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) 710-0267, 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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