NOVEL TARGETS AND THERAPY DEVELOPMENT FOR ISCHEMIC STROKE   

RELEASE DATE: July 23, 2004                

RFA Number:  RFA-HL-05-004  

EXPIRATION DATE:  January 12, 2005

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

COMPONENTS OF PARTICIPATING ORGANIZATION:  
National Heart, Lung, and Blood Institute (NHLBI)
(http://www.nhlbi.nih.gov)
National Institute of Neurological Disorders and Stroke (NINDS)
(http://www.ninds.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):  93.839, 93.853
 
LETTER OF INTENT RECEIPT DATE: December 10, 2004   
APPLICATION RECEIPT DATE: January 11, 2005   
 
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 

Ischemic stroke is the third leading cause of death in the United States. With the 
aging of the population, the number of stroke patients in the US is likely to grow. 
There is a critical need to develop safe and effective therapies to improve the 
clinical management of stroke patients. Thus, the NHLBI and the NINDS invite 
research applications that will improve the understanding of brain hemostasis, 
identify new molecular targets, explore promising agents, and develop novel 
therapeutics for cerebral ischemia. This program intends to support basic, 
translational, and early clinical studies. 

RESEARCH OBJECTIVES

Ischemic stroke is a leading cause of death and long-term disability in the United 
States. There are approximately 750,000 ischemic strokes annually in the US, of 
which about 150,000 are fatal. The estimated costs to the healthcare system exceed 
$35 billion per year. The majority of ischemic strokes are due to arterial 
occlusions, which can rapidly produce a core of infarcted brain tissue surrounded 
by hypoxic but potentially salvageable tissue, i.e., the ischemic penumbra. The 
goal of therapy is rapid restoration of blood flow with preservation of the 
ischemic penumbra and minimal neuronal damage.

The lack of knowledge about brain hemostasis has been a significant impediment to 
the development of new therapies for stroke. Recent data have demonstrated that 
hemostasis is organ-specific and its fine regulation in the cerebrovasculature is 
likely to have features that are characteristic of the brain. Plasminogen 
activators seem to have special functions within the brain in addition to 
fibrinolysis. They interact with cellular receptors and engage specific signal 
transduction pathways. Moreover, tPA has been shown to be neurotoxic, vasoactive, 
and to alter blood-brain-barrier function. This knowledge adds a level of 
complexity and presents challenges to thrombolytic therapy, since the concepts and 
treatments developed for myocardial infarction and acute coronary syndromes may not 
be applicable or safe for the therapy of stroke. Thus, the major focus of this 
initiative is basic research on hemostasis and thrombosis in the brain along with 
inflammatory and other sequelae of these processes.

The only FDA approved drug for the treatment of acute thrombotic stroke is tissue 
plasminogen activator (tPA). Currently, 1-3% of stroke patients in the US receive 
this therapy; presentation beyond the three-hour therapeutic time window is the 
leading reason for treatment disqualification. Several phase III trials of 
intravenous fibrinolytics administered 3-6 hours from symptom onset have failed to 
show a treatment benefit. Fibrinolytic therapies for stroke have been hampered by a 
risk of hemorrhage. Treatment strategies are needed that can be administered over 
longer periods with low risk of hemorrhage.

The rate of ischemic stroke in the pediatric population is about 3.3/100,000 
children.  The causes of stroke vary but prothrombotic state and heart disease 
appear to contribute significantly. Ischemic stroke is also a serious complication 
in up to 30% children with sickle cell disease (SCD). The treatment of stroke in 
children is not well studied and the sickle cell population may offer opportunities 
in this area.
 
There is a critical need to identify new therapeutic targets and develop treatment 
strategies that a) have lower bleeding risk, b) can be used over longer time-
windows, and c) minimize neuronal damage.  Opportunities also exist to develop 
combination treatments with less collateral damage.  New methods of controlling 
inflammation and complement activation to limit neuronal or endothelial injury, and 
ways of inhibiting platelet plug formation may facilitate the development of safer 
and more effective treatment strategies. Novel fibrinolytic agents also offer 
promise in acute cerebral ischemia and there are at least three potential 
directions: (I) designer plasminogen activators with improved potency and lower 
bleeding potential, (II) direct use of plasmin, and (III) targeted delivery at 
preferred sites of action.

Complementary pharmacologic agents have been effective in increasing reperfusion in 
coronary vessels when combined with fibrinolytics; however, development of these 
agents for acute stroke poses special challenges due to the greater vulnerability 
of brain parenchyma to hemorrhagic transformation. Examples of promising 
complementary agents are activated protein C and PECAM-1 (platelet endothelial cell 
adhesion molecule 1) with anti-inflammatory and anti-apoptotic properties, platelet 
antagonists, direct thrombin inhibitors, low molecular weight heparins, tissue 
factor/FVIIa inhibitors, and soluble endothelial ADPase (CD39).

Hemorrhage reduction strategies may include: (a) combined local use of inhibitors, 
such as neuroserpin, with fibrinolytic agents and (b) compounds that limit injury 
to the blood-brain barrier, such as matrix metalloproteinase inhibitors. Such 
approaches need to be rigorously tested in appropriate animal models or in early 
clinical studies. 

The ultimate goals of this initiative are to improve understanding of brain 
hemostasis and to develop safe and effective therapies for patients with ischemic 
stroke. Animal studies and Phase I/II clinical trials are encouraged but Phase III 
clinical trials will not be supported. Collaboration among investigators in diverse 
areas is also encouraged.  

Examples for research topics

Areas of investigation that would be appropriate for this RFA include but are not 
limited to:

o  Characterize unique properties of hemostasis, thrombosis, and inflammation in 
the brain with an outlook toward new therapeutic development 

o  Identify and characterize biomarkers for rapid diagnosis that would enable 
earlier treatment of ischemic stroke, e.g., P-selectin, CD40L, CRP, tissue factor, 
and cell microparticles

o  Studies of stroke in sickle cell disease 

o  Develop selective and safer thrombolytic therapies 

o  Investigate agents for prevention of cell death and neuroprotection  

o  Explore antithrombotic agents, such as CD39, PARs antagonists, and inhibitors to 
FXa, thrombin, complements, or inflammation 

o  Develop effective combination or sequential therapies, such as mechanical 
reperfusion linked to fibrinolytic agents 

MECHANISM OF SUPPORT
 
This RFA will use the NIH R01 award mechanism.  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 DECEMBER 1, 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. It also uses the modular budgeting format. 
(see http://grants.nih.gov/grants/funding/modular/modular.htm).   Specifically, if 
you are submitting an application with direct costs in each year of $250,000 or 
less, use the modular budget format. Otherwise follow the instructions for non-
modular budget research grant applications.  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_2003/index.htm.  

FUNDS AVAILABLE

The NHLBI intends to commit approximately $ 4.0 million and the NINDS intends to 
commit approximately $ 1.0 million in FY 2006 to fund 10 to 15 new and/or 
competitive continuation grants in response to this RFA. 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. Research projects involving extensive animal studies and/or human trials can 
request up to $500,000 per year for direct costs with appropriate justification. 
Facilities and administrative costs (F&A) for consortia are not 
included in this direct cost ceiling.  Please see 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-040.html for more 
information on the exclusion of the facilities and administrative (F&A) costs 
requested by consortium participants or contact the Grants Management Specialist 
listed under “where to send inquiries”, below. 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 NHLBI and the NINDS 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

The goal of this initiative is to develop new targets and therapies for ischemic 
stroke by focusing on basic, translational, and early clinical research. In order 
to be responsive to the RFA, studies must propose approaches to identify novel 
targets in basic and/or preclinical studies, or to develop new therapeutic 
strategies in clinical studies. Phase I/II clinical trials, but not phase III 
trials will be supported. Studies purely on pathogenesis of ischemic stroke will 
not be considered responsive to this RFA. The expectation is that the results from 
studies supported under this RFA will contribute to the development of novel 
therapeutic agents or approaches for cerebral ischemia.

For clinical studies, a Data and Safety Monitoring Plan (e.g., creation of a Data 
Safety and Monitoring Board (DSMB), refer to Federal Citation at the end of the 
document); documented ability to enroll a specified number of patients; semi-annual 
reports; special expertise or facilities; review between Phase I and Phase II; and 
coordination among investigators (e.g., annual meetings), etc., must be included.

Note that all applications that list direct costs equal or greater than $500,000 in 
any given year of the proposed research must have a data sharing plan (refer to 
Federal Citation at the end of the document).

General Clinical Research Centers

Applications from institutions that have a General Clinical Research Center (GCRC) 
funded by the NIH National Center for Research Resources (NCRR) may wish to 
identify the GCRC as a resource for conducting the proposed research. If so, a 
letter of agreement from either the GCRC program director or the principal 
investigator should be included with the application. 

Grantee’s Meeting

The NHLBI and the NINDS will sponsor annual meetings to encourage exchange of 
information among investigators who participate in this program. In their budgets, 
applicants should include funds for annual one-day grantees’ meetings.  Applicants 
should also include a statement in their applications indicating their willingness 
to participate in these meetings.
 
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:
  
Ahmed A.K. Hasan, M.D., Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute 
6701 Rockledge Drive
Rockledge II, Room 10180, MSC 7950
Bethesda, MD  20892
Telephone: (301)435-0064
FAX: (301)480-1046
Email: hasana@nhlbi.nih.gov

Stephen Goldman, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute 
6701 Rockledge Drive
Rockledge II, Room 10192, MSC 7950
Bethesda, MD  20892
Telephone: (301)435-0565
FAX: (301)480-1046
Email: goldmans@nhlbi.nih.gov

Thomas P. Jacobs, Ph.D.
Stroke Program Director
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd, Room 2112
Bethesda, MD 20892-9525
Telephone: (301) 496-1431
FAX: (301) 480-2424   
Email: TJ12G@nih.gov

Scott Janis, Ph.D.
Clinical Trials Program Manager
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd, Room 2210
Bethesda, MD 20892-9520
Telephone: (301) 496-9135
FAX: (301) 480-1080   
Email: sj151t@nih.gov

o Direct your questions about peer review issues to:

Valerie Prenger, Ph.D.
Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Room 7214, MSC 7924
Bethesda, MD  20892-7924
Telephone: (301) 435-0270
FAX: (301) 480-0730
Email: PrengerV@nhlbi.nih.gov
 
o Direct your questions about financial or grants management matters to:

Robert Vinson
Division of Extramural Affairs
National Heart, Lung, and Blood Institute 
Building RKL II, Room 7156
Bethesda, MD  20892-7926
Telephone: (301) 435-0166
FAX: (301)480-0166  
Email: VinsonR@nhlbi.nih.gov

Tina Carlisle
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd, Room 3264
Bethesda, MD 20892
Telephone: (301) 496-3938
FAX: (301) 496-3929
Email: carlit@ninds.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 Dr. Valerie Prenger at the 
address listed under WHERE TO SEND INQUIRIES.

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

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the application.  
Type the RFA number on the label.  Failure to use this label could result in 
delayed processing of the application such that it may not reach the review 
committee in time for review.  In addition, the RFA title and number must be typed 
on line 2 of the face page of the application form and the YES box must be marked. 
The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/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 Dr. Valerie Prenger at the address listed 
under WHERE TO SEND INQUIRIES. 
 
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 NHLBI. 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 
NHLBI 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 NHLBI or NINDS National Advisory Council. 

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of biological 
systems, improve the control of disease, and enhance health.  In the written 
comments, reviewers will be asked to 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 $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 rational 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. The policy is at: http://grants.nih.gov/grants/policy/data_sharing/

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: December 10, 2004  
Application Receipt Date: January 11, 2005   
Peer Review Date: May-June, 2005  
Council Review: October, 2005  
Earliest Anticipated Start Date: December 1, 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 

ANIMAL WELFARE PROTECTION:  Recipients of PHS support for activities involving 
live, vertebrate animals must comply with PHS Policy on Humane Care and Use of 
Laboratory Animals 
(http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as mandated 
by the Health Research Extension Act of 1985 
(http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal 
Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as 
applicable.

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 patients. (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:  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. Also, please see 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html for the current 
NIH policy on sharing of model organisms for biomedical research.

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. 

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

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:   The 
Department of Health and Human Services (DHHS) issued final modification to the 
“Standards for Privacy of Individually Identifiable Health Information”, the 
“Privacy Rule,” on August 14, 2002.  The Privacy Rule is a federal regulation under 
the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that 
governs the protection of individually identifiable health information, and is 
administered and enforced by the DHHS Office for Civil Rights (OCR).  

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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