PROGRESSION OF CARDIOVASCULAR DISEASE IN TYPE 1 DIABETES   

RELEASE DATE:  December 4, 2003
 
RFA Number:  RFA-HL-04-013

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 Diabetes and Digestive and Kidney Diseases (NIDDK)
 (http://www.niddk.nih.gov)
  
CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.837, 93.847 

LETTER OF INTENT RECEIPT DATE:  February 24, 2004
APPLICATION RECEIPT DATE:  March 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 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 

The National Heart, Lung and Blood Institute (NHLBI) and the National 
Institute of Diabetes, Digestive and Kidney diseases (NIDDK) invite 
investigator initiated applications for basic and clinical studies to 
enhance our understanding of the onset and progression of 
cardiovascular disease (CVD) in patients with type 1 diabetes. Classic 
CVD risk factors such as hyperglycemia, hypertension, dyslipidemia, and 
central obesity increase the risk of CVD in patients with type 1 
diabetes, but do not fully explain the significantly higher incidence 
of CVD in type 1 diabetes.  Thus type 1 diabetes may lead to unique 
mechanisms for the onset and progression of CVD, as well as influencing 
mechanisms known for type 2 diabetes and the general population. 
Identification of the mechanisms that trigger early development of 
atherosclerosis in type 1 diabetes is important for development of 
interventions to prevent and treat CVD in this population. This Request 
for Applications (RFA) seeks basic and clinical studies that will 
enhance our understanding of the effects of type 1 diabetes and its 
metabolic complications on the early development and fast progression 
of cardiovascular disease in these patients.
 
RESEARCH OBJECTIVES
 
Background

Prevention and treatment of micro-and macro-vascular complications 
remain critical problems in the management of patients with diabetes 
mellitus.  Patients with type 1 diabetes have a 4-9 fold increased risk 
in developing cardiovascular disease (CVD) and 75% will die from CVD, 
the leading cause of mortality in these patients. Type 1 diabetes 
constitutes 5-10% of diabetes in the United States and affects an 
estimated 1 million individuals. Endothelial dysfunction and 
accelerated atherosclerosis occur at an early age and progress at a 
faster rate in people with type 1 diabetes. 

Type 1 diabetes, unlike type 2, is characterized by autoimmune 
destruction of pancreatic beta cells, leading to an inability of the 
pancreas to make insulin. Daily administration of exogenous insulin is 
essential for life, but current therapeutic regimens do not replicate 
normal glucose homeostasis and are associated with substantial short 
and long term complications.   

Endothelial dysfunction is a condition in which the vascular 
endothelium undergoes changes in the expression of molecules, such as 
endothelin, FGF, angiotensin II, PGDF, VCAM, adhesion molecules, and 
others. Also, blunting of the nitric oxide-dependent vasodilatory 
responses can occur. Endothelial dysfunction has been documented in 
patients with both type 1 and type 2 diabetes, as well as in 
individuals at high risk for cardiovascular disease. Studies on the 
mechanisms and agents that trigger endothelial dysfunction in patients 
with type 1 diabetes are needed to elucidate the relevant role of 
endothelial dysfunction in the development of atherosclerosis in the 
type 1 population. 

It is now accepted that inflammation plays a key role in cardiovascular 
disease. Inflammatory factors, such as cytokines and adhesion 
molecules, have been shown to be involved in the development and 
propagation of the atherosclerotic lesion. In animal models of obesity 
it has been suggested that specific mediators of proinflamatory 
responses may contribute to insulin resistance. Although specific 
mechanisms have not been elucidated, obese humans and patients with 
type 2 diabetes have elevated levels of TNF alpha, IL-6 and C-Reactive 
Protein (CRP). CD40 ligand, a proinflamatory and atherogenic cytokine, 
and CRP were also reported to be elevated in type 1 diabetic patients. 
Thus, the autoimmune etiology of type 1 diabetes and the potential role 
of inflammation in the development of atherosclerosis, point to 
inflammation and the immune system as target areas for more 
investigation. 

Controlling high blood glucose levels is beneficial in reducing or 
delaying the development of microvascular complications in type 1 
diabetes, but its effect on macrovascular complications is not as 
clear. Recent findings from the long term follow-up of participants in 
the Diabetes Control and Complications Trial (DCCT) demonstrated 
decreased incidence of atherosclerosis, assessed in carotid ultrasound 
and coronary computerized tomography, in the study participants who 
intensively controlled blood glucose.  The difference between the 
intensive and conventional treatment groups became manifest well beyond 
the 6.5 year clinical trial; the reduction in atherosclerosis was seen 
in the follow-up study in which glucose control was similar in the two 
groups.  Of note, recent findings from the follow-up study also 
demonstrate persistent reduction in the risk of microvascular 
complications continue 7-8 years after the completion of the study, 
even in the presence of similar glycemic levels. Studies on the 
mechanism of CVD in type 1 diabetes may have to consider the possible 
“metabolic memory” effect, whereby a history of elevated glucose levels 
leads to enduring effects on the vasculature.

Recent data in vitro have implicated hyperglycemia-derived oxygen free 
radicals as mediators of diabetic complications. Overproduction of 
superoxides by the mitochondrial electron-transport chain seems to 
activate pathways that have been suggested to be involved in the 
vascular complications caused by hyperglycemia. Despite the evidence of 
the role of oxidative stress in the development of cardiovascular 
complications in patients with diabetes clinical trials using 
antioxidants have failed to demonstrate any beneficial effect. Thus, 
research is needed to translate the basic science findings on oxidative 
stress into improved outcomes.

Recent studies suggest that factors related to insulin resistance might 
predict coronary artery disease in patients with type 1 diabetes. 
Insulin resistance is a condition in which peripheral tissues like 
skeletal muscle and adipose tissue are inefficient or unable to utilize 
glucose for tissue specific processes like protein synthesis or 
lipogenesis, respectively. As a result, there is an increase in insulin 
levels and requirements and an elevation in fasting and postprandial 
glucose and lipid levels in the circulation. Insulin resistance has 
been associated with the development of atherosclerosis and is a major 
risk factor for heart disease in patients with type 2 diabetes. 
Patients with type 1 diabetes are not immune to insulin resistance and 
the development of “double diabetes”.  Intensive insulin therapy may 
even increase the development of obesity and insulin resistance.  For 
patients with type 2 diabetes, insulin resistance is associated with 
endothelial dysfunction, but little is known about the impact of 
insulin resistance on the vasculature of patients with type 1 diabetes, 
and its contribution to alterations in vascular permeability and 
acceleration of cardiovascular disease.

Receptors for advanced glycation end products (RAGE) play a role in the 
atherogenic process in diabetic animal models, likely by mediating 
inflammation and activation of vascular adhesion molecules. Blockade of 
RAGE stabilizes the atherosclerotic plaque and delays atherogenesis in 
mice. Besides AGEs, several ligands for RAGE have been identified, such 
as the S100/calgranulins which are members of a family of 
proinflamatory cytokines. An increased expression of RAGE and its 
ligands occurs under diabetic conditions and suggests the important 
role of these receptors in diabetic vasculopathies. Due to its great 
potential as a therapeutical target, more research is needed to better 
understand the physiological and pathological role of these receptors 
as well as the mechanisms involved in receptor activation. 

Similarly, another family of receptors, the nuclear receptor peroxisome 
proliferator-activated receptor (PPAR) has been shown to be of great 
importance for treatment of type 2 diabetes. PPAR gamma agonists reduce 
circulating levels of free fatty acids, increase glucose metabolism, 
increase insulin sensitivity as well as to have actions in the 
vasculature through anti-inflammatory effects. However, PPARs are also 
proatherogenic by promoting foam cell formation and acting on cell 
types that are involved in atherogenic processes. Research is needed to 
elucidate the role of PPARs and other nuclear receptors in the 
initiation and progression of atherosclerosis in type 1 diabetes. 

The abnormal lipid profile observed in type 1 diabetic patients is 
believed to be largely a consequence of the dysregulation of lipid 
metabolism. Nuclear magnetic resonance spectroscopy has shown 
differences in lipoprotein particle size.  Human aortic endothelial 
cells incubated with LDL from type 1 diabetic patients showed an 
increase in the activity of several endothelial-related cellular 
mechanisms. In a recent study, increased intraabdominal fat was 
directly correlated to increased hepatic lipase activity in subjects 
with type 1 diabetes. Given the significance of dyslipidemia in the 
overall development of CVD, the role of lipids and lipid metabolic 
pathways in type 1 diabetes needs further investigation.  

Cardiovascular complications of type 1 diabetes often accompany signs 
of nephropathy. Indeed, both microalbuminuria and depression in 
glomerular filtration are epidemiologically linked to cardiovascular 
events. This connection may reflect parallel accrual of macrovascular 
and microvascular injury with the renal damage being more accessible to 
clinical measurement. However, the kidney damage may also engender 
nontraditional risk factors for macrovascular injury. For example, 
accumulation of homocysteine, disturbances in calcium-phosphorous 
metabolism and renal hypertension may accelerate cardiovascular injury. 
Understandings the nexus of diabetic nephropathy and cardiovascular 
disease requires further study.

For patients with type 2 diabetes, progress has been made in 
elucidating mechanisms for their accelerated onset of CVD. Some but not 
all of these mechanisms are likely to be relevant for CVD in type 1 
diabetes.  Identification of common or unique pathways between the two 
types of diabetes mellitus will advance our understanding of type 1 
diabetes research considerably and offer new tools for the development 
of new therapies and tailored interventions.

Objectives and Scope

The causes of the increased incidence and earlier onset of 
cardiovascular disease in patients with type 1 diabetes are still 
unknown. The question remains whether the importance of the known risk 
factors for CVD in type 2 diabetes, like inflammation, endothelial 
dysfunction and dyslipidemia, also applies to type 1 diabetes or 
whether other factors of unknown etiology are responsible for the 
enhanced cardiovascular complications in this group. Fostering research 
with a focus on the vascular wall and endothelia dysfunction in the 
setting of type 1 diabetes will increase our knowledge of the factors 
that contribute to the development of cardiovascular disease in these 
patients. Understanding the mechanisms involved will provide the 
necessary information to develop a better rationale for prevention and 
treatment programs tailored to individuals with type 1 diabetes.

The objective of this initiative is to investigate and elucidate the 
elements and mechanisms involved in the development of accelerated 
cardiovascular disease in type 1 diabetes.  These studies may range 
from basic studies on the mechanism of CVD in type 1 diabetes to 
clinical studies that would use new analyses of existing datasets or 
collection of additional data and biological specimens in ongoing 
investigations. 

Appropriate topics for investigation under this RFA would include, but 
are not limited to:

o Evaluate the role of inflammation and immune factors in the onset and 
progression of atherosclerosis, plaque stability, endothelial 
dysfunction, and vascular changes leading to cardiovascular disease in 
type 1 diabetes.

o Evaluate the role of hyperglycemia and insulin resistance on the 
onset and progression of atherosclerosis, on plaque stability, and in 
precipitating pathologic changes in endothelial function and vascular 
permeability in type 1 diabetes.

o Elucidate the role of receptors, such as RAGE and nuclear receptors, 
in type 1 diabetic cardiovascular complications.

o Investigate vascular lipid metabolism and its regulation by factors 
such as hyperglycemia, inflammation  and insulin resistance and their 
contribution to cardiovascular complications of type 1 diabetes. 

o Examine the mechanisms whereby nephropathy in type 1 diabetes is 
linked to and may accelerate cardiovascular disease.

o Investigate the mechanisms of cardiovascular complications in 
existing cohorts of type 1 diabetes by utilizing stored samples or data 
collections.  For these studies, both government and non-government 
supported clinical trials and epidemiologic studies are eligible. 
Analysis of large public access databases and other databases is also 
encouraged. 

MECHANISM OF SUPPORT
 
This RFA will use 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 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 30, 
2004. 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/grants/policy/nihgps_2001/part_i_1.htm.  

Applications submitted by foreign institutions can request facilities 
and administrative (F&A) costs up to a maximum of eight percent.  
Please see the web site 
HTTP://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-028.html
for more information on allowable F&A costs 
for foreign grants and domestic grants with foreign components.

FUNDS AVAILABLE 
 
The participating ICs intend to commit up to a total of $3,000,000 in 
FY 2004 to fund 6 to 8 new grants in response to this RFA. An applicant 
may request a project period of up to 4 years and a budget for direct 
costs of up to $400,000 per year. 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 ICs 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 

Grantee's Meetings

Upon initiation of the program, the NHLBI and the NIDDK 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, 
most likely in Bethesda, Maryland.  Applicants should also include a 
statement in their applications indicating their willingness to 
participate in these meetings.  The first such meeting likely will take 
place in about 6 months after the award is issued.

Restrictions and Exclusions

This RFA is intended to support multidisciplinary R01 research programs 
studying the complications of cardiovascular disease in type 1 diabetes 
and must propose mechanistic studies. To be responsive to this RFA, the 
studies must be unequivocally and directly relevant to type 1 diabetes 
and not to other forms of diabetes. Applications that propose new large 
epidemiological studies or large clinical trials will be considered 
unresponsive to this initiative. Ancillary studies to completed or 
ongoing clinical studies are within the scope of the initiative.  
 
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:

Cristina Rabadan-Diehl, Ph.D.
Division of Heart and Vascular Diseases
National Heart,Lung, and Blood Institute
6701 Rockledge Drive
Rockledge II, Room 10186
Bethesda, MD  20892-7164
Telephone:  (301) 435-0550
FAX:  (301) 480-2858
Email: rabadanc@nhlbi.nih.gov

Teresa L. Z. Jones, MD
Program Director for Diabetes Complications
DEM/NIDDK/NIH
6707 Democracy Blvd. Room 651
Bethesda, MD 20892-5460  
Telephone: (301) 435-2996
FAX: (301) 480-3503
Email: jonest@extra.niddk.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
Bethesda, MD 20817 (for express/courier service)
Telephone:  (301) 435-0270
FAX:  (301) 480-0730
Email:  ClarkA@nhlbi.nih.gov

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

Susan Lowenthal  
Grants Management Specialist NHLBI  
6701 Rockledge Drive  
Rockledge II, Room 7155
Bethesda, MD 20817  
Telephone: (301) 435-0159
FAX: (301) 480-3310
Email: lowenths@nhlbi.nih.gov
 
Kathleen J. Shino, MBA
Supervisory Grants Management Specialist NIDDK
6707 Democracy Blvd., Room 708
Bethesda, MD 20892-5456
Telephone: (301) 594-8869
FAX: (301) 594-9523
Email: shinok@extra.niddk.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. Anne 
Clark 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 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 and 
all copies of the appendix material must be sent to Dr. Anne Clark 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 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?  

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: February 24, 2004
Application Receipt Date: March 24, 2004
Peer Review Date: June/July 2004
Council Review: September 2004
Earliest Anticipated Start Date: September 30, 2004

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 

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the 
policy of the NIH that women and members of minority groups and their 
sub-populations must be included in all NIH-supported clinical research 
projects unless a clear and compelling justification is provided 
indicating that inclusion is inappropriate with respect to the health 
of the subjects or the purpose of the research. This policy results 
from the NIH Revitalization Act of 1993 (Section 492B of Public Law 
103-43).

All investigators proposing clinical research should read the "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research - Amended, October, 2001," published in the NIH Guide 
for Grants and Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition 
of clinical research; updated racial and ethnic categories in 
compliance with the new OMB standards; clarification of language 
governing NIH-defined Phase III clinical trials consistent with the new 
PHS Form 398; and updated roles and responsibilities of NIH staff and 
the extramural community.  The policy continues to require for all NIH-
defined Phase III clinical trials that: a) all applications or 
proposals and/or protocols must provide a description of plans to 
conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) 
investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS: The NIH maintains a policy that children (i.e., individuals 
under the age of 21) must be included in all human subjects research, 
conducted or supported by the NIH, unless there are scientific and 
ethical reasons not to include them. This policy applies to all initial 
(Type 1) applications submitted for receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should 
read the "NIH Policy and Guidelines" on the inclusion of children as 
participants in research involving human subjects that is available at 
http://grants.nih.gov/grants/funding/children/children.htm

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:  
NIH policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for 
research involving human subjects.  You will find this policy 
announcement in the NIH Guide for Grants and Contracts Announcement, 
dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

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). 
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.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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