NEUROBIOLOGY OF PERSISTENT PAIN MEDIATED BY THE TRIGEMINAL NERVE 

RELEASE DATE:  September 16, 2003

PA NUMBER:  PAS-03-173

March 2, 2006 (NOT-OD-06-046) – Effective with the June 1, 2006 submission date, 
all R03, R21, R33 and R34 applications must be submitted through Grants.gov using 
the electronic SF424 (R&R) application. Accordingly, this funding opportunity 
expires on the date indicated below. A replacement R21 (PAS-06-199) 
funding opportunity announcement has been issued for the submission date 
of June 1, 2006 and submission dates thereafter. 

EXPIRATION DATE:  

Expiration Date for R21 Applications: July 02, 2006
Expiration Date for R01 Applications: July 01, 2006, unless reissued.  

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATIONS:  

National Institutes of Health (NIH)
 (http://www.nih.gov/)

COMPONENTS OF PARTICIPATING ORGANIZATIONS:

National Institute of Neurological Disorders and Stroke (NINDS)
 (http://www.ninds.nih.gov)
National Institute of Dental and Craniofacial Research (NIDCR)
 (http://www.nidcr.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):  No. 93.853 (NINDS); 93.121 
(NIDCR)

THIS PAS CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements 
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PA 

The National Institute of Neurological Disorders and Stroke (NINDS), along 
with the National Institute of Dental and Craniofacial Research (NIDCR), 
invite applications to advance our understanding of the neurobiology of 
persistent pain mediated by the trigeminal nerve and to develop effective 
therapeutic strategies to alleviate pain associated with disorders of 
myofascial, nervous, or skeletal tissues of the head and face, which are 
innervated by this nerve.  The purpose of this initiative is to foster 
research that addresses the mechanisms of pain onset, chronic pain 
conditions, and responsiveness to pain therapy through novel basic and 
clinical research.  Current knowledge of the neurobiology and neurochemistry 
of nociception, pain modulation and pain perception needs to be further 
developed and correlated with clinical manifestations of craniofacial pain to 
improve therapeutic strategies.  This Program Announcement with Set-Aside 
funds (PAS) contributes to the goals of the NIH Pain Consortium, which is co-
chaired by NINDS, NIDCR, and the National Institute of Nursing Research 
(NINR).

RESEARCH OBJECTIVES

Chronic pain is a debilitating condition that adversely affects the lives of 
millions of people.  A diverse group of disorders arises from trauma, 
pathology, structural or degenerative changes, and sometimes unknown causes 
that affect the deep tissues of the head and face and often lead to severe, 
chronic pain.  The trigeminal brainstem complex, which processes nociceptive 
input from craniofacial structures differs notably from spinal pain systems.  
The unique nature of nociceptive processing and varied etiology of pain 
conditions mediated by the trigeminal nerve contribute to the lack of 
understanding of the basic mechanisms of pain onset, and the development of 
chronic pain and abnormal pain responses (allodynia, hyperalgesia).  These 
conditions hinder the development of effective treatment strategies to 
alleviate chronic pain in structures served by this nerve.  Pain disorders 
mediated by the trigeminal nerve are often associated with severe and 
persistent pain of deep tissues, which may be of neuronal, muscular, joint, 
or vascular origin.  Chronic pain mediated by the trigeminal nerve complex is 
a predominant feature of conditions such as migraine disorder, trigeminal 
neuralgia (TN), temporomandibular disorders (TMD), and dry eye syndrome. 

This diverse group of disorders involves neurochemical, physiological and 
molecular changes associated with deep tissue and nerve injury, which are 
signaled by the peripheral and central nervous system components of the 
trigeminal nerve.  This nerve conveys afferent signals of tactile, thermal, 
and nociceptive stimuli from numerous structures of the head, including 
facial skin, jaw musculature, temporomandibular joints, ears, cornea, dura, 
and cranial vasculature.  It also sends efferent signals that control the 
muscles of mastication.  Nociceptive processing by the trigeminal complex 
differs from that by the spinal system serving the trunk and extremities: 
Specialized structures of the head are innervated by unique fiber 
contributions and nociceptive afferents are uniquely distributed and 
connected within the trigeminal spinal nucleus.  Currently, the pain 
syndromes that involve the deep tissues of the head and face are categorized 
primarily on symptomatic, rather than on pathophysiologic grounds.

Migraine is a disabling disorder, of which headache is one of several 
components.  Studies suggest that the trigeminal nerve complex provides the 
signaling pathway for generation of pain associated with migraine.  Pain 
often manifests in the periorbital facial area, the somatic territory 
innervated by the ophthalmic division of the trigeminal nerve.  Afferents 
arising from this division of the nerve also innervate proximal regions of 
the cerebral blood vessels and meningeal vasculature and sinuses.  
Stimulation of perivascular trigeminal sensory afferent fibers releases 
vasoactive neuropeptides, which elicits dilation of the innervated vessels 
and transduction of central nociceptive information.  It has been suggested 
that the pain experience may be generated by neurogenic inflammation of the 
meninges or sensitization of central trigeminal neurons.  Although the 
chemical activation of these perivascular nerve fibers originates in deep 
tissues, it is referred to the periorbital area by convergence of trigeminal 
visceral and somatic fibers in the brainstem.  The pain of migraine is 
perceived in the somatic territory of the nerve.

Trigeminal neuralgia is characterized by intense pain arising from abnormal 
processing of signals from one or more of the peripheral branches of the 
trigeminal nerve.  Innocuous stimuli to the territory innervated by the 
trigeminal nerve, such as a light breeze or movement, may trigger sudden, 
severe, electric shock-like or stabbing pain.  Most often, the pain presents 
intermittently, affecting one side of the jaw or cheek.  The etiology of TN 
remains uncertain, but one postulate is that vascular compression may occur 
at the point of entry of the nerve into the brainstem.  The compression is 
thought to cause myelin damage leading to generation of abnormal impulses.  
The pain is perceived as arising from tactile stimuli to the face, but may 
actually be referred to the unaffected skin region from afferent signals 
arising from nociceptive stimuli to deep muscular or vascular tissues. 

Temporomandibular disorders encompass a group of conditions characterized by 
orofacial pain and tenderness of the masticatory muscles, the 
temporomandibular joint and associated structures, or both.  Pain and 
dysfunction most commonly are of myofascial origin, but may also arise from 
intra-articular derangements, such as dislocation of the jaw, damage of the 
condyle, or arthritic changes.  Localization, duration and temporal patterns 
of pain vary, but typically it is described as aching pain in the 
temporomandibular region that persists beyond the duration of the 
precipitating cause.  The pain may be debilitating and may last for months or 
even years.  

Dry eye syndrome is a painful condition characterized by a chronic lack of 
sufficient lubrication and moisture of the cornea.  It may be associated with 
damage to the trigeminal nerve and is often a symptom of systemic diseases 
such as lupus and rheumatoid arthritis.  

Craniofacial/deep tissue persistent pain conditions are diverse, but shared 
objectives for future research directions on these disorders can be defined.  
Appropriate mechanism-based models are needed to optimize basic and clinical 
research.  The factors that influence the age-at-onset and gender selectivity 
associated with these conditions need to be identified and considered when 
developing treatment strategies.  Inadequate diagnostic criteria that often 
lead to inappropriate or untimely treatment of these conditions need to be 
better defined and used.  A better understanding of the basic mechanisms 
underlying the onset of pain, the shift to a chronic pain state and the 
development of abnormal pain responses must be gained in order to develop 
effective pain therapies.  Progress towards effective pain management of 
these disorders lags behind that for other pain conditions.  

GOALS

The current PAS encourages the integration of basic research on the 
neurobiology of persistent pain mediated by the trigeminal nerve with 
clinical observations in humans suffering from these pain conditions.  This 
PAS encourages the translation of relevant research using animal models into 
clinical trials aimed at improving pain treatment in humans.  Carefully 
designed studies that cut across scientific disciplines will be necessary to 
accomplish these goals.  Experts from many clinical and basic research arenas 
will be needed to establish correlations between clinical manifestations and 
underlying mechanisms that are crucial to development and assessment of 
effective therapeutic interventions.  Investigators in the fields of 
neurobiology, genetics, immunology, endocrinology, anesthesiology, neurology, 
and epidemiology are encouraged to submit proposals that will contribute to 
the successful achievement of the goals of this PAS.  Potential research 
questions include, but are not limited to the following issues:

o Development of model systems that appropriately mimic the clinical features 
of syndromes associated with deep tissue pain in the head and neck region, in 
order to provide optimal tools for basic and clinical studies;

o Effective application of research paradigms in animal models and in human 
studies of persistent trigeminal nerve mediated pain into clinical research 
on human subjects in order to develop mechanistically derived pain therapies 
(development and application of clinically relevant assays of pain in human 
studies);

o Characterization of the immune and inflammatory mechanisms in the 
pathophysiology of craniofacial/deep tissue persistent pain through 
determination of the role of glial cells and cytokine release in central and 
peripheral pain pathways, and clinical assessment of relevant findings; 

o Discovery of mechanisms of plasticity at the neurochemical, molecular and 
cellular level, which contribute to abnormal pain responses (hyperalgesia, 
allodynia) and persistent pain associated with disorders of tissues 
innvervated by the trigeminal nerve;

o Neuroimaging of pain signaling pathways to elucidate the roles of central 
(including descending modulation) and peripheral plasticity in mediating the 
onset, persistence, and management of chronic pain associated with migraine 
and other pain disorders of the head and neck;

o Characterization of changes in gene and protein expression along the 
components of the trigeminal nerve complex in response to nociceptive stimuli 
using gene chip technology, and determination of how these changes contribute 
to development of chronic pain and abnormal pain responses; 

o Identification of the factors that contribute to the high level of co-
morbidity of craniofacial with musculoskeletal, gastrointestinal, and pelvic 
pain disorders through exploration of the central integration and processing 
of afferent input from craniofacial structures with that from non-
craniofacial structures; 

o Elucidation of the role of acid-sensitive ion channels in deep tissues of 
the head and neck in onset of pain and the development of abnormal pain 
responses and chronic pain;

o Determination of factors that underlie gender, age, and ethnic variations 
in pain experience of craniofacial disorders in order to provide more 
appropriate and individualized pain management for these groups; 

o Characterization of sensory, cognitive, affective, and other biobehavioral 
responses to noxious stimulation and pain perception in humans;
   
o Determination of the usefulness of exercise in pain management through 
clinical trials (inhibition of hyperalgesia and allodynia, and alleviation of 
chronic pain);

o Determination of the role of growth factors in pathophysiology of chronic 
pain associated with head and neck structures disorders and integration of 
relevant findings with clinical trials to assess pain therapies;

o Determination of the role of hormonal systems (genomic and non-genomic 
effects) and the potential interactions between steroidal hormones and growth 
factors in pathophysiology and management of pain associated with migraine 
headache and other pain disorders of head and neck structures; 

o Development and testing of novel mechanism-based therapies for improved 
management of chronic pain associated with craniofacial disorders through 
appropriate clinical trials.

SUMMARY

The purpose of this PAS is to stimulate novel, multidisciplinary research 
that will lead to better understanding and treatment of craniofacial/deep 
tissue persistent pain.  Integration of preclinical and clinical research 
will be a critical factor towards achieving this goal.  

MECHANISMS OF SUPPORT 

This PAS will use the NIH R01 and R21 award mechanisms.  As an applicant, you 
will be solely responsible for planning, directing, and executing the 
proposed project.  For further information on the R21 mechanism, including 
Institute-specific information, see 
http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html.
 
This PAS uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (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.  Otherwise follow the instructions for non-
modular research grant applications.  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

NINDS has set aside $1,200,000 total costs, in addition to funds available 
for applications sent in response to this program announcement that score 
within the NINDS payline (see NINDS Funding Strategy 
http://www.ninds.nih.gov/funding/ninds_funding_strategy.htm), depending on the 
overall scientific merit of the application and the availability of funds 
throughout the duration of this solicitation ($400,000/year for 3 years).

The NIDCR has set aside $300,000 in total costs in FY 2004 and 2005 to fund 
one meritorious application each year that is appropriate to basic science 
related to the NIDCR mission.

Although the National Institute on Drug Abuse (NIDA) is not a co-sponsor of 
this PA, it is interested in the support of research related to pain mediated 
by the trigeminal nerve.  As such, the NIDA would be interested in 
meritorious applications submitted in response to this announcement that are 
relevant to its mission and competitive within its funding plan.  Direct your 
questions about research/scientific issues to: David Thomas, Ph.D.; National 
Institute of Drug Abuse; Telephone: (301)443-6975; Email: dt78k@nih.gov.

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 and 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 your inquiries concerning this PAS and welcome the opportunity 
to answer questions from potential applicants.  Inquiries may fall into two 
areas:  scientific/research and financial or grants management issues:

o Direct your questions about scientific/research issues to:

Linda 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

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

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

Denise Chatman
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd., Room 3269
Bethesda, MD  20892
Telephone:  (301) 496-3993
Email: dc55g@nih.gov

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

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which 
are available at http://grants.nih.gov/grants/dates.htm.  Application 
deadlines are also indicated in the PHS 398 application kit.

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.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: 
Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following steps:
   
1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,
  
3) Identify, in a cover letter sent with the application, the staff member 
and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types.  Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five 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)

APPLICATION PROCESSING: Applications must be mailed on or before the receipt 
dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  The CSR will 
not accept any application in response to this PAS that is essentially the 
same as one currently pending initial review unless the applicant withdraws 
the pending application.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude the 
submission of a substantial revision of an application already reviewed, but 
such application must include an Introduction addressing the previous 
critique.  

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.

PEER REVIEW PROCESS

Applications submitted for this PAS will be assigned on the basis of 
established PHS referral guidelines.  Appropriate scientific review groups 
convened in accordance with the standard NIH peer review procedures 
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a written critique
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.  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.   

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 will be assessed.  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 CONSIDERATIONS 

Sharing Research Data:  Applicants requesting more than $500,000 in direct 
costs in any year of the proposed research are expected to 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.

AWARD CRITERIA

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

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program 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 

DATA AND SAFETY MONITORING PLAN:  Data and safety monitoring is required for 
all types of clinical trials, including physiologic, toxicity, and dose-
finding studies (phase I); efficacy studies (phase II), efficacy, 
effectiveness and comparative trials (phase III). The establishment of data 
and safety monitoring boards (DSMBs) is required for multi-site clinical 
trials involving interventions that entail potential risk to the 
participants.  (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).  

SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, 
investigators submitting an NIH application seeking more than $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.  See 
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.

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 
PA 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) 
http://www.cfda.gov/ 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.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


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Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
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Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
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