MYELODYSPLASTIC SYNDROME (MDS): SEEKING CURE THROUGH DISCOVERY ON PATHOGENESIS 
AND DISEASE PROGRESSION 
 
RELEASE DATE:  May 21, 2004
 
RFA Number:  RFA-HL-04-033 

EXPIRATION DATE: February 17, 2005

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) 93.839
 
LETTER OF INTENT RECEIPT DATE:  January 16, 2005
APPLICATION RECEIPT DATE:  February 16, 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 

This Request for Applications solicits applications that seek new discoveries in 
the etiology and pathophysiology of myelodysplastic syndromes (MDS) with the aim 
to develop new and curative treatment options in the future.  A separate RFA 
HL-04-034 (please see 
http://grants.nih.gov/grants/guide/rfa-files/RFA-HL-04-034.html)
is directed towards myeloproliferative disorders.  Applicants are directed to 
apply to one or the other but not both RFAs. 

BACKGROUND      

The frequency and incidence of MDS is increasing in the US population and is 
thought to be influenced by factors such as advancing age, the use of cytotoxic 
and mutagenic therapies for cancer, and greater exposure to environmental toxins.  
While some patients have an insidious onset of the disease that can even be 
remitting, others experience dramatic presentations including marrow failure or 
acute hematologic malignancy, which rapidly becomes fatal.  The highly variable 
nature of MDS creates difficulties in the characterization and study of the 
syndromes and/or diseases that constitute evolving dysplasia of the hematopoietic 
system and transformation into malignancy.  

The etiology and pathophysiology of myelodysplasia is poorly understood. The 
conditions may arise or evolve from fundamental defective stem cell biology or 
later disrupted and/or disordered cell lineage differentiation, maturation and 
proliferation of the hematopoietic system.  In some patients the diagnosis is 
associated with genetic constitutional abnormalities.  The occurrence of these 
blood disorders is also increasingly identified in patients following successful 
cancer therapy and/or transplantation procedures and presents as a secondary 
malignancy.  

Myelodysplastic syndromes are considered clonal stem cell diseases that are 
characterized by peripheral cytopenias in the setting of a normocellular or 
hypercellular bone marrow that morphologically shows bilineage or trilineage 
dysplasia.  Mechanisms of disease include pluripotent stem cell damage, 
abnormalities in proliferation, differentiation, and apoptosis leading to an 
ineffective hematopoiesis.  The most common diagnosis include refractory anemia 
(RA), refractory anemia with ringed sideroblast (RARS), refractory anemia with 
excess blast (RAEB), and refractory anemia with excess blast in transformation 
(RAEB-T).  MDS has a high propensity for transformation to myeloid leukemia but 
can transform into acute leukemia of other hematopoietic lineage.  Overlapping 
features of MDS with aplastic anemia, T-cell large granular lymphocyte 
lymphoproliferative disorder, and paroxysmal nocturnal hemoglobinuria suggest a 
shared pathophysiologic mechanism of marrow failure.  A category of secondary MDS 
is used when typical biologic characteristics of MDS occur after known 
constitutional or acquired abnormalities (e.g. association with genetic disorders 
or anti-neoplastic therapy).  In addition, some clinical entities are being 
reclassified into "mixed" myeloproliferative and myelodysplastic disorders, such 
as chronic myelomonocytic leukemia, atypical myeloid leukemia, and juvenile 
myelomonocytic leukemia.    

However, diagnostic criteria can be imprecise and treatment empiric until 
malignant transformation is evident.  Other than hematopoietic stem cell 
transplantation (HSCT), no curative therapies are available.  Many patients do not 
have access to nor are appropriate candidates for intensive HSCT therapy.  
Furthermore, successful outcome following transplant is limited by associated 
toxicities and complications.  Otherwise, traditional chemotherapy, radiation, 
immunotherapy, biologic modifiers, growth factors,  and transfusion support have 
been used with limited success and are primarily palliative.  Therefore, new and 
improved therapies that will be acceptable for an older patient population are 
needed.

RESEARCH OBJECTIVES

Research that uncovers critical genetic, biochemical and molecular pathways that 
operate in the emergence and progression of MDS is needed.  Through basic stem 
cell biologic experimentation, the mechanisms of disease mutagenesis, evolution, 
and progression can be studied. The use of gene expression analysis and 
identification of relevant gene products and cellular molecular profiles may be 
instrumental in discovering key features of disease pathogenesis.  Animal models 
may be required for hypothesis testing and pre-clinical therapeutic exploration.  
Identifying biologic markers of MDS should improve disease characterization, 
earlier diagnosis, and identification of targets that can be exploited for either 
preventative or therapeutic intervention.

SCOPE OF RESEARCH

This RFA intends to encourage basic research on the pathogenesis and disease 
progression of MDS.  Applications focused on understanding the genetic and 
cellular processes associated with MDS are responsive to this RFA.  Interventional 
clinical trials will be considered unresponsive.      

Examples of research on MDS that would be of interest would include but not be 
exclusive to: 1.) detection of early diagnostic biologic markers of MDS, 2.) 
cellular and molecular profiles for defining stages of MDS evolution, 3.) 
correlation of molecular profiles with chromosomal and gene specific alterations 
or mutations associated with MDS, 4.) cytometric characterization of premalignant 
clones and subpopulations in MDS, 5.) identification of mechanisms for induction 
of MDS through environmental or specific toxin exposure, and 6.) stem cell 
biologic and animal disease models specific to MDS in order to explore etiologic 
hypothesis and therapeutic interventions.  

Laboratory and clinical correlative studies may be used to define meaningful 
disease characteristics to improve early diagnosis and serve as basis for the 
development of novel, safer, and more effective therapy.  The following examples 
illustrate patient groups that are of interest.     

o patients with refractory anemia (RA), refractory anemia with ringed sideroblast 
(RARS), refractory anemia with excess blast (RAEB), refractory anemia with excess 
blast in transformation (RAEB-T), and transformation to acute leukemia with pre-
existing MDS characteristics. 

o patients with dysplastic features associated with peripheral cytopenias, 
aplastic anemia, T-cell large granular lymphocyte lymphoproliferative disorder, 
paroxysmal nocturnal hemoglobinuria, and marrow failure.  

o patients with secondary MDS who demonstrate typical biologic characteristics of 
MDS occurring after known constitutional or acquired abnormalities (e.g. 
association with genetic disorders or anti-neoplastic therapy).  

o patients with a diagnosis reclassified as having mixed myelo-proliferative and 
myelodysplastic features including chronic myelomonocytic leukemia, atypical 
myeloid leukemia, and juvenile myelomonocytic leukemia. (An application that 
includes the study of these diseases that are not specific to either MPD or MDS 
must be submitted to either HL-04-033 or to HL-04-034 and can not be submitted to 
both RFAs.)

MECHANISM OF SUPPORT
 
This RFA will use the NIH RO1 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 September 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 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_2003/index.htm.  

FUNDS AVAILABLE
 
The NHLBI intends to commit approximately $ 3,000,000 (total costs) in FY 2005 to 
fund up to 10 new grants in response to this RFA. An applicant may request a 
project period of up to four years and a budget for direct costs (excluding Fiscal 
and Administrative costs) of up to $350,000 per year. 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 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

An individual principal investigator who submits an application to HL-04-033 RFA 
titled "Myelodysplastic Syndrome (MDS): Seeking Cure through Discovery on 
Pathogenesis and Disease Progression" will not be eligible to submit an identical 
application to HL-04-034 RFA entitled "Genetic and Cellular Discovery Toward 
Curative Therapy in Myeloproliferative Disorders (MPD)".  This restriction does 
not apply to institutions (as described above) providing the two applications are 
from different principal investigators.  There can be no over lap in research 
funding between two grants submitted from the same institution in response to 
HL-04-034 and HL-03-033.  Further, each application to this RFA must clearly 
demonstrate a sole focus of research on myelodysplastic syndrome as described in 
this document. 

Applicants are referred to the NIH suggested strategic plan described in the 
report of the March 3, 2003 State of the Science (SOTS) Implementation Working 
Group Meeting for Myeloproliferative, Myelodysplastic, and Marrow Failure 
Syndromes (http://www.webtie.org/SOTS/Meetings/Leukemia/FnlRep703.pdf). The lack 
of public databases on patients with MDS is considered to be a major barrier in 
generating new hypotheses that can advance knowledge and improve treatment.  A 
requirement in this RFA is that grantees, who create genomics or proteomics data, 
are required to enter the information into a public database (at least five 
samples).  The data should meet MIAME standards 
(http://www.mged.org/Workgroups/MIAME/miame.html), and be accompanied by adequate 
phenotype information to characterize the cell types and clinical stages in a 
multi-step process of disease transformation.  Such databases include the Gene 
Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo) at the NCBI, or ArrayExpress 
(http://www.ebi.ac.uk/arrayexpress/) at the EBI.

Alternatively, applicants may wish to establish collaborations with experts in 
genomics or proteomics funded by the NIH to generate and release 
genomics/proteomics data into the public domain quickly.  These collaborations 
should be documented in a letter included in the application.  A minimum 
requirement in this regard is for applicants to describe plans to share and 
analyze independently at least five duplicate or split samples by the applicant 
and the genomics/proteomics collaborator.  The analysis may be complementary or 
overlapping, but differences in the grantee's and collaborating 
genomics/proteomics center's results should be resolved between them in order to 
improve the quality of the public database.  Again, data should be accompanied by 
adequate phenotype information to characterize the cell types and clinical stages 
in a multi-step process of disease transformation. Public databases available for 
reporting include the Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo) at 
the NCBI, or ArrayExpress (http://www.ebi.ac.uk/arrayexpress/) at the EBI.  

Examples of genomics/proteomic centers which could provide suitable collaborators 
include, but are not limited to, existing NIH programs, such as: the NCI 
Director's Challenge (http://dc.nci.nih.gov/organization/principalInvestigators); 
the Cancer Genome Anatomy Project (http://cgap.nci.nih.gov/) or contact Dr. Greg 
Riggins at griggin1@jhmi.edu; the NHLBI shared microarray facilities, contact to 
Dr. Jane Ye at yej@nhlbi.nih.gov; and the NHLBI Proteomics Initiative 
(http://www.nhlbi.nih.gov/resources/medres/proteomics/index_contacts.htm). 

Applicants may specifically request in their budgets up to $10,000 direct cost per 
sample per year ($50,000 over the grant period) to support independent 
genomic/proteomic analyses of the split samples as described above.  In the event 
that collaborations are not possible, the attempts should be documented, and 
applicants must describe plans to make their data available to the wider 
scientific community in a timely fashion.  Comparable funds may be requested to 
convert existing private databases into public ones.       

Investigators should budget for and be prepared to come to a yearly meeting in 
Bethesda for up to two days. These meetings will be for the sharing of scientific 
information and planning activates of wider interest to the research and clinical 
communities. One expectation is that investigators will determine codification of 
phenotypes for clinical, cellular, genetic, and proteomic investigations. An NHLBI 
repository is available for materials and samples that the investigators agree 
should be preserved as a wider resource 
(http://www.nhlbi.nih.gov/resources/medres/reposit/contents.htm).  Applicants should also 
include a statement in the applications indicating their willingness to 
participate in these meetings and activities.
 
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 or research issues to:

Jean Henslee-Downey, M.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10042
Bethesda, MD  20892
Telephone:  (301) 435-0078
FAX:  (301) 480-1060
Email: downeyj@nhlbi.nih.gov 

o Direct your questions about peer review issues to:

Valerie L. Prenger, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7178 (MSC 7924)
Bethesda, MD  20892-7924 (20817 for Courier)
Telephone:  (301) 435-0270
Fax:  (301) 480-0730
E-mail:  prengerv@nhlbi.nih.gov

Direct your questions about financial or grants management matters to:

Robert Vinson, Jr.
DEA-GOB/NHLBI/NIH
Rockledge II, Room 7158
Bethesda, MD  20892 - 7950 (20817 for overnight couriers)
Telephone:  (301) 435-0169
FAX: (301) 480-3310
Email: vinsonr@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 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 Chief, NHLBI Review Branch 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/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 as well as all 
five sets of the appendix material must be sent to:
 
Valerie L. Prenger, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7178 (MSC 7924)
Bethesda, MD  20892-7924 (20817 for Courier)
Telephone:  (301) 435-0270
Fax:  (301) 480-0730
E-mail:  prengerv@nhlbi.nih.gov
 
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 NHBLI. 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 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 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.

Applications that include research plans for a clinical interventional study will 
be considered unresponsive to this RFA.  

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?  
Does the research plan meet the data sharing requirements of the RFA?

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?  

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.  

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:  January 16, 2005
Application Receipt Date:  February 16, 2005
Peer Review Date:  May/June 2005
Council Review:  September 2005
Earliest Anticipated Start Date:  September 30, 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:  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).  

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

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

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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