INTERSTITIAL CYSTITIS / PAINFUL BLADDER SYNDROME: EPIDEMIOLOGY
 
RELEASE DATE:  January 22, 2004
 
RFA Number:  RFA-DK-04-009

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

COMPONENTS OF PARTICIPATING ORGANIZATION:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
 (http://www.niddk.nih.gov/)
Office of Research on Women’s Health (ORWH)
 (http://www4.od.nih.gov/orwh/)

CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.849

LETTER OF INTENT RECEIPT DATE: February 23, 2004
APPLICATION RECEIPT DATE: March 22, 2004
  
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism 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 Division of Kidney, Urologic and Hematologic Diseases (DKUHD) of the 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and 
the Office of Research on Women’s Health (ORWH) invites cooperative agreement 
applications for investigation of the epidemiology of interstitial cystitis 
and painful bladder syndrome (IC/PBS).  The purpose of this solicitation will 
be to establish a study group that will develop and conduct epidemiologic 
investigations using a population based sampling strategy to identify and 
characterize patients with symptoms consistent with interstitial cystitis or 
painful bladder syndrome.  The studies will characterize the patients 
clinically and demographically, establish risk factors, duration of symptoms, 
current methods of treatment and describe the economic burden of disease.  
The study protocol(s) must include the provision for an intensive clinical 
evaluation of a subset of the symptomatic subjects and matched controls, 
utilizing clinicians experienced in the diagnosis of interstitial cystitis. 

RESEARCH OBJECTIVES

Background

Interstitial Cystitis is a chronic disorder, diagnosed primarily in women, 
characterized by pelvic pain associated with the bladder as well as problems 
as urinary frequency and urgency. Despite considerable effort the etiology of 
interstitial cystitis has not been established.  Published studies on the 
epidemiology of Interstitial Cystitis (IC) have several limitations; the 
primary one is the lack of well-defined diagnostic criteria suitable for use 
in epidemiological investigation. Also most published studies have not used 
population-based sampling and have relied on extrapolation of results from 
samples of patients seeking medical care to population wide data. Very few 
epidemiological studies have focused on risk factors for IC and the few 
published studies which do mention risk factors focus on exacerbating factors 
of IC, making the identification of precipitating or risk factors difficult.

The NIDDK has a longstanding interest in clinical and epidemiological 
research for interstitial cystitis. Diagnostic Criteria for clinical trials 
on Interstitial Cystitis were established in 1988, following a workshop of 
experts convened to develop the criteria.  In 1991 the Interstitial Cystitis 
Database (ICDB) study was initiated.  The ICDB Study was a 5-year prospective 
cohort study of over 600 men and women with symptoms of urinary urgency, 
frequency, and pelvic pain.  Reports published from this study have described 
the longitudinal changes of urinary symptoms, the impact of interstitial 
cystitis on quality of life, treatment patterns and the relationship between 
findings from bladder biopsies and patient symptoms.  The findings from that 
study and other smaller international studies have indicated that the NIDDK 
Research Criteria for IC are too restrictive for epidemiological and 
population based studies. Applying the strict NIDDK Research Criteria 
definition to epidemiological and population based studies has been shown to 
exclude many persons who would be diagnosed to have IC by clinical experts.  
Thus, a new, more inclusive categorization of IC/PBS must be developed and 
utilized for epidemiological and population based studies.   

On October 29, 2003, the NIDDK convened a taskforce on the epidemiology of 
IC.  At that meeting, the importance of conducting research on population 
based samples was reaffirmed.  A summary of the workshop can be found at 
http://www.niddk.nih.gov/fund/other/conferences.htm.

As noted above, there are no commonly accepted standard definitions for 
either interstitial cystitis (IC) or painful bladder symptom (PBS) suitable 
for epidemiologic studies.  Recent reports have shown significantly higher 
prevalence estimates based on survey methods than the estimates derived from 
physician-based diagnoses. It is suspected that this disparity is in part due 
to missed diagnoses by clinicians who are not familiar with the symptoms 
associated with either IC or PBS.   Therefore it is important that there be a 
comparison of clinical assessment and questionnaire methods and that a 
representative sample of questionnaire identified patients be evaluated by 
clinicians who have demonstrated expertise in the assessment and diagnosis of 
IC/PBS.

Objectives of research program:

The objectives of the research program described in this RFA are to:

1) develop a population sampling strategy to survey the prevalence of persons 
with symptoms consistent with the diagnosis of interstitial cystitis or 
painful bladder syndrome;

2) develop working diagnostic categories and/or methods for assessing the 
severity of symptoms consistent with interstitial cystitis and painful 
bladder syndrome;  

3) develop questionnaire(s) to assess IC/PBS using both current examples of 
symptom assessment and advice of IC/PBS experts.

4) conduct well designed population based studies, which will estimate the 
prevalence of persons with symptoms consistent with IC/PBS and determine the 
characteristics of that population; 

5) provide for clinical evaluations of a subset of symptomatic individuals 
and control subjects by clinicians with demonstrated expertise in 
interstitial cystitis;

6) assess issues such as quality of life, severity of pain, and the impact of 
pain on the quality of life;

7) determine the socioeconomic impact of IC/PBS. 

The applicants should formulate a series of proposed research questions to be 
examined.  Potential issues to be addressed could include, but are not 
limited to, the following:

1) What is the prevalence of IC/PBS in the general population by demographic 
age, sex, and race/ethnic subgroups;

2) What are risk factors for the onset of IC/PBS;

3) What is the extent of health care utilization for persons with IC/PBS.

4) What are the most frequently used forms of treatment, including both 
conventional medical therapy and complementary or alternative therapies;

5) What are the most common associated clinical disorders;

6) What is the family history of IC/PBS.

7) If feasible, what is the longitudinal history of symptom severity in 
persons with IC/PBS;

The investigators, as part of a Cooperative Agreement, will work closely with 
the NIDDK Project Officer and Project Scientist, as well as an NIDDK 
appointed External Advisory Committee, to define the criteria for patient 
inclusion in the sample.  The exact method of population based sampling will 
be delineated by the Epidemiological Center in this application.  The final 
format for sampling will be determined after consultation with the External 
Advisory Committee. It is necessary that proposals include the ability to 
perform more intensive evaluation on a sample of symptomatic subjects and on 
control subjects, by a clinic experienced in diagnosing IC, at one or more 
clinical evaluation centers.  The clinical evaluation centers should have the 
ability to obtain urine and/or blood samples for biomarker evaluation. 

MECHANISM OF SUPPORT
 
This RFA will use the NIH cooperative agreement (U01) 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. The 
total project period for applications submitted in response to this RFA will 
be five years.  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 under 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.  Modular budgets will not be used.  
Follow the instructions for non-modular budget research grant applications.  
This program does not require cost sharing as defined in 
http://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm. 

The NIH U01 is a cooperative agreement award mechanism.  Under the 
cooperative agreement mechanism, the Principal Investigator retains the 
primary responsibility and dominant role for planning, directing, and 
executing the proposed project, with NIH staff being substantially involved 
as a partner with the Principal Investigator, as described under the section 
"Cooperative Agreement Terms and Conditions of Award”.  Plans for 
continuation of the project beyond the initially awarded period or for 
reissuance of the RFA or other announcement are indefinite. 

FUNDS AVAILABLE 
 
The NIDDK intends to commit approximately $1,000,000 in total costs in FY 
2004 to fund a new grant in response to this RFA. An applicant should request 
a project period of up to 5 years and a budget of up to $1,000,000 in total 
costs for each of those years. Although the financial plans of the NIDDK 
provide support for this program, awards pursuant to this RFA are contingent 
upon the availability of funds and the receipt of meritorious applications.  
 
ELIGIBLE INSTITUTIONS
 
You may submit an application 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. 

Principal investigators must demonstrate expertise in epidemiology, 
population-based sampling methodology, and survey methodology.  Investigators 
are encouraged to contact the existing NIDDK ICCRN Centers to serve as one or 
more clinical evaluation centers.  

SPECIAL REQUIREMENTS

Cooperative Agreement Terms and Conditions of Award

The following terms and conditions will be incorporated into the award 
statement and provided to the Principal Investigator(s) as well as the 
institutional official(s) at the time of the award. 
 
These special Terms of Award are in addition to and not in lieu of otherwise 
applicable OMB administrative guidelines, HHS Grants Administration 
Regulations at 45 CFR Parts 74 and 92, and the NIH Grants Policy statement.

The administrative and funding instrument used for this program is a 
cooperative agreement (U01), an "assistance" mechanism (rather than an 
"acquisition" mechanism) in which substantial NIH scientific and/or 
programmatic involvement with the awardee is anticipated during the 
performance of the activity.  Under the cooperative agreement, the NIDDK 
purpose is to support and/or stimulate the recipient's activity by 
involvement in and otherwise working jointly with the award recipient in a 
partner role, but it is not to assume direction, prime responsibility, or a 
dominant role in the activity.

Consistent with this concept, the dominant role and prime responsibility for 
the activity resides with the awardees for the project as a whole, although 
specific tasks and activities in carrying out the studies will be shared 
among the awardees and the NIDDK Project Scientist or designee.

Under the cooperative agreement, a relationship will exist between the 
recipient of these awards and the NIDDK, in which the performers of the 
activities are responsible for the requirements and conditions described 
below, and agree to accept program technical assistance, advice, and/or other 
coordination above and beyond normal program stewardship from a named NIDDK 
Project Scientist in achieving the project objectives.

Failure of an awardee to meet the performance requirements, including these 
special terms and conditions of award, or significant changes in the level of 
performance, may result in a reduction of budget, withholding of support, 
suspension and/or termination of the award.

A) Awardees Rights and Responsibilities

The Awardee is responsible for:

1. Research design and protocol development, including definition of 
objectives and approaches, planning, implementation, participant enrollment 
and follow-up, data collection, quality control, final data analysis and 
interpretation and publication of results.

2.  Establishing a Steering Committee to coordinate and manage the project. 
The awardee will name investigators to serve as members on a Steering 
Committee and other subcommittees, as appropriate, meeting periodically. The 
Awardee will be required to accept and implement the common protocol and 
procedures approved by the Steering Committee. 

3. Implementing the core data method and strategy collectively decided upon 
by the Steering Committee.  It is the responsibility of each site to ensure 
that data will be submitted in a timely way to the central Data Coordinating 
Center.  Individual sites must demonstrate the ability to implement the 
strategy specifically designed for individual study populations. 

4.  Establishing mechanisms for quality control and monitoring.  Awardees are 
responsible for ensuring accurate and timely assessment of the progress of 
each study, including development of procedures to ensure that data 
collection and management are adequate for quality control and analysis.

5. Submitting interim progress reports, when requested, to the NIDDK Project 
Officer, including as a minimum, summary data on protocol performance. Such 
reports are in addition to the annual awardee noncompeting continuation 
progress report. 

6.  Establishing procedures, where applicable, for all participating 
institutions in coordinated awards to comply with FDA regulations for studies 
involving investigational agents or devices and to comply with the 
requirements of 45 CFR Part 46 for the protection of human subjects, and the 
NIH policy requirements for the inclusion of women, minorities and children.

7.  Cooperating in the reporting of the study findings.  The awardee will 
retain custody of and have primary rights to the data developed under this 
award, subject to the Government rights of access consistent with current 
HHS, PHS and NIH Policies.  The NIDDK will have access to and may 
periodically review all data generated under an award.  Where warranted by 
appropriate participation, plans for joint publication with NIDDK of pooled 
data and conclusions are to be developed by the Principal Investigator or 
Steering Committee, as applicable.  NIH policies governing possible co-
authorship of publications with NIDDK staff will apply in all cases.  In 
general, to warrant co-authorship, NIDDK staff must have contributed to the 
following areas: (a) design of the concepts or experiments being tested; (b) 
performance of significant portions of the activity; and (c) preparation and 
authorship of pertinent manuscripts.

8.  Support or other involvement of industry or any other third party in the 
study—e.g., participation by the third party; involvement of study resources 
or citing the name of the study or NIDDK support; or special access to study 
results, data findings, or resources—may be advantageous and appropriate.  
However, except for licensing or patents or copy rights, support or 
involvement of any third party will occur only following notification of and 
concurrence by NIDDK.

9.  Study investigators are encouraged to publish and to release publicly and 
disseminate results and other products of the study, in accordance with study 
protocols and governances.

10. The NIDDK has established Central Biosample, Genetic, and Data 
Repositories for the archival and storage of data and biosamples collected in 
large, multi-site studies funded by NIDDK.  The Data Coordinating Center 
(DCC) will work with the NIDDK Biosample Repository to coordinate procedures 
for coding, shipping, receipt, and storage of study samples that are to be 
maintained in the Repository.  In addition, the DCC will coordinate with the 
NIDDK Data Repository to prepare the collected data for eventual archiving 
and distribution.  All samples and data transferred to the Repositories will 
be under the custodianship of the NIDDK, although the study’s Steering 
Committee will have proprietary control of and exclusive access to the 
samples and data for an agreed-upon period of time.  Subsequently samples and 
data will be available to the wider scientific community in accordance with 
the NIH policy on Data Sharing 
(http://grants.nih.gov/grants/policy/data_sharing, 
http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm#go
als, and 
http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm)
through a process that will include prioritized distribution based on review 
of the scientific merit of the proposed use.  Therefore, it is expected that 
samples and data collected will be available to the broader scientific 
community, after a proprietary period, at no charge other than the cost of 
reproduction and distribution. 

B) NIH Staff Responsibilities

An NIDDK Project Scientist will have substantial involvement in the project 
above and beyond normal stewardship and monitoring of the award, as described 
below.

1.  Being the contact point for all facets of the scientific interaction with 
the awardee.  As required for the coordination of activities and to expedite 
the progress, NIDDK may designate additional NIDDK staff to provide advice to 
the awardee on specific scientific and/or analytic issues.  Such staff may 
include another Project Scientist or Analyst, who will provide direct 
technical assistance to the awardees to optimize the conduct and/or analysis 
of the study; or who may assist in the coordination of activities across 
multiple sites. 

2.  Convening the first meeting of and subsequent participation in the 
Steering Committee that oversees study conduct.  The NIDDK Project Scientist 
or designee will be a full participant and voting member of the Steering 
Committee and, if applicable, subcommittees.

3. Serving as a resource with respect to other ongoing NIDDK activities that 
may be relevant to the protocol to facilitate compatibility and avoid 
unnecessary duplication of effort.

4. Providing substantial involvement assisting in the design and coordination 
of research activities for awardees in reviewing and approving the 
establishment of mechanisms for quality control and study monitoring.

An NIDDK Program Director include identified in the Notice of Grant award 
will be responsible for the normal stewardship and monitoring of the award.  
The Program Director may also serve as the Project Officer.

The NIDDK Program Director responsibilities include:

1. Retaining overall programmatic responsibility for the award, and will 
clearly specify to the awardee the name(s) and roles(s) of any additional 
individuals with substantial involvement in the project and the lines of 
reporting authority.

2. Interacting with the principal investigator on a regular basis to monitor 
study progress.  Monitoring may include: regular communications with the 
principal investigator and staff, periodic site visits for discussion with 
awardee research teams, observation of field data collection and management 
techniques, quality control, fiscal review, and other relevant matters; as 
well as attendance at Steering Committee and related meetings. The NIDDK 
retains, as an option, periodic external review of progress.

3.  Reviewing and approving protocols to insure they are within the scope of 
peer review and for safety considerations, as required by Federal 
regulations.  The NIDDK Program Director will monitor protocol progress, and 
may request that a protocol be closed to accrual for reasons including: (a) 
accrual rate insufficient to complete study in a timely fashion; (b) accrual 
goals met early; (c) poor protocol performance; (d) study results that are 
already conclusive; and (e) emergence of new information that diminishes the 
scientific importance of the study question.  The NIDDK will not permit 
further expenditures of NIDDK funds for a study after requesting closure 
(except for patients already on-study).

4. Making recommendations for continued funding based on: a) overall study 
progress, including sufficient patient and/or data accrual; b) cooperation in 
carry out the research ( e.g. attendance at Steering Committee meetings, 
compliance with terms of award and reporting requirements); and/or  c) 
maintenance of a high quality of research.

C.  Joint Responsibilities

In addition to the interactions defined above, NIDDK Staff and Awardees shall 
share responsibility for the following activities:

1.  Steering committee.

A Steering Committee organized by the Principal Investigator will be the main 
oversight body of the study.

The Steering Committee has primary responsibility to design research 
activities, establish priorities, develop protocols and manuals, 
questionnaires, and other data recording forms, establish and maintain 
quality control, review progress, and cooperate on the publication of 
results.  Major scientific decisions regarding the core data will be 
determined by the Steering Committee.  The Steering Committee will document 
progress in written reports to the NIDDK Program Director, and will provide 
periodic supplementary reports upon request.

The Steering Committee will be composed of the Principal Investigator and co-
investigators as deemed necessary, and the NIDDK Project Scientist or 
designee.  An initial meeting of the Steering Committee will be convened 
early after award by the NIDDK Project Scientist or designee.  The final 
structure of the Steering Committee will be established at the first meeting.  
The NIDDK Project Scientist or designee will have voting membership on the 
Steering Committee, and as appropriate, its subcommittees. 

A Chairperson, other than the NIDDK representative, will be selected by a 
vote of the members. The Chairperson is responsible for coordinating the 
Committee activities, for preparing meeting agendas, and for scheduling and 
chairing meetings.

It is assumed that the Steering Committee will meet in person quarterly until 
the protocol is established and then every four to six months as necessary.  
The committee will meet monthly by telephone conference call.

D) Establishment of an External Advisory Committee (EAC).

Since there will not be any clinical trials conducted as part of these 
epidemiologic studies there will not be a need for a Data and Safety 
Monitoring Board; however, the NIDDK will establish an External Advisory 
Committee which will provide clinical expertise in Interstitial Cystitis as 
well as expertise in biostatistics, epidemiology, population sampling, etc.  
 
The EAC will be advisory to the NIDDK and serve as consultants to the 
investigator(s) during development of the epidemiologic inclusion criteria, 
sampling design, statistical analysis, etc. It is assumed that the EAC will 
meet in person with Investigators and NIDDK staff frequently during 
development of the sampling protocol.  It will then meet semi-annually in 
person with the Epidemiological Center and NIDDK staff to review progress.

The EAC will be advisory to the NIDDK staff as well as the Epidemiological 
Center investigators and will participate in a consultative manner. 

It is assumed that the EAC will meet with the Steering Committee 
approximately every six months, and more frequently by conference call as 
necessary until the protocol is established and operative. Then the EAC will 
meet annually or more frequently if necessary.  

5) Arbitration

Any disagreement that may arise in scientific/programmatic matters (within 
the scope of the award), between award recipient and the NIDDK may be brought 
to arbitration.  An arbitration panel will be composed of three members; one 
selected by the investigators, a second member selected by NIDDK, and the 
third member selected by the two prior members.  This special arbitration 
procedure in no way affects the awardee's right to appeal an adverse action 
that is otherwise appealable in accordance with the PHS regulations at 42 CFR 
part 50, Subpart D and HHS regulation at 45 CFR part 16, or the rights of 
NIDDK under applicable statutes, regulations and terms of the award.

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:

Paul W. Eggers Ph.D. 
Urology and Kidney Epidemiology Program Director
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 6157
Bethesda, MD  20892-5458
Telephone:  (301) 594-8305
Fax:  (301) 480-3510
Email:  pe39h@nih.gov 

Leroy M. Nyberg, M.D., Ph.D.
Urology Program Director
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 617
Bethesda, MD  20892-5458
Telephone:  (301) 594-7717
Fax:  (301) 480-3510
Email:  ln10f@nih.gov

Lisa Begg, Dr.P.H., R.N.
Director of Research Programs
Office of Research on Women's Health
DHHS/NIH/OD
Bethesda, MD. 20892
phone:  301/496-7853
fax: 301/402-1798
email: beggl@od.nih.gov

o Direct your questions about peer review issues to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 752
Bethesda, MD 20892-5452
Telephone:  (301) 594-8885
FAX:  (301) 480-3505
Email:  fc15y@nih.gov

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

Donald Ellis
Grants Management Specialist
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rom 743
Bethesda, Maryland 20892-5456
Telephone: (301) 594-8849
FAX: (301) 480-3504
Email:  de30z@nih.gov 

Helen Ling
Grants Management Specialist
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 732
Bethesda, MD 20892-5456
Telephone:  (301) 594-8857
FAX:  (301) 480-3504
Email: hl12d@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 NIDDK 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, Room 752
Bethesda, MD  20892-5452
(For express/courier service: Bethesda, MD  20817)
Telephone:  (301) 594-8897
FAX:  (301) 480-3505

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001, updated 9/9/2003).  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.
 
SUPPLEMENTARY INSTRUCTIONS: 

1) Proposed Population Sampling Concept:  The general concept for a 
population based sampling protocol, with proposed statistical analyses, 
should be included in the application.  The general concept must be 
consistent with the scientific focus of the RFA. Applicants must describe the 
feasibility of conducting the study and the estimated success at enrollment.  
The sampling concept should include estimates of numbers of persons to be 
contacted and to be enumerated in the study.  Also, estimates of number by 
gender, age, ethnicity, and race should be given with the justification for 
using those estimates. Additionally, the methodology to be used to 
extrapolate the sampling to the general population should be specified.

2) Proposed Clinical Evaluation Protocol: The intensive clinical evaluation 
protocol would include what percentage of enrolled participants will be 
selected for the clinical evaluation protocol, how these participants will be 
selected, what will the intensive clinical evaluation protocol include, where 
will the evaluation be conducted and by whom, listing the qualifications of 
both the site (s) and the clinician(s).  

3) Evidence of Institutional Support:  There should be evidence of strong 
institutional support for the study, including adequate space and equipment 
to conduct the study.  An organizational structure for the Center should be 
set forth in the application, delineating lines of authority and 
responsibility for dealing with problems in all general areas as well as 
willingness to participate in the cooperative agreement arrangement as 
delineated in this RFA. 

4) Evidence of Cooperation from Participating Clinical Evaluation Centers:  
There should be documented agreement between the principal investigator and 
institutions at which the intensive clinical evaluation protocols will be 
conducted.  This should include delineation of clinical staff, 
responsibilities, and qualifications as well as amount of space and necessary 
diagnostic equipment available for the study.

5) Personnel Requirements:  The application must describe the expertise of 
the key epidemiological, technical, administrative and clinical personnel and 
must include a mechanism for replacing key professional or technical 
personnel should the need arise.

BUDGET

The Principal Investigator should prepare a budget for each year of the five 
years of the program not to exceed $1,000,000 total costs (direct and 
facilities and administrative costs) per year.  The first 8 months of year 1 
will be a period of intensive protocol development with bi-monthly meetings 
of the Steering Committee to be held either in the Washington, D.C. area or 
at the site of the IC Epidemiological Center (approximately 50% each place).  
Beginning in year 2 and for the duration of the program, applicants should 
budget for three meetings each year of the Steering Committee to be generally 
held in the Washington, D.C. area or at the funded site.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the 
application.  Type the RFA number on the label.  Failure to use this label 
could result in delayed processing of the application such that it may not 
reach the review committee in time for review.  In addition, the RFA title 
and number must be typed on line 2 of the face page of the application form 
and the YES box must be marked. The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the Checklist, and three signed, photocopies, in 
one package to:
 
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application and all 
appendices must be sent to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 752 
Bethesda, MD  20892-5452
(Courier use ZIP 20817)

APPLICATION PROCESSING: Applications must be received by the application 
receipt date listed in the heading of this RFA.  If an application is 
received after that date, it will be returned to the applicant without 
review.

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks. 
 
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 Center 
for Scientific Review and responsiveness by the National Institute of 
Diabetes and Digestive and Kidney Diseases.  Incomplete and/or non-responsive 
applications will not be reviewed and will be returned to the applicant 
without further consideration.

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 National Institute of Diabetes and Digestive and Kidney 
Diseases in accordance with the review criteria stated below.  As part of the 
initial merit review, all applications will:

o Receive a written critique.
o Undergo a process in which only those applications deemed to have the 
highest scientific merit will be discussed and assigned a priority score.
o Receive a second level review by the National Diabetes and Digestive and 
Kidney Diseases 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 
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, weighing 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.

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 
priority score:

Applicants are expected to address issues identified under the following 
sections in this RFA: 

SPECIAL REQUIREMENTS; SUBMITTING AN APPLICATION/SUPPLEMENTAL INSTRUCTIONS.  
All applications will be reviewed according to the criteria listed below.  In 
the written comments, reviewers will be asked to discuss the following 
aspects of the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the goals of this solicitation.  
Each of the criteria will be addressed and considered in assigning the 
overall score, weighting them as appropriate for each application

o Study design 
o Qualifications and experience
o Institutional resources
o Proposed Population Sampling Methodology
o Proposed clinical evaluation methodology
o Qualifications and experience of Principal Investigator, Clinical expert(s) 
and technical personnel

In addition to the above criteria, applications will also be reviewed with 
respect to the following:

o PROTECTIONS:  The adequacy of the proposed protection for participants in 
all clinical studies. 

o INCLUSION:  The adequacy of plans to include subjects from both genders, 
all racial and ethnic groups (and subgroups), and children as appropriate for 
the scientific goals of the research.  Plans for the recruitment and 
retention of subjects will also be evaluated. (See Inclusion Criteria 
included in the section on Federal Citations, below)

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 recruitment and retention of subjects will also be 
evaluated. 

ADDITIONAL REVIEW CONSIDERATIONS:

Sharing Research Data:

Applicants requesting more than $500,000 in direct costs in any year of the 
proposed research must include a data sharing plan in their application.  The 
reasonableness of the data sharing plan or the rationale for not sharing 
research data will be assessed by the reviewers.  However, reviewers will not 
factor the proposed data sharing plan into the determination of scientific 
merit or priority score. 

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 23, 2004      
Application Receipt Date:           March 22, 2004        
Peer Review Date:                   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 

SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, 
investigators submitting and NIH application seeing $500,000 or more in 
direct costs in any single year are expected to include a plan for data 
sharing or state why this is not possible.  
http://grants.nih.gov/grants/policy/data_sharing. Investigators should seek 
guidance from their institutions, on issues related to institutional 
policies, local IRB rules, as well as local, state and Federal laws and 
regulations, including the Privacy Rule.  Reviewers will consider the data 
sharing plan but will not factor the plan into the determination of the 
scientific merit of the priority score. 

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

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

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

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

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

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 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 research and his/her institution.  The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including 
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 can be found at: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.
 
URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites.   Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

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

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance 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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