BARIATRIC SURGERY CLINICAL RESEARCH CONSORTIUM RELEASE DATE: November 1, 2002 RFA: DK-03-006 (Reissued as RFA-DK-08-501) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov) LETTER OF INTENT RECEIPT DATE: February 18, 2003 APPLICATION RECEIPT DATE: March 18, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Organization of the Bariatric Surgery Clinical Research Consortium 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 Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Reference List o Required Federal Citations: PURPOSE OF THIS RFA The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites applications for establishment of a Bariatric Surgery Clinical Research Consortium (BSCRC)to focuses on bariatric surgery and its role in the understanding and treatment of obesity and its complications. Bariatric surgery involves reducing the size of the gastric reservoir, with or without a degree of associated malabsorption, with a goal of inducing weight loss among patients with extreme obesity.(American Society for Bariatric Surgery, 2001) The objective of this Request for Applications (RFA) is to establish and maintain a Bariatric Surgery Clinical Research Consortium consisting of a group of between four and six interactive Clinical Centers (CCs) and a Data Coordinating Center (DCC). The goal of the BSCRC is to facilitate coordinated clinical, epidemiological, and behavioral research in the field of bariatric surgery, through the cooperative development of common clinical protocols and a bariatric surgery database to collect information from participating CCs. This is a one-time solicitation to support a Clinical Research Consortium for five years. RESEARCH OBJECTIVES A. Background Obesity is increasing at alarming rates in the US, with more than 25% of adult Americans now considered obese (BMI>30).(U.S.Department of Health and Human Services, 2001) Of even more concern, there are large increases in the prevalence of higher levels of obesity (Class II, BMI 35-39.9 and Class III BMI >40).(Flegal, K. M., Carroll, M. D., Kuczmarski, R. J., & Johnson, C. L., 1998) In some minority populations, such as African American women ages 40- 60, the percentage of individuals with a BMI >40 exceeds 10%.(Flegal, K. M., Carroll, M. D., Kuczmarski, R. J., & Johnson, C. L., 1998) Along with this increase in the prevalence of obesity has come a rise in the incidence and prevalence of obesity-related co-morbid condition, such as type 2 diabetes.(Harris, M. I. et al., 1998) Although prevention of overweight and obesity remains the primary public health goal, more effective treatments for those who are already obese are crucial. Numerous studies have shown that obesity treatments using behavioral therapy to improve diet and physical activity levels can lead to weight losses of approximately five to ten percent over four to six months.(Wadden, T. A. & Foster, G. D., 2000) With such weight losses come improvements in obesity- related co-morbidities, such as hypertension, dyslipidemia, hyperinsulinemia, and progression to diabetes. (Knowler, W. C. et al., 2002) However, these improvements are not maintained if weight is regained, and in a majority of cases, rebound in weight gain above the pre-intervention weight is the ultimate outcome. Therefore, better means to induce substantial weight loss in the extremely obese population, as well as to maintain weight loss over the longer term, are treatment goals. The most effective means currently available to induce substantial weight loss, with long-term maintenance of much of that weight loss, is through bariatric surgery. A 1991 NIH Consensus Conference found that gastric restrictive or bypass surgery could be considered in well-informed and motivated patients with severe obesity (BMI >40) or less severe obesity (BMI >35) with high-risk co- morbid conditions.(1992) It was noted that insufficient data were available on which to base recommendations for patient selection using objective clinical features alone, and that additional research was needed to determine predictive factors. Since 1991, bariatric surgical procedures have become established modalities in the treatment of extreme obesity. It is estimated that 40,000 bariatric surgical procedures were carried out in the US in 2001, with many more predicted in 2002.(NIDDK Working Group on Bariatric Surgery Executive Summary, 2002) Although systematic long-term follow-up across multiple sites is lacking, individual researchers have published case series with excellent follow-up.(Pories, W. J. et al., 1995; Brolin, R. E., 2001) These studies suggest that bariatric surgery can have a long-lasting outcome on some co- morbid conditions, particularly type 2 diabetes. The Swedish Obese Subjects (SOS) is an ongoing non-randomized multi-center trial investigating the long- term effects of surgically induced weight loss on obesity-related morbidity and mortality,(Sjostrom, C. D., Peltonen, M., Wedel, H., & Sjostrom, L., 2000) and may answer some, but not all, questions regarding the health impact of bariatric surgery. One limitation of this study is that most procedures were restrictive in nature, with more limited weight loss than is common with gastric bypass procedures. Some of the research questions posed by the Consensus Panel in 1991 remain unanswered a decade later. These include the mechanisms whereby surgical treatment produces weight reduction, mechanisms of improvement in co-morbid risk factors or disease, safety and efficacy of bariatric surgery in defined subgroups, safety and efficacy of differing bariatric surgical procedures, and impact of bariatric surgery on subsequent pregnancy. The panel also noted the need for improved reporting of surgical results, and clearer outcomes assessment, including psychosocial outcomes. The importance of including meaningful control or comparison groups was also noted, although challenges in obtaining truly comparable groups were acknowledged. In 2001, NIDDK, in conjunction with the American Society for Bariatric Surgery, sponsored a workshop on Research Considerations in Obesity Surgery,(Kral, J. G. et al., 2002) which provided an update on bariatric surgery and posed research questions that might be answered by future studies. Some of the research topics proposed included the impact of bariatric surgery on subsequent pregnancy, impact of age on outcomes, and the effect of operations with greater malabsorptive potential on nutritional status. In May 2002, NIDDK convened a Working Group on Research in Bariatric Surgery that brought together investigators from a variety of disciplines to assist NIDDK in identifying areas of scientific opportunity pertaining to bariatric surgery and its impact on obesity and co-morbid conditions. A number of topics were identified as research opportunities, including using bariatric surgery as a model to understand underlying pathophysiology of obesity-related diseases, and evaluation of the safety and efficacy of bariatric surgical procedures, including their impact on weight loss, co-morbid conditions, psychosocial status, quality of life, and economic factors. Studies looking at both short- term and long-term outcomes were felt to be critical. The need for refining phenotyping to better predict outcomes, and hence improve risk/benefit ratio of an individual patient was also considered essential. A consortium of centers performing bariatric surgical procedures on large numbers of patients would permit collaborative studies in more basic areas, including studies on energy balance, nutrient absorption, physiology and metabolism, and the genetics of severe obesity. Establishing a bariatric surgery database, to collect hypothesis-driven data on multiple variables of clinical and scientific interest was considered a potential strength of such a collaboration, which could provide information on clinically important predictors and outcomes, as well as economic and quality of life data. A Bariatric Surgery Clinical Research Consortium (BSCRC) will accelerate clinical research and progress in understanding the pathogenesis of severe obesity and its complications, as well as in understanding the risks and benefits of bariatric surgery as a treatment modality. Use of standardized definitions, clinical protocols, and data collection instruments will enhance the ability to provide meaningful evidence-based recommendations for patient evaluation, selection, and follow-up care. Also, the BSCRC will help pool the necessary clinical expertise and administrative resources to facilitate the conduct of multiple and novel clinical studies in a timely, efficient manner. This, in turn, will promote rapid dissemination of research findings to health care professionals. B. Research Scope 1. Study Goals and Objectives The objective of this Request for Applications (RFA) is to establish and maintain a Bariatric Surgery Clinical Research Consortium consisting of a group of interactive Clinical Centers (CCs) and a Data Coordinating Center (DCC). The goal of the BSCRC is to facilitate coordinated clinical, epidemiological, and behavioral research in the field of bariatric surgery. CCs and the DCC will work cooperatively to develop common clinical protocols, as well as to develop and implement a database to collect information from participating clinical centers. It is anticipated that the BSCRC will carry out one or more studies per year during the five year period, ranging from small pilot studies to larger studies (such as studies on quality of life or economic factors). The Bariatric Surgery Clinical Consortium should provide the preliminary data and background for further investigator-initiated research. For example, the Consortium might investigate metabolic and endocrine changes with bariatric surgery, generating information to allow the investigators to submit a separate application for a full-scale clinical investigation through the RO1 mechanism. The Consortium also is expected to interact with basic and laboratory research investigators with interest in these diseases by providing laboratory specimens, tissues, or opportunities to assess hypotheses on the pathogenesis, prevention or treatment of obesity and its co-morbid conditions. The Consortium can also provide a focus for training in clinical investigation. 2. Study Timeline During the first 10-12 months, investigators will collaboratively develop the protocols, with IRB and other approvals obtained by the end of the first year. Database development and implementation will also take place during this phase (Phase 1). Short-term and longer-term studies, as described below, will be instituted during years 2-4 (Phase 2), with continued follow- up, study analysis, and close out during the final year (phase 3). All projects must be completed within the five-year duration of this research program. 3. Research Approaches a. Database The Consortium will initially focus upon development of a clinical database of patients undergoing bariatric surgery, including elements of medical history, physical examination, and laboratory results. Development of the database will necessitate agreement on standardized definitions, means of assessing symptoms and quality of life, standardized forms and questionnaires, time- points for data collection, and agreed-upon essential information for the characterization of a patient cohort. The database may also include control subjects and family members for genetic studies. The database should be designed so that the information collected is based on the need to answer specific scientific questions. Each CC must provide a brief description of their suggestions for a database, including which data they believe should be acquired in the database, a discussion of the pros and cons of various non-surgical control groups, as well as discussion of the types of scientific questions such a database might answer. The DCC must propose a research plan that includes the structure of a large database and an information core that they believe should be collected on all participants that are prospectively enrolled, including potential and actual bariatric surgical patients and non-surgical control patients. b. Clinical Studies The BSCRC will carry out one or more clinical studies each year, with a mix of short-term and longer-term studies. These nature and content of these studies will be developed by the steering committee during the first year of funding. So that NIDDK can better evaluate the potential range of studies that might be developed by the BSCRC, this application requires that each CC propose a research plan that includes two clinical research protocols as models that could be used in the Consortium environment. IT IS SUGGESTED THAT EACH PROTOCOL PROPOSAL BE APPROXIMATELY THREE PAGES IN LENGTH, INCLUDING TABLES OR FIGURES. The protocols must demonstrate knowledge of the fields of bariatric surgery and extreme obesity, and the research questions should reflect the unique opportunities provided by large and sustained weight losses due to surgical treatment. Each clinical protocol must require sufficient subjects to necessitate the use of a Consortium with multicenter participation. Applicants must indicate the number of patients required for each study based on sample size calculations. One protocol must be a short-term study (one year or less) focusing on the pathophysiology of an obesity-related co-morbid condition or the impact of bariatric surgery on appetite, nutrient metabolism, and/or energy expenditure. The other protocol must propose a longer-term study (one to three years). All projects must be completed within the five-year duration of this research program. CC and DCC applicants will not include a Data and Safety Monitoring Plan (DSMP) for these protocols within this application. The DSMP will be developed by the DCC, and approved by the Steering Committee and Data Safety Monitoring Board (DSMB) prior to the implementation of any clinical protocols. The CCs must state a willingness to follow the Data and Safety Monitoring Plan that is developed and approved. THESE ARE EXAMPLES ONLY. APPLICANTS SHOULD NOT FEEL LIMITED TO THE SUBJECTS MENTIONED BELOW AND ARE ENCOURAGED TO SUBMIT OTHER TOPICS PERTINENT TO THE OBJECTIVES OF THE RFA. It is anticipated that in the initial one or two years, trials and investigations will be selected (with modifications) from the studies proposed by the successful CCs in their applications, but investigators should not anticipate that the studies they propose as part of this application will necessarily be included, with or without modification, in the final research plan. Short-term study (one year or less) o Studies evaluating the short-term impact of bariatric surgery on an obesity- related co-morbid condition, such as non-alcoholic steatohepatitis o Studies investigating the impact of bariatric surgery on appetite, nutrient absorption, nutrient metabolism, or energy expenditure o Studies investigating the effects of surgically-induced weight loss on beta cell function and insulin resistance o Studies evaluating changes in neuroendocrine or gastrointestinal hormones with surgically induced weight loss Longer-term study (one to three years) o Studies investigating predictors of successful weight loss o Studies investigating impact of surgery on obesity-related co-morbid conditions o Studies investigating the impact of bariatric surgery on fitness, body composition, or long-term energy balance o Studies evaluating predictors of risk or adverse outcomes following bariatric surgery o Studies of behavioral, psychosocial, and economic outcomes of bariatric surgery As a part of each protocol proposal (within the 3 pages), please submit a SAMPLE PATIENT CARE BUDGET for the first year in which the protocol would be implemented. A table must be included for each protocol showing estimated costs per patient for conducting the protocol. Investigators must only prepare budgets for their own CC to conduct the proposed study or trial, and not for the entire BSCRC. The CC must state the total number of patients required by the entire Consortium to complete each proposed study or trial. The sample budget for each CC must include the number of patients available for the proposed protocol at that CC. A budget based on the costs per patient for recruiting and maintaining the specified number of subjects at the applicant's center must be included for each protocol. Budget requests for per-patient costs should be based on the two specific protocols proposed in the application and reflect anticipated costs for simultaneous implementation of these protocols in the first year. Funding may not be requested for the purchase of expensive equipment. The budget for each clinical protocol must be developed on a cost per patient basis and include all direct and any applicable facilities and administrative costs. Therefore, a per capita cost for each of these studies proposed should be included in the budget proposal. Patient care costs for both protocols combined are limited to $100,000 (total costs) per year. Patient care costs should include costs of carrying out the proposed study at your institution, including any medications, imaging, clinical evaluations, and laboratory studies or tissue analyses that you do not propose to be centrally assessed (costs of laboratory or other sample analysis that are centrally assessed, as well as costs for shipment and storage of samples will be included in the DCC budget). ROUTINE (NON-RESEARCH RELATED) PATIENT CARE COSTS, SUCH AS ROUTINE LABORATORY AND IMAGING EVALUATIONS, MAY NOT BE INCLUDED IN THE BUDGET; NOR MAY THE COSTS RELATED TO THE SURGICAL PROCEDURE ITSELF (INCLUDING PREOPERATIVE, POSTOPERATIVE, AND FOLLOW-UP CARE) BE INCLUDED. APPLICATIONS INCLUDING SURGICAL OR ROUTINE PATIENT CARE COSTS IN THE SAMPLE BUDGET WILL BE RETURNED WITHOUT REVIEW. This is a sample budget only. On the actual budget page, you should note patient care costs of $100,000 total costs per year for each of the five years, and need not provide budget details. Note that Core costs, as opposed to Patient Care costs, will be submitted as part of the regular budget on the budget page, with appropriate level of detail. ORGANIZATION OF THE BARIATRIC SURGERY CLINICAL RESEARCH CONSORTIUM The BSCRC will consist of the following components: the NIH, four to six CCs, a DCC, a Steering Committee and its subcommittees, a Data and Safety Monitoring Board (DSMB), and other committees as needed. The responsibilities of each component of the BSCRC are described in the Terms and Conditions of Award. NIDDK. The NIDDK will be responsible for organizing and providing support for the BSCRC and will be involved substantially with the awardees as a "partner", consistent with the Cooperative Agreement mechanism. A designated NIDDK Project Scientist, who will also serve as Program Director, will monitor subject recruitment and study progress, ensure disclosure of conflicts of interest and adherence to NIDDK policies. The NIDDK Project Scientist, together with the NIDDK Grants Management Specialist, will be responsible for fiscal management of the network, including calculation of capitation budget rates and awards. The NIDDK will appoint the Chairperson of the Steering Committee and all members of the DSMB. Clinical Centers. All individual CCs will be required to participate in a cooperative and interactive manner with one another and with the DCC in all aspects of the BSCRC (see Terms and Conditions of Award). Data Coordinating Center (see Terms and Conditions of Award). Study Governance Steering Committee. A Steering Committee will be the main governing body of the BSCRC (see Terms and Conditions of Award). An Executive Committee comprised of the Study Chair and Co-Chair, the Principal Investigator of the Coordinating Center, and the NIDDK Project Scientist also will be convened to effect management decisions required between Steering Committee meetings, as needed for efficient progress of the trial. For each investigational protocol, one CC or subcommittee will take the lead responsibility for drafting the protocol, with the assistance of the DCC, although the Steering Committee will provide input and will be responsible for assuring development of a common protocol to be implemented by the CCs. The final decision of which common protocol(s) will first be implemented will be determined by a vote of the entire steering committee, and will be subject to additional review by the DSMB and NIDDK. Other subcommittees of the Steering Committee will be established as necessary. For example, a Publications Committee would be helpful to facilitate the process for authorship selection and to supervise preparation of manuscripts, and a Database Subcommittee would supplement the activities of the Steering Committee and propose the content and structure of the database. Data Safety and Monitoring Board. An independent Data and Safety Monitoring Board (DSMB) will be established by the NIDDK to review protocols and monitor patient safety and performance of each study. As a part of its responsibilities, the DSMB will submit recommendations to the NIDDK regarding the continuation of each study. The DSMB will be responsible for final approval of the Data Safety Monitoring Plan developed by the DCC. Each investigational protocol will be implemented in a minimum of two and optimally in all of the CCs, depending on the number of patients and investigational expertise needed for the study. As specific protocols are developed, support will depend on the availability of funds and will be provided on a per patient basis. All participating CCs must be willing to accept this funding arrangement for each new protocol conducted. Clinical protocols must be approved by local institutional review boards, the Steering Committee, the BSCRC Data and Safety Monitoring Board, and the NIDDK before initiation. The exact number of protocols supported in the five-year program will depend on the nature and extent of the investigations proposed by the Steering Committee. A database will be developed; epidemiological studies and other clinical studies may be performed. Planning may be done for large clinical trials that would be submitted as separate R01s if further funding is necessary. The BSCRC investigators are also encouraged to seek out separate funding for special projects and to develop collaboration with laboratory and basic research investigators to draw upon the resources (clinical data, serum, tissue, DNA) made available by the BSCRC. Any specific collaboration involving the resources of the BSCRC will require approval by the Steering Committee. MECHANISM OF SUPPORT This RFA will use NIH cooperative agreement (UO1) award mechanism. The NIH UO1 is a cooperative agreement award mechanism in which 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" This RFA is a one-time solicitation. The total project period for applications submitted in response to this RFA will be five years. The anticipated award date is September 30,2003 This RFA uses just-in-time concepts. Modular budgets will not be used. Follow the instructions for non-modular research grant applications. FUNDS AVAILABLE It is anticipated that between four and six awards for CCs and one award for a DCC will be made under this RFA. NIDDK intends to commit approximately 3 million dollars in total costs to the Bariatric Surgery Research Consortium per year. Total costs include Direct Costs and Facility and Administrative Costs, also called indirect costs or overhead. It is anticipated that the award for the DCC will be no more than $1.2 million total costs per year. The amount awarded to each CC per year may vary, but will be limited to no more than $300,000 total costs/CC/year. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of an award will also vary in all years. Future year costs will be distributed based on the recommended protocols, database development, epidemiological studies, pilot studies or planning studies for future clinical trials. AWARDS MADE TO A PARTICULAR CENTER UNDER THIS RFA WILL DEPEND IN PART ON THE PROTOCOLS CARRIED OUT BY THE BSCRC AND MAY BE MORE OR LESS THAN THE REQUESTED BUDGET. FUNDS WILL NOT BE AVAILABLE TO SUPPORT THE COSTS OF THE SURGERY ITSELF, PRE- OR POST OPERATIVE CARE, OR ROUTINE PATIENT CARE COSTS. 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 a sufficient number of applications of outstanding scientific and technical merit. Designated funding levels are subject to change at any time prior to final award, due to unforeseen budgetary, administrative, or scientific developments. 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 only. This geographic constraint will be necessary because of the need for close communication among members of the program, the requirement for frequent steering committee meetings, and site visits for data verification. 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. All current policies and requirements that govern the research grant programs of the National Institutes of Health (NIH) will apply to grants awarded under this RFA. Among the disciplines and expertise that may be appropriate for this program are surgery, internal medicine, nutrition, behavioral science, and clinical trials management. A DCC will be a part of this BSCRC. In order to ensure that data analysis is done independently of data acquisition, the DCC cannot have the same Principal Investigator as a CC. Within the Consortium an institution may apply for both a CC and the DCC, but each must have separate principal investigators and submit a separate application with a specific plan of how the independent operation (i.e., confidentiality of the study-wide data) of each unit of the CC and DCC will be maintained. In addition, there should be no overlap in personnel between the CC and DCC. SPECIAL REQUIREMENTS Only CCs that are currently conducting bariatric surgical procedures may apply. To be eligible, a CC (including affiliated hospitals participating in the study) must have performed a minimum of 100 bariatric surgical procedures during 2002, and must have a minimum of two surgeons performing bariatric surgery who confirm willingness to collaborate with the Consortium. Evidence of experience with laparoscopic bariatric surgery is also a requirement. The BSCRC will be a collaborative effort that will require frequent interactions of awardees among themselves and with the NIDDK. Applicants must explicitly indicate their willingness to: o Participate in Steering Committee meetings (expected to occur approximately 6 times during the first year and 3 times per year in subsequent years, in or near Bethesda, MD), site visits required by the NIDDK, and regular telephone conference calls, o Cooperate with other awardees in the development and design of research protocols, o Abide by common definitions; common methods for patient selection and enrollment; and common protocols, procedures, tests, and reporting forms as chosen by majority vote of the Steering Committee, o Actively seek to implement each consortium-wide protocol approved by the DSMB and the NIDDK, o Comply with study policies and quality assurance measures approved by the Steering Committee, o Agree to oversight of the study by a Data and Safety Monitoring Board (DSMB), o Accept awards for the support of research based on per-patient (capitated) rates and the actual numbers of subjects enrolled, followed, and completing the study (Clinical Centers only), o Transmit study data to the Data and Coordinating Center in a timely and accurate manner (Clinical Centers only), o Report all adverse events in accordance with procedures established by the Steering Committee and NIDDK policies, o Cooperate with other awardees in the publication of study results and the eventual release to the scientific community of study procedures and other resources, o Accept the Cooperative Agreement Terms and Conditions of Award given below. Cooperative Agreement Terms and Conditions of Award The cooperative agreement is an award instrument establishing an "assistance" relationship (in contrast to an "acquisition" relationship) between NIDDK and a recipient, in which substantial NIDDK scientific and/or programmatic involvement with the recipient is anticipated during performance of the activity. The NIDDK purpose is to support and/or stimulate the recipient's activity by involvement in and facilitation of the activity in a "partner" role. The dominant role and prime responsibility for the planned activity reside with the awardees for the project as a whole, although specific tasks and activities in carrying out the activity will be shared among the awardees and NIDDK Project Scientist. The terms and conditions below elaborate on these interactions and responsibilities, and the awardee agrees to these collaborative actions toward achieving the project objectives. It is anticipated that these terms and conditions will enhance the relationships among the awardees and with the NIDDK Project Scientist, and will facilitate the successful conduct and completion of the study. These agreements will be in addition to, and not in lieu of, the relevant NIH procedures for grants administration. The terms will be as follows: 1) Awardees Rights and Responsibilities The awardee(s) will have lead responsibilities in all aspects of their protocols, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, and collaboration with other investigators. Modifications will be approved by the Steering Committee and the Data and Safety Monitoring Board. Awardees will retain custody of and have primary rights to their data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. The collaborative protocol and governance policies will call for the continued submission of data centrally to the DCC for a collaborative database; the submission of copies of the collaborative data sets to each principal investigator upon completion of the study; procedures for data analysis, reporting and publication; and procedures to protect and ensure the privacy of medical and genetic data (if any) and records of individuals. The NIDDK Project Scientist, on behalf of the NIDDK, will have the same access, privileges and responsibilities regarding the collaborative data as the other members of the Steering Committee. The Data Coordinating Center will be involved in collaborations with the NIDDK and the Clinical Centers during all phases of the trial and will maintain or contract with the Central Laboratory. The DCC will also coordinate with the NIDDK Biosample Repository, if it is available and chosen by the NIDDK as the study repository. If the NIDDK Biosample Repository is not available or is not chosen as the sample repository by the NIDDK at the time the study is in the protocol development phase, the DCC will be required to maintain or contract with a repository for central storage and distribution of serum, tissue, and other samples. In addition, the DCC will coordinate with the NIDDK Data Repository, if it is available, to prepare the data for eventual archiving and distribution. Thus, the awardee is expected to work cooperatively with Clinical Centers and sponsoring organizations and oversee the implementation of and adherence to a common protocol, as well as assure quality control of the data collected and storage of collected tissue specimens. In addition to organizing and attending regular meetings (including conference calls), the Data Coordinating Center will be expected to maintain close communications with the NIDDK Project Scientist, NIDDK Database Coordinator, and the Principal Investigators of the Clinical Centers. Awardees are encouraged to publish and to publicly release and disseminate results, data and other products of the study, concordant with the study protocol and governance and the approved plan for making data and materials available to the scientific community and the NIDDK. However, during or within three years beyond the end date of the project period of NIDDK support, unpublished data, unpublished results, data sets not previously released, or other study materials or products are to be made available to any third party only with the approval of the Steering Committee. Support or other involvement of industry or any other third party in any study performed by the Consortium -- e.g., participation by the third party; involvement of project resources or citing the name of the project or the NIDDK support; or special access to project 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 to, and concurrence by, NIDDK. Upon completion of the project, the DCC is expected to put all study intervention materials and procedure manuals into the public domain and/or make them available to other investigators, according to the approved plan for making data and materials available to the scientific community and the NIDDK, for the conduct of research at no charge other than the costs of reproduction and distribution. Indeed, NIH policy requires that investigators make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication [NIH Grants Policy Statement (http://grants.nih.gov/grants/policy/nihgps; Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources: Final Notice, December 1999 (http://www.ott.nih.gov/policy/rt_guide_final.html)]. It is expected that the specimens and data collected in projects funded by this RFA will eventually be made available to the broader scientific community, after the proprietary period. This RFA has a special requirement that applicants acknowledge in a "Sharing Plan" in the proposal that they will share the specimens and data collected with the wider scientific community, through eventual transfer of these materials to the NIDDK Central Biosample and Data Repositories or through another mechanism determined by NIDDK. A data sharing plan as approved, after negotiation with the applicant when necessary, will be a condition of the award. Evaluation of the Non-competing Grant Progress Report (PHS 2590) will include assessment of the effectiveness of research resource release. 2) NIDDK Staff Responsibilities The NIDDK will be responsible for organizing and providing support for the BSCRC and will be involved substantially with the awardees as a "partner", consistent with the Cooperative Agreement mechanism. A designated NIDDK Project Scientist, who will also serve as Program Director, will monitor subject recruitment and study progress, ensure disclosure of conflicts of interest and adherence to NIDDK policies. The NIDDK Project Scientist, together with the NIDDK Grants Management Specialist, will be responsible for fiscal management of the network, including calculation of capitation budget rates and awards. The Project Scientist will have substantial scientific- programmatic involvement in quality control, interim data analysis, safety monitoring, and final data analysis and interpretation, preparation of publications, and coordination and performance monitoring. The dominant role and prime responsibility for these activities 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. NIH staff will also participate in key subcommittees. The NIDDK will appoint the Chairperson of the Steering Committee and all members of the DSMB. The NIDDK reserves the right to terminate or curtail the Consortium (or an individual award) in the event of (a) failure to develop or implement a mutually agreeable collaborative protocol, (b) substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breach of the protocol, (c) substantive changes in the agreed-upon protocol with which NIDDK cannot concur, (d) reaching a major study endpoint substantially before schedule with persuasive statistical significance, or (e) human subject ethical issues that may dictate a premature termination. 3) Collaborative Responsibilities Clinical Centers. All individual CCs will be required to participate in a cooperative and interactive manner with one another and with the DCC in all aspects of the BSCRC. The Principal Investigator at each Clinical Center will have primary responsibility for study design and implementation, including subject recruitment and safety. With the assistance of Co-Investigators as appropriate, the Principal Investigator will hire and supervise relevant personnel, obtain Institutional Review Board (IRB) approval for BSCRC protocols, oversee data collection and adherence to quality assurance measures, and prepare budgets and annual reports. Data Coordinating Center. The DCC will support protocol development, provide sample size calculations, statistical advice, questionnaires, and data analysis; support development, implementation, and maintenance of a database of clinical information, serum, and tissue samples; develop the data safety and monitoring plan, support manuscript preparation; and provide overall study coordination and quality assurance, including coordination of the activities and meetings (including conference calls) of the Data and Safety Monitoring Board, the Steering Committee and other standing committees. The DCC will prepare protocols for submission to the DSMB, and prepare confidential data analyses and reports for the DSMB. The DCC will be responsible for the preparation of the Data and Safety Monitoring Plan that will be submitted to the DSMB and the Steering Committee for their approval prior to the implementation of any study protocols. The Data Coordinating Center will be responsible for acquiring and administering subcontracts for a central laboratory. Examples of the types of centralized laboratory functions that may be required include analyses such as blood lipid and lipoprotein subtypes, glycosylated hemoglobin, and insulin levels. Costs for shipping, processing, and analysis must be included in the DCC budget. Specimens, including serum, tissue, and possibly DNA, will be stored in a specimen repository. It is anticipated that the Central NIDDK Biosample Repository will be used as a repository for the BSCRC, and the DCC will be required to coordinate with the NIDDK repository if it is selected by NIDDK as the study repository. Costs for shipment of specimens and specimen storage in a repository, whether or not it is the Central NIDDK Biosample Repository, must be included in the DCC budget. If the NIDDK Biosample Repository is not available or chosen as the sample repository by the NIDDK at the time the study is in the protocol development phase, the DCC will be required to maintain or contract with a different repository for central storage and distribution of serum, tissue, and other samples. No subcontract(s) will be awarded until the Steering Committee has met and approved their structure and duties. The DCC must also propose how it would identify subcontractors for a central laboratory and a repository through a competitive process. The DCC will be subject to annual administrative review. Steering Committee. A Steering Committee will be the main governing body of the BSCRC. This committee will have the primary responsibility for approval of the common protocols, facilitating the conduct of participant follow-up, monitoring completeness of data collection and timely transmission of data to the DCC, and reporting various study results. It will also be responsible for establishing study policies in such areas as access to patient data, publications and presentations, and performance standards. Each member of the Steering Committee will have one vote and all major scientific decisions will be determined by a majority vote of the Steering Committee. A Chairperson will be chosen from among the Steering Committee members (but not the NIDDK Project Scientist or Data Coordinating Center Principal Investigator), or alternatively, from among experts in an appropriate scientific field who is not participating directly in the study. Subcommittees may be established on topics such as database development, protocol development, publications and presentations, core measures, quality control, recruitment, and protocol adherence, among others. Each Consortium CC Awardee and the DCC Awardee agree to the governance of the study through the Steering Committee. The Steering Committee voting membership shall consist of the Principal Investigators of the CCs and the DCC, and the NIDDK Project Scientist. Meetings of the Steering Committee will ordinarily be held by telephone conference calls or in the Bethesda, MD area. The NIDDK Project Scientist (and other NIH scientists) may work with awardees on issues coming before the Steering Committee and, as appropriate, other committees, e.g., issues of recruitment, intervention, follow-up, quality control, standards and methods, adherence to protocol, assessment of problems affecting the study and potential changes in the protocol, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and development of solutions to major problems such as insufficient participant enrollment. Regardless of the number of NIH staff participating in technical advisory roles, the NIDDK will be limited to one vote on the Steering Committee. Executive Committee. An Executive Committee comprised of the Study Chair and Co-Chair, the Principal Investigator of the Coordinating Center, and the NIDDK Project Scientist also will be convened to effect management decisions required between Steering Committee meetings, as needed for efficient progress of the trial. Data Safety and Monitoring Board. An independent Data and Safety Monitoring Board (DSMB) will be established by the NIDDK to review protocols and monitor patient safety and performance of each study. As a part of its responsibilities, the DSMB will submit recommendations to the NIDDK regarding the continuation of each study. The DSMB will be responsible for final approval of the Data Safety Monitoring Plan developed by the DCC. 4) Arbitration Any disagreement that may arise in 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 Steering Committee (with the NIDDK member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NIDDK, and the third member selected by the two prior 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. A website on the NIDDK homepage containing information pertaining to this RFA is located at http://www.niddk.nih.gov/fund/crfo/faqsforbscrc.htm. Answers to frequently asked questions and other information updates concerning this RFA posted on the site as they are developed. Applicants are strongly encouraged to visit this website on a regular basis in the course of preparing their applications. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues that are not addressed by the website to: Susan Z. Yanovski, M.D. Director, Obesity and Eating Disorders Program Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 665, MSC 5450 Bethesda, MD 20892-5450 Telephone: (301) 594-8882 FAX: (301) 480-8300 Email: sy29f@nih.gov o Direct your questions about peer review issues that are not addressed by the website to: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 752, MSC 5452 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 that are not addressed by the website to: Ms. Sharon Bourque Grants Management Specialist Division of Extramural Affairs National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 719, MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-8846 FAX: (301) 480-3504 Email: sb114m@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 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 Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 752, MSC 5452 Bethesda, MD 20892-5452 Telephone: (301) 594-8885 FAX: (301) 480-3505 SUBMITTING AN APPLICATION A. Submission Instructions Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 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. 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, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 752, MSC 5452 Bethesda, MD 20892-5452 Telephone: (301) 594-8885 FAX: (301) 480-3505 Email: fc15y@nih.gov 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. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. B. Application Requirements 1. CC and DCC Applications Applicants must describe plans to accommodate the stated program requirements, criteria, and staff involvement. Applicants must address points discussed in the RESEARCH OBJECTIVES and SPECIAL REQUIREMENTS sections of this RFA. In addition, applicants must address the following issues that are important to the successful development of a collaborative program: willingness to participate on the Steering Committee and appropriate subcommittees, to work cooperatively with other members of the Steering Committee, and to follow the common protocols established by the Steering Committee. This RFA has a special requirement that applicants acknowledge in a "Sharing Plan" in the proposal that they will share the specimens and data collected with the wider scientific community, through eventual transfer of these materials to the NIDDK Central Biosample and Data Repositories or through another mechanism determined by NIDDK. The application should follow the instructions in the PHS 398 application form http://grants.nih.gov/grants/funding/phs398/phs398.html. Applications for both the CC and the DCC may not exceed 25 pages for sections a-d, excluding appendices. This page limit includes protocol descriptions. Clinical Center Applications The applicant must submit two clinical research protocols as models that could be used in the Consortium environment, as described in the section entitled "Research Scope." For each of the two protocols include a description, in approximately three pages, of the rationale, research aims, outcome measures, and study design. In addition,(within the three pages) provide a description of the proposed patient populations with an estimate of the expected distribution of male and female patients, ages, racial and ethnic distribution, approximately and assurances of the applicant's access to the patient populations. The CC principal investigator must indicate for each protocol how many patients meeting proposed criteria are available in his/her CC and how many will be required from the entire Consortium (all of the CCs). In the discussion of outcome measures, appropriate objective measures of primary and secondary outcome must be indicated. Include, within the three pages, a sample patient care budget for the first year in which the protocol would be implemented, in tabular form, for the above protocols, as described under "Research Scope." This sample budget should show patient care costs ONLY for each protocol, on a capitated basis (See Research Scope). Total patient care costs for both protocols combined must not exceed $100,000/year. Each CC must also provide a brief description of their suggestions for a database, including which data they believe should be acquired in the database, a discussion of the pros and cons of various non-surgical control groups, as well as discussion of the types of scientific questions such a database might answer. To promote development of a collaborative program, the issues discussed below must be addressed in each application for a CC within the BSCRC. This material is in addition to the submission of a research plan, as described in the section entitled Research Scope. o Qualifications and experience. Applicants for CCs must demonstrate experience and expertise to conduct clinical studies in bariatric surgical patients. This must include documentation of experience in the pre-operative, operative, and post operative care of extremely obese patients undergoing bariatric surgical procedures, as well as on-going support and follow-up for post surgical patients. Include a short description of your procedures for short-term and long-term patient follow-up. A minimum of 100 bariatric surgical procedures during 2002 at the applicant institution or its affiliated hospitals participating in the study is required. An institution (including its affiliated hospitals participating in the study) must have a minimum of two surgeons who perform bariatric surgical procedures and who confirm willingness to collaborate with the Consortium. Evidence of experience with laparoscopic bariatric surgery is also a requirement. Experience with more than one type of bariatric surgical procedures (for example, gastric bypass, vertical banded gastroplasty, biliopancreatic diversion, laparoscopic banding, etc.), while not required, is encouraged. o Clinical Center population. CCs must discuss the number of patients with extreme obesity who are potential candidates for bariatric surgery each year, the number evaluated, and the number undergoing the procedures, including age range, gender, and racial/ethnic distribution, as well as the recruitment source. Because of the lack of data on the safety of bariatric surgical procedures in pediatric populations, children and adolescents under age 18 will not be included in this protocol; however, it is expected that patients between the ages of 18 and 21 would be studied, if they are appropriate surgical candidates. o Applicants for a CC from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources are encouraged to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC Project Coordinator or Principal Investigator must be included with the application. o Willingness to participate in a BSCRC. The principal investigator must state his/her general support of collaborative research and interaction with the NIDDK, the other CCs, and the DCC through the Consortium concept. Applicants must discuss their willingness, and that of the institutions involved, to accept a per patient basis (capitation) of operational costs for each protocol. CCs must be able to interact with the DCC to transmit and edit data and must discuss their capability to participate in a distributed data entry system. o CC applicants will not include a Data Safety Monitoring Plan (DSMP) within this application. The DSMP will be developed by the DCC, and approved by the Steering Committee and DSMB prior to the implementation of any clinical protocols. The CCs must state a willingness to follow the Data and Safety Monitoring Plan that is developed and approved. o Institutional resources for patient care and follow-up including personnel, space, and special laboratory facilities must be described. o Each CC must provide a plan for which data they believe should be included in the database, including a discussion of the pros and cons of various non- surgical control groups, and a discussion of the types of scientific questions such a database might answer. Applications for a DCC: o Qualifications and experience. The applicant for a DCC must demonstrate experience in the area of in coordinating multi-center clinical trials and epidemiological studies in all phases: protocol and manual of operations development, staff training in study procedures, research instrument development, data collection and management, quality assurance, data analysis, distributed data entry, electronic communications, administrative management and coordination. Specific experience in coordinating or monitoring studies of obese patients or surgical procedures is not required, but the applicant may wish to include a surgeon or obesity specialist in the application as a collaborator or advisor. The DCC must propose a research plan that includes the structure of a large database and an information core that they believe should be collected on all participants that are prospectively enrolled, including potential and actual bariatric surgical patients and non-surgical control patients. o Study design and management. DCC proposals must discuss the applicant's familiarity and experience with various aspects of study design that would be important in developing clinical protocols, for example: eligibility criteria; baseline and outcome measures; methods of randomization; important considerations for making sample size and power calculations; methods and frequency of data collection and entry; monitoring accuracy of data collection; quality control procedures including training and certification for multiple protocols, some of which may occur simultaneously; managing labeling and handling of serum and tissue samples (see below); and plans for statistical analysis. The DCC proposal must also describe their familiarity with development of data safety and monitoring plan and administrative support of a Data and Safety Monitoring Board. o The applicant for the DCC must delineate how laboratory specimens will be handled. NIDDK anticipates that some clinical outcome measures may be centrally assessed. Laboratories responsible to the DCC will manage specimens and laboratory studies as required by the Steering Committee. o DCC applicants will not include a DSMP within this application. The Data and Safety Monitoring Plan will be developed by the DCC, and approved by the Steering Committee and DSMB prior to the implementation of any clinical protocols. The DCC must state their willingness to develop the Data and Safety Monitoring Plan once clinical protocols are developed. C. Budget and Related Issues Applicants must complete the budget information as directed in the PHS 398 5/01 rev) application form. The applicants shall not submit budget information in modular format and cost projections must adequately correspond to the scope of research proposed. Applications for CCs: For each year, each CC must include the core budget costs (not to exceed $200,000 total costs) and patient care costs (not to exceed $100,000 total Core Budget The underlying concept of the BSCRC is that a core effort is essential to maintain the infrastructure required to perform multiple clinical trials or clinical studies. Based on this approach, it is estimated that the individual CCs will require a minimum level of effort to sustain the organizational aspects of the Clinical Research Consortium. Therefore, individual CCs must submit requests for a CORE BUDGET not to exceed $200,000 total costs per year. Escalation of costs is allowed at 3%/year in future years, but must not exceed $200,000 in any year. It is anticipated that this core budget will cover a maximum of 30% effort for the combined leadership (Principal Investigator and any Co-Investigators). It should also include a Clinical Coordinator at 50% effort, Secretarial/Data Entry Support at 30% effort, and other necessary supplies and equipment. During the first year, the core budget should also include travel costs for two people to attend six BSCRC meetings in Bethesda, MD ($1500/person/meeting or $9000 per person, $18,000 total). In subsequent years, budget sufficient travel funds for two people to attend three BSCRC meetings in Bethesda, MD ($1500/person/meeting or $4500 per person, $9000 total. Patient Care Budget In addition to the core budget, each CC will be provided funds for implementation of protocols. The precise number of protocols conducted will be determined by the BSCRC Steering Committee and will depend on availability of funds. It is anticipated that after the first year, one or more protocols will be active each year. CCs may request PATIENT CARE costs to be used on a per patient basis (capitation). This amount must be placed in the patient care category. Escalation is allowed at 3%/year in future years, but must not exceed $100,000 total costs in any year. Therefore, the maximum total costs for each CC to implement the protocols are $100,000 per year. Routine (non- research related) patient care costs, such as routine laboratory and imaging evaluations, may not be included in the budget; nor may the costs related to the surgical procedure itself (including preoperative, postoperative, and follow-up care be included. Because actual patient care costs related to protocols will vary with the protocols developed by the Steering Committee, APPLICANTS SHOULD LIST $100,000 TOTAL COSTS/YEAR IN THE BUDGET SECTION UNDER "PATIENT CARE COSTS" AND SHOULD NOT PROVIDE BUDGET DETAILS. However, a proposed "sample budget" for patient care costs during the first year in which a protocol would be implemented should be included in the body of the application along with the protocol description (see Research Scope). o Note that ongoing annual budgets for protocols will be based on the protocols approved by the BSCRC Steering Committee and will be funded through a per patient basis (capitation) funding mechanism. The individual CCs will be expected to project patient enrollment for a specific protocol during a specified time frame; continuation and level of funding for each CC will be based on actual recruitment and overall performance. Patient care costs will be adjusted on a yearly basis based on the protocols developed and the number of patients entered by each center. The BSCRC awards will be subject to administrative review annually. DCC Budget: Applicants for the DCC must prepare budgets for five 12-month periods (not to exceed $1.2 million total cost per year) that roughly correspond with the standard coordinating center responsibilities outlined in other sections of this RFA. In the first year, DCC applicants must include all costs associated with the organization of all administrative aspects of the BSCRC to be developed and with the initiation of one protocol to be developed and started. For subsequent years, applicants may assume that one or more protocols a year will be active, i.e. either in the protocol development, implementation, or analysis and writing phase. The DCC budget must include costs for administrative support of the Data and Safety Monitoring Board (including yearly face-to-face meetings and semi-annual telephone calls) and the cost of face-to-face steering committee meetings up to six times during the first year and three times/year in subsequent years in Bethesda, MD, exclusive of travel and per diem for CC investigators, as well as telephone conference calls of the executive committee and subcommittees. It should also include the costs of developing and maintaining, the bariatric surgery database. The DCC budget must also include the cost of shipping and analysis of serum and tissue specimens that are to be assessed by the Central Laboratory, as well as shipment and storage of serum, tissues, and other samples in a repository, which may be administered through a subcontract from the DCC or through the NIDDK Biosample Repository. The DCC should include in their budget, as examples, the costs involved in central analysis of a lipid profile (Total Cholesterol, HDL Cholesterol, and Triglycerides) as well as serum insulin and glycosylated hemoglobin. While the actual award may vary, the DCC may estimate $300,000 total costs/year for consortium/contractual agreements with a central laboratory and/or sample and data repositories, including costs of shipping. The DCC will be subject to administrative review annually. All protocols must be performed in a manner consistent with United States Food and Drug Administration guidelines. APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the (IC). Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the (IC) 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, generally the top half of the applications under review, 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 the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The criteria of Significance, Approach, and Innovation will relate primarily to the two protocols submitted as a part of this application, as well as to the recommendations for information to be acquired in the database. The protocol and database descriptions are being requested in order to allow reviewers to evaluate the scientific thinking of the investigators, and their likely ability to contribute to protocol and database development. The actual protocols and database will be developed by the Steering Committee, after study funding. The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your 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, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? Since the final study design(s) will be developed collaboratively by the Steering Committee for the protocols, the peer review group will focus on evidence that the applicant has carefully thought about the issues involved and possesses the knowledge necessary to contribute meaningfully to the final design, including understanding of the scientific, ethical, and practical issues underlying the proposed study. (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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, CC and DCC applications will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. CC and DCC applicants will not include a DSMP, for these protocols within this application. The Data and Safety Monitoring Plan will be developed by the DCC, and approved by the Steering Committee and DSMB prior to the implementation of any clinical protocols. The CCs must state a willingness to follow the Data and Safety Monitoring Plan that is developed and approved. The DCC must state their willingness to develop the Data and Safety Monitoring Plan once clinical protocols are developed. 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) o DATA SHARING: The adequacy of the proposed plan to share data. A data sharing plan will be developed by the DCC, but all applicants (CC and DCC) must acknowledge in a "Sharing Plan" in the proposal that they will share the specimens and data collected with the wider scientific community through eventual transfer of these materials to the NIDDK Central Biosample and Data Repositories or through another mechanism determined by NIDDK. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. Note that the actual budget for each CC and the DCC will be determined when the protocols are developed after funding. The Sample Patient Care Budget proposed in the protocols is an example only. o OTHER REVIEW CRITERIA: Review of CC applicants also will be based on the following specific criteria: o Scientific and technical merit of the proposed approach to managing the requirements of the study as outlined in the RFA. o Staff Qualifications: Specific competence and previous experience of professional, technical, and administrative staff relevant to the operation of a CC in the proposed study. o Recruitment Capability: Evidence of successful experience in recruitment and retention of research subjects in multicenter clinical trials. Evidence of ability to recruit, enroll, and maintain minority subjects in a randomized trial or other clinical studies at the proposed center. This includes documentation of access to an adequate patient population for the proposed protocols. o Resources: Documented adequacy of the proposed facility, space, and resources for the work proposed. This includes evidence of an appropriate organizational structure and institutional support. o Data and Sample Management: Adequacy of plans to ensure accurate collection and timely transmission of study data to the DCC and patient samples to the Specimen Core. Documented experience in meticulous and expeditious handling of laboratory specimens and study data. o Knowledge of Problems: Demonstrable knowledge of the potential problems associated with the conduct of this study and possible solutions. o Cooperative Experience: Evidence of prior experience in working collaboratively in carrying out a developed study protocol. Evidence of willingness to work cooperatively in this study. o Collaborations between CCs within the BSCRC: For those applicants that propose collaborative efforts between two groups to form a single CC, additional factors to be considered would include the advantages of the collaboration in terms of cost, recruitment, or facilities; the commitment of the participants to the collaboration; and the adequacy of plans to coordinate efforts. DCC: Considerations for the review of applications for the DCC for the BSCRC include the following issues: o Understanding of the scientific, statistical, logistical, and technical issues underlying multi-center studies, including conduct of clinical studies in surgical patients, and knowledge necessary to assume to lead in the area of study design, statistics, logistics, data acquisition and management, identification of and coordination with central laboratories and serum/tissue/data repositories, handling of laboratory specimens, quality control, data analysis, and Consortium coordination. o Adequacy of the proposed plans for acquisition, transfer, management, and analysis of data, quality control of data collection and monitoring, and overall coordination of the BSCRC activities. o Plans for data sharing and access through coordination with NIDDK Biosample and Data Repository or another mechanism determined by NIDDK. o The expertise, training, and experience of the investigators and staff, including the administrative abilities of the Principal Investigator and co- investigators, and the time they plan to devote to the effective coordination of the BSCRC. o The administrative, supervisory, and collaborative arrangements for achieving the goals of the program, including willingness to cooperate with the principal investigators of the CCs and the NIDDK. o Facilities, equipment, and organizational structure to effectively coordinate the BSCRC activities in implementing the protocols, providing for specialized laboratory testing, and data collection. o Experience in developing a Data Safety and Monitoring Plan for multisite clinical trials. o Expertise in setting up and managing databases RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: February 18, 2003 Application Receipt Date: March 18, 2003 Peer Review Date: June/July 2003 Council Review: September, 2003 Earliest Anticipated Start Date: September 30, 2003 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. REFERENCE LIST Gastrointestinal surgery for severe obesity: National Institutes of Health Consensus Development Conference Statement (1992). Am J Clin Nutr 55:615S- 619S. NIDDK Working group on bariatric surgery: Executive Summary (2002). American Society for Bariatric Surgery (2001). Rationale for the surgical treatment of morbid obesity. http://www.asbs.org/html/rationale/rationale.html [On-line]. Brolin, R. E. (2001). Gastric bypass. Surg Clin North Am 81:1077-1095. Flegal, K. M., Carroll, M. D., Kuczmarski, R. J., & Johnson, C. L. (1998). Overweight and obesity in the United States: prevalence and trends, 1960- 1994. Int J Obes Relat Metab Disord 22:39-47. Harris, M. I., Flegal, K. M., Cowie, C. C., Eberhardt, M. S., Goldstein, D. E., Little, R. R., Wiedmeyer, H. M., & Byrd-Holt, D. D. (1998). Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, 1988-1994 [see comments]. Diabetes Care 21:518-524. Knowler, W. C., Barrett-Connor, E., Fowler, S. E., Hamman, R. F., Lachin, J. M., Walker, E. A., & Nathan, D. M. (2002). Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. NEJM 346:393-403. Kral, J. G., Brolin, R. E., Buchwald, H., Pories, W. J., Sarr, M. G., Sugerman, H. J., & Wolfe, B. M. (2002). Research considerations in obesity surgery. Obes Res 10:63-64. Pories, W. J., Swanson, M. S., MacDonald, K. G., Long, S. B., Morris, P. G., Brown, B. M., Barakat, H. A., deRamon, R. A., Israel, G., & Dolezal, J. M. (1995). Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg 222:339-350. Sjostrom, C. D., Peltonen, M., Wedel, H., & Sjostrom, L. (2000). Differentiated long-term effects of intentional weight loss on diabetes and hypertension. Hypertension 36:20-25. U.S. Department of Health and Human Services. The Surgeon General's call to action to prevent and decrease overweight and obesity. 2001. Rockville, MD, U.S. GPO, Washington, DC. Ref Type: Pamphlet Wadden, T. A. & Foster, G. D. (2000). Behavioral treatment of obesity. Med Clin North Am 84(vii):441-61. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). 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. Because of the lack of data on the safety of bariatric surgical procedures in pediatric populations, children and adolescents under age 18 will not be included in studies carried out by the BSCRC; however, it is expected that patients between the ages of 18 and 21 would be studied, if they are appropriate surgical candidates. 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 must 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. 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 No. 93.848,and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284)and administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92 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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