CLINICAL STUDY OF VESICOURETERAL REFLUX IN CHILDREN RELEASE DATE: July 8, 2004 RFA Number: RFA-DK-04-019 September 16, 2009 - This RFA has been reissued as (RFA-DK-09-502). (see amendment NOT-DK-04-010) EXPIRATION DATE: March 17, 2005 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.849 NIDDK Kidney Diseases, Urology and Hematology Research LETTER OF INTENT RECEIPT DATE: February 16, 2005 APPLICATION RECEIPT DATE: March 16, 2005 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The Division of Kidney, Urologic, and Hematologic Diseases (DKUHD) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites cooperative agreement applications for pediatric nephrology/urology clinical treatment centers (CTC) and a data coordinating center (DCC)for the design and conduct of treatment trials and studies in children with vesicoureteral reflux (VUR). The primary goals of this study are to determine: the relationship between renal scarring and decline in renal function, the risk factors for decline in renal function, the impact of prophylactic antibiotic use on preservation of renal function, and the role for surgical intervention in the preservation of renal function and prevention of recurrent urinary tract infections. RESEARCH OBJECTIVES Background Vesicoureteral reflux (VUR), the retrograde flow of urine from the bladder to the upper urinary tract, is one of the most common problems for which children are referred to pediatric nephrologists and urologists. Clinical management strategies range from observation, to prophylactic antibiotic administration to various types of surgical intervention. There are no long-term, well documented studies, which demonstrate the effectiveness of these various clinical management strategies in preventing deterioration of renal function. In addition, there are many other topics related to VUR for which there is poorly documented data. For example, in the scientific literature there is a lack of consistent correlation of VUR and renal scarring, as well as a lack of correlation of antibiotic use, urinary tract infection and renal scarring. Likewise, it is unclear whether surgical intervention improves outcome, and if a delay abrogates potential benefit from intervention. On May 18, 2003, the NIDDK sponsored a strategic planning workshop on the potential for conducting a randomized controlled trial in children diagnosed with VUR. A summary of the meeting and list of participants may be found at http://www.niddk.nih.gov/fund/divisions/KUH/kuhconferences.htm. As indicated above, the two big issues facing physicians who take care of this group of patients are: a) when, and what type of surgical intervention is indicated, and b) if and when antibiotic use is indicated. There are also difficulties in choosing appropriate outcome measures of clinical significance. These difficulties are compounded in children, since growth and development create the need for long-term outcome measures. Research Scope and Goals The primary goals of this program are to study disease progression in a cohort of 600 children with mild to moderate VUR (grade I – III/IV) and to determine which interventions are most beneficial. Examples that illustrate possible areas of research are presented below. They are intended only to provide a broad direction for research and should be considered illustrative and not restrictive. Some potential areas of research are: o The relationship between the extent of scarring and renal function o An assessment of the effect of surgical intervention on preserving renal function o A comparison of the long-term outcomes of the different surgical approaches o A comparison of the long-term efficacy of prophylactic antibiotic use in the different grades of VUR o Delineation of early biomarkers for change in renal function o The impact of dysfunctional elimination syndrome (DES) o Family history/heritability of VUR Applicants should propose testable hypotheses on critical issues that can be resolved in the context of this study. MECHANISM OF SUPPORT This RFA will use NIH 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. 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 2005. Applications that are not funded in the competition described in 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. It also uses the modular budgeting as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format. Otherwise follow the instructions for non-modular budget research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm. The NIH U01 is a cooperative agreement award mechanism. In 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.” FUNDS AVAILABLE The NIDDK intends to commit approximately $3 million in FY 2005 to fund five Clinical Treatment Center (CTC) grants and one Data Coordinating Center grant in response to this RFA. An applicant should request a project period of up to five years. It is anticipated that the award for the DCC will not exceed $800,000 total costs, excluding subcontract facility and administrative (F&A) costs (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-040.html) . The amount awarded to each CTC will not exceed $440,000 total costs per year, excluding subcontract facility and administrative (F&A) costs (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-040.html). Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size of each award will also vary. Although the financial plans of the IC(s) provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic institutions/organizations o Foreign institutions are not eligible to apply as the applicant organization; however consortia agreements to foreign institutions are permitted 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. Each CTC must have at least one Pediatric Nephrologist and at least one Pediatric Urologist as investigators. The Principal Investigator or Co- Principal Investigator for a CTC may be either of those specialists. The Principal Investigator of a CTC should have demonstrated experience in enrolling patients in long-term, multicenter clinical trials and should be familiar with clinical trial design concepts. The Principal Investigator of the Data Coordinating Center (DCC) should have demonstrated expertise in multicenter clinical trial design and in biostatistics. It is anticipated that the DCC will also include experts in project management, data collection, quality control, and other areas related to the efficient and effective implementation of multicenter clinical trials. SPECIAL REQUIREMENTS The ability to recruit and retain a sufficient number of participants into this study is the most important requirement for a successful Clinical Coordinating Center. As preliminary evidence of that ability, each Clinical Treatment Center applicant must provide an accurate, verifiable, historical record of the number of eligible VUR patients seen per year for the past three years. This record should be categorized by age, gender, race and the grade of VUR. It is expected that during the study each Clinical Coordinating Center will recruit a total of 120 eligible participants over a period of 24 months. The Clinical Coordinating Centers and the Data Coordinating Center must also agree to participate in a collaborative and interactive manner with the other funded centers to develop the study protocols and carry out the study. Cooperative Agreement Terms and Conditions of Award A. Applicability. These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS grant administration regulations in 45 CFR part 74 and 92, and other HHS, PHS and NIH grant administration policy statements. The administrative and funding instrument used to pay research projects involving clinical trials, prevention and control interventions, or epidemiological surveys in excess of $500,000 direct cost per year (at a single institution or in the aggregate for studies proposing multi- institutional collaborative arrangements submitted as either subcontracts to a single application or as separate applications) shall be a cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIDDK scientific and/or programmatic involvement with the awardee is anticipated during 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 the above concept, the dominant role and prime responsibility for the activity reside with the awardee(s) 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. B. Awardee Rights and Responsibilities. The Awardee is responsible for: 1. Research design and protocol development, including definition of objectives and approaches, planning, implementation, participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and publication of results. 2. Establishing a Steering Committee to coordinate and manage the project. Awardee(s) will name investigators to serve as members on a Steering Committee and other subcommittees, as appropriate, meeting periodically. Awardees will be required to accept and implement the common protocol(s) and procedures approved by the Steering Committee. 3. Designating Protocol Chairs. The Principal Investigators (for studies involving multiple coordinated awards) shall designate a single Protocol Chairperson (if the Principal Investigator does not assume this role) for each protocol within the described research plan. The Protocol Chairperson shall function as the scientific coordinator for the protocol and shall assume responsibility for obtaining approval to implement the protocol from the Steering Committee and for developing and monitoring the protocol. Any significant modifications to approved protocols must be submitted to the Steering Committee by the Protocol Chairperson. 4. Implementing the core data collection method and strategy collectively decided upon by the Steering Committee. For a study involving multiple institutions, it is the responsibility of each awardee/site to ensure that data will be submitted in a timely way to the central Data Coordinating Center. Additionally, individual investigators/sites must demonstrate the ability to implement the strategy specifically designed for their individual study population. 5. 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: (1) adequate for quality control and analysis; (2) for clinical trials, as simple as appropriate in order to encourage maximum participation of physicians and patients and to avoid unnecessary expense; and (3) sufficiently staffed across the participating institutions. For research involving multiple awards, strategies for the analyses of pooled data will be developed by the Steering Committee. 6. Submitting interim progress reports, when requested, to the NIDDK Program Director including as a minimum, summary data on protocol performance. For coordinated multiple awards or a multi-site single award, the Steering Committee may require additional information from individual awardees/sites. Such reports are in addition to the annual awardee noncompeting continuation progress report. 7. 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. 8. Cooperating in the reporting of the study findings. The awardee(s) will retain custody of and have primary rights to the data developed under these awards, 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. 9. 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 of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NIDDK. 10. 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. 11. 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, processing, 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/ and, http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm#goals, 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. C. NIDDK 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 (s). As required for the coordination of activities and to expedite 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. For multi-institutional protocols, 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. Substantial involvement assisting in the design and coordination of research activities for awardees as elaborated below: a. Assisting by providing advice in the management and technical performance of the investigations, coordinating clearances for investigational agents held by NIDDK. The NIDDK may reserve the right to cross file or independently file an Investigational New Drug Application form with the FDA. b. For multi-institutional protocols, through participation in the Steering Committee and with the agreement of the Principal Investigator(s) of any coordinating center and data management centers, the NDDK Project Scientist or designee may coordinate activities among awardees by assisting in the design, development, and coordination of a common research or clinical protocol and statistical evaluations of data; in the preparation of questionnaires and other data recording forms; and in the publication of results. c. Reviewing and approving advice regarding the establishment of mechanisms for quality control and study monitoring. An NIDDK Program Director 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 Scientist. 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 role (s) of any additional individuals with substantial involvement in the project and the lines of reporting authority. 2. Interacting with the principal investigator(s) on a regular basis to monitor study progress. Monitoring may include: regular communications with the principal investigator and staff, periodic site visits for discussions 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, data safety and monitoring board, 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 study 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) patient safety and regulatory concerns; (e) study results that are already conclusive; and (f) 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 carrying out the research (e.g., attendance at Steering Committee meetings, implementation of group decisions, compliance with the terms of award and reporting requirements); and/or c) maintenance of a high quality of research, which will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements. D. 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 (or P.I. of the Coordinating Center in the case of multiple coordinated awards) will be the main oversight body of the study. The Steering Committee has primary responsibility to design research activities, establish priorities, develop common protocols and manuals, questionnaires and other data recording forms, establish and maintain quality control among awardees, review progress, monitor patient accrual, coordinate and standardize data management, 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 all Principal Investigator(s), (including those of data coordinating /statistical centers, if any) 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. Such a committee usually will meet at least twice yearly. 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. 2. Data Safety and Monitoring Board. An independent Data and Safety Monitoring Board will be established by the NIDDK for Phase III clinical trials. The Data and Safety Monitoring Board will review interim results periodically and report to the Steering Committee and NIDDK. In all other studies where warranted, the NIDDK Program Director will facilitate and the awardee shall allow for interim data and safety monitoring through the establishment of an independent (external) Data and Safety Monitoring Board. E. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NIDDK may be brought to arbitration. An arbitration panel will be composed of three members --one selected by the awardee (or the Steering Committee, with the NIDDK member not voting), a second member selected by NIDDK, and the third member elected by the two prior selected members. These special arbitration procedures in no way affect the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. 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: Marva M. Moxey-Mims, M.D. Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Room 639 Bethesda, Maryland 20892-5458 Telephone: (301) 594-7717 FAX: (301) 480-3510 Email: email@example.com Leroy M. Nyberg, M.D., Ph.D. Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Room 627 Bethesda, MD 20892-5458 Telephone: (301) 594-7717 FAX: (301) 480-3510 E-mail: firstname.lastname@example.org Stuart Howards, M.D. Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Room 627 Bethesda, MD 20892-5458 Telephone: (301) 594-7717 FAX: (301) 480-3510 E-mail: email@example.com o Direct your questions about peer review issues to: Francisco O. Calvo, Ph.D. Chief, Review Branch National Institute of Diabetes, Digestive, and Kidney Diseases 6707 Democracy Boulevard, Room 752 Bethesda, Maryland 20892-5452 Telephone: (301) 594-8897 Fax: (301) 480-3505 Email: firstname.lastname@example.org o Direct your questions about financial or grants management matters to: Carolyn Kofa Grants Management Specialist National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Room 727 Bethesda, Maryland 20892-5452 Telephone: (301) 594-7687 FAX: (301) 480-3504 Email: email@example.com 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 IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Chief, Review Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, 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). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS: BUDGET: Clinical Centers should prepare a budget for each year of the program not to exceed $440,000 total costs (direct and facilities and administrative costs) per year. The funds for the DCC should not exceed $800,000 total costs per year. The first 8 months of year 1 will be a period of intensive protocol development with meetings of the steering committee to be held every other month, generally in the Washington DC area. The total percent effort of the Principal Investigator and co-investigator during this time should be reflected on the budget page. It is anticipated that recruitment for the clinical trial will begin in year 2. Applicants should budget for key personnel for study coordination and data entry. Beginning in year 2 and for the duration of the program applicants should budget for travel to three meetings of the Steering Committee each year. These will generally be held in the Washington DC, area. The DCC should budget for all key personnel, describe % effort and description of responsibilities. 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/labels.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, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to: Chief, Review Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 752 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this 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 CSR and responsiveness by the NIDDK. Incomplete and/or nonresponsive applications will not be reviewed. 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, all applications will: o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a written critique o Receive a second level review by the National Diabetes and Digestive and Kidney 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 the written comments, reviewers will be asked to evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: 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 (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: 1) Qualifications of Principal Investigator for CTC: The applicant must have demonstrated experience in enrolling patients in long-term clinical trials. 2) Qualifications for Clinical Investigators for each CTC: Each CTC must have at least on Pediatric Nephrologist and one Pediatric Urologist as investigators. 3) Recruitment and Retention Capabilities: The application should discuss the number of participants the Clinical Center anticipates will be recruited for clinical trials. The application should provide evidence that the investigators are capable of enrolling 5-7 participants per month for two years. Applicants should describe the target population from which they expect to recruit the required number of subjects as study participants. They must also discuss plans for recruitment of minorities. The applicant should include a brief discussion of previous relevant research efforts. The applicant should discuss in detail the recruitment strategies which will be utilized to procure the expected number of study participants. Specific plans and previous experience in retaining randomized study participants for the duration of clinical trial should also be discussed. Each Clinical Treatment Center applicant must provide an accurate, verifiable, historical record of the number of eligible VUR patients seen per year for the past three years. This record should be categorized by age, gender, race and the grade of VUR. 4) Proposed Clinical Trial Concept: The general concept draft for a single randomized controlled clinical trial to be considered by the Steering Committee of the Cooperative Treatment Group should be included in the application. The general concept draft should not exceed two pages, and it must be consistent with the scientific focus of this RFA. Concept issues to be considered are identification of the intervention(s) and rationale, primary and secondary outcome measures, sample size estimates and proposed subgroup analyses. 5) Evidence of Institutional Support: There should be evidence of strong institutional support for the Clinical Treatment Center, including adequate space in which to conduct clinical activities and office space for staff. 6) Collaborative relationship between Pediatric Nephrology and Pediatric Urology. The applicant should describe any already existing collaborative clinical relationships between pediatric nephrology and pediatric urology. 7) The Data Coordinating Center should provide evidence of experience in developing and conducting other multicenter clinical trials. They should also submit a Clinical Trial Concept, as describer in item 4 above. Also, methods for data collection, quality assurance, forms generation, meeting planning, etc., should be discussed and delineated in the proposal. 8) Organizational Structure of Centers: Each applicant should include an organizational structure of their CTC or DCC, delineating lines of authority and responsibility. PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS SHARING RESEARCH DATA: Applicants must describe their willingness to submit data generated through this project to relevant publicly available databases (http://grants.nih.gov/grants/policy/data_sharing/). The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed in all proposals 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 16, 2005 Application Receipt Date: March 16, 2005 Peer Review Date: June 2005 Council Review: September 2005 Earliest Anticipated Start Date: October 2005 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS ANIMAL WELFARE PROTECTION: Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable. HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose- finding studies (phase I); efficacy studies (phase II); efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). SHARING RESEARCH DATA: Investigators submitting an NIH application seeking $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 or 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 "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. 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 RFA 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). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on “Am I a covered entity?” Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
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