  The term 
"pharmacoresistance" applied in the context of animal models is defined 
as persistent seizure activity not responding or with very poor 
response to at least two antiepileptic drugs (AEDs) at maximum 
tolerated doses.  Proposals that address the use and validation of 
either pediatric or adult models to identify effective therapeutic 
agents for resistance are welcomed.
  
A second important focus of the RFA is the need to identify therapies 
that can modify the progression of disease leading to chronic epilepsy.  
Models that incorporate processes involved in epileptogenesis need to 
be validated as potential research tools.  For many decades animal 
models have been used to discover new anticonvulsant therapies. 
Screening has largely been based on utilization of acutely induced 
seizures in "normal brain" systems.  While these models can be used for 
evaluating symptomatic treatments for the convulsions associated with 
epilepsy, they do not allow testing of candidate therapies that may 
slow the progression or reverse the pathophysiology of epileptogensis.  
A common assumption is that a latency period exists between some insult 
(genetic or environmental) and the manifestation of epileptic symptoms.  
Antiepileptogenic or intervention models that allow the measurement of 
a block or delay in development of chronic epilepsy in adult or 
pediatric populations are encouraged.  

This RFA is intended to encourage the development of alternative models 
that may increase the range of anticonvulsant treatments identified and 
may more closely reflect the course of resistance and epileptogenesis.
 
Proposals should:

o provide the rationale for model choice, including relevance of proposed 
model to the human condition and criteria for interpretation of results
o utilize animals with a propensity for spontaneous seizures resulting 
from either electrically or chemically induced status  
o propose candidate drugs, estimate throughput and screening costs 
o define outcome measures (such as prevention, modification of disease 
progression, improved behavioral or cognitive outcomes, prevention of 
neuronal loss)
o explain methods for reporting baseline responses

This effort will establish standard assays that can be employed by 
researchers to continue the search for treatments of drug resistant 
epilepsy and for epileptogenesis.  It will also provide a profile of the 
actions of standard drugs that can be used to evaluate new therapies and 
to provide clues to novel targets and mechanisms of action. 

MECHANISM OF SUPPORT
 
This RFA will use the NIH R21 award mechanism 
(http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html).  As an 
applicant you will be solely responsible for planning, directing, and 
executing the proposed project.  This RFA is a one-time solicitation.  
Future unsolicited, competing-continuation applications based on this 
project will compete with all investigator-initiated applications and 
will be reviewed according to the customary peer review procedures.  
The anticipated award date is July 1, 2004.  Applications that are not 
funded in the competition described in this RFA may be resubmitted as 
NEW investigator-initiated applications using the standard receipt 
dates for NEW applications described in the instructions to the PHS 398 
application.  

This RFA uses just-in-time concepts.  It also uses the modular 
budgeting format. (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).   
Specifically, if you are submitting an application with direct costs in 
each year of $250,000 or less, use the modular format.  This program 
does not require cost sharing as defined in the current NIH Grants 
Policy Statement at 
http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.  

FUNDS AVAILABLE
 
The NINDS intends to commit approximately $1,500,000 in FY 04 to fund 4 
to 6 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 $275,000 over a two-year period.  Because the nature and scope of 
the proposed research will vary from application to application, it is 
anticipated that the size and duration of each award will also vary.  
Although NINDS's financial plans are to provide support for this 
program, awards pursuant to this RFA are contingent upon the 
availability of funds and the receipt of a sufficient number of 
meritorious applications.  
 
ELIGIBLE INSTITUTIONS
 
You may submit (an) application(s) if your institution has any of the 
following characteristics: 
   
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, 
hospitals, and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign
o Faith-based or community-based organizations 

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with their 
institution to develop an application for support.  Individuals from 
underrepresented racial and ethnic groups as well as individuals with 
disabilities are always encouraged to apply for NIH programs.   
 
WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity 
to answer questions from potential applicants.  Inquiries may fall into 
three areas:  scientific/research, peer review, and financial or grants 
management issues:

o Direct your questions about scientific/research issues to:

James P. Stables, PD.,MSA
NINDS/NIH
Neuroscience Center Suite 2106, MSC 9525
6001 Executive Blvd
Rockville, MD 20892
Telephone:  (301) 496-1846
FAX:  (301) 402-2157
Email: js131e@nih.gov

o Direct your questions about peer review issues to:

Alan Willard, Ph.D.
Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd, Rm. 3208
Rockville, MD 20892-9529 (for courier service)
(301) 496-9223 (v)
(301) 402- 0182 (f)
aw135y@nih.gov

o Direct your questions about financial or grants management matters to:

Michael Loewe
Grants Management Officer
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd, Rm. 3258
Rockville, MD 20892-9525
(301) 496-9231 (v)
(301) 402-0219 (f)
ml70m@nih.gov
 
LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that 
includes the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o 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 IC staff to estimate the potential review 
workload and plan the review.
 
The letter of intent is to be sent by the date listed at the beginning 
of this document.  The letter of intent should be sent to:

James P. Stables, PD.,MSA
NINDS/NIH
Neuroscience Center Suite 2106, MSC 9525
6001 Executive Blvd
Rockville, MD 20892
Telephone:  (301) 496-1846
FAX:  (301) 402-2157
Email: js131e@nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001). Applications must 
have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) 
number as the Universal Identifier when applying for Federal grants or 
cooperative agreements. The DUNS number can be obtained by calling 
(866) 705-5711 or through the web site at http://www.dunandbradstreet.com. 
The DUNS number should be entered on line 11 of the face page of the 
PHS 398 form. The PHS 398 document is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an 
interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.
 
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications 
requesting up to $250,000 per year in direct costs must be submitted in 
a modular grant format.  The modular grant format simplifies the 
preparation of the budget in these applications by limiting the level 
of budgetary detail.  Applicants request direct costs in $25,000 
modules.  Section C of the research grant application instructions for 
the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 
5/2001) application form must be affixed to the bottom of the face page 
of the application.  Type the RFA number on the label.  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. The RFA 
label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: 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 
must be sent to:

Alan Willard, Ph.D.
Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd, Rm. 3208
Rockville, MD 20892-9529 (for courier service)
(301) 496-9223 (v)
(301) 402- 0182 (f)
aw135y@nih.gov
 
APPLICATION PROCESSING: Applications must be received on or before the 
application receipt date listed in the heading of this RFA.  If an 
application is received after that date, it will be returned to the 
applicant without review. 

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and 
funding assignment within 8 weeks.
 
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.  However, when a previously unfunded application, 
originally submitted as an investigator-initiated application, is to be 
submitted in response to an RFA, it is to be prepared as a NEW 
application.  That is the application for the RFA must not include an 
Introduction describing the changes and improvements made, and the text 
must not be marked to indicate the changes.  While the investigator may 
still benefit from the previous review, the RFA application is not to 
state explicitly how.

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the 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 
evaluated for scientific and technical merit by an appropriate peer 
review group convened by the NINDS in accordance with the review 
criteria stated below.  As part of the initial merit review, all 
applications will:

o Receive a written critique
o Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications 
under review, will be discussed and assigned a priority score
o Receive a second level review by the appropriate National Advisory 
Council or Board. 
 
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: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment

The scientific review group will address and consider each of these 
criteria in assigning the application's overall score, weighting them 
as appropriate for each application.  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.

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?

APPROACH: Are the conceptual framework, 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?

INNOVATION: Does the project employ novel concepts, approaches or 
methods?  Are the aims original and innovative?  Does the project 
challenge existing paradigms or develop new methodologies or 
technologies?

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)?

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?  

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the 
following items will be considered in the determination of scientific 
merit and the priority score:

o model selection and relevance to human syndromes 
o drug selection, realistic testing throughput and screening costs
o criteria for interpretation of results     
o demonstration of spontaneous seizures 
o clearly defined and measurable outcomes

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals 
are to be used in the project, the five items described under Section f 
of the PHS 398 research grant application instructions (rev. 5/2001) 
will be assessed.  

ADDITIONAL CONSIDERATIONS  

DATA SHARING: The adequacy of the proposed plan to make available data 
generated from the validation process. 

BUDGET: The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date: October 21, 2003 
Application Receipt Date: November 21, 2003
Peer Review Date: February 2004
Council Review: May 2004
Earliest Anticipated Start Date: July 1, 2004

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.

REQUIRED FEDERAL CITATIONS

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: 
The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom of 
Information Act (FOIA) under some circumstances.  Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA.  It is important for 
applicants to understand the basic scope of this amendment.  NIH has 
provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application. In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

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.  Furthermore, we caution reviewers that their anonymity 
may be compromised when they directly access an Internet site.

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 of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject 
to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review.  Awards are made under the 
authorization of Sections 301 and 405 of the Public Health Service Act 
as amended (42 USC 241 and 28) and under Federal Regulations 42 CFR 52 
and 45 CFR Parts 74 and 92.  All awards are subject to the terms and 
conditions, cost principles, and other considerations described in the 
NIH Grants Policy Statement.  The NIH Grants Policy Statement can be 
found at http://grants.nih.gov/grants/policy/policy.htm 

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the 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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