INTERSTITIAL CYSTITIS / PAINFUL BLADDER SYNDROME: EPIDEMIOLOGY RELEASE DATE: January 22, 2004 RFA Number: RFA-DK-04-009 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENTS OF PARTICIPATING ORGANIZATION: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov/) Office of Research on Women’s Health (ORWH) (http://www4.od.nih.gov/orwh/) CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.849 LETTER OF INTENT RECEIPT DATE: February 23, 2004 APPLICATION RECEIPT DATE: March 22, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The Division of Kidney, Urologic and Hematologic Diseases (DKUHD) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Office of Research on Women’s Health (ORWH) invites cooperative agreement applications for investigation of the epidemiology of interstitial cystitis and painful bladder syndrome (IC/PBS). The purpose of this solicitation will be to establish a study group that will develop and conduct epidemiologic investigations using a population based sampling strategy to identify and characterize patients with symptoms consistent with interstitial cystitis or painful bladder syndrome. The studies will characterize the patients clinically and demographically, establish risk factors, duration of symptoms, current methods of treatment and describe the economic burden of disease. The study protocol(s) must include the provision for an intensive clinical evaluation of a subset of the symptomatic subjects and matched controls, utilizing clinicians experienced in the diagnosis of interstitial cystitis. RESEARCH OBJECTIVES Background Interstitial Cystitis is a chronic disorder, diagnosed primarily in women, characterized by pelvic pain associated with the bladder as well as problems as urinary frequency and urgency. Despite considerable effort the etiology of interstitial cystitis has not been established. Published studies on the epidemiology of Interstitial Cystitis (IC) have several limitations; the primary one is the lack of well-defined diagnostic criteria suitable for use in epidemiological investigation. Also most published studies have not used population-based sampling and have relied on extrapolation of results from samples of patients seeking medical care to population wide data. Very few epidemiological studies have focused on risk factors for IC and the few published studies which do mention risk factors focus on exacerbating factors of IC, making the identification of precipitating or risk factors difficult. The NIDDK has a longstanding interest in clinical and epidemiological research for interstitial cystitis. Diagnostic Criteria for clinical trials on Interstitial Cystitis were established in 1988, following a workshop of experts convened to develop the criteria. In 1991 the Interstitial Cystitis Database (ICDB) study was initiated. The ICDB Study was a 5-year prospective cohort study of over 600 men and women with symptoms of urinary urgency, frequency, and pelvic pain. Reports published from this study have described the longitudinal changes of urinary symptoms, the impact of interstitial cystitis on quality of life, treatment patterns and the relationship between findings from bladder biopsies and patient symptoms. The findings from that study and other smaller international studies have indicated that the NIDDK Research Criteria for IC are too restrictive for epidemiological and population based studies. Applying the strict NIDDK Research Criteria definition to epidemiological and population based studies has been shown to exclude many persons who would be diagnosed to have IC by clinical experts. Thus, a new, more inclusive categorization of IC/PBS must be developed and utilized for epidemiological and population based studies. On October 29, 2003, the NIDDK convened a taskforce on the epidemiology of IC. At that meeting, the importance of conducting research on population based samples was reaffirmed. A summary of the workshop can be found at http://www.niddk.nih.gov/fund/other/conferences.htm. As noted above, there are no commonly accepted standard definitions for either interstitial cystitis (IC) or painful bladder symptom (PBS) suitable for epidemiologic studies. Recent reports have shown significantly higher prevalence estimates based on survey methods than the estimates derived from physician-based diagnoses. It is suspected that this disparity is in part due to missed diagnoses by clinicians who are not familiar with the symptoms associated with either IC or PBS. Therefore it is important that there be a comparison of clinical assessment and questionnaire methods and that a representative sample of questionnaire identified patients be evaluated by clinicians who have demonstrated expertise in the assessment and diagnosis of IC/PBS. Objectives of research program: The objectives of the research program described in this RFA are to: 1) develop a population sampling strategy to survey the prevalence of persons with symptoms consistent with the diagnosis of interstitial cystitis or painful bladder syndrome; 2) develop working diagnostic categories and/or methods for assessing the severity of symptoms consistent with interstitial cystitis and painful bladder syndrome; 3) develop questionnaire(s) to assess IC/PBS using both current examples of symptom assessment and advice of IC/PBS experts. 4) conduct well designed population based studies, which will estimate the prevalence of persons with symptoms consistent with IC/PBS and determine the characteristics of that population; 5) provide for clinical evaluations of a subset of symptomatic individuals and control subjects by clinicians with demonstrated expertise in interstitial cystitis; 6) assess issues such as quality of life, severity of pain, and the impact of pain on the quality of life; 7) determine the socioeconomic impact of IC/PBS. The applicants should formulate a series of proposed research questions to be examined. Potential issues to be addressed could include, but are not limited to, the following: 1) What is the prevalence of IC/PBS in the general population by demographic age, sex, and race/ethnic subgroups; 2) What are risk factors for the onset of IC/PBS; 3) What is the extent of health care utilization for persons with IC/PBS. 4) What are the most frequently used forms of treatment, including both conventional medical therapy and complementary or alternative therapies; 5) What are the most common associated clinical disorders; 6) What is the family history of IC/PBS. 7) If feasible, what is the longitudinal history of symptom severity in persons with IC/PBS; The investigators, as part of a Cooperative Agreement, will work closely with the NIDDK Project Officer and Project Scientist, as well as an NIDDK appointed External Advisory Committee, to define the criteria for patient inclusion in the sample. The exact method of population based sampling will be delineated by the Epidemiological Center in this application. The final format for sampling will be determined after consultation with the External Advisory Committee. It is necessary that proposals include the ability to perform more intensive evaluation on a sample of symptomatic subjects and on control subjects, by a clinic experienced in diagnosing IC, at one or more clinical evaluation centers. The clinical evaluation centers should have the ability to obtain urine and/or blood samples for biomarker evaluation. MECHANISM OF SUPPORT This RFA will use the NIH cooperative agreement (U01) award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. The total project period for applications submitted in response to this RFA will be five years. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2004. Applications that are not funded under this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. This RFA uses just-in-time concepts. Modular budgets will not be used. Follow the instructions for non-modular budget research grant applications. This program does not require cost sharing as defined in http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. The NIH U01 is a cooperative agreement award mechanism. Under the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award . Plans for continuation of the project beyond the initially awarded period or for reissuance of the RFA or other announcement are indefinite. FUNDS AVAILABLE The NIDDK intends to commit approximately $1,000,000 in total costs in FY 2004 to fund a new grant in response to this RFA. An applicant should request a project period of up to 5 years and a budget of up to $1,000,000 in total costs for each of those years. Although the financial plans of the NIDDK provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of meritorious applications. ELIGIBLE INSTITUTIONS You may submit an application if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign institutions/organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. Principal investigators must demonstrate expertise in epidemiology, population-based sampling methodology, and survey methodology. Investigators are encouraged to contact the existing NIDDK ICCRN Centers to serve as one or more clinical evaluation centers. SPECIAL REQUIREMENTS Cooperative Agreement Terms and Conditions of Award The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator(s) as well as the institutional official(s) at the time of the award. These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grants Administration Regulations at 45 CFR Parts 74 and 92, and the NIH Grants Policy statement. The administrative and funding instrument used for this program is a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. Under the cooperative agreement, the NIDDK purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NIDDK Project Scientist or designee. Under the cooperative agreement, a relationship will exist between the recipient of these awards and the NIDDK, in which the performers of the activities are responsible for the requirements and conditions described below, and agree to accept program technical assistance, advice, and/or other coordination above and beyond normal program stewardship from a named NIDDK Project Scientist in achieving the project objectives. Failure of an awardee to meet the performance requirements, including these special terms and conditions of award, or significant changes in the level of performance, may result in a reduction of budget, withholding of support, suspension and/or termination of the award. A) Awardees Rights and Responsibilities The Awardee is responsible for: 1. Research design and protocol development, including definition of objectives and approaches, planning, implementation, participant enrollment and follow-up, data collection, quality control, final data analysis and interpretation and publication of results. 2. Establishing a Steering Committee to coordinate and manage the project. The awardee will name investigators to serve as members on a Steering Committee and other subcommittees, as appropriate, meeting periodically. The Awardee will be required to accept and implement the common protocol and procedures approved by the Steering Committee. 3. Implementing the core data method and strategy collectively decided upon by the Steering Committee. It is the responsibility of each site to ensure that data will be submitted in a timely way to the central Data Coordinating Center. Individual sites must demonstrate the ability to implement the strategy specifically designed for individual study populations. 4. Establishing mechanisms for quality control and monitoring. Awardees are responsible for ensuring accurate and timely assessment of the progress of each study, including development of procedures to ensure that data collection and management are adequate for quality control and analysis. 5. Submitting interim progress reports, when requested, to the NIDDK Project Officer, including as a minimum, summary data on protocol performance. Such reports are in addition to the annual awardee noncompeting continuation progress report. 6. Establishing procedures, where applicable, for all participating institutions in coordinated awards to comply with FDA regulations for studies involving investigational agents or devices and to comply with the requirements of 45 CFR Part 46 for the protection of human subjects, and the NIH policy requirements for the inclusion of women, minorities and children. 7. Cooperating in the reporting of the study findings. The awardee will retain custody of and have primary rights to the data developed under this award, subject to the Government rights of access consistent with current HHS, PHS and NIH Policies. The NIDDK will have access to and may periodically review all data generated under an award. Where warranted by appropriate participation, plans for joint publication with NIDDK of pooled data and conclusions are to be developed by the Principal Investigator or Steering Committee, as applicable. NIH policies governing possible co- authorship of publications with NIDDK staff will apply in all cases. In general, to warrant co-authorship, NIDDK staff must have contributed to the following areas: (a) design of the concepts or experiments being tested; (b) performance of significant portions of the activity; and (c) preparation and authorship of pertinent manuscripts. 8. Support or other involvement of industry or any other third party in the study e.g., participation by the third party; involvement of study resources or citing the name of the study or NIDDK support; or special access to study results, data findings, or resources may be advantageous and appropriate. However, except for licensing or patents or copy rights, support or involvement of any third party will occur only following notification of and concurrence by NIDDK. 9. Study investigators are encouraged to publish and to release publicly and disseminate results and other products of the study, in accordance with study protocols and governances. 10. The NIDDK has established Central Biosample, Genetic, and Data Repositories for the archival and storage of data and biosamples collected in large, multi-site studies funded by NIDDK. The Data Coordinating Center (DCC) will work with the NIDDK Biosample Repository to coordinate procedures for coding, shipping, receipt, and storage of study samples that are to be maintained in the Repository. In addition, the DCC will coordinate with the NIDDK Data Repository to prepare the collected data for eventual archiving and distribution. All samples and data transferred to the Repositories will be under the custodianship of the NIDDK, although the study’s Steering Committee will have proprietary control of and exclusive access to the samples and data for an agreed-upon period of time. Subsequently samples and data will be available to the wider scientific community in accordance with the NIH policy on Data Sharing (http://grants.nih.gov/grants/policy/data_sharing, http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm#go als, and http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm) through a process that will include prioritized distribution based on review of the scientific merit of the proposed use. Therefore, it is expected that samples and data collected will be available to the broader scientific community, after a proprietary period, at no charge other than the cost of reproduction and distribution. B) NIH Staff Responsibilities An NIDDK Project Scientist will have substantial involvement in the project above and beyond normal stewardship and monitoring of the award, as described below. 1. Being the contact point for all facets of the scientific interaction with the awardee. As required for the coordination of activities and to expedite the progress, NIDDK may designate additional NIDDK staff to provide advice to the awardee on specific scientific and/or analytic issues. Such staff may include another Project Scientist or Analyst, who will provide direct technical assistance to the awardees to optimize the conduct and/or analysis of the study; or who may assist in the coordination of activities across multiple sites. 2. Convening the first meeting of and subsequent participation in the Steering Committee that oversees study conduct. The NIDDK Project Scientist or designee will be a full participant and voting member of the Steering Committee and, if applicable, subcommittees. 3. Serving as a resource with respect to other ongoing NIDDK activities that may be relevant to the protocol to facilitate compatibility and avoid unnecessary duplication of effort. 4. Providing substantial involvement assisting in the design and coordination of research activities for awardees in reviewing and approving the establishment of mechanisms for quality control and study monitoring. An NIDDK Program Director include identified in the Notice of Grant award will be responsible for the normal stewardship and monitoring of the award. The Program Director may also serve as the Project Officer. The NIDDK Program Director responsibilities include: 1. Retaining overall programmatic responsibility for the award, and will clearly specify to the awardee the name(s) and roles(s) of any additional individuals with substantial involvement in the project and the lines of reporting authority. 2. Interacting with the principal investigator on a regular basis to monitor study progress. Monitoring may include: regular communications with the principal investigator and staff, periodic site visits for discussion with awardee research teams, observation of field data collection and management techniques, quality control, fiscal review, and other relevant matters; as well as attendance at Steering Committee and related meetings. The NIDDK retains, as an option, periodic external review of progress. 3. Reviewing and approving protocols to insure they are within the scope of peer review and for safety considerations, as required by Federal regulations. The NIDDK Program Director will monitor protocol progress, and may request that a protocol be closed to accrual for reasons including: (a) accrual rate insufficient to complete study in a timely fashion; (b) accrual goals met early; (c) poor protocol performance; (d) study results that are already conclusive; and (e) emergence of new information that diminishes the scientific importance of the study question. The NIDDK will not permit further expenditures of NIDDK funds for a study after requesting closure (except for patients already on-study). 4. Making recommendations for continued funding based on: a) overall study progress, including sufficient patient and/or data accrual; b) cooperation in carry out the research ( e.g. attendance at Steering Committee meetings, compliance with terms of award and reporting requirements); and/or c) maintenance of a high quality of research. C. Joint Responsibilities In addition to the interactions defined above, NIDDK Staff and Awardees shall share responsibility for the following activities: 1. Steering committee. A Steering Committee organized by the Principal Investigator will be the main oversight body of the study. The Steering Committee has primary responsibility to design research activities, establish priorities, develop protocols and manuals, questionnaires, and other data recording forms, establish and maintain quality control, review progress, and cooperate on the publication of results. Major scientific decisions regarding the core data will be determined by the Steering Committee. The Steering Committee will document progress in written reports to the NIDDK Program Director, and will provide periodic supplementary reports upon request. The Steering Committee will be composed of the Principal Investigator and co- investigators as deemed necessary, and the NIDDK Project Scientist or designee. An initial meeting of the Steering Committee will be convened early after award by the NIDDK Project Scientist or designee. The final structure of the Steering Committee will be established at the first meeting. The NIDDK Project Scientist or designee will have voting membership on the Steering Committee, and as appropriate, its subcommittees. A Chairperson, other than the NIDDK representative, will be selected by a vote of the members. The Chairperson is responsible for coordinating the Committee activities, for preparing meeting agendas, and for scheduling and chairing meetings. It is assumed that the Steering Committee will meet in person quarterly until the protocol is established and then every four to six months as necessary. The committee will meet monthly by telephone conference call. D) Establishment of an External Advisory Committee (EAC). Since there will not be any clinical trials conducted as part of these epidemiologic studies there will not be a need for a Data and Safety Monitoring Board; however, the NIDDK will establish an External Advisory Committee which will provide clinical expertise in Interstitial Cystitis as well as expertise in biostatistics, epidemiology, population sampling, etc. The EAC will be advisory to the NIDDK and serve as consultants to the investigator(s) during development of the epidemiologic inclusion criteria, sampling design, statistical analysis, etc. It is assumed that the EAC will meet in person with Investigators and NIDDK staff frequently during development of the sampling protocol. It will then meet semi-annually in person with the Epidemiological Center and NIDDK staff to review progress. The EAC will be advisory to the NIDDK staff as well as the Epidemiological Center investigators and will participate in a consultative manner. It is assumed that the EAC will meet with the Steering Committee approximately every six months, and more frequently by conference call as necessary until the protocol is established and operative. Then the EAC will meet annually or more frequently if necessary. 5) Arbitration Any disagreement that may arise in scientific/programmatic matters (within the scope of the award), between award recipient and the NIDDK may be brought to arbitration. An arbitration panel will be composed of three members; one selected by the investigators, a second member selected by NIDDK, and the third member selected by the two prior members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR part 50, Subpart D and HHS regulation at 45 CFR part 16, or the rights of NIDDK under applicable statutes, regulations and terms of the award. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Paul W. Eggers Ph.D. Urology and Kidney Epidemiology Program Director National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 6157 Bethesda, MD 20892-5458 Telephone: (301) 594-8305 Fax: (301) 480-3510 Email: pe39h@nih.gov Leroy M. Nyberg, M.D., Ph.D. Urology Program Director National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 617 Bethesda, MD 20892-5458 Telephone: (301) 594-7717 Fax: (301) 480-3510 Email: ln10f@nih.gov Lisa Begg, Dr.P.H., R.N. Director of Research Programs Office of Research on Women's Health DHHS/NIH/OD Bethesda, MD. 20892 phone: 301/496-7853 fax: 301/402-1798 email: beggl@od.nih.gov o Direct your questions about peer review issues to: Francisco O. Calvo, Ph.D. Chief, Review Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 752 Bethesda, MD 20892-5452 Telephone: (301) 594-8885 FAX: (301) 480-3505 Email: fc15y@nih.gov o Direct your questions about financial or grants management matters to: Donald Ellis Grants Management Specialist National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rom 743 Bethesda, Maryland 20892-5456 Telephone: (301) 594-8849 FAX: (301) 480-3504 Email: de30z@nih.gov Helen Ling Grants Management Specialist National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 732 Bethesda, MD 20892-5456 Telephone: (301) 594-8857 FAX: (301) 480-3504 Email: hl12d@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIDDK staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Chief, Review Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 752 Bethesda, MD 20892-5452 (For express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8897 FAX: (301) 480-3505 SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001, updated 9/9/2003). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS: 1) Proposed Population Sampling Concept: The general concept for a population based sampling protocol, with proposed statistical analyses, should be included in the application. The general concept must be consistent with the scientific focus of the RFA. Applicants must describe the feasibility of conducting the study and the estimated success at enrollment. The sampling concept should include estimates of numbers of persons to be contacted and to be enumerated in the study. Also, estimates of number by gender, age, ethnicity, and race should be given with the justification for using those estimates. Additionally, the methodology to be used to extrapolate the sampling to the general population should be specified. 2) Proposed Clinical Evaluation Protocol: The intensive clinical evaluation protocol would include what percentage of enrolled participants will be selected for the clinical evaluation protocol, how these participants will be selected, what will the intensive clinical evaluation protocol include, where will the evaluation be conducted and by whom, listing the qualifications of both the site (s) and the clinician(s). 3) Evidence of Institutional Support: There should be evidence of strong institutional support for the study, including adequate space and equipment to conduct the study. An organizational structure for the Center should be set forth in the application, delineating lines of authority and responsibility for dealing with problems in all general areas as well as willingness to participate in the cooperative agreement arrangement as delineated in this RFA. 4) Evidence of Cooperation from Participating Clinical Evaluation Centers: There should be documented agreement between the principal investigator and institutions at which the intensive clinical evaluation protocols will be conducted. This should include delineation of clinical staff, responsibilities, and qualifications as well as amount of space and necessary diagnostic equipment available for the study. 5) Personnel Requirements: The application must describe the expertise of the key epidemiological, technical, administrative and clinical personnel and must include a mechanism for replacing key professional or technical personnel should the need arise. BUDGET The Principal Investigator should prepare a budget for each year of the five years of the program not to exceed $1,000,000 total costs (direct and facilities and administrative costs) per year. The first 8 months of year 1 will be a period of intensive protocol development with bi-monthly meetings of the Steering Committee to be held either in the Washington, D.C. area or at the site of the IC Epidemiological Center (approximately 50% each place). Beginning in year 2 and for the duration of the program, applicants should budget for three meetings each year of the Steering Committee to be generally held in the Washington, D.C. area or at the funded site. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application and all appendices must be sent to: Francisco O. Calvo, Ph.D. Chief, Review Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 752 Bethesda, MD 20892-5452 (Courier use ZIP 20817) APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the Center for Scientific Review and responsiveness by the National Institute of Diabetes and Digestive and Kidney Diseases. Incomplete and/or non-responsive applications will not be reviewed and will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the National Institute of Diabetes and Digestive and Kidney Diseases in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique. o Undergo a process in which only those applications deemed to have the highest scientific merit will be discussed and assigned a priority score. o Receive a second level review by the National Diabetes and Digestive and Kidney Diseases Advisory Council. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In written comments, reviewers will be asked to evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score, weighing them as appropriate for each application: O Significance O Approach O Innovation O Investigator O Environment The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers. ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and priority score: Applicants are expected to address issues identified under the following sections in this RFA: SPECIAL REQUIREMENTS; SUBMITTING AN APPLICATION/SUPPLEMENTAL INSTRUCTIONS. All applications will be reviewed according to the criteria listed below. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the goals of this solicitation. Each of the criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application o Study design o Qualifications and experience o Institutional resources o Proposed Population Sampling Methodology o Proposed clinical evaluation methodology o Qualifications and experience of Principal Investigator, Clinical expert(s) and technical personnel In addition to the above criteria, applications will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for participants in all clinical studies. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for recruitment and retention of subjects will also be evaluated. ADDITIONAL REVIEW CONSIDERATIONS: Sharing Research Data: Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: February 23, 2004 Application Receipt Date: March 22, 2004 Peer Review Date: July, 2004 Council Review: September, 2004 Earliest Anticipated Start Date: September 30, 2004 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, investigators submitting and NIH application seeing $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing. Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit of the priority score. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a)all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the Standards for Privacy of Individually Identifiable Health Information , the Privacy Rule on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS OFFICE for Civil Rights (OCR). Those who comply with the Privacy Rule (classified under the rule as covered entities must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the research and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including complete Regulation Text and a set of decision tools on am I a covered entity? Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress can be found at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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