PROTEOMIC AND METABOLOMIC APPROACHES TO DIAGNOSE DIABETES AND PRE-DIABETES
 
RELEASE DATE:  March 18, 2004
 
PA NUMBER:  PAR-04-076 (see addendum NOT-DK-04-008)

Department of Health and Human Services (DHHS)

EXPIRATION DATE:  July 21, 2004

PARTICIPATING ORGANIZATION: 
National Institutes of Health (NIH)
 (http://www.nih.gov/)
 
COMPONENT OF PARTICIPATING ORGANIZATION:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
 (http://www.niddk.nih.gov/)
 
CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.847
 
LETTER OF INTENT RECEIPT DATE:  June 18, 2004
APPLICATION RECEIPT DATE:  July 20, 2004 

THIS PAR CONTAINS THE FOLLOWING INFORMATION

o Purpose of this PAR
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 PAR

Over 5 million adults in the U.S. have undiagnosed type 2 diabetes, and 
another 38 million with pre-diabetes are at increased risk for developing 
diabetes. The lack of a simple and reliable way to detect diabetes and pre-
diabetes has hindered identification of these individuals and provision of 
effective therapies. The National Institute of Diabetes and Digestive and 
Kidney Diseases (NIDDK) encourages the application of proteomic and other 
novel technology to develop new diagnostic tests and/or to identify new 
biomarkers for the diagnosis of pre-diabetes and/or diabetes that do not 
require fasting or glucose administration.

RESEARCH BACKGROUND AND OBJECTIVES

Diabetes is a metabolic disease characterized by hyperglycemia that in 2002 
affected nearly 9% of U.S. adults. Over 90% of the people with diabetes have 
type 2 diabetes. The symptoms of type 2 diabetes develop gradually. Some 
people have no symptoms until after they develop complications, which could 
have been prevented or delayed with early diagnosis and effective treatment.  
Additionally, 38 million U.S. adults aged 40-74 have pre-diabetes.  Pre-
diabetes is defined as impaired fasting glucose or impaired glucose tolerance 
(http://www.diabetes.org/diabetes-prevention/pre-diabetes.jsp).  These 
individuals have glucose levels above normal but below the level needed for 
diagnosis of diabetes.  They are at increased risk of cardiovascular disease 
compared to those with normal glucose tolerance and at substantial risk for 
developing diabetes.  

Clinical trials have demonstrated effective interventions for preventing or 
delaying complications in those with diabetes and for preventing or delaying 
onset of diabetes in those with pre-diabetes.  However, millions of Americans 
are not receiving effective therapy, in part due to the limitations of 
current methods of diagnosing diabetes and pre-diabetes.   The oral glucose 
tolerance test (OGTT), the gold standard for diagnosis of diabetes and pre-
diabetes is inconvenient requires fasting and is not highly reproducible. The 
fasting blood glucose (FBG) is less burdensome but much less sensitive, 
particularly in older Americans who have the highest prevalence of diabetes 
and pre-diabetes. The quantitation of Hemoglobin A1c (a glycated form of 
hemoglobin) from blood has been widely used as test for assessing the 
adequacy of glycemic control and risk of complications in diabetic patients, 
but this test is not sufficiently sensitive to detect the range of glucose 
values typically seen in pre-diabetes or new onset type 2 diabetes. 
Furthermore, there are many variants of hemoglobin present in blood, 
particularly in minority populations disproportionately affected by diabetes, 
and this adds additional uncertainty to the use of this test.

A simplified, less burdensome approach to the diagnosis of diabetes and pre-
diabetes would facilitate increased recognition and improved care of these 
conditions.  Many proteins and other blood components may be modified in 
individuals with elevated blood glucose.  Identification of these molecules 
or of identifiable correlates of hyperglycemia would facilitate development 
of potential new laboratory tests for diagnosis of diabetes and pre-diabetes.  
With this initiative we are encouraging scientists with expertise in 
proteomics and metabolomics to develop new tests to detect pre-diabetes and 
diabetes that correlate with the results of the OGTT but do not require 
fasting or administration of glucose. 

Proteomic and metabolomic approaches have been successfully used for studying 
complex biological problems and for the identification of disease markers. 
Recent developments indicate that these technologies could be used or 
appropriately modified for developing new methods to diagnose diabetes and 
pre-diabetes. For example mass spectrometry has been successfully used for the 
identification and quantitation of large number of proteins from plasma. 
Similar studies were performed for quantifying large number of metabolites. In 
some cases fractionation prior to the mass spectrometric analysis was shown to 
be very effective for increasing the number of proteins and metabolites that 
could be identified and perhaps further development in fractionation 
methodologies could be the key for the identification of novel biomarkers. The 
use of isotopically labeled reagents recently made many proteomic 
methodologies usable for quantitative studies and further development of these 
reagents might also lead to a more comprehensive analysis of the sera proteome 
and possible identification of novel biomarkers.

This initiative solicits the application of proteomic and metabolomic 
technologies for the development of novel methodologies and/or identification 
of new biomarkers for the diagnosis of pre-diabetes and of type 2 diabetes 
that do not require fasting or glucose administration. To facilitate this 
effort, plasma from well-characterized individuals of diverse racial and 
ethnic backgrounds with normal glucose tolerance (NGT), impaired glucose 
tolerance (IGT) and type 2 diabetes will be made available to investigators 
for validation of potential new diagnostic tests.  

The novel diagnostic test could ultimately be used in place of the OGTT, if 
adequately validated, or for the identification of high-risk individuals who 
should undergo testing for diabetes and pre-diabetes using a more functional 
assay such as the OGTT. Focused deployment of the OGTT in appropriately 
selected individuals would reduce costs, limit burden, and improve the yield 
of diagnostic testing for diabetes and pre-diabetes.  

The NIDDK will make available citrated plasma and blood cell samples from 
individuals with normal glucose tolerance, impaired glucose tolerance and 
newly diagnosed type 2 diabetes for use in the R21 and for the R33 phases to 
all awardees. Applicants should specify how these samples will be used to 
identify and validate new biomarkers that can distinguish among these 
conditions.  

The NIDDK will provide the following samples to all awardees of the R21 phase:
o 1ml (4X250µl) of sera from 10 patients with normal glucose tolerance (NGT) 
o 1ml (4X250µl) of sera from 10 patients with impaired glucose tolerance (IGT)
o 1ml (4X250µl) of sera from 10 patients with newly diagnosed type 2 diabetes
o The corresponding blood cell pellet from each NGT, IGT and diabetic patient 
will also be provided. The cell pellet for each patient will not be divided in 
four aliquots as for the plasma but will be provided in a single vial.
 
The above conditions are diagnosed using the oral glucose tolerance test 
(OGTT). Briefly, after a fast of 8 to 12 hours, a person’s blood glucose is 
measured before and 2 hours after drinking a glucose-containing solution. 
Determination of NGT is made when glucose rises to no higher than 140 mg/dl 2 
hours after the drink. IGT is diagnosed when the glucose level is between 140 
and 199 mg/dl 2 hours after the drink. Diabetes is diagnosed if blood glucose 
rises to 200 mg/dl or above.  For clinical diagnosis of diabetes this 
measurement must be confirmed on a subsequent measurement.

A similar set of samples but from a larger population will be provided for the 
R33 phase at the time of the award for this phase. We expect to be able to 
provide plasma and blood cell samples from approximately 200 patients with 
IGT, 200 patients with NGT and 50 diabetic patients. 

To be considered for the transition to the R33 phase the applicant must show 
that he/she has identified differences between the pre-diabetes, diabetes, and 
normal patient samples provided by NIDDK for the R21 phase (i.e. have 
identified at least one potential biomarker for pre-diabetes and/or diabetes). 
These differences should be determined in a reproducible (analysis in 
triplicate) and quantitative way and with a throughput that shows promise for 
translation to a clinical setting. In addition the investigator can include in 
the proposal the use of samples from other clinical studies for optimizing or 
further validating the methodology.

For the purpose of assessing research progresses and facilitating interaction 
between the 4-5 funded principal investigators a workshop will be held in 
May/June 2006 in Bethesda, MD. All funded principal investigators are required 
to attend and collaborators are encouraged to participate.  Funds for 
attending this meeting should be included in the budget proposal.

MECHANISMS OF SUPPORT

This special emphasis PAR will use the NIH Exploratory/Development Research 
Grant (R21) combined with the Exploratory/Development Research Grant Phase 2 
(R33). The R33 is an NIH grant mechanism that provides a second phase for the 
support of innovative exploratory and development research initiated under the 
R21 mechanism.  The transition of the R21 to the R33 phase will be expedited 
and is dependent on completion of negotiated milestones. As an applicant you 
will be solely responsible for planning, directing, and executing the proposed 
project. This PAR is a one-time solicitation.  Future unsolicited, competing-
continuation applications based on this project will have to be submitted 
using a standard RO1 or R21 mechanism, will compete with all investigator-
initiated applications and will be reviewed according to the customary peer 
review procedures. The anticipated award date is April 1, 2005. Applications 
that are not funded in the competition described in this PAR 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 PAR uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  Otherwise follow the instructions for non-
modular research grant applications.  This program does not require cost 
sharing as defined in the current NIH Grants Policy Statement at 
http://odoerdb2.od.nih.gov/gmac/nihgps_2003/index.htm.  

Specific features of this Phased Innovation Award (R21/33) Program 
Announcement include: 

o The total project period for an application in response to this PAR may not 
exceed 2 years for the R21 phase and 3 years for the R33 phase.

o Single submission and evaluation of both a feasibility/pilot phase (R21) and 
an expanded development phase (R33) as one application. 

o Expedited transition of the R21 feasibility phase to an R33 development 
phase. However, the award of the R33 funds will be based on program 
priorities, the availability of funds and the successful completion of 
negotiated scientific milestones as determined by program staff in the context 
of peer review recommendations

o Responsibility for the planning, direction and execution of the proposed 
research project will be solely that of the applicant.  Except as otherwise 
stated in this PAR, awards will be administered under the NIH grants policy 
as stated in the NIH Grants Policy Statement, December 2003, available from 
the internet only at  http://odoerdb2.od.nih.gov/gmac/nihgps_2003/index.htm.

o The Phased Innovation Award must have a section labeled Milestones at the 
end of the Research Plan of the R21 application.  This section must include 
well-defined quantifiable milestones for the completion of the R21 portion of 
the application, a discussion of the suitability of the proposed milestones 
for assessing the success in the R21 phase, and a discussion of the 
implications of successful completion of the milestones for the proposed R33 
study.

FUNDS AVAILABLE
 
The NIDDK intends to commit approximately $1 million in direct cost for FY 
2005 to fund 4 to 5 new grants in response to this PAR. An applicant may 
request a project period of 2 years for the R21 phase and 3 years for the R33 
phase. The R21 phase may not exceed $250,000 direct costs per year. The R21 
budgets can exceed this cap to accommodate F&A costs to subcontracts to the 
project, in which case a non-modular budget format must be used.  The R33 
application has a budgetary limit of $500,000 direct costs for each year. This 
limit cannot be exceeded to accommodate F&A to subcontracts. Awards pursuant 
to this PAR 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
 
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 

Applicants from institutions, which have a General Clinical Research Center 
(GCRC) funded by the NIH National Center for Research Resources, may wish to 
identify the GCRC as a resource for conducting the proposed research. In such 
a case, a letter of agreement from either the GCRC program director or 
principal investigator should be included with the application.  
 
WHERE TO SEND INQUIRIES

We encourage inquiries concerning this PAR 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:

Salvatore Sechi, Ph.D.
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd. Rm. 611
Bethesda, MD 20892-5460
Telephone: (301) 594-8814
FAX: (301) 480-2688
E-mail: ss24q@nih.gov

o Direct your questions about peer review issues to:

Francisco O. Calvo, Ph.D.
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 752
Bethesda, MD  20892-5452
Telephone:  (301) 594-8897
FAX:  (301) 480-3505
E-mail: fc15y@nih.gov 

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

Ms. Kathleen Shino
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Rm.708
Bethesda, MD 20892-5460
Telephone: (301) 594-8869
FAX: (301) 594-9523
E-mail: ks48e@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 PAR 

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, Review Branch 
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 752
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD  20817)
Telephone:  (301) 594-8885
FAX:  (301) 480-3505

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

SUPPLEMENTARY INSTRUCTIONS:

I. SPECIFIC INSTRUCTIONS FOR PREPARING THE COMBINED R21/R33 PHASED INNOVATION 
AWARD APPLICATION:

The R21/R33 application must include the specific aims for each phase and 
clear measurable goals (milestones) that would demonstrate feasibility and 
justify transition to the R33 phase.  Applications must include a specific 
section labeled Milestones following the Research Plan of the R21 phase. 
Milestones should be well described, quantifiable and scientifically justified 
and not simply a restatement of the specific aims. A discussion of the 
milestones relative to the progress of the R21 phase, as well as, the 
implications of successful completion of the milestones for the R33 phase 
should be included. 

The Milestones section should be indicated in the Table of Contents. 
Applications lacking this information, as determined by the NIH program staff, 
will be returned to the applicant without review.  For funded applications, 
completion of the R21 milestones will elicit an NIH expedited review that will 
determine whether or not the R33 should be awarded. The release of R33 funds 
will be based on successful completion of negotiated scientific milestones, 
program priorities, and on the availability of funds. The expedited review may 
result in additional negotiations of award.

The R21/R33 combined applications must be submitted as a single application, 
with one face page.  Although it is submitted as a single application, it 
should be clearly organized into two phases. To accomplish a clear distinction 
between the two phases, applicants are directed to complete Sections a-d of 
the Research Plan twice. One write-up of Sections a-d and milestones for the 
R21 phase and sections a-d again for the R33 phase. The Form 398 Table of 
Contents should be modified to show sections a-d for each phase as well as the 
milestones.  There is a page limit of 25 pages for the composite a-d text of 
all applications (i.e., section a-d and milestones for the R21 phase plus 
sections a-d for the R33 phase must be contained within the 25 page limit for 
R21/R33 applications.)

In preparing the R21/R33 application, investigators should consider the fact 
that applications will be assigned a single priority score. For this reason, 
the clarity and completeness of the application with regard to specific goals 
and feasibility milestones for each phase are critical. The presentation of 
milestones that are not sufficiently scientifically rigorous to be valid for 
assessing progress in the R21 phase will reflect upon the scientific judgment 
of the applicant in this application.

Item 7a, DIRECT COSTS REQUESTED FOR INITIAL PERIOD OF SUPPORT.
For the R21 phase of the combined R21/R33 application, direct costs are 
limited to a maximum of $250,000 per year for a maximum of two years and the 
award may not be used to supplement an ongoing project. The non-modular budget 
format must be used for the combined R21/R33 application. The requested 
budgets can exceed this cap to accommodate for F&A costs to subcontracts to 
the project only for the R21 phase.  Insert the first year of R21 support in 
item 7a.

Item 8a, DIRECT COSTS REQUESTED FOR PROPOSED PERIOD OF SUPPORT.
Insert sum of all years of requested support in item 8a.The statement in item 
7a above pertaining to subcontract costs also applies here. 

2.  Page 2 - Description:
As part of the description, identify concisely the research team, the 
fundamental research to be performed or the technology/tool to be developed, 
its innovative nature, its relationship to presently available knowledge or 
capabilities, and its expected impact on the diagnosis, treatment or 
prevention of type 2 diabetes or its complications.

3. Budget:
The application should provide a DETAILED BUDGET for Initial Budget Period 
(form page 4), for each of the initial years of the R21 and R33 phases as well 
as a budget for the entire proposed period of support (form page 5).  Form 
pages should indicate which years are R21 and R33.  All budgets should include 
a justification for each item requested.

Funds for attending a meeting in May/June 2006 in Bethesda, MD should be 
included in the budget proposal.

4.  Research Plan:
Item a, Specific Aims: The applicants must present specific aims that the 
applicant considers to be scientifically appropriate for the relevant phases 
of the project. The instructions in the PHS 398 booklet for this section of 
research grant applications suggest that the applicant state the hypotheses to 
be tested.  Furthermore for the R21 phase, preliminary data are not required, 
although they should be included when available. 

The applicant must include a plan for analyzing the samples provided by NIDDK 
for the R21 and for the R33 phase (see research background and objectives 
section at the beginning of this PAR). The applicant might also include a plan 
for the analysis of additional samples from other patients but a plan for 
analyzing the samples provided by NIDDK is the minimum requirement. 

Similarly, one of the milestones must be the identification of a potential 
biomarker for pre-diabetes and/or diabetes using the samples provided by 
NIDDK. The investigator can include additional milestones. For examples, 
additional milestones could be related to methodology developments or to the 
analysis of samples from other patients.

Item b, Background and Significance:
Elaborate on the innovative nature of the proposed research. Clarify how the 
fundamental research or tools/technologies to be developed as proposed in this 
project will result in a significant improvement over existing approaches.  
Explain the potential of the proposed studies for having a broad impact on a 
compelling area of type 2 diabetes research. Clearly identify how the project, 
if successful, would result in new capabilities for the treatment and 
prevention of type 2 diabetes and its complications.

Item c, Preliminary Studies/Progress Report:
While preliminary data are not required for the submission of the R21 phase, 
this section should provide current thinking or evidence in the field to 
substantiate the feasibility of the R33 phase.  While preliminary data are not 
required for submission of the R21 phase, easily understandable data that 
provide relevant information to aid the review should be included when 
available. The R33 phase need not repeat information already provided in the 
R21 phase.

Item d, Research Design and Methods:
Follow the instructions in the PHS 398 booklet.  In addition a specific 
section labeled Milestones must follow the Research Design and Methods section 
of the R21 phase.  Milestones should be well described, quantifiable, and 
scientifically justified and not be simply a restatement of the specific aims. 
The milestones should not be a reiteration of the Specific Aims of the 
research project, but should be tangible accomplishments.  A discussion of the 
milestones relative to the success of the R21 phase, as well as the 
implications of successful completion of the milestones for the R33 phase and 
the page number of the milestones section should be listed. This section 
should be indicated in the Table of Contents. 

For funded applications, completion of the R21 milestones will elicit an 
Institute expedited review that will determine whether or not the R33 should 
be awarded. The release of R33 funds will be based on successful completion of 
milestones, program priorities and on the availability of funds. The expedited 
review may result in additional negotiations of award.

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
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:

Chief, Review Branch 
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 752
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD  20817)
 
APPLICATION PROCESSING: Applications must be received on or before the 
application receipt date listed in the heading of this PAR.  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 PAR that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application. The 
CSR will not accept any application that is essentially the same as one 
already reviewed.  This does not preclude the submission of a substantial 
revision of an unfunded version of an application already reviewed, but such 
application must include an Introduction addressing the previous critique.  

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIDDK. Applications lacking the milestones section and 
description, as indicated in the “Supplementary instruction” section of this 
PAR, will not be reviewed.  Incomplete and/or non-responsive applications will 
not be reviewed. Applications that are complete and responsive to the PAR will 
be evaluated for scientific and technical merit by an appropriate peer review 
group convened by the NIDDK 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 Diabetes and Digestive and 
Kidney 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: Are the investigator appropriately trained and well suited to 
carry out this work? Is the work proposed appropriate to the experience level 
of the principal investigator and other researchers (if any)?  

ENVIRONMENT: Does the scientific environment in which the work will be done 
contribute to the probability of success? Do the proposed experiments take 
advantage of unique features of the scientific environment or employ useful 
collaborative arrangements? Is there evidence of institutional support?  

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

The initial review group will evaluate the specific goals for each phase and 
the feasibility of the milestones that would justify expansion to the R33 
phase.  The initial review group will evaluate how appropriate, realistic and 
quantifiable the proposed research milestones are, and whether the milestones 
are adequate for the demonstration and feasibility for transition to the R33 
development phase.  The initial review group will also assess the timeframe 
for achieving the milestones and whether they are appropriate.  A single 
priority score will be assigned to each scored application.  As with any grant 
application, the initial review group has the option of recommending support 
for a shorter duration than that requested by the applicant, and basing the 
final merit rating on the recommended portion of the application.  

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human 
subjects and protections from research risk relating to their participation in 
the proposed research will be assessed. (See criteria included in the section 
on Federal Citations, below).
 
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans 
to include subjects from both genders, all racial and ethnic groups (and 
subgroups), and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 
evaluated. (See Inclusion Criteria in the sections on Federal Citations, 
below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to 
be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed.  

ADDITIONAL CONSIDERATIONS  

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:          June 18, 2004
Application Receipt Date:               July 20, 2004
Peer Review Date:                       October/November 2004
Council Review:                         February 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:  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. 
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 PAR 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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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