PULMONARY COMPLICATIONS OF SICKLE CELL DISEASE

RELEASE DATE:  January 16, 2004

RFA NUMBER:   RFA-HL-04-015 (see addendum NOT-HL-04-106)

Department of Health and Human Services (DHHS)

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

COMPONENT OF PARTICIPATING ORGANIZATION:
National Heart, Lung, and Blood Institute (NHLBI)
 (http://www.nhlbi.nih.gov) 

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):  (93.938, 93.939)

LETTER OF INTENT RECEIPT DATE: April 26, 2004
APPLICATION RECEIPT DATE: May 24, 2004 

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements 
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citation

PURPOSE OF THIS RFA

The purpose of this initiative is to stimulate translational research on the 
pulmonary complications of sickle cell disease.  The RFA encourages 
collaborative research between investigators in hematology and pulmonary science 
that combines basic and clinical approaches.  

Acute chest syndrome affected 29% of all sickle cell disease patients followed 
in the Cooperative Study of Sickle Cell Disease (CSSCD) between 1979 and 1988. 
Chronic pulmonary disease, characterized by perfusion/diffusion defects and 
pulmonary hypertension, also has emerged as a significant problem. Both acute 
chest syndrome and chronic sickle cell pulmonary disease are responsible for 
significant morbidity and mortality, especially in adult patients.  This RFA 
will support 3-5 programs where pulmonary and sickle cell disease researchers 
conduct both basic science and clinical investigation to elucidate mechanisms 
for these complications and develop new treatments. 

RESEARCH OBJECTIVES

For many years, it has been recognized that sickle cell disease affects the 
lungs, yet the mechanisms are still not well-defined. The second most common 
acute complication of this disorder is the so-called "sickle cell acute chest 
syndrome," which is characterized by lung infiltrates, with or without fever. 
While some episodes are secondary to pneumonia, many are not. Other associated 
conditions include embolism of peripheral blood clots and/or fat (see below). 
The CSSCD (1978-1988) database recorded acute chest syndrome in 29% of patients. 
About half of these patients had only one episode of acute chest syndrome, but 
some patients had six or more. Risk factors included age and genotype. Episodes 
occurred more frequently in younger patients, in Hb SS genotype, and least 
frequently in Hb S?+ thalassemia. The ?-thalassemia gene did not alter the 
incidence of acute chest syndrome. In 1995, the Multicenter Study of Hydroxyurea 
showed that administration of hydroxyurea to sickle cell anemia patients 
decreased by half the incidence of both painful episodes and acute chest 
syndrome events. A collaborative study of the etiology of acute chest syndrome 
with bronchoscopy and a comprehensive search for microbial pathogens suggested a 
vascular etiology in some cases (fat emboli), and in other cases, viral or 
bacterial agents were identified. Thus, infection and embolization may increase 
hypoxia, red cell sickling, and vaso-occlusion.

Little is known about the clinical course of sickle cell acute chest syndrome.  
It would be useful to know in which proportion of cases the initial infiltrate 
progresses to more extensive disease, and if progression is affected by 
antibiotics, intravenous fluids, or transfusions.  Sickle cell acute chest 
syndrome can be associated with multi-organ failure but the frequency of this 
association and their pathogenetic relationships are unknown. 

The syndrome of chronic sickle cell lung disease is also recognized. This 
syndrome is characterized by abnormalities in pulmonary function tests 
(primarily perfusion and diffusion defects), chest x-rays, blood gases, and 
non-invasive cardiac studies. However, the detailed anatomical and physiological 
abnormalities that occur in chronic lung damage in sickle cell disease are not 
well-described. Development of pulmonary hypertension is typically associated 
with changes in the vessel walls, such as intramural and perivascular connective 
tissue deposition, hyperplasia/hypertrophy of smooth muscle cells, and sometimes 
intramural thrombosis with recanalization. Since patients with sickle cell 
disease have a higher than normal incidence of pulmonary hypertension, 
pathological red cells may initiate or amplify remodeling of hypertensive lung 
vessels.  In pulmonary hypertension, death often occurs suddenly, and this 
association should be understood more thoroughly.  A CSSCD study of 209 adult 
sickle cell deaths found that a relatively large number (37%) occurred suddenly 
in patients without apparent damage to vital organs. 

Clearly, the acute and chronic lung syndromes require more study before therapy 
can be improved.  Since lung perfusion pressure is one of the lowest in the 
body, these syndromes are likely to be associated with vascular occlusion. Red 
blood cells arrive at the pulmonary capillaries already deoxygenated, so in 
sickling disorders, red cells are either sickled or the blood is markedly 
viscous when it reaches the pulmonary capillary bed. No good data exist on the 
ability of sickle cells to adhere to the endothelium of the pulmonary 
microvasculature. Evidence exists that the vasculature of the lung differs from 
the vasculature elsewhere in structure as well as responsiveness to chemical 
signals. Investigation of the interaction of these differences with sickle cells 
may provide insight into causes of pulmonary complications in sickle cell 
disease.

This initiative aims to encourage research on the effects of sickle cell disease 
on the lung and pulmonary vasculature. Examples might include, but are not 
limited to:

1. Improved definition of the pathophysiology of "acute chest syndrome" with 
particular emphasis on the abnormalities of pulmonary circulation that may 
occur. The role of infection and embolism, if any, should be more clearly 
defined. The use of new diagnostic techniques is encouraged.

2. Better measures of the chronic effects of sickle cell disease on lung 
function with newer diagnostic methods that focus, e.g. on vascular effects. 
Emphasis could be placed on ways to determine the role of abnormal lung 
physiology on sudden death syndrome in sickle cell disease.

3. Correlation of various phenotypes of sickle cell disease (haplotype 
differences, double heterozygosities, etc.) on the manifestations of acute and 
chronic pulmonary problems. The role of cellular viscosity and whole blood 
viscosity in these differences could be investigated.

4. Study of sickle cell adhesion to pulmonary vascular endothelium with 
comparison of their adhesion to systemic vessel endothelium. These studies also 
could include variables such as macro- versus microvascular origin of  
endothelium, shear stress, hypoxemia, etc. Studies of cell-to-cell interactions 
that may play a role in cell binding, receptors, adherence proteins, and the 
state of the red cells (e.g. density, state of hemoglobin S polymerization, 
etc.) could be performed.

5.  Study of the effect of sickle erythrocyte adherence on endothelial function: 
permeability, secondary adherence of platelets and neutrophils, effects on 
release of endothelial-derived vaso-active substances, such as nitric oxide and 
endothelin.

6. Controlled trials of therapies for acute and chronic sickle cell lung 
disease. The role of exchange transfusion, anti-thrombotic agents, nitric oxide, 
prostacyclin, arginine, or other modalities could be investigated. For example, 
it might be useful to monitor pulmonary vascular flow and pressure before, 
during, and after exchange transfusions for severe acute chest syndrome. Such 
studies, which could show how transfusions affect these patients, may involve 
invasive procedures within an intensive care medical setting. 

7. Determination of the utility of echocardiography (ECHO) for detection of 
early pulmonary hypertension.  Correlation of exercise ECHO findings with 
variables such as RBC rheology and endothelial adherence, sickle haplotypes, 
frequency and severity of painful episodes, and humoral indices of activation of 
platelets and the coagulation system could provide new data.

8. Studies of the physiological basis of sleep hypoxemia in sickle cell 
patients, its relationship to acute and chronic pulmonary dysfunction, and its 
contribution to sickle cell pathology are appropriate. 

9. The impact of asthma and related therapies, such as the use of 
vasoconstrictive decongestants, on the severity of acute and chronic sickle cell 
pulmonary complications is of interest.

MECHANISM OF SUPPORT

This RFA will use the NIH R01 (Investigator-initiated research project grant) 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 program will compete 
with all investigator-initiated applications and will be reviewed according to the 
customary peer review procedures.  The anticipated award date is April, 2005. 
Applications that are not funded in the competition described in this RFA may be 
resubmitted as NEW investigator-initiated applications using the standard receipt 
dates for NEW applications described in the instructions to the PHS 398 application.

This RFA uses just-in-time concepts, and the modular 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 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_2001/part_i_1.htm.

FUNDS AVAILABLE

The participating organizations intend to commit approximately $6 million in total 
costs in FY 2005 to fund 3 to 4 new and/or competitive continuation grants in response 
to this RFA.  An applicant may request a budget for total costs of up to $2 million 
per year and a project period of up to 4 years.

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 also will 
vary. Although the financial plans of the participating organizations 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 under-represented racial and ethnic groups as well as 
individuals with disabilities are always encouraged to apply for NIH programs.   

SPECIAL REQUIREMENTS

1.  The intent of this initiative is to integrate clinical and basic scientific 
research on the pulmonary effects of sickle cell disease.  To be considered responsive 
to this announcement, both clinical and basic research must be proposed, and at least 
one of the specific aims must be clinical. Translation of findings from basic to 
clinical studies is an important goal of this initiative, so there must be involvement 
of researchers with experience and/or training in pulmonary medicine and hematology.

2. In order for a specific aim to be considered clinical for this RFA, the 
investigator must directly interact with the patient, and studies must include 
subjects with the disease of interest. Biomedical and behavioral studies of etiology, 
pathogenesis, prevention, diagnosis, and treatment of pulmonary complications in 
sickle cell disease are responsive.  Small population-based epidemiologic studies, 
where the research can be completed within 4 years, also may be proposed.  However, 
clinical research projects focused on large epidemiologic studies or Phase III 
clinical trials will be considered unresponsive to this RFA. In studies involving the 
use of specimens, the investigators must have direct interaction with the patient and 
relate the research results to the patient status or outcome for this to be considered 
a clinical project.  The requirement for investigator interaction with study 
participants is intended to eliminate research on archived tissue.

3.  All basic research specific aims must be related to the overall clinical focus of 
the grant application. 

4.  Applicants are encouraged to establish links with existing resources, including 
General Clinical Research Centers, the NHLBI Program in Genomic Applications, and 
NHLBI clinical research networks, as appropriate.

5.  Each grant application must have a well-delineated organizational structure and 
administrative mechanism that fosters interactions between pulmonary and sickle cell 
investigators, establishes regular communication, encourages the translation of basic 
research findings to clinical applications, and ensures a productive research effort.

6.  Applicants should provide a detailed data and safety monitoring plan for the 
clinical research proposed. The monitoring plan will be considered as part of the peer 
review of the application.  This plan should address informed consent, recruitment, 
reporting of adverse events, patient safety, oversight of clinical issues in the 
protocols, storage and analysis of confidential data, and dissemination of any 
research results.  NHLBI may wish to convene a Data and Safety Monitoring Board to 
oversee the clinical projects in the grants funded by this initiative.  This will be 
determined after review and selection of the grants. Costs associated with a Data and 
Safety Monitoring Board (DSMB) should be included in all budgets whether the DSMB is 
convened by the investigator group or by the NHLBI.

7. Applicants should budget for travel to Bethesda, Maryland for an annual meeting of 
the grantees in this program. Scientific progress in this program will be discussed at 
this annual meeting. Applicants should also include a statement in their applications 
indicating their willingness to participate in these meetings.

Exclusions

Applications proposing programs that do not include clinical research will be 
considered non-responsive to the RFA. Certain types of investigations, although 
potentially of scientific interest, will not be appropriate for support by this 
program.  Investigators wishing to develop proposals related to excluded categories 
are strongly encouraged to contact the NHLBI (see Inquiries, below) for information 
about other opportunities. 

Examples of excluded research are: 
o   Phase III clinical trials
o   applications that do not include studies in humans;
o   projects having a primary focus on research resource development.

General Clinical Research Center (GCRC)

Applicants from institutions that have a GCRC funded by the NIH National Center for 
Research Resources 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 principal investigator should be included with the application.

Additional Considerations

All grant applications submitted in response to this RFA should include sample size 
and statistical power calculations appropriate to the proposed study design.  In 
addition, applications that include development of research resources are encouraged 
to describe a plan to share such resources with other researchers. This could include 
appropriate information technology (such as DNA/protein microarray databases) or 
shipment of tissues. Please note that applications having a primary focus on research 
resource development will be considered non-responsive. 

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:

o Direct your questions about scientific/research issues to:

Henry Chang, M.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Rockledge II, Room 10158 (MSC 7950)
Bethesda, MD  20892 - 7950 (20817 for overnight couriers)
Telephone:  (301) 435-0067
FAX: (301) 480-0868
Email: changh@nih.gov

Andrea L. Harabin, Ph.D.
Senior Scientific Advisor, Lung Biology and Disease Program
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Rockledge II, Room 10108 (MSC 7952)
Bethesda, MD  20892 - 7952 (20817 for overnight couriers)
Telephone:  (301) 435-0222
FAX: (301) 480-3557
Email: HarabinA@nhlbi.nih.gov

o Direct your questions about peer review issues to:

Anne Clark, 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:  ClarkA@nhlbi.nih.gov

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

Marsha Mathis
DEA-GOB/NHLBI/NIH
Rockledge II, Room 7158
Bethesda, MD  20892 - 7950 (20817 for overnight couriers)
Telephone:  (301) 435-0170
FAX: (301) 480-3510
Email: MathisM@nhlbi.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 NHLBI 
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. Anne Clark at the address listed 
under WHERE TO SEND INQUIRES.

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet 
(D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when 
applying for Federal grants or cooperative agreements. The DUNS number can be obtained 
by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. 
The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The 
PHS 398 document is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format.  For 
further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: 
GrantsInfo@nih.gov.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:  Applications requesting up to 
$250,000 per year in direct costs must be submitted in a modular grant format.  The 
modular grant format simplifies the preparation of the budget in these applications by 
limiting the level of budgetary detail.  Applicants request direct costs in $25,000 
modules.  Section C of the research grant application instructions for the PHS 398 
(rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes 
step-by-step guidance for preparing modular grants.  Additional information on modular 
grants is available at: http://grants.nih.gov/grants/funding/modular/modular.htm.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application 
form must be affixed to the bottom of the face page of the application.  Type the RFA 
number on the label.  Failure to use this label could result in delayed processing of 
the application such that it may not reach the review committee in time for review.  
In addition, the RFA title and number must be typed on line 2 of the face page of the 
application form and the YES box must be marked. The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the 
application, including the Checklist, and three signed photocopies, in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application and all five 
collated sets of the appendix material must be sent to Dr. Anne Clark at the address 
listed under WHERE TO SEND INQUIRES. 

Please note that applications delivered by individuals are no longer accepted; all 
applications must either come via courier delivery or via the US Postal Service: 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html)

APPLICATION PROCESSING: Applications must be received by 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. 
Principal investigators should not send supplementary material without first 
contacting the Scientific Review Administrator (SRA).  The SRA will be identified in 
the letter sent to you indicating that your application has been received.  If you 
have not received such a letter four weeks after submitting the application, contact 
Dr. Anne Clark at the address listed under WHERE TO SEND INQUIRIES.

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 be 
returned to the applicant without further consideration prior to the Initial Review 
Group meeting.  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 National Heart, Lung, and Blood 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 these criteria 
in assigning your 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, you 
may propose to carry out important work that by its nature is not innovative but is 
essential to move a field forward.

Each project will be evaluated with respect to the following criteria:

(1) 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?

(2) 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?  Is it 
likely that the approach will identify new mechanisms or treatments?

(3) 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?

(4) 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)?

(5) 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 and employ collaborations between 
hematologists and pulmonologists? Is there evidence of institutional support?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the application will 
also be reviewed with respect to the following:

o 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).

o 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 
included in the section on Federal Citations, below)

o 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

o DATA SHARING:  The adequacy of the proposed plan to share data or resources.  
Applicants who request more than $500,000 in direct costs in any year of the research 
must include a data sharing plan in their application. The reasonableness of the plan 
or the rationale for not sharing research data will be reviewed, but it will not 
factor into the scientific merit or priority score (see below).

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

o MONITORING PLAN: The safety and data monitoring plan will be evaluated for adequacy 
(see Monitoring Plan and Data Safety and Monitoring Board, below).

RECEIPT AND REVIEW SCHEDULE    

Letter of Intent Receipt Date:  April 26, 2004
Application Receipt Date:  May 24, 2004
Peer Review Date:  Oct/Nov, 2004
Council Review:  Feb 27, 2005
Earliest Anticipated Start Date:  April 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 

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:  Research components involving Phase I and II 
clinical trials must include provisions for assessment of patient eligibility and 
status, rigorous data management, quality assurance, and auditing procedures.  In 
addition, it is NIH policy that all clinical trials require data and safety 
monitoring, with the method and degree of monitoring being commensurate with the risks 
(NIH Policy for Data Safety and 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 award in a public archive, 
which can provide protections for the data and manage the distribution for an 
indefinite period of time.  If so, the application should include a description of the 
archiving plan in the study design and include information about this in the budget 
justification section of the application. In addition, applicants should think about 
how to structure informed consent statements and other human subjects procedures given 
the potential for wider use of data collected under this award.

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

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

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH 
funding must be self-contained within specified page limitations. Unless otherwise 
specified in an NIH solicitation, Internet addresses (URLs) should not be used to 
provide information necessary to the review because reviewers are under no obligation 
to view the Internet sites.   Furthermore, we caution reviewers that their anonymity 
may be compromised when they directly access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the 
health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led 
national activity for setting priority areas. This RFA is related to one or more of 
the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal 
Domestic Assistance No. 93.837, and is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.  Awards are 
made under authorization of Sections 301 and 405 of the Public Health Service Act as 
amended (42 USC 241 and 284) and administered under NIH grants policies described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 
and 45 CFR Parts 74 and 92. 

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 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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