UNDERSTANDING AND PREVENTING BRAIN TUMOR DISPERSAL

RELEASE DATE:  March 25, 2004
 
PA NUMBER:  PAS-04-079

The R01 portion of this funding opportunity has been replaced by PAS-07-196,
which now uses the electronic SF424 (R&R) application for February 5, 2007 
submission dates and beyond.

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, the R21 portion of this funding opportunity 
expires on the date indicated below. Other mechanisms relating to this announcement will continue to 
be accepted using paper PHS 398 applications until the stated expiration date below, or transition 
to electronic application submission. A replacement R21 (PAS-06-201) funding opportunity announcement 
has been issued for the submission date of June 1, 2006 and submission dates thereafter.

EXPIRATION DATE: for R21 Applications: March 2, 2006
Expiration Date for R01 Non-AIDS Applications: November 2, 2006
Expiration Date for R01 AIDS and AIDS-Related Applications: January 3, 2007

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 Neurological Disorders and Stroke (NINDS)
 (http://www.ninds.nih.gov)
National Cancer Institute (NCI)
 (http://www.nci.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):  93.853 (NINDS), 93.393 (NCI) 

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
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 Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PA  

Many brain tumors are highly invasive and therefore extremely difficult to 
treat. Cells from the primary tumor often infiltrate into surrounding brain 
tissues, so that removal of the main tumor mass is not sufficient to prevent 
recurrence.  The goal of this Program Announcement with set-aside funds (PAS) 
is to promote studies that: (1) identify the properties of brain tumor cells 
that cause them to migrate; (2) determine how interaction of tumor cells with 
normal brain elements affects migration; and (3) translate understanding of 
these parameters into interventions that target invading tumor cells.  
Interdisciplinary studies that apply new concepts and methodologies from 
developmental neuroscience, genomics, precursor cell biology and other 
related fields are particularly encouraged.

RESEARCH OBJECTIVES

Background

In November 2000, NINDS and NCI conducted a joint, comprehensive planning 
effort called the Brain Tumor Progress Review Group (BT-PRG).  The goal of 
the BT-PRG was to identify the highest priorities in brain tumor research 
(for a complete description of the results of the BT-PRG, see 
http://prg.nci.nih.gov/brain/finalreport.html).  One of the key scientific 
goals established through this planning process was to increase our 
understanding of brain tumor dispersal and translate this understanding into 
more effective therapies for this devastating group of diseases.   

Malignant brain tumors consist of a core mass and surrounding individual 
cells that infiltrate into adjacent brain tissue.  In recent years, 
technologies for imaging and surgically removing brain tumors have improved.  
However, neurosurgeons continue to observe that radical resection of primary 
gliomas, the most common type of brain tumor, is often followed by growth of 
secondary tumors that are not treatable by radiation or chemotherapy.  This 
observation suggests that invading cells are able to activate a molecular and 
cellular program that makes them impervious to conventional therapies.

The early stages of tumor cell migration are difficult to detect.  Invading 
cells can follow myelinated axons, the basement membranes of blood vessels or 
other basement membrane-like structures, as well as the perivascular space. 
Invasiveness does not always correlate with degree of malignancy. Low-grade 
astrocytomas, for example, sometimes infiltrate extensively.  Migration of 
cells from high-grade gliomas, however, often occurs more rapidly.  When a 
glioma is removed a new tumor generally forms within a few centimeters of the 
original tumor mass, but satellite foci can develop at significantly greater 
distances.

Invasiveness of brain tumors presents many problems for treatment.  Even 
radical resection (e.g. hemispherectomy) may leave behind migrating cells 
that give rise to secondary tumor foci.  Treatment of the core tumor mass by 
radiation or chemotherapy is similarly problematic.  In all these 
interventions, a choice must be made between treating as large an area as 
possible around the tumor and preserving quality of life for the patient.  
One important example of this problem involves childhood brain tumors, 
particularly primitive neuroectodermal tumors that arise during brain 
development.

To understand how brain tumor dispersal can be controlled, we must determine 
what causes tumor cells to migrate and investigate how migrating cells 
interact with normal neurons, glia, and extracellular matrix (ECM).  Several 
kinds of cell-cell interactions may be critical, including gap-junctional 
communication, neurotransmitter-mediated events, synaptic disruption, and 
interactions with the immune system. It is likely that invading cells 
misexpress genes that control cell migration during normal development and 
also activate novel pathways that promote invasiveness.  Examples of 
candidate gene products that could control migration include specific motor 
proteins, cytoskeletal elements, small GTPases that regulate interactions 
between external signals and the cytoskeleton, cell surface receptors 
involved in cell migration, proteases that remodel the ECM, ion channels that 
induce changes in cell shape or volume, G protein-coupled receptors, and ECM 
molecules produced by both tumor and surrounding normal cells.  In addition 
to understanding what causes dispersal, identifying the genes that control 
the interrelated process of cell proliferation in migrating cells is also 
important.  These cells often exhibit transient cell cycle arrest, which 
protects them from chemotherapy and radiation.

Determining the properties unique to invading brain tumor cells, and 
understanding how these cells interact with normal brain elements will 
suggest rational strategies for blocking tumor dispersal.  For example, once 
genes that promote or prevent migration have been identified, their 
activities can potentially be modulated through strategies such as the use of 
targeted antibodies, antisense oligonucleotides, siRNA, or the introduction 
of specific exogenous genes or cells.  The ultimate goal is to develop 
interventions that block infiltration but cause minimal damage to adjacent 
brain tissue.  Such interventions could potentially transform brain tumor 
into a manageable chronic disease. 

Scope

Applications submitted in response to this PAS should focus on either: (1) 
determining the causes of brain tumor dispersal; (2) understanding the 
interactions of migrating tumor cells with normal brain elements; or (3) 
developing interventions that target migrating tumor cells.  Analysis of 
either pediatric or adult brain tumors is appropriate.   Studies that apply 
insights from other fields (e.g. developmental neuroscience, glial cell 
biology, stem or precursor cell biology) to the analysis of tumor spread are 
within the scope of this PAS and are encouraged. Translational studies using 
cell or animal models of brain tumor migration to test possible therapeutic 
interventions are also encouraged. This PAS is intended to promote 
interdisciplinary collaborations, as well as interactions between basic 
scientists and clinicians. Possible areas of investigation include, but are 
not limited to:

o Analysis of candidate genes and signal transduction pathways that control 
brain tumor cell dispersal
o Genomic or proteomic expression profiling aimed at identifying novel genes 
or proteins that control brain tumor cell dispersal
o Analysis of molecular and cellular mechanisms that control normal brain 
cell migration and potentially regulate the dispersal of brain tumor cells
o Determination of the cells of origin and specific properties of migrating 
brain tumor cells 
o Analysis of the interactions of brain tumor cells with normal brain 
elements that may contribute to understanding tumor dispersal
o Studies of extracellular matrix properties that potentially control normal 
and aberrant migration of cells in the CNS
o Determination of what causes brain tumor cells to exit the cell cycle 
during migration and reenter it during subsequent cell proliferation
o Studies of neural progenitor cell biology that may shed light on brain 
tumor dispersal
o Investigation of why invading brain tumor cells are resistant to 
chemotherapy or radiation 
o Establishment of novel in vitro and in vivo migration assays that can be 
used to elucidate mechanisms of brain tumor cell dispersal.  Brain slice or 
whole animal models in which tumor cells can be studied as they move through 
the normal CNS are particularly encouraged.
o Development of novel methodologies that permit more effective visualization 
of migrating brain tumor cells 
o Development of therapeutic interventions that target migrating brain tumor 
cells and prevent them from forming new tumors.  These could include 
targeting immune cells towards migrating tumor cells, introducing therapeutic 
genes or cells expressing such genes, using chemoattractants to bring tumor 
cells back to the main tumor mass, or other novel strategies.

MECHANISMS OF SUPPORT 

This PAS will use the NIH research project grant (R01) and 
exploratory/developmental grant (R21) award mechanisms.  As an applicant, you 
will be solely responsible for planning, directing, and executing the proposed 
project.  The proposed project period during which the research will be 
conducted should adequately reflect the time required to accomplish the stated 
goals and should be no more than 5 years for R01 grants.  Applicants are 
encouraged to contact program staff for advice about choosing the appropriate 
grant mechanism.

R21 grants are one-time awards intended to encourage new 
exploratory/developmental research projects by providing support for the 
early stages of their development.  For example, such projects could assess 
the feasibility of a novel area of investigation or a new experimental system 
that has the potential to enhance health-related research.  These studies may 
involve considerable risk but may lead to a breakthrough in a particular 
area, or to the development of novel techniques, agents, methodologies, 
models or applications that could have major impact on a field of biomedical, 
behavioral, or clinical research.

Applications for R21 awards should describe projects distinct from those 
supported through the traditional R01 mechanism.  For example, long-term 
projects, or projects designed to increase knowledge in a well-established 
area will not be considered for R21 awards.  Applications submitted under 
this mechanism should be exploratory and novel.  These studies should break 
new ground or extend previous discoveries toward new directions or 
applications.

R21 applications may request a project period of up to two years with a 
combined budget for direct costs of up $275,000 for the two year period.  For 
example, you may request $100,000 in the first year and $175,000 in the 
second year.  The request should be tailored to the needs of your project.  
Normally, no more than $200,000 may be requested in any single year. 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.

Competing continuation applications submitted in response to this PAS will 
compete with all investigator-initiated applications and be referred and 
reviewed according to the customary peer review procedures.  Responsibility 
for the planning, direction, and execution of the proposed project will be 
solely that of the applicant. The earliest anticipated award date is April 1, 
2005.

FUNDS AVAILABLE

NINDS has set aside $1,000,000 in total costs per year for applications sent 
in response to this PAS.  This is in addition to funds available for 
applications that score within the NINDS payline (see NINDS Funding Strategy 
http://www.ninds.nih.gov/funding/ninds_funding_strategy.htm) and depends on 
the overall scientific merit of the applications and the availability of 
funds throughout the duration of this solicitation (3 years).  NCI will 
consider programmatic priority, as reflected in this PAS, and scientific 
merit in making funding decisions regarding applications assigned to it in 
response to this PAS.  Applications submitted in response to this PAS will 
compete with all investigator-initiated applications for funding.  

The total project period for an application submitted in response to this PAS 
may not exceed 5 years. Because the nature and scope of the research proposed 
may vary, it is anticipated that the size of each award will also vary. 
Although the financial plans of the Institute provide support for this 
program, awards pursuant to this PAS are contingent upon the availability of 
funds and the receipt of a sufficient number of meritorious applications. At 
this time, it is not known if this PAS will be reissued.

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

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

Grantees will be required to attend at least one meeting per year that 
fosters collaboration among basic neuroscientists, developmental 
neuroscientists, neuroimmunologists, neurologists, neurosurgeons, and neuro-
oncologists and facilitates the bidirectional translation of basic and 
clinical results.  Attendance at these meetings must be described in annual 
progress reports.

Plan for Dissemination of Data and Biomaterials

Sharing of biomaterials, data, and software in a timely manner is essential 
for rapid progress in biomedical research.  All applicants who respond to 
this PAS must propose plans for sharing data and biomaterials generated 
through the grant.  PHS policy requires that investigators make unique 
research resources available for research purposes to qualified individuals 
within the scientific community when they have been published (see the NIH 
Grants Policy Statement at 
http://grants.nih.gov/grants/guide/notice-files/not96-184.html).  
In addition, NIH recently released a statement on the sharing of research 
data that applies to all investigator-initiated applications with direct 
costs greater than $500,000 in any single year 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html). 

The Initial Review Group will evaluate the proposed sharing plan and comment 
on its adequacy in an administrative note in the summary statement.  
Reviewers will not factor the proposed data-sharing plan into the 
determination of scientific merit or priority score.  The adequacy of the 
plan will be considered by NIH staff in determining whether the grant shall 
be awarded. The sharing plan as approved, after negotiation with the 
applicant when necessary, will be a condition of the award.

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:

Direct inquiries regarding scientific/research issues to:

Dr. Robert Finkelstein
NINDS
Neuroscience Center, Rm 2143
6001 Executive Blvd.
Bethesda, MD  20892-9527
Telephone:  (301) 496-5745
FAX:  (301) 401-1501
Email:  [email protected]

Dr. Steven Krosnick
NCI
Clinical Grants and Contracts Branch
Cancer Therapy Evaluation Program
Division of Cancer Treatment and Diagnosis
6130 Executive Blvd, EPN 7009
Bethesda, MD  20892
Telephone:  (301) 496-8866
FAX:  (301) 480-4663
Email: [email protected]

Direct inquiries regarding financial or grants management matters to:

Ms. Kathleen Howe
Grants Management Branch
NINDS
6001 Executive Boulevard, Rm 3266
Bethesda, MD 20892
Telephone: (301) 496-7392
Email: [email protected]

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: [email protected].

The title and number of this program announcement must be typed on line 2 of 
the face page of the application form and the YES box must be checked.

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.

SUPPLEMENTARY INSTRUCTIONS:  All instructions for the PHS 398 (rev. 5/2001) 
must be followed, with these exceptions:

o   Research Plan

For R21 applications only, items a   d of the Research Plan (Specific Aims, 
Background and Significance, Preliminary Studies, and Research Design and 
Methods) may not exceed a total of 15 pages.  No preliminary data is required 
for R21 proposals, but may be included if it is available.  Please note that 
a Progress Report is not needed for R21 awards; competing continuation 
applications for an exploratory/developmental grant will not be accepted.

Appendix.  Use the instructions for the appendix detailed in the PHS 398 
except that for R21 applications, no more than 5 manuscripts, previously 
accepted for publication, may be included.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting 
up to $250,000 per year in direct costs must be submitted in the 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 received by or 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.  An appropriate scientific review group 
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 do they advance scientific knowledge?  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).
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

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 REVIEW CONSIDERATIONS 

Sharing Research Data 

Applicants requesting $500,000 or more 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 $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 AMENDMENT "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 PAS 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 
PAS 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 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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