DEVELOPING TRANSLATIONAL RESEARCH ON MECHANISMS OF EXTINCTION LEARNING

RELEASE DATE:  August 20, 2003

RFA Number:  RFA-MH-04-005

National Institute of Mental Health (NIMH)
 (http://www.nimh.nih.gov)
National Institute on Drug Abuse (NIDA)
 (http://www.nida.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):  93.272, 92.279

LETTER OF INTENT RECEIPT DATE:  November 18, 2003

APPLICATION RECEIPT DATE:  December 18, 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  Special Requirements
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 National Institute of Mental Health (NIMH) and the National Institute on 
Drug Abuse (NIDA) seek to encourage the development of collaborative research 
projects between basic scientists studying animal models of extinction learning 
and clinicians focused on the treatment and prevention of anxiety and drug 
addiction in humans.  Recent advances in characterizing the neural mechanisms 
mediating extinction learning in both animals and humans present new 
opportunities for translational research focused on understanding how deficits 
in extinction learning are related to psychiatric disorders characterized by 
maladaptive fear responses (e.g., PTSD, phobias, OCD, panic disorder, GAD).  
Accordingly, the NIMH and NIDA are issuing this RFA to foster collaborations 
between basic and clinical researchers who are focusing their research interests 
on extinction mechanisms.  The goal of this RFA is to promote the development 
of innovative pilot projects that incorporate multidisciplinary approaches to 
the study of extinction learning and to accelerate the development of novel 
pharmacological, behavioral, and cognitive therapies for anxiety and drug 
disorders that are marked by deficits in extinction learning and/or the 
inability to consolidate safety signals.  

RESEARCH OBJECTIVES

Background

NIMH estimates that anxiety and related fear disorders affect more than 19 
million people in the US alone, resulting in significant losses in productivity, 
reductions in quality of life, and increased rates of suicide.  In addition, 
according to the 2001 National Household Survey on Drug Abuse, the estimated 
number of past month illicit drug users in the US was 15.9 million.  
Furthermore, of all adults diagnosed with severe mental illness, it is 
estimated that 20.3 percent are also dependent on or abuse alcohol or illicit 
drugs.

Studies of fear conditioning in animals have led to significant advances in our 
understanding of the behavioral and neural mechanisms mediating the acquisition, 
consolidation, and expression of fear responses.  However, much less is known 
about how fear associations are acquired and consolidated in humans and the 
neural substrates involved in uncoupling these associations in order to 
eliminate maladaptive fear responses.  The inability to extinguish fearful 
responses when they are no longer appropriate is a hallmark of most anxiety 
disorders, and in particular, PTSD.  Consequently, the objective of most 
behavioral therapies is to reduce resistance to extinction learning and promote 
the formation of new associations that eliminate the fear response.  Recent 
findings characterizing extinction processes in animals suggest that the neural 
populations mediating extinction memory are distinct from those mediating the 
acquisition, memory, and expression of fear responses.  These findings suggest 
the field is now poised to generate data providing additional insights into the 
neural and behavioral mechanisms underlying the ability to extinguish 
previously learned fear associations.

Extinction is also significant in substance use disorders, and addressing it in 
treatment is presumably relevant to outcome.  Drug addiction is a chronic 
relapsing disorder that has many characteristics that may include a persistent 
desire or compulsion to use a drug, loss of control of drug intake, reduction 
in other important activities because of drug use, continued use despite 
knowledge of harm, marked tolerance, characteristic withdrawal symptoms, and an 
increased negative emotional state or stress when the drug is unavailable.  The 
process of becoming addicted to drugs often begins with non-compulsive or 
occasional use, which, over time, can lead to intense craving and compulsive, 
uncontrollable drug taking, and relapse following periods of abstinence.  This 
process has been characterized as one of learning, involving instrumental and 
classical conditioning.  Moreover, basic drug addiction research has shown that 
exposure to drugs of abuse involves neuroadaptations in learning and memory 
systems and that extinction of drug-associated stimuli and responses can 
decrease drug-seeking behavior and modify the underlying neural substrates.  In 
contrast, research has shown that relapse behavior occurs following exposure to 
drug-related cues; for example, in the absence of specific extinction 
procedures, the motivation to self-administer cocaine increases during a 60-day 
course of abstinence.  However, knowledge of these processes is often not 
incorporated explicitly into treatment.

As with anxiety disorders, the field is now poised to investigate the mechanisms 
underlying extinction of learned associations and drug-taking behaviors.  Basic 
research on extinction learning can now be used to inform and accelerate the 
development of novel therapies for these disorders.  In turn, clinical studies 
of substance abuse disorder can lead to the development and validation of animal 
models.  In addition, because anxiety and substance use disorder often co-occur, 
this initiative provides a unique opportunity to investigate the role of 
extinction in treating these comorbid disorders.

Objectives and Scope

At a recent workshop organized by NIMH entitled "Mechanisms of Extinction 
Learning:  Basic, Clinical and Translational Research," current findings from 
basic research on extinction mechanisms and from clinical research on treatment 
strategies for anxiety disorders were presented, evaluated, and discussed.  
There was agreement that knowledge gained from animal studies on the normative 
mechanisms of extinction learning and consolidation (neurobiological, 
behavioral, and molecular) could inform the development of improved treatments 
for anxiety disorders and drug addiction.  Another opportunity for translational 
advances is clinical studies of patients suffering from fear and anxiety 
disorders that can inform the development of animal models that more closely 
parallel the behavioral and psychological abnormalities associated with these 
disorders.  Specific issues related to the unique circumstances surrounding the 
etiology and treatment of human disorders were identified and recommendations 
were made to refine existing animal models to better reflect the factors 
contributing to the onset, time-course, and successful treatment of these 
disorders in humans.  Clinical and basic scientists agreed that collaborative 
activities between these two groups of researchers could accelerate the 
development of novel treatments for anxiety disorders and substance abuse.  
Accordingly, NIMH and NIDA are issuing this RFA to build on recent basic and 
clinical research findings regarding the mechanisms underlying extinction 
learning and exposure therapy, resistance to extinction and current treatment 
procedures, and factors that contribute to the consolidation of extinction 
learning and the prevention of relapse.  Some of the scientific areas that are 
likely to have important implications for understanding the basic mechanisms 
underlying extinction processes and that would benefit from translational 
approaches include:

1) In humans and animals, recent studies have begun to elucidate the respective 
roles of the amygdala, prefrontal cortex, and anterior cingulate cortex in 
extinction learning and its consolidation.  Of primary importance is 
establishing the extent and limits of the homology of these regions and their 
connections between rodents and primates (human and non-human).  If multiple 
sites of plasticity for extinction processes exist, as suggested by these recent 
studies, what are the implications of this for translational research and 
therapy development?

2) During behavioral therapy, habituation procedures are often used in 
conjunction with other forms of exposure.  Are habituation and extinction 
mediated by separate neurobiological mechanisms?  Additional studies comparing 
the effects of extinction versus habituation in both humans and animals are 
necessary to determine if there is a clinically relevant distinction between 
these two forms of learning.  Similarly, animal studies focused on identifying 
the neural circuitry mediating these different forms of learning could provide 
important insights with clinical relevance.

3) While there is a large literature on the effects of context during fear 
conditioning and, to a lesser degree, during extinction, much of this work has 
been done in animals.  More recent clinical studies suggest that contextual cues 
can be used to strengthen extinction learning and prevent relapse.  Additional
work in both animals and humans incorporating multiple contextual factors 
(external and internal cues, cognitive instruction, etc.) is critical to 
determining the role of context in extinction learning and consolidation.

4) Various neurotransmitter systems have been implicated in both the acquisition 
and consolidation of fear conditioning and extinction and certain agonists and 
antagonists have been shown to block or facilitate these processes.  
Identification of compounds potentially capable of altering these processes, and 
the characterization of their effects could provide novel insights into the 
neuropharmacological substrates mediating anxiety disorders and drug addiction.  
Identification of suitable candidate compounds for future use in clinical trials 
would be a significant advance.

5) Very few animal or human studies have examined early risk factors (e.g., 
social, behavioral, environmental, and genetic) that contribute to the inability 
to extinguish inappropriate fear responses or consolidate safety signals.  
Accordingly, research aimed at identifying both external conditions and internal 
characteristics that impact extinction mechanisms in later life is critical.

Specific activities to be supported under this RFA include: 1) the development, 
organization, and implementation of collaborative research networks; 2) pilot 
studies to demonstrate the feasibility of particular translational research 
approaches; 3) the development of basic research methodologies that could be 
applied to a clinical setting.  Emphasis should be placed on how data will be 
integrated between basic and clinical studies so that the goal of achieving 
clinical relevance may be realized.  Applications must include a short 
introductory paragraph in the research plan section identifying which of these 
categories is relevant for the application.  It is expected that these initial 
collaborative activities will lead to larger research proposals (e.g., R01 
applications) focused on specific hypotheses about the neural basis of 
extinction and the development of novel approaches to the treatment of disorders 
characterized by deficits in extinction learning.

Some examples of potential research topics for both human and animal studies 
include, but are not limited to:

o  Imaging and lesion studies in both animals and humans focused on identifying 
the neural substrates critical for extinction learning, retention, and 
consolidation, including the development of extinction paradigms for use with 
fMRI.

o  Neurophysiological studies in humans (e.g., Event-related Potentials (ERP)) 
and animals (single and/or multipleunit recordings)) focused on identifying the 
neural processes mediating extinction and how those processes may be disrupted 
in subjects with extinction deficits.

o  Extinction studies in patients with anxiety and/or substance abuse disorders 
aimed at determining whether they have compromised extinction mechanisms or show 
resistance to extinction.

o  Studies evaluating the effectiveness of combinations of behavioral and 
pharmacological treatments for facilitating extinction and preventing relapse.

o  Behavioral and neurobiological studies examining ways in which to enhance the 
potency of exposure therapy using contextual cues, neutral stimuli, concurrent 
exciters, spaced and massed exposure that could lead to more enduring behavioral 
changes in animal models and clinical populations.  Are the effects of context 
different for humans and animals?

o  Identification of the optimal time-course and arousal level for successful 
extinction training and consolidation and follow-up studies to evaluate 
potential for relapse.

o  Characterization and identification of developmental factors that might 
predispose subjects to poor extinction, including the development of primate 
models to assess the effects of early aversive experiences on adult conditioning 
and extinction mechanisms.

o  Identification of molecular and genetic factors contributing the inability to 
extinguish memories associated with anxiety or drug abuse disorders.

o  Studies using immediate-early gene expression and gene knock-out techniques 
to elucidate the circuitry critical for extinction learning and consolidation as 
well as to identify the time-course over which extinction learning and 
consolidation occur.

o  Studies examining how individual differences contribute to the rate of 
extinction learning and probability of relapse.

o  Studies to determine whether there are differences in the ability to 
extinguish acute fear reactions versus generalized anxiety and the implications 
of these results for treating different forms of anxiety.

o  Combine operant and classical conditioning extinction procedures in the 
development of novel animal models and behavioral therapies.

o  Study the role of placebos in facilitating extinction of drug abuse (e.g., 
use of de-nicotinized cigarettes to eliminate smoking behavior).

Investigators are encouraged to consider designing their research so as to 
permit the analysis of data by gender whenever possible.

This RFA seeks to foster the development of new collaborations as well as novel 
and innovative research focused on facilitating extinction learning in clinical 
populations.  Accordingly, its intent is to support work that has not yet 
amassed substantial preliminary data.  However, applications should include any 
data demonstrating the feasibility of their research approach.

Applications are expected to have well-documented plans for how collaborations 
between basic and clinical scientists are to be implemented and the nature of 
the activities to be supported.  The contributions of each investigator should 
be clearly stated.  For applications seeking support for pilot studies and the 
development of novel research methodologies, it is expected that there will be a 
concrete plan to integrate research findings across laboratories.  In addition, 
the potential relevance for clinical treatment must be established.

In order to be judged responsive, applications submitted under this RFA must be 
focused on integrating basic and clinical research on extinction learning and 
consolidation and show the relevance of this research for the understanding and 
treatment of anxiety disorders and drug addiction.  Only applications that have 
a significant translational component will be deemed responsive.  Research on 
other forms of learning and memory or applications focused primarily on fear 
conditioning are not appropriate for this RFA.  Similarly, applications focused 
exclusively on basic mechanisms of extinction learning are not appropriate.  
Applicants are strongly encouraged to contact one of the NIH program staff 
listed under INQUIRIES with any questions regarding the responsiveness of their 
proposed project to the goals of this RFA.

MECHANISM OF SUPPORT

This RFA will use the NIH Exploratory/Developmental Grant (R21) award mechanism.  
Under this RFA, applicants may request direct costs of up to $150,000 per year 
for up to three years.  This limit on direct costs includes any direct costs of 
a subcontract but does not include the indirect costs on the subcontract.  These 
awards are not renewable.  As an applicant you will be solely responsible for 
planning, directing, and executing the proposed project.  This RFA is a one-time 
solicitation.  The earliest anticipated award date is July 1, 2004.

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, since all applications will have direct costs in each year that 
are less than $250,000, the modular format should be used.

RESUBMISSION OF UNFUNDED APPLICATIONS

Applications that are not funded in the competition described in this RFA may be 
submitted as NEW investigator-initiated applications only, as described at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-019.html).  
These NEW applications must be submitted on the standard receipt dates 
(http://grants.nih.gov/grants/funding/submissionschedule.htm).  Those 
who wish to resubmit their applications as R21s, will also submit them as NEW, 
and will be expected to conform to the requirements of the standard NIH 
Exploratory/Developmental Grant award mechanism, which limits the award to 2 
years with a combined direct cost budget of up to $275,000 for the 2-year 
period, and limits the application to a 15-page research plan 
(see http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html).

FUNDS AVAILABLE

The NIMH intends to commit approximately $1,250,000 and NIDA plans to commit 
approximately $500,000 in FY 2004 to fund 5 to 8 new grants in response to this 
RFA.  An applicant may request a project period of up to 3 years and a budget 
for direct costs of up to $150,000 per year.  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 
the financial plans of the Institutes 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
o  Faith-based or community-based organizations

Foreign institutions are not eligible to apply.

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.

SPECIAL REQUIREMENTS

One of the primary goals of the NIH is the translation of basic research into 
clinical practice.  In accordance with this goal, NIMH and NIDA are using this 
RFA to facilitate the establishment of synergistic research programs between 
basic and clinical researchers in order to foster the development of effective 
treatments for diseases characterized by deficits in extinction learning.  To 
achieve these goals, there are two special requirements for applications 
submitted in response to this RFA:

(1) All applications to this RFA must include a minimum collaborative 
arrangement involving two investigators, one basic behavioral or neuroscientist 
and one clinical researcher.  Each investigator must demonstrate their 
commitment to the project by allotting a significant percentage of effort to the 
project.  Each primary investigator must devote equal amounts of time to the 
project.  Larger groups of collaborators are encouraged.  Investigators need not 
demonstrate any history of prior collaboration as long as they can specify 
factors that will facilitate the success of the collaborations.

(2) During the course of the award period, the principal investigators along 
with their primary collaborators will be invited to meet with NIH staff in a 
public forum to review and share scientific progress.  Other scientists external 
to and knowledgeable about these areas of research also may be invited to 
participate.  NIMH and NIDA will organize this meeting.  Application budget 
requests should include travel funds for the Principal Investigator and primary 
collaborator(s) to attend one meeting in the Washington DC area during the 
award period.

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:

Kathleen C. Anderson, Ph.D.
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7172, MSC 9637
Bethesda, MD  20892-9637
Telephone:  (301) 443-1576
FAX:  (301) 443-4833
Email: kanders1@mail.nih.gov

Bruce N. Cuthbert, Ph.D.
Division of Mental Disorders, Behavioral Research and AIDS
National Institute of Mental Health
6001 Executive Boulevard, Room 6186, MSC 9625
Bethesda, MD  20892-9625
Telephone: (301) 443-3728
FAX:  (301) 443-4611
Email:  bcuthber@mail.nih.gov

David Shurtleff, Ph.D.
Division of Neuroscience & Behavioral Research
National Institute on Drug Abuse
6001 Executive Boulevard, Room 4282, MSC 9555
Bethesda, MD  20892-9555
Telephone:  (301) 443-1887
FAX:  (301) 594-6043
Email:  dshurtle@mail.nih.gov

o  Direct your questions about review matters to:

Michael Kozak, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6138, MSC 9608
Bethesda, MD  20892-9608
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 443-1340
FAX:  (301) 594-0702
Email:  kozakm@mail.nih.gov

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

Carol Robinson 
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6118, MSC 9605
Bethesda, MD  20892-9605
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 443-3858
FAX:  (301) 443-6885
Email:  crobinso@mail.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:

Kathleen C. Anderson, Ph.D.
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7172, MSC 9637
Bethesda, MD  20892-9637
Telephone:  (301) 443-1576
FAX:  (301) 443-4833
Email: kanders1@mail.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.

SUPPLEMENTARY INSTRUCTIONS:  Applications must include a short introductory 
paragraph in the research plan section identifying which of the categories of 
specific activities are relevant for the application.  That is, does the 
application propose: 1) the development, organization, and implementation of 
collaborative research networks; 2) pilot studies to demonstrate the feasibility 
of particular translational research approaches; and/or 3) the development of 
basic research methodologies that could be applied to a clinical setting. 

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:

Jean G. Noronha, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6154, MSC 9609
Bethesda, MD  20892-9609
Rockville, MD 20852 (for express/courier service)
Telephone:  (301) 443-3367
FAX:  (301) 443-4720
Email:  jnoronha@mail.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 NIMH and NIDA.  Incomplete 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 NIMH 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 Institute's National 
Advisory 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 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 and the type of application?  Does the applicant acknowledge potential 
problem areas and consider alternative tactics?  Are both basic and clinical 
research components incorporated into the proposal and do they represent a 
feasible and potentially valuable translational project?

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?  Does the collaborative network or team involve both basic 
and clinical expertise?  Is the work proposed appropriate to the experience 
level of the principal investigator and collaborative researchers?

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:

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK:  The involvement of human 
subjects and protections from research risk relating to their participation in 
the proposed research will be assessed. (See criteria included in the section on 
Federal Citations, below).

INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH:  The adequacy of plans 
to include subjects from both genders, all racial and ethnic groups (and 
subgroups), and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 
evaluated. (See Inclusion Criteria in the sections on Federal Citations, below).

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.

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

SPECIFIC R21 REVIEW CRITERIA

Innovation of the project and potential significance of the proposed research 
will be major considerations in the evaluation of the R21 exploratory grant 
mechanism.  Because the R21 is designed to support innovative ideas, preliminary 
data as evidence of feasibility of the project are not required.  However, the 
applicant is responsible for presenting the background literature that provides 
some basis for the approach and for developing a rigorous research plan.  
Relevant pilot data should be cited when available.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:    November 18, 2003
Application Receipt Date:         December 18, 2003
Peer Review Date:                 March 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 

HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against these 
risks, the potential benefits of the research to the subjects and others, and the 
importance of the knowledge gained or to be gained.
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm.

MONITORING PLAN AND DATA AND SAFETY MONITORING BOARD:  Research components 
involving Phase I and II clinical trials must include provisions for assessment 
of patient eligibility and status, rigorous data management, quality assurance, 
and auditing procedures.  In addition, it is NIH policy that all clinical trials 
require data and safety monitoring, with the method and degree of monitoring 
being commensurate with the risks (NIH Policy for Data and Safety Monitoring, 
NIH Guide for Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH:  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 clinical research projects unless a clear and 
compelling justification is 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 clinical research should read the "NIH Guidelines 
for Inclusion of Women and Minorities as Subjects in Clinical Research - 
Amended, October, 2001," published in the NIH Guide for Grants and Contracts on 
October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: 
a) all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting analyses, 
as appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:  
The NIH maintains a policy 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 that is available at 
http://grants.nih.gov/grants/funding/children/children.htm

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:  NIH policy 
requires education on the protection of human subject participants for all 
investigators submitting NIH proposals for research involving human subjects.  
You will find this policy announcement in the NIH Guide for Grants and 
Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

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 RFA 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.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  The 
Department of Health and Human Services (DHHS) issued final modification to the 
"Standards for Privacy of Individually Identifiable Health Information", the 
"Privacy Rule," on August 14, 2002.  The Privacy Rule is a federal regulation 
under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 
that governs the protection of individually identifiable health information, and 
is administered and enforced by the DHHS Office for Civil Rights (OCR).  Those 
who must comply with the Privacy Rule (classified under the Rule as "covered 
entities") must do so by April 14, 2003 (with the exception of small health 
plans which have an extra year to comply).

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution.  The OCR website 
(http://www.hhs.gov/ocr/) provides information on 
the Privacy Rule, including a complete Regulation Text and a set of decision 
tools on "Am I a covered entity?"  Information on the impact of the HIPAA 
Privacy Rule on NIH processes involving the review, funding, and progress 
monitoring of grants, cooperative agreements, and research contracts can be 
found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

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 284 and administered under NIH grants policies described at 
http://grants.nih.gov/grants/policy/policy.htm 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 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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