EPIDEMIOLOGY OF CHRONIC PELVIC PAIN OF THE BLADDER AND INTERSTITIAL CYSTITIS

Release Date:  July 13, 2000

RFA:  DK-00-018 (Request for competing applications from current awardee, see NOT-DK-00-018)

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  October 13, 2000
Application Receipt Date:       November 13, 2000

PURPOSE

The Division of Kidney, Urologic, and Hematologic Diseases (DKUHD) of 
the National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK) has a longstanding interest in supporting basic and clinical 
research studies of interstitial cystitis.  During the past decade it 
has become evident that interstitial cystitis represents one of a 
number of symptom complexes of chronic pelvic pain of bladder origin.  
Currently the magnitude of the burden of the chronic pelvic pain of the 
bladder symptom complex on the health of the U.S. population is not 
known.  In addition, risk factors for these complexes and their impact 
on quality of life are also largely unknown.  Previous studies of 
interstitial cystitis have focused almost entirely on highly selected 
populations and do not provide adequate population estimates of its 
burden or the impact of the more inclusive complex of chronic pelvic 
pain of the bladder.  The NIDDK invites cooperative agreement 
applications for investigators to utilize ongoing prospective cohort 
studies, clinical trials, and large patient databases to design 
epidemiological, quality of life, and health resource utilization 
studies for chronic pelvic pain of bladder origin and interstitial 
cystitis.  The overall intent of this solicitation is to obtain 
accurate epidemiological information on chronic pelvic pain of bladder 
origin in the U.S. population over a wide age range, in women and men, 
and in representative racial and ethnic groups.  Because the number of 
cases of chronic pelvic pain of bladder origin and interstitial 
cystitis identified from a single prospective cohort study, clinical 
trial, or patient database may be too small and/or may represent a 
select population which will not permit generalization of the findings, 
this Request for Applications (RFA) requires that investigators 
participating as an Epidemiology Study Center combine their data for 
further analysis.  This RFA also seeks a Data Analysis/Administrative 
Core to analyze combined data and to perform certain administrative 
functions to facilitate collaboration between the Epidemiology Study 
Centers.

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, 
“Epidemiology of Chronic Pelvic Pain of the Bladder and Interstitial 
Cystitis”, 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/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic, for-profit and non-profit, 
institutions, public and private organizations, such as universities, 
colleges, hospitals, units of State and local government, and eligible 
agencies of the Federal government.  Foreign institutions are not 
eligible to apply.  Racial/ethnic minorities, women, and persons with 
disabilities are encouraged to apply as Principal Investigators.  

Eligible applicants may include Principal Investigators of ongoing 
prospective cohort studies or individuals who obtain permission from 
the Principal Investigator of a cohort study, to access their 
populations for studies as described in this RFA.  If the applicant is 
not the Principal Investigator of the ongoing cohort study proposed to 
be accessed to conduct an ancillary study of the epidemiology of 
chronic pelvic of the bladder and interstitial cystitis in response to 
this RFA, then the applicant must provide written assurance from the 
Principal Investigator of the parent study that the proposed study is 
technically and administratively feasible. In the case when the 
applicant proposes to access participants of a multi-center clinical 
trial assurance must be provided by the trial’s Publications, 
Presentations, and Ancillary Studies Subcommittee (or equivalent review 
group) and included in the application.  Individuals with access to 
large patient databases, for example from a health maintenance 
organization, are also encouraged to apply.  Similarly, applicants 
proposing to access large databases must also provide written assurance 
of their ability to directly access patients and/or their medical 
records or data files to obtain the required information for the 
studies described in this RFA.  Cohort studies and clinical trials 
acceptable for access to achieve the goals of this Request for 
Applications may be supported by either a governmental and/or non-
governmental source.  An institution or organization may apply for both 
an Epidemiology Study Center and the Data Analysis/Administrative Core.  
The same person may serve as the Principal Investigator of an 
Epidemiology Study Center and the Data Analysis/Administrative Core.  
However, separate applications are required for an Epidemiology Study 
Center and a Data Analysis/Administrative Core.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for these awards 
will be the cooperative agreement (U01).  The cooperative agreement is 
an assistance mechanism in which substantial NIDDK scientific and 
programmatic involvement is anticipated during the performance of the 
activity.  Under the cooperative agreement, the NIDDK’s purpose is to 
support and encourage the recipient’s activities by working jointly 
with the awardees in a partnership role, but not to assume direction, 
prime responsibility, or dominance.  Details of the responsibilities, 
relationships, and governance of a study funded under a cooperative 
agreement are described under the section entitled, “Terms and 
Conditions of Award.”  The total project period for applications 
submitted in response to this RFA must not exceed five years.  The 
anticipated award date is July 3, 2001.  At this time, the NIDDK has 
not determined whether or how this solicitation will be continued 
beyond the present RFA.

FUNDS AVAILABLE

The NIDDK plans to make four awards for Epidemiology Study Centers and 
one award for a Data Analysis/Administrative Core.  Approximately 
$1,500,000 total cost (direct plus Facilities and Administrative (F&A) 
costs)is expected to be available per year of support under this RFA.  
It is anticipated that the award for each Epidemiology Study Center 
will be about $285,000 total cost per year and the award for the Data 
Analysis/Administrative Core will be about $350,000 total cost per 
year.  

The number of awards to be made is dependent on the receipt of a 
sufficient number of applications of high scientific merit and 
availability of funds.  Although this program is provided for in the 
financial plans of the NIDDK, awards pursuant to this RFA are 
contingent upon the availability of funds and the receipt of a 
sufficient number of applications of outstanding scientific and 
technical merit.

RESEARCH OBJECTIVES

Background

Interstitial cystitis is one of a constellation of diseases and 
disorders that are characterized by chronic pelvic pain associated with 
bladder symptoms of urinary frequency and urgency.  Although there have 
been several published studies of the epidemiology of interstitial 
cystitis, they have focused almost totally on women and on non-minority 
populations.  There is very little information on the broader, more 
inclusive disorder of chronic pelvic pain and associated bladder 
symptoms in any population.  Estimates of the prevalence of 
interstitial cystitis in the U.S. vary ten-fold from 67 per 100,000 
women participating in the Nurses Health Study I and Nurses Health 
Study II to 870 per 100,000 persons in the National Health Interview 
Survey.  The disparity in prevalence rates appears to be related 
primarily to the definitions utilized to ascertain cases.  The few 
epidemiological studies of interstitial cystitis reported to date have 
many shortcomings.  Major limitations of these studies include the 
absence of racial and ethnic diversity, the small number of men 
studied, and the limited age range of the populations examined.  This 
has resulted in inadequate information among children and young adults, 
men, and minority populations.  Another significant limitation is the 
use of select populations, including physician-based and urology 
clinic-based sources of participants.  Perhaps the greatest limitation 
is that studies performed to date have restricted their focus to 
interstitial cystitis.  This approach undoubtedly underestimates the 
burden of chronic pelvic pain of bladder origin.  Recently, a telephone 
survey of over 5,000 women aged 18 to 50 years conducted in the U.S. 
found a prevalence of 14.7% for chronic pelvic pain of all causes.  
Importantly, over one-half of the cases of chronic pelvic pain had no 
diagnosis based on participant self-report.

Chronic pelvic pain of bladder origin is a symptom complex found in 
children and adults of all ages, in males and females, and in different 
racial and ethnic groups.  However, since it is not a clinical 
diagnostic category or a clinical designation, the symptom complex is 
frequently incorrectly designated by the primary care physician and is 
given various clinical labels by the diagnosing physician who is 
usually a urologist.  For example, the symptom complex is frequently 
called interstitial cystitis if it is present in women, and in men the 
diagnostic label of prostadynia and/or chronic abacterial prostatitis 
is used much more often.  Other diagnostic categories for women include 
urethral syndrome, non-infectious cystitis and frequency-urgency pain 
syndrome while in men it has been called testalgia, orchalgia, and non-
specific urethritis.  Children are usually given the diagnosis of 
dysfunctional voiding, Hinman syndrome, or tethered cord syndrome.  
These disorders are primarily identified via patient report of 
symptoms, have vague diagnostic criteria and usually no objective 
markers to establish a diagnosis or to adequately assess their 
severity.    Moreover, these disorders do not have disease 
classification codes in the International Classification of Diseases, 
and the time from symptom appearance to clinical diagnosis may be many 
years, making the identification of precipitating or risk factors 
difficult.  Studies of interstitial cystitis are also plagued by many 
of these same difficulties.  Despite similar obstacles, investigators 
have made substantial advances in understanding the epidemiology of 
other symptom-based complexes/syndromes, such as chronic fatigue 
syndrome.

Importantly, few epidemiological studies have focused on risk factors 
for chronic pain of bladder origin and interstitial cystitis and the 
few studies that have been performed have focused only on factors 
exacerbating symptoms in patients with interstitial cystitis.  
Epidemiological studies, including case-control studies, are necessary 
to further define possible risk factors for both chronic pelvic pain of 
bladder origin and interstitial cystitis.  In cross-sectional studies 
of predominantly white women with interstitial cystitis, quality of 
life was substantially reduced.  In addition, a recent study has shown 
that many prescription and non-prescription therapies are utilized in 
the treatment of patients with interstitial cystitis, suggesting that 
the economic burden of this symptom complex and chronic pelvic of the 
bladder may be substantial.  Additional studies are necessary to 
further study both quality of life and health resource utilization 
among persons with chronic pelvic pain of the bladder and interstitial 
cystitis.

Research Goals and Scope of the Activity

The intent of this RFA is to solicit applications from investigators 
proposing to serve as Epidemiology Study Centers or a Data 
Analysis/Administrative Core to develop and conduct a multi-
institution, collaborative research program of the epidemiology, risk 
factors, quality of life and functional status, and health resource 
utilization of chronic pelvic pain of the bladder and interstitial 
cystitis.  Investigators will cooperate in a collaborative manner to 
develop a protocol to assess the incidence, prevalence, and gender, 
racial/ethnic distribution, quality of life, and health resource 
utilization of chronic pelvic pain of bladder origin and interstitial 
cystitis in their respective cohort studies, and/or clinical trials, 
and/or patient databases.  An important part of this protocol will be 
the development of common definitions of chronic pelvic pain of bladder 
origin and interstitial cystitis so that data can be pooled, thereby 
improving the statistical precision of estimates of incidence and 
prevalence, to permit subgroup analyses, and to identify candidate risk 
factors.  The level and patterns of health resource utilization will 
also be investigated.  Investigators will focus on identifying risk 
factors for chronic pelvic pain of bladder origin and interstitial 
cystitis through a variety of epidemiological approaches, including 
nested case-control studies. Quality of life and functional status will 
be measured using generic instruments.  Development of disease/complex-
specific instruments to measure quality of life, however, will be 
considered by the collaborative study group.  Health resource 
utilization will be assessed uniformly in a representative number of 
cases and non-cases by the participating investigators.  The overall 
intent of this solicitation is to obtain accurate data on chronic 
pelvic pain of bladder origin and interstitial cystitis in all ages, in 
males and in females, and in a wide range of racial and ethnic groups.

The specific goals of this solicitation are as follows:

1. to develop uniform clinical definitions for chronic pelvic pain of 
bladder origin and interstitial cystitis for use by the Epidemiology 
Study Centers in the individual cohort studies, clinical trials, and/or 
large databases in order to permit combination and analysis of data 
across study sites.

2. to document the overall prevalence of the chronic pelvic pain of 
bladder origin symptom complex and interstitial cystitis and to 
determine prevalence by age, gender, and race/ethnicity.

3. to determine the incidence of  chronic pelvic pain of bladder origin 
and interstitial cystitis based on race/ethnicity, gender, and other 
relevant clinical and demographic factors.

4. to identify possible risk factors for the chronic pelvic pain 
associated with the bladder symptom complexes.

5. to assess quality of life, functional status, and co-morbid medical 
conditions for these symptom complexes.

6. to estimate health resource utilization related to chronic pelvic 
pain of bladder origin and interstitial cystitis compared to a control 
population.

Study Phases

The timetable for the study may be subdivided into three phases over a 
five-year period.

Phase I  (Months 1-6):  Protocol Development.  This phase includes the 
development of common and accepted definitions of chronic pelvic pain 
of bladder origin symptom complex and interstitial cystitis.  
Standardized questionnaires to be administered to study participants 
will be developed based on these accepted definitions.  Protocols will 
also be established for carrying out the prevalence, incidence, and 
risk factor studies.  Instruments to assess quality of life and 
functional status will be selected from among those currently available 
or complex-specific instruments will be developed and validated by the 
collaborative study group.  Data collection instruments and forms to 
assess health resource utilization will also be developed and evaluated 
prior to implementation.

Phase II (Months 6-54):  Epidemiological Studies Implementation.  It is 
anticipated that the first study to be conducted will determine 
prevalence (first 12 months of Phase II).  Upon the establishment of 
the prevalence of chronic pelvic pain of bladder origin and 
interstitial cystitis the incidence will be assessed over a 36-month 
period (months 18-54 of Phase II).  During the same period of time 
during which the incidence study is conducted, studies of risk factors, 
quality of life and functional status, and health resource utilization 
will be performed.  Concurrent with studies in Phase II will be 
analysis of the prevalence data and preparation and publication of 
manuscripts in peer-reviewed scientific journals. Interim analyses of 
findings from the incidence, risk factor, quality of life and 
functional status, and health resource utilization studies will also be 
performed.

Phase III (Months 55-60):  Final Data Analysis and Close-out of the 
Epidemiology Study Centers and the Data Analysis/Administrative Core.  
Final analysis of results from the incidence, risk factor, quality of 
life and functional status, and health resource utilization studies 
will be performed during a six-month period in Phase III.  In addition, 
manuscripts will be prepared during this phase for publication in peer-
reviewed scientific journals.  The Epidemiology Study Centers and the 
Data Analysis/Administrative Core will also be closed-out during months 
59 and 60.

STUDY COMPONENTS	

Epidemiology Study Center

The Epidemiology Study Center investigators will have direct 
responsibility for accessing their cohort study participants, clinical 
trial subjects, and/or database subjects (or their medical 
records/patient data files) to assess, in a uniform manner, the 
prevalence, incidence, and risk factors for chronic pelvic pain of 
bladder origin and interstitial cystitis.  Studies on quality of life 
and functional status and health resource utilization will also be 
performed in a comparable manner across study sites.  The Epidemiology 
Study Center will be responsible for assuring high rates of response to 
questionnaires, high level of data quality, and timely, accurate 
transmission of data to the Data Analysis/Administrative Core.  They 
will also be responsible for suggesting analyses to the Data 
Analysis/Administrative Core.

Data Analysis/Administrative Core

The Data Analysis/Administrative Core will be responsible for 
establishing a database to accommodate data sent by the Epidemiology 
Study Centers, including relevant demographic and clinical information 
to be transferred from the primary databases established for the 
primary focus of the cohort studies, clinical trials, and patient 
databases.  They will also conduct analyses as suggested by the 
Epidemiology Study Centers as well as propose original analyses to the 
collaborative group for their consideration.  The Data 
Analysis/Administrative Core will also prepare reports on the progress 
of the various studies, including data quality control, and interim and 
final results.  The Data Analysis/Administrative Core will also be 
responsible for arranging meeting and conference calls of the Steering 
and Planning Committee, arranging for meeting of the group of external 
advisors, and other administrative functions necessary to coordinate 
the efficient operation of the collaborative study group.

Steering and Planning Committee

The primary governing body of the study will be the Steering and 
Planning Committee comprised of each of the Principal Investigators of 
the Epidemiology Study Centers and the Principal Investigator of the 
Data Analysis/Administrative Core, the Chairperson of the Steering and 
Planning Committee, and the NIDDK Project Scientists (described in 
detail under Terms and Conditions).  The Steering and Planning 
Committee will develop the epidemiological definitions for chronic 
pelvic pain of bladder origin and interstitial cystitis, participant 
questionnaires and data collection forms, and design epidemiological 
studies to elucidate risk factors.  They will evaluate currently 
available quality of life and functional status assessment instruments 
for their utility in this study as well as design data collection 
instruments for the study of health resource utilization.  The Steering 
and Planning Committee will review analyzed data and write manuscript 
describing the findings.

Group of External Advisors

An independent group of experts in areas such as urology, 
urogynecology, pain epidemiology, and biostatistics who are not 
otherwise involved in the study will be recruited by the NIDDK to 
evaluate the proposed protocol and review periodically the progress of 
the study (described in detail under Terms and Conditions).

Project Scientists

The NIDDK will identify two Project Scientists for the study.  The 
Project Scientists will assist the Steering and Planning Committee and 
group of external advisors in carrying out the study (described in 
detail under Terms and Conditions).

SPECIAL REQUIREMENTS

Terms and Conditions of Award

The following terms and conditions will be incorporated into the award 
statement and provided to each Principal Investigator as well as to the 
institutional officials at the time of the award.  These terms are in 
addition to, not in lieu of, otherwise applicable Office of Management 
and Budget (OMB) administrative guidelines, HHS Grant Administration 
Regulations at 45 CFR Part 74 and 92, and other HHS and NIH Grants 
Administration policy statements.

1. Collaborative Responsibilities.  The administrative and funding 
instrument used for this program is the cooperative agreement (U01), an 
“assistance” mechanism (rather than an “acquisition” mechanism), in 
which substantial NIH scientific and/or programmatic involvement with 
awardees is anticipated during the performance of the activity.  Under 
the cooperative agreement, the NIH 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 the cooperative agreement concept, the 
dominant role and prime responsibility for the planned activity reside 
with the awardees for the project as a whole, although specific tasks 
and activities in carrying out the activity will be shared among the 
awardees and NIDDK Project Scientists.

2.  Awardees’ Rights and Responsibilities.  Awardees will have 
substantial and lead responsibilities in all tasks and activities.  
These include protocol development, accessing study participants or 
their data, data collection, data quality control, final data analysis 
and interpretation, and preparation of publications.  The awardees 
agree to work cooperatively with the other Epidemiology Study Centers 
and agree to follow the common protocol developed by the Steering and 
Planning Committee.  The awardees agree also to transmit the agreed 
upon study data in a timely manner to the Data Analysis/Administrative 
Core for combination and analysis.  Awardees will retain custody of and 
have primary rights to their data developed under these awards, subject 
to Government (e.g., NIDDK, NIH, or PHS) rights or access consistent 
with current HHS and NIH policies.

3.  NIDDK Staff Responsibilities.  The NIDDK will name two Project 
Scientists from within the Division of Kidney, Urologic and Hematologic 
Diseases whose function will be to assist the Steering and Planning 
Committee in carrying out the study.  One Project Scientist will have 
clinical expertise in urology and the other will have experience in the 
development and conduct of multi-center clinical studies.  The Project 
Scientists will have substantial scientific-programmatic involvement in 
protocol development, quality control, interim data analysis, and final 
data analysis and interpretation, preparation of publications, and 
coordination and performance monitoring.  The NIDDK Project Scientists 
will have voting membership on the Steering and Planning Committee and 
will have one vote between them.  One of the NIDDK Project Scientists 
will also serve as Executive Secretary of the group of external 
advisors.  The NIDDK reserves the right to terminate or curtail the 
study (or an individual award) in the event of difficulties in 
accessing the cohort studies, clinical trials, or patient databases or 
poor response rates to the questionnaires, in timely data reporting, 
achieving high levels of data quality, or other major breaches of the 
protocol, or human subject ethical issues that may dictate a premature 
termination.

4. Governance. 

The Steering and Planning Committee, composed of each of the Principal 
Investigators of the Epidemiology Study Centers, the Principal 
Investigator of the Data Analysis/Administrative Core, the NIDDK 
Project Scientists, and the Chairman of the Steering and Planning 
Committee, will be the main governing board of the study.  This 
committee will have the primary responsibility for developing the 
common  protocol, facilitating the conduct and monitoring of the 
epidemiological, quality of life and functional status, and health 
resource utilization studies, and reporting the study results.  Each 
member of the Steering and Planning Committee will have one vote (NIDDK 
Project Scientists will have one vote between them), and all major 
scientific decisions will be determined by a majority vote of the 
Steering and Planning Committee.  A Chairperson will be chosen from 
among the Steering and Planning Committee members (but not one of the 
NIDDK Project Scientists) or alternatively, from among experts in the 
field of urology or epidemiology who are not participating directly in 
the study.

An independent group of external advisors, selected by the Director, 
NIDDK, will review periodically the progress of the study.  This group 
will include experts in the relevant medical, epidemiological, 
statistical, and ethics fields who are not otherwise involved in the 
study.  The external advisors will review the study protocol and 
evaluate results, monitor data quality, and provide operational and 
policy advice to the Steering and Planning Committee and to the NIDDK 
regarding the status of the study.  One of the NIDDK Project Scientists 
will serve as Executive Secretary of the group.  The members of the 
group will review progress and report to the NIDDK at least once each 
year, or more often if necessary. 

5. Arbitration

Any disagreement that may arise on scientific/programmatic matters 
(within the scope of the award) between recipients and the NIDDK may be 
brought to arbitration.  An arbitration panel will be composed of three 
members, one selected by the Steering and Planning Committee (with the 
NIDDK member not voting) or by the individual awardee in the event of 
an individual disagreement, a second member selected by NIDDK, and the 
third member selected by the two prior selected 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 45 CFR 
Part 16.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

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 
biomedical and behavioral research projects involving human subjects, 
unless a clear and compelling rationale and justification is provided 
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 1003-43).  
All investigators proposing research involving human subjects should 
read the “NIH Guidelines for Inclusion of Women and Minorities as 
Subjects in Clinical Research” which have been published in the Federal 
Register of March 28, 1994 (FR 59 14508-14513) and in the NIH GUIDE FOR 
GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11, available 
on the web at:  
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.  
It is recognized that in cases where recruitment of all of the participants 
of an established cohort study or clinical trial has been completed, the 
gender and racial/ethnic characteristics of the population intended to be 
accessed in response to this RFA is fixed.  However, if the applicant 
proposes to utilize a subset of the cohort study or clinical trial population, 
a sampling scheme must be proposed that ensures adequate representation of 
women and minority subjects. 

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS

It is the policy of the NIH that children (i.e., individuals under the 
age of 21) must be included in all human subjects research, conducted 
or supported by the NIH, unless there are scientific and ethical 
reasons not to include them.  All investigators proposing research 
involving human subjects should read the “NIH Policy and Guidelines” on 
the Inclusion of Children as Participants in Research Involving Human 
Subjects that was published in the NIH Guide for Grants and Contracts, 
March 6, 1998, and is available at the following URL address:  
http://grants.nih.gov/grants/guide/notice-files/not98-025.html.  It is 
also recognized that in cases where the participants of a cohort study 
or clinical trial have already been recruited, the age distribution of 
the population intended for use in response to this RFA cannot be 
modified.  However, if the applicant proposes to utilize a subset of 
the cohort study or clinical trial population, and children are 
included in the whole study population, a sampling scheme must be 
proposed that ensures adequate representation of children. 

Investigators also may obtain copies of these policies from the program 
staff listed under INQUIRIES.  Program staff may also provide 
additional relevant information concerning the policy.

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.  Reviewers are cautioned that 
their anonymity may be compromised when they directly access an 
Internet site.

LETTER OF INTENT

Prospective applicants are asked to submit, by October 13, 2000, a 
letter of intent that includes a descriptive title of the proposed 
research, name, address, and telephone number of the Principal 
Investigator, identities of other key personnel and participating 
institutions, and number and title of the RFA in response to which the 
application may be submitted.  Although a letter of intent is not 
required, is not binding, and does not enter into the review of a 
subsequent application, the information it contains allows the NIDDK 
staff to estimate the potential review workload and plan the review.  
The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes, Digestive, and Kidney Diseases
Room 653, MSC 5452
6707 Democracy Boulevard
Bethesda, Maryland 20892-5452 (for courier service use 20817)
Telephone:  (301) 594-8885
Fax:  (301) 480-3505
Email:  hagana@extra.niddk.nih.gov

APPLICATION PROCEDURES

Applications must be submitted on the standard research grant 
application form PHS 398 (rev. 4/98).  Application kits are available 
at most institutional offices of sponsored research and may be obtained 
from the Division of Extramural Outreach and Information Resources, 
National Institutes of Health, 6701 Rockledge Drive, MSC 7910, 
Bethesda, Maryland 20892-7910, telephone (301) 435-0714, E-mail: 
GrantsInfo@nih.gov.

The RFA label available in the form PHS 398 must be affixed to the 
bottom of the face page.  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.  For purposes of identification 
and processing, item 2 of the face page of the application must be 
marked “YES” and the RFA number and the words “Epidemiology of Chronic 
Pelvic Pain of the Bladder and Interstitial Cystitis” must be typed in.

The RFA label and line 2 of the application should both indicate the 
RFA number.  The RFA label must be affixed to the bottom of the face 
page.  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.

The sample RFA label available at:  
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been 
modified to allow for this change.  Please note this is in pdf format.

Submit a signed, typewritten original of the application, including the 
checklist, and three signed photocopies in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (For express/courier service)

At the time of submission, two additional copies of the application 
must be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes, Digestive, and Kidney Diseases
Room 653 MSC 5452
6707 Democracy Boulevard
Bethesda, Maryland 20892-5452 (For express/courier service, use 20817)

Applications must be received by November 13, 2000.  If an application 
is received after this date it will be returned to the applicant 
without review.  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.  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 application 
already reviewed, but such an application must follow the guidance in 
the PHS 398 applications instructions for the preparation of revised 
applications, including an introduction addressing the previous 
critique.

Information to be Included in Applications

Details of the Proposed Study Protocol:  Applicants for the 
Epidemiology Study Center should describe a research plan involving 
multi-center participation to address the objectives of the study and 
to reach the study goals.  Applicants should outline the rationale and 
background of the proposed epidemiological, quality of life and 
functional status, risk factor and health resource utilization studies.  
An application for the Epidemiology Study Center should provide 
evidence of the size (by ten-year age intervals) of the prospective 
cohort study, clinical trial, and/or patient database to be accessed 
and its racial, ethnic, and gender composition.  Applicants must also 
describe the feasibility of contacting study participants initially and 
obtaining follow-up information and their experience in such an 
undertaking.  The means by which information is to be obtained from 
participants (i.e., telephone contact, mail, in-person, access to 
medical records, etc.) should also be specified.  Recommendations 
should also be made regarding which generic measure(s) of quality of 
life should be implemented by the study group and if necessary, a 
rationale for developing complex-specific quality of life and 
functional status instruments.  Plans for acquiring information on 
health resource utilization should be included in the application.  
Applications for the Data Analysis/Administrative Core should include 
plans for data collection, and overall quality control of the study. 
Information on proposed plans for study-wide data analysis should also 
be included for each of the major areas of study.  A plan for the 
acquisition of data from the primary database of the ongoing cohort 
studies, clinical trials, and patient databases to be included in the 
database established under this RFA should be proposed.  A description 
of anticipated problems in carrying out this study and their proposed 
solutions should be included in the application.

Institutional Support:  There should be evidence of strong 
institutional support for the study, including adequate space in which 
to conduct data analysis/management (for the Data 
Analysis/Administrative Core) activities.  An organizational structure 
for the study should be set forth in the application, delineating lines 
of authority and responsibility for dealing with anticipated problems 
in all general areas as well as stated willingness to follow the 
commonly agreed upon protocol.

Previous Experience:  The applicant should include a succinct 
discussion of previous relevant research efforts in epidemiological 
studies and any relevant experience/success in working collaboratively 
with investigators outside their own research institution.

Suggested Personnel Requirements:  The application must describe the 
expertise of key scientific, technical and administrative personnel and 
include a mechanism for replacing key professional or technical 
personnel should the need arise.  For the Epidemiology Study Center, 
expertise in epidemiology is necessary.  Medical expertise in urology 
is also important.  Members may be full-time or part-time and may serve 
in more than one capacity, as appropriate.  The expertise required for 
the Data Analysis/Administrative Core must also include expertise in 
epidemiology, biostatistics, data management, computer programming and 
database development.  Consultants in urology and quality of life are 
also advisable.

Budget Preparation by Year

Applicants for the Epidemiology Study Centers and the Data 
Analysis/Administrative Core must include an adequately justified year-
by-year budget, reflecting the major changes in proposed activities as 
the studies progress through their various phases.

During Phase I (First 6 months of Year 1), the budget will be for 
development of the protocol by the Epidemiology Study Centers in 
collaboration with the Data Analysis/Administrative Core.  The Data 
Analysis/Administrative Core will begin to create the database 
necessary to accommodate pooled data for the prevalence, incidence, 
quality of life and functional status, and health resource utilization 
studies.  A database for relevant clinical and demographic information 
obtained from the “parent” (primary) database for the ongoing 
studies/patient databases will also be established.   The travel budget 
for Phase I should be estimated based on travel for two key 
investigators to attend two-day, bimonthly meetings of the Steering and 
Planning Committee in the Washington, D. C. area.

During Phase II (Second six months of Year 1, Years 2, 3, 4, and the 
first 6 months of Year 5).  The budget should reflect the initiation of 
the prevalence, incidence, quality of life and functional status, risk 
factor, and health resource utilization studies. Demographic and 
clinical information from the parent database of the ongoing cohort 
studies/clinical  trials and large databases will also be obtained.  
Interim data analysis and preparation of reports to the Steering and 
Planning Committee and the group of external advisors will also occur.  
Manuscripts describing the findings of the studies will also be 
prepared.  It is anticipated that the final results of the prevalence 
study will become available in Phase II.  Interim reports will be 
prepared for studies of incidence, risk factors, quality of life and 
functional status, and health resource utilization.  This phase of the 
program will require meeting approximately every six months in the 
Washington, D.C. area.  The travel budget for Phase II should be 
estimated based on travel for the Principal Investigator and the 
Project Coordinator for both the Epidemiology Study Center and the Data 
Analysis/Administrative Core.  Budgets for the Data 
Analysis/Administrative Core should include travel for any consultants.

During Phase III (Final 6 months of Year 5).  The major activities 
include final data analysis of the incidence, risk factor, quality of 
life and functional status, and health resource utilization studies.  
Manuscripts suitable for submission to peer-reviewed scientific 
journals will also be prepared during this phase.  Three meetings of 
the investigators should be budgeted for the final six-month period of 
the grant.

For an Epidemiology Study Center, the budget should request support for 
the minimum number of full and/or part-time staff to successfully carry 
out the proposed studies.  An Epidemiology Study Center personnel list 
could include a principal investigator, co-investigator, study 
coordinator, and data entry clerk.

For applications for the Data Analysis/Administrative Core, the budget 
should include the time and effort of key personnel for database 
management, programming, data analysis, and administrative functions to 
support the collaborative group.  Travel by Data 
Analysis/Administrative Core staff to Washington, D.C. for the 
following meetings should be budgeted:  group of external advisors (one 
meeting per year for each of five years) and the Steering and Planning 
Committee (four in Year 1-Phase I and two meetings annually during 
Years 2-4, and three meetings in Year 5).

The following is a list of yearly major activities to assist in the 
preparation of budgets for each of the five years of the program.

Year 1 (months 1-6):  Develop the study protocol for the collaborative 
studies.  The database will be established by the Data 
Analysis/Administrative Core for the prevalence study and initial work 
will begin for the remaining studies.  The database for relevant 
demographic and clinical information to be obtained from the parent 
database of the accessed studies will also be established.

Year 1 (months 7-12):  Initiate the prevalence study.  Refine the 
protocol for incidence, risk factor, quality of life and functional 
status, and health resource utilization studies.  Database development 
will continue by the Data Analysis/Administrative Core. Obtain relevant 
demographic and clinical information from parent databases.

Year 2 (12 months):  Begin the incidence and risk factor studies.  At 
the end of Year 2, begin writing papers on the design of the study and 
prevalence study findings.  Continue database development (Data 
Analysis/Administrative Core).  Obtain relevant demographic and 
clinical information from parent databases.

Year 3 (12 months):  Continue incidence and risk factor studies.  
Implement quality of life, functional status and health resource 
utilization studies.  Manuscripts describing the prevalence will be 
completed in Year 3.  Obtain relevant demographic and clinical 
information from parent databases.

Year 4 (12 months):  Continue incidence study and complete risk factor 
studies.  Continue quality of life and health resource utilization 
studies.  Interim analyses continue for these studies.  Obtain relevant 
demographic and clinical information from parent databases.

Year 5 (months 1-6):  Complete incidence, quality of life, functional 
status, and health resource utilization studies.  Interim analysis 
continues for these studies.  Obtain final demographic and clinical 
information from parent databases.

Year 5 (months 7-12):  Complete final data analysis for the incidence, 
risk factor, quality of life, functional status, and health resource 
utilization studies.  Prepare manuscripts and report results at 
scientific meetings and in peer-reviewed scientific journal articles.  
Close-out of both the Epidemiology Study Centers and the Data 
Analysis/Administrative Core will take place during the final two 
months of the program.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR 
and for responsiveness by the NIDDK.  Incomplete and/or non-responsive 
applications 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 NIDDK in accordance with the review 
criteria stated below.  As part of the initial merit review, a process 
will be used by the initial review group in which all applications 
deemed to have the highest scientific merit, generally the top half of 
the applications under review, will be discussed, assigned a priority 
score, and receive a second level of review by the National Diabetes 
and Digestive and Kidney Disease Advisory Council.

Review Criteria

Applicants are encouraged to submit and describe their own ideas about 
how best to meet the goals of the cooperative study as outlined in this 
RFA, and are expected to address issues identified under INFORMATION TO 
BE INCLUDED IN APPLICATIONS.  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 pursuit of these goals.  Each of these 
criteria will be addressed and considered in assigning the overall 
score, weighting them as appropriate for each application.  Note that 
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.

Review Criteria for Epidemiology Study Centers

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, and methods adequately 
developed, well integrated, and appropriate to the aims of the project?  
Does the applicant acknowledge potential problem areas and consider 
alternative tactics?  What is the total sample size of the cohort, 
clinical trial, and/or database?  What is the racial/ethnic, gender, 
and age composition of the population to be accessed?  How stable 
(number of study subjects lost to follow-up, out migration, etc.) is 
the target population and what has been the response rate of the 
population for previous ancillary studies? The applicant must provide 
plans to ensure the complete, reliable, and timely transmission of 
study data to the Data Analysis/Administrative Core.  Knowledge of the 
possible problems associated with the conduct of epidemiological 
studies at disparate institutions using different epidemiological 
studies and anticipating possible solutions is necessary.

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?  
Is the investigator experienced in collaborating with other 
investigators in a multi-center study?

Necessary Expertise:  Documented experience in epidemiology is 
required.  Demonstrated knowledge of clinical aspects of chronic pelvic 
pain of bladder origin and/or interstitial cystitis from either a 
consultant or co-investigator is recommended.  Consultants in the 
fields of quality of life and health resource utilization are also 
necessary.

Staff Qualifications:  Documented specific competence and relevant 
experience of professional, technical, and administrative staff 
pertinent to the operation of an Epidemiology Study Center.

Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Documented adequacy of 
the proposed facility and space is necessary.   Is there evidence of 
institutional support and commitment for the proposed program? 

Access to an Established Prospective Cohort Study, Clinical Trial 
Population, and/or Large Patient Database:  Evidence of the ability to 
conduct the epidemiological, quality of life and functional status, 
risk factor, and health resource utilization studies as described in 
this RFA is necessary.  Examples of ancillary studies utilizing the 
cohort, clinical trial, and/or database should be provided.  Assurance 
that an ancillary study focused on the goals of the RFA can recruit a 
sufficient number of participants must be clearly described.  
Documentation must be provided on the ability to re-contact study 
subjects or ongoing access to patient data/medical records or patient 
data files, in order to carry out incidence surveys and other studies 
requiring follow-up data.  Applicants other than the Principal 
Investigator of the prospective cohort study must provide written 
documentation that the cohort study is available for the purposes 
specified in the RFA.  Investigators proposing the use of a clinical 
trial population must provide written assurance from their Steering and 
Planning Committee that the participants can be accessed as an 
ancillary study to the ongoing trial.  Similarly, written documentation 
indicating access is required from applicants proposing to use large 
patient databases.

Review Criteria for a Data Analysis/Administrative Core:

Significance:  Does the study address an important problem?  If the 
aims of the applications 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, and methods adequately 
developed, well integrated, and appropriate to the aims of the project?  
Does the applicant acknowledge potential problem areas and consider 
alternative tactics?  Experience in developing databases for combining 
data from the Epidemiology Study Centers, plans for analysis of the 
pooled data, and efforts to ensure high quality data collection should 
be described.  Plans are also necessary for the timely and secure 
transmission of data from the Epidemiology Study Centers to the Data 
Analysis/Administrative Core.

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?  
Is the investigator experienced in collaborating with other 
investigators in a multi-center study?  Documented experience in 
epidemiology and biostatistics is required.  Demonstrated knowledge of 
clinical aspects of chronic pelvic pain of bladder origin and/or 
interstitial cystitis from either a co-investigator or consultant will 
be judged.  The level of expertise of consultants in quality of life 
and health resource utilization will be considered.  Experience in 
database development, database management, and statistical analysis is 
required.  The ability of the investigators from the Data 
Analysis/Administrative Core to take the lead in developing a 
cooperative relationship among the participating Epidemiology Study 
Centers and exercise appropriate leadership in matters of study design, 
data acquisition, data management, data quality, and data analysis, 
will be evaluated.

Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Documented adequacy of 
the proposed facility and space is necessary.  Is there evidence of 
institutional support and commitment for the proposed program? 

In addition to the above criteria, in accordance with NIH policy, all 
applications will be reviewed with respect to the following.

The reasonableness of the proposed budget.

The adequacy of the proposed protection for humans and the environment, 
to the extent they may be adversely affected by the studies described 
in this RFA.  The scientific review group will also examine the safety 
of the research environment.

Schedule

Letter of Intent Receipt Date:  October 13, 2000
Application Receipt Date:       November 13, 2000
Special Review Committee:       March/April 2001
NDDK Advisory Council:          May 30-31, 2001
Anticipated Award Date:         July 3, 2001

AWARD CRITERIA
Award criteria that will be used to make award decisions include:

Scientific merit as determined by peer review
Availability of funds
Cost
The size, age, racial and ethnic composition of the population proposed 
to be accessed

INQUIRIES

Written and telephone inquiries concerning this RFA are strongly 
encouraged.  The opportunity to clarify any issues or questions form 
potential applicants is welcome.

For information relating to the NIDDK, programmatic inquiries may be 
made to:

John W. Kusek, Ph.D.
Clinical Trials Program Director or
Leroy M. Nyberg, Ph.D., M.D.
Urology Program Director
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Room 617 MSC 5458
6707 Democracy Boulevard
Bethesda, Maryland 20892-5458 (for express or courier service use 
20817)
Telephone:  (301) 594-7735
FAX:  (301) 480-3510 
Email:  kusekj@ep.niddk.nih.gov
nybergl@ep.niddk.nih.gov

Fiscal and administrative inquiries may be directed to:

Trude Hilliard
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Room 642 MSC 5456
6707 Democracy Boulevard
Bethesda, Maryland 20892-5456 (for express/courier service use 20817)
Telephone:  (301) 594-8859
FAX:  (301) 480-3504
Email:  hilliardt@extra.niddk.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance 
Nos. 93.849 and 93.864.  Awards are made under authorization of the 
Public Health Service Act, Title IV, Part A (Public Law 78-410), as 
amended by Public Law 99-158, 42 USC 241 and 285) and administered 
under Public Health Service grants policies and Federal Regulations 42 
CFR 52 and 45 CFR Part 74.  This program is not subject to the 
intergovernmental review requirements of Executive Order 12372 or 
Health Systems Agency review.

The Public Health Service strongly encourages all grant and contract 
recipients to provide a smoke-free work place and promote the non-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 Public Health Service mission to protect and advance the physical 
and mental health of the American people.



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