MECHANISMS OF OROFACIAL PAIN: ANATOMY, GENOMICS AND PROTEOMICS

RELEASE DATE:  November 19, 2003

RFA Number:  RFA-DE-05-004

Department of Health and Human Services (DHHS)
 
PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH)
 (http://www.nih.gov)

COMPONENTS OF PARTICIPATING ORGANIZATION:  
National Institute of Dental and Craniofacial Research (NIDCR) 
 (http://www.nidr.nih.gov)
National Institute of Neurological Disorders and Stroke (NINDS)
 (http://www.ninds.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S) 93.121 (NIDCR) 93.853 
(NINDS)
 
LETTER OF INTENT RECEIPT DATE:  April 19, 2004
APPLICATION RECEIPT DATE:  May 14, 2004

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 Supplementary Instructions
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 Dental and Craniofacial Research (NIDCR), 
along with the National Institute of Neurological Disorders and Stroke 
(NINDS), invites applications to stimulate and support innovative, 
interdisciplinary research studies to elucidate the molecular 
mechanisms underlying orofacial pain, particularly the discovery of 
proteins and protein networks critical to processing nociceptive 
information. 

The purpose of this RFA is to encourage the use of genomic and 
proteomic approaches and imaging techniques to clarify the molecular 
events involved in: 1) acute orofacial pain, 2) the transition from 
unrelieved acute pain to chronic pain (i.e. neuroplasticity), 3) 
neuronal hyperexcitability as manifested by hyperalgesia and allodynia, 
and 4) chronic orofacial pain disorders of an inflammatory and 
neuropathic origin. This improved understanding could lead to new 
therapeutic interventions to effectively treat chronic pain conditions. 
Collaborative projects involving interdisciplinary teams of 
investigators are strongly encouraged. This Request for Applications 
contributes to the goals of the NIH Pain Consortium, which is co-
chaired by NIDCR, NINDS, and the National Institute of Nursing Research 
(NINR).

RESEARCH OBJECTIVES 

Background

Chronic pain affects a large percentage of the population with an 
annual cost of about $100 billion. Orofacial pain is reported by more 
than 20% of the population and is one of the most common reasons for 
visits to a physician. Inappropriate treatment of acute pain can lead 
to chronic pain. Compounding the problem is the fact that chronic pain 
is not well treated with current therapeutics. Opiates are the drugs of 
choice for chronic pain but have negative aspects of tolerance and 
other, potentially dangerous, side effects and are not always 
completely successful in alleviating the pain. Thus, in order to 
effectively treat chronic pain conditions a better understanding of the 
underlying etiology and molecular pathogenesis of these conditions is 
needed. Through this approach, key molecules will be identified that 
could serve as new therapeutic targets.

A noxious stimulus causes acute pain and responses to this stimulus are 
protective reactions. Normally, once the noxious stimulus is removed, 
pain disappears. However, in some instances, for example if there is 
tissue damage, the acute pain persists in the absence of noxious 
stimuli. This chronic pain may be due to persistent tissue inflammatory 
responses, damage to the nervous system (neuropathic pain), or 
unrelieved acute pain. Neuropathic pain is associated with neuronal 
hyperexcitability in damaged areas, spinal cord, and brain and leads to 
heightened responses to stressful stimuli. It is clear that neuronal 
plasticity plays a role in chronic pain, but the triggers that initiate 
this process and the changes that occur in the peripheral and central 
nervous systems have not been clearly identified. However, they may 
include changes in gene expression, redistribution of key membrane 
receptors or ion channels, changes in neuronal phenotype, alterations 
in synaptic connectivity, recruitment of silent nociceptors, and loss 
of fibers.
    
A number of orofacial disorders such as temporomandibular joint 
disorders (TMJD), dental pain and trigeminal neuralgia are associated 
with chronic pain. The pathophysiology of these disorders is poorly 
understood.  Thus, there is a need to examine the pain experience at 
all levels of basic and clinical research. This will entail delineation 
of peripheral nervous system and central nervous system circuitry 
involved in the detection of noxious stimuli and the modulation of pain 
signals, identification of the brain areas responsible for processing 
and integrating this information, discovery of key proteins involved in 
transmission of nociceptive stimuli from the periphery to the brain, 
and assembly of an integrated picture of pain processes. Ion channels, 
ligand-gated ion channels, neurotrophic factors and their receptors, 
transcription factors, serine/threonine and tyrosine kinases, and cell 
adhesion molecules are examples of gene families thought to play 
important roles in responses to noxious stimuli. Peripheral nociceptor 
fields, spinal and brainstem relay points, and cerebral cortex are 
anatomical areas of major interest in pain pathways and are locations 
where modulation of synaptic activity may alter the pain response. 
Identifying proteins whose levels of expression, post-translational 
modification, and subcellular distribution are altered in chronic pain 
disorders will be important in elucidating nervous system plasticity in 
response to noxious stimuli.

Neuroimaging approaches are important in delineating specific brain 
regions that process pain signals. Examination of these active areas 
with genomic and proteomic approaches will help to identify changes in 
protein expression that may be important in pain sensation. Functional 
imaging may identify changes in neurotransmitter receptor activity, 
which, in turn, can elucidate signaling pathways active in processing 
pain signals.

Computer analyses can be performed to establish the existence of 
integrated genetic networks of expressed genes related to pain and 
inflammatory processes.  By comparing molecular profiles in chronic 
orofacial pain and in control samples, additional targets for potential 
therapeutic intervention may be identified. 

Research Objectives and Scope

The objective of this RFA is to encourage the use of genomic and 
proteomic approaches for the identification of molecular mechanisms 
involved in orofacial pain disorders in order to gain a better 
understanding of the pathophysiology of these disorders. Such 
experimental approaches will reveal the molecular networks that 
regulate orofacial pain and clarify the pathogenic mechanisms leading 
to orofacial pain disorders. In addition, these investigations coupled 
with molecular imaging and biocomputational technologies will provide a 
basis for gene-based diagnostic criteria and insights for developing 
novel prevention and therapeutic strategies that are case and patient 
specific. To accomplish the goals of this solicitation, the 
establishment of interdisciplinary teams of investigators with 
expertise in biology, genomics, proteomics, and imaging as well as in 
clinical and computational sciences is encouraged. 

The following are some examples of research topics relevant to this RFA 
but not limited to….

o Elucidation of genes, proteins, and protein modifications involved in 
the transition from acute to chronic pain using genomic and proteomic 
approaches;
o Examination of the changes in gene and protein expression in 
trigeminal ganglion, spinal cord, brain stem, and cortex in chronic 
pain states;
o Characterization of changes in protein expression in the neuronal 
hyperexcitatory state found in chronic pain and the process involved in 
the induction of hyperexcitability at peripheral nociceptors, spinal 
cord, ascending pain tracts and in the brain;
o Identification of functional protein networks involved in transducing 
noxious stimuli into pain signals both peripherally and centrally;
o Elucidation of the roles of central (including descending modulation) 
and peripheral (including effector function of afferent fibers) 
neuronal plasticity in mediating the onset of chronic pain in 
craniofacial regions;
o Determination of the differences in the molecular mechanisms leading 
to chronic pain caused by inflammatory or neuropathic injury;
o Establishment of new model systems that better mimic clinical 
features of orofacial pain disorders, including those in which deep 
tissue pain is involved;
o Identification of cortical brain areas important in orofacial pain 
processing through the use of neuroimaging;
o Elucidation of the role of estrogen (genomic and non-genomic effects) 
in the pathophysiology of pain including the influence of estrogen on 
neurotrophic growth factor expression;
o Investigations of orofacial pain using patient material (cell lines, 
DNA from patient cohorts, etc.) for gene discovery, linkage and 
candidate gene analyses, and SNP analysis.

Applicants are encouraged to obtain biological samples from the NIDCR 
TMJ Implant Registry and Repository (http://Tmjregistry.org). Prior to 
requesting samples, applicants should contact Dr. James Fricton 
[frict001@umn.edu] at the University of Minnesota School of Dentistry, 
Minneapolis, Minnesota. 

MECHANISM OF SUPPORT
 
This RFA will use the NIH R01 award mechanism(s).  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 April 2005. 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 and the modular budgeting formats 
(see http://grants.nih.gov/grants/funding/modular/modular.htm).  This 
program does not require cost sharing as defined in the current NIH 
Grants Policy Statement at 
http://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm.
 
FUNDS AVAILABLE 
 
The NIDCR intends to commit approximately $3.0 million in FY 05 or FY 
06 to fund 8 to 10 new grants in response to this RFA. The NINDS 
intends to commit $700,000 in FY 05 to fund approximately 2 new grants 
in response to this RFA. The NINDS is especially interested in 
meritorious applications that are relevant to its mission, including 
those that relate to neuropathic pain and neurogenic inflammatory pain 
of craniofacial structures. An applicant may request a project period 
of up to 5 years and a budget for direct costs of up to $250,000 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 ICs 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 institutions/organizations
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.

SPECIAL REQUIREMENTS

To the extent possible, applicants should make data from these studies 
(including gene sets, protein sets, brain images, etc.) available in a 
form and in a manner that expedites their usefulness to a wide range of 
researchers. NIH believes that data sharing is essential for expedited 
translation of research results into knowledge, products, and 
procedures to improve human health.  The NIH endorses the sharing of 
final research data to serve these and other important scientific 
goals.  The NIH expects and supports the timely release and sharing of 
final research data from NIH-supported studies for use by other 
researchers. NIH recognizes that data sharing may be complicated or 
limited, in some cases, by institutional policies, local IRB rules, as 
well as local, state and Federal laws and regulations, including the 
Privacy Rule (available at http://www.hhs.gov/ocr/). The Privacy Rule 
is a federal regulation that governs how certain health care providers, 
health care clearinghouses, and health plans, known as "covered 
entities," use and disclose identifiable health information.  As NIH 
stated in the March 1, 2002 draft data sharing statement 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-035.html), 
the rights and privacy of people who participate in NIH-sponsored 
research must be protected at all times. Thus, data intended for 
broader use should be free of identifiers that would permit linkages to 
individual research participants and variables that could lead to 
deductive disclosure of the identity of individual subjects.
 
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:

John W. Kusiak, Ph.D.
Director
Molecular and Cellular Neurobiology Program
Division of Basic and Translational Sciences
National Institute of Dental and Craniofacial Research
National Institutes of Health
45 Center Drive, Building 45, Room 4AN-18A
Bethesda, MD 20892-6402
Telephone: 301-594-7984
FAX: 301-480-8319
Email: kusiakj@mail.nih.gov

Linda L. Porter, Ph.D.
Systems and Cognitive Neuroscience
National Institute of Neurological Disorders and Stroke 
6001 Executive Blvd., Room 2113
Bethesda, MD  20892-9521
Telephone:  301-496-9964
FAX: 301-402-2060 
Email: lp216a@nih.gov

o Direct your questions about peer review issues to:

H. George Hausch, Ph.D.
Acting Director
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
National Institutes of Health
45 Center Drive, Building 45, Room 4AN-44F
Bethesda, MD 20892-6402
Telephone: 301-594-2904
FAX: 301-480-8303
Email: hauschg@mail.nih.gov

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

Mary Daley
Chief Grants Management Officer
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
National Institutes of Health
45 Center Drive, Building 45, Room 4AN-44B
Bethesda, MD  20892-6402
Telephone: 301-594-4808
FAX: 301-480-3562
Email: daleym@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:

John W. Kusiak, Ph.D.
Director
Molecular and Cellular Neurobiology Program
Division of Basic and Translational Sciences
National Institute of Dental and Craniofacial Research
National Institutes of Health
45 Center Drive, Building 45, Room 4AN-18A
Bethesda, MD  20892-6402
Telephone: 301-594-7984
FAX: 301-480-8319
Email: kusiakj@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

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/labels.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 and 
all copies of the appendix material must be sent to:

H. George Hausch, Ph.D
Acting Director 
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
National Institutes of Health
45 Center Drive, Building 45, Room 4AN-44F
Bethesda, MD 20892-6402
 
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 from the previous unfunded 
version of the application.  

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NIDCR. Incomplete and/or nonresponsive 
applications will not be reviewed.  

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 NIDCR in accordance with the review 
criteria stated below.  As part of the initial merit review, all 
applications will:

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 written critique
o Receive a second level review by the NIDCR 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 evaluate the 
application in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals. The 
scientific review group will address and consider each of the following 
criteria in assigning the application’s overall score, weighting them 
as appropriate for each application. 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
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:

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.
  
ADDITIONAL REVIEW CONSIDERATIONS

SHARING RESEARCH DATA: Applicants requesting more than $500,000 in 
direct costs in any year of the proposed research must include a data 
sharing plan in their application. The reasonableness of the data 
sharing plan or the rationale for not sharing research data will be 
assessed by the reviewers. However, reviewers will not factor the 
proposed data sharing plan into the determination of scientific merit 
or priority score.

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: April 19, 2004
Application Receipt Date: May 14, 2004
Peer Review Date: October 2004
Council Review: January 2005
Earliest Anticipated Start Date: April 2005

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 

SHARING RESEARCH DATA:  Starting with the October 1, 2003 receipt date, 
investigators submitting an NIH application seeking $500,000 or more in 
direct costs in any single year are expected to include a plan for data 
sharing or state why this is not possible. 
http://grants.nih.gov/grants/policy/data_sharing  Investigators should 
seek guidance from their institutions, on issues related to 
institutional policies, local IRB rules, as well as local, state and 
Federal laws and regulations, including the Privacy Rule. Reviewers 
will consider the data sharing plan but will not factor the plan into 
the determination of the scientific merit or the priority score.

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.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of 
research on hESCs can be found at http://stemcells.nih.gov/index.asp and 
at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  
Only research using hESC lines that are registered in the NIH Human 
Embryonic Stem Cell Registry will be eligible for Federal funding (see 
http://escr.nih.gov).   It is the responsibility of the applicant to 
provide, in the project description and elsewhere in the application as 
appropriate, the official NIH identifier(s) for the hESC line(s) to be 
used in the proposed research.  Applications that do not provide this 
information will be returned without review. 

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.

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.healthypeople.gov/.

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 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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