CLINICAL RESEARCH NETWORK IN NON-ALCOHOLIC STEATOHEPATITIS (NASH) Release Date: February 12, 2001 RFA: RFA-DK-01-025 - (Reissued as RFA-DK-08-505) National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: June 15, 2001 Application Receipt Date: July 20, 2001 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites applications for establishment of a Clinical Research Network that focuses upon the etiology, contributing factors, natural history, complications, and therapy of non-alcoholic steatohepatitis (NASH). NASH is a common but poorly understood liver disease that is characterized by accumulation of fat in the liver (steatosis), accompanied by inflammation, cell injury and fibrosis (hepatitis) that closely resembles alcoholic liver disease but occurs in patients who drink little or no alcohol. NASH is most common in adults above the age of 40 who are overweight or have diabetes, insulin resistance or hyperlipidemia. However, the disease also occurs in children and in persons who are not obese or diabetic. Currently, there are no effective therapies for NASH and its natural history and prognosis are not well understood. The objective of this Request for Applications (RFA) is to establish and maintain the infrastructure required for a NASH Clinical Research Network consisting of a group of interactive Clinical Centers CCs) and a Data Coordinating Center (DCC). The goal of this NASH Clinical Research Network is to facilitate and perform clinical, epidemiological and therapeutic research in NASH. This is a one-time solicitation to support a Clinical Research Network for five years. 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, Clinical Research Network in Non-Alcoholic Steatohepatitis (NASH), is related to the priority areas of chronic disabling conditions and diabetes. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted only from domestic institutions. 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. For- profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the federal government may apply. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. 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 hepatology, pediatrics, internal medicine, epidemiology, physiology, pharmacology, therapeutic development, and clinical trials management. A DCC will be a part of this NASH Clinical Research Network. 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 Network 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. MECHANISM OF SUPPORT This RFA will use the cooperative agreement (U01) administrative and funding mechanism of support. Under the cooperative agreement, the NIH assists, supports, and/or stimulates, and is substantially involved with recipients in conducting a study by facilitating performance of the effort in a "partner" role. Details of the responsibilities, relationships, and governance of a study funded under a cooperative agreement are discussed later in this document under the section entitled Organization of NASH Clinical Research Network. The total project period for applications submitted in response to this RFA will be five years. This RFA is a one-time solicitation. Although not co- sponsoring this RFA, other Institutes have interest in the research area discussed in this RFA. The anticipated award date is April 1, 2002. FUNDS AVAILABLE A maximum of six awards for CCs and one award for a DCC will be made under this RFA. It is anticipated that the award for the DCC will be approximately $600,000 direct costs (no more than $900,000 total costs) per year. The amount awarded to each CC per year will vary between $150,000 to $250,000 direct costs (no more than $350,000 total costs) per year. The total costs for the Network will be limited to $3 million total costs per 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. 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. RESEARCH OBJECTIVES Background Non-alcoholic steatohepatitis (NASH), also known as fatty liver hepatitis, is a clinical-pathological condition that only recently has been recognized to be a common and potentially severe form of liver disease. NASH is usually defined on the basis of liver biopsy histology, characterized by accumulation of fat in hepatocytes, spotty necrosis, inflammation, Mallory bodies and fibrosis. These features resemble alcoholic liver disease, but this condition occurs in persons who drink little alcohol or none at all. NASH appears to be common, although its prevalence in the population is not well defined. Selected autopsy series have found fatty hepatitis in 3 percent of lean and up to 19 percent of obese subjects. NASH is most common in middle- aged persons but is found in all age groups including children. NASH typically occurs in persons who are overweight or diabetic, but it has recently been shown to occur in subjects with normal body weight and normal glucose tolerance. In some series, NASH has been found to be the single most common cause of serum aminotransferase abnormalities identified during routine blood testing. The prognosis and natural history of NASH have not been well defined. In many patients, fatty liver is a benign condition and does not result in permanent injury or structural abnormalities in the liver. In other patients, however, progressive fibrosis occurs that leads to cirrhosis and end-stage liver disease. In the advanced stages of disease, the classical histological findings of NASH (marked fatty change and Mallory bodies) may no longer be present and the cause of the liver disease considered to be cryptogenic. The cause of NASH is not yet defined. The association of NASH with obesity and diabetes suggests that there is an underlying metabolic dysfunction, perhaps insulin resistance or inability to metabolize excess free fatty acids. However, accumulating evidence indicates that there is a second factor that ultimately leads to cell injury and inflammation in fatty liver. The suspected second hit may be intracellular oxidative stress that can be induced by multiple mechanisms, such as excess iron accumulation, endotoxin exposure, pro-inflammatory cytokines or other unknown factors. Understanding the pathogenesis of NASH is of great importance in ultimately finding a treatment, cure or means of prevention of this disease. At present there is no clear means of treatment or prevention of NASH. Weight loss is usually recommended, but rarely achieved, and its ultimate effect on the course of this disease has not been shown. Several approaches to therapy have been evaluated in small clinical trials, including vitamin E, ursodiol, metformin and the thiazolidinediones. These studies have been promising but ultimately inconclusive, because of small sample size, lack of adequate follow up and lack of use of liver histology (as opposed to serum aminotransferase levels) as an endpoint for evaluating the benefit of therapy. A NASH Clinical Research Network will accelerate clinical research and progress in understanding the pathogenesis of NASH defining its natural history, and developing safe and effective means of treatment. The variable manifestations of NASH and its insidious and slowly progressive natural history makes it difficult to accumulate an adequate number of patients followed for an adequate period of time in one center. Furthermore, a common and coordinated approach to evaluation and therapy will reduce the number of patients needed at each CC. Also, the NASH Clinical Research Network mechanism will help pool the necessary clinical expertise and administrative resources to facilitate the conduct of multiple and novel therapeutic trials in a timely, efficient manner. This, in turn, will promote rapid dissemination of research findings to health care professionals. Organization of the NASH Clinical Research Network The NASH Clinical Research Network will be a cooperative network of four to six CCs and one DCC. CCs will be responsible for proposing protocols, participating in their overall development, conducting the research, and disseminating research findings. 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 NASH Clinical Research Network. The DCC will support protocol development, provide sample size calculations, statistical advice, questionnaires, and data analysis, support manuscript preparation, and provide overall study coordination and quality assurance, including coordination of the activities of the Data and Safety Monitoring Board, the Steering Committee and other standing committees. Applicants for the DCC should also propose a Specimen Core (serum and tissue) facility for central storage of specimens. This specimen core will not be awarded until the Steering Committee has met and approved its structure and duties. Governance A Steering Committee will be the main governing body of the NASH Clinical Research Network. At a minimum, the Steering Committee will be composed of the principal investigators of each CC in the Network, the principal investigator of the DCC and the NIDDK Project Scientist. The first meeting of the Steering Committee will be convened by the NIDDK Project Scientist. By the end of the second meeting of the Committee, the NIDDK will name a study Chairperson from one of the CC to oversee and guide Steering Committee activities. The Steering Committee will meet as often as three to six times during the first 12 months of the study, and two to four times thereafter. All major scientific decisions will be determined by a majority vote of the Steering Committee. Each CC, the DCC, and the NIDDK Project Scientist will have one vote. The Steering Committee will have primary responsibility for the general organization of the NASH Clinical Research Network, finalizing common clinical protocols, facilitating the development of a standardized nomenclature, diagnostic criteria, histological definitions, and necessary components to the common database on patients. The Steering Committee will be responsible for the conduct and monitoring of studies and reporting study results. Topics for investigational and treatment protocols will be proposed and prioritized by the Steering Committee. For each investigational or therapeutic protocol, one CC will take the lead responsibility for drafting the protocol, although the Steering Committee will provide input and will be responsible for assuring development of a common protocol to be implemented by the CCs. A Pathology Committee will supplement the activities of the Steering Committee and will ensure a consistency of processing and interpretation of liver biopsies. This committee will be composed of the hepatic pathologist from each CC as well as a lead hepatic pathologist who will be appointed by the NIDDK. The lead hepatic pathologist will be either one of the hepatic pathologists from the CCs or the DCC, or an outside pathologist chosen specifically for this task. 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. An independent Data and Safety Monitoring Board 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 Data and Safety Monitoring Board will submit recommendations to the NIDDK regarding the continuation of each study. Each investigational or therapeutic 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 the CCs must be willing to pursue this funding arrangement for each new protocol conducted. Clinical protocols must be approved by local institutional review boards and the NASH Clinical Network Data and Safety Monitoring Board 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. Databases may 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 NASH Clinical Research Network 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 NASH Clinical Research Network Database. Any specific collaboration involving the resources of the NASH Clinical Research Network will require approval by the Steering Committee. Research Scope The objective of this RFA is to establish a NASH Clinical Research Network that will accelerate advances in the understanding and clinical management of this common liver disease. The Network should initially focus upon development of a clinical database of patients with NASH. An essential first step will be to develop common definitions, nomenclature and terms for the clinical diagnosis and staging of NASH. In particular, histological criteria for the diagnosis as well as an accepted method of staging and grading the disease is needed. Also important are clinical definitions, means of assessing symptoms and quality of life, standardized forms and questionnaires, and agreed upon essential information for the diagnosis and characterization of a patient cohort. The database can also include control subjects and family members for genetic studies. The database should be designed to address specific questions and to provide appropriate reagents or patient populations for clinical or laboratory investigation. The NASH Clinical Network should also provide the preliminary data and background for further investigator-initiated research. For instance, the Network might generate a pilot study of therapy and clinical information to allow the investigators to submit a separate application for a full-scale clinical trial (R01). The Network also is expected to interact with basic and laboratory research investigators with interest in these diseases by providing reagents, specimens or opportunities to assess hypotheses on the pathogenesis, prevention or treatment of the disease. The Network can also provide a focus for training in clinical investigation. All projects must be completed within the five-year duration of this research program. THESE ARE EXAMPLES ONLY. APPLICANTS SHOULD NOT FEEL LIMITED TO THE SUBJECTS MENTIONED ABOVE AND ARE ENCOURAGED TO SUBMIT OTHER TOPICS PERTINENT TO THE OBJECTIVES OF THE RFA. It is not the intent of the Network to provide support for only one or two protocols that run for the entire seven years. Multiple trials or clinical and epidemiological investigations will be conducted, possibly two to four a year, some large and some small. It is anticipated that in the initial one or two years, trials and investigations will be selected from the studies proposed by the successful CCs in their applications. Each CC within the Network should propose a research plan that includes the structure of a large database as well as two clinical research protocols as models that could be used in the Network environment. The protocols should demonstrate knowledge of the disease and its pathogenesis. Each protocol should require sufficient subjects to necessitate the use of a Network with multicenter participation. Applicants should indicate knowledge of 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) and one a long- term study (one to three years). The research plan should follow the instructions in the PHS 398 application form (revised 4/98, http://grants.nih.gov/grants/funding/phs398/phs398.html). For the overall structure and factors that are included in the common database of patients include a justification for necessary information on patients to be included. For each of the two protocols include a description in approximately two pages of the rationale, research aims, outcome measures, and study design. In addition, provide a description of the proposed patient populations with an estimate of the expected distribution of male and female patients, ages, and assurances of the applicant"s access to the patient populations. The CC principal investigator should 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 Network (all of the CCs). In the discussion of outcome measures, it will be important to indicate appropriate objective measures of primary and secondary outcome. The CC principal investigators are encouraged to explore, within the context of their proposed protocols, new technologies to monitor disease progression and response to therapy. Funding for the relevant technology should be presently available for each protocol proposed. It will also be important to include strategies to assure adherence to therapy as part of the protocol. SPECIAL REQUIREMENTS 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, unless otherwise provided for in these terms or by action of the Steering Committee. Modifications and ancillary protocols 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 the Specimen Core facility. Thus, the awardee is expected to work cooperatively with Clinical Centers and sponsoring organizations in a multicenter trial 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, the Data Coordinating Center will be expected to maintain close communications with the NIDDK Project Scientist 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 Network -- 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. 2) NIDDK Staff Responsibilities The NIDDK will name a Project Scientist from within the Division of Digestive Diseases and Nutrition whose function will be to assist the Steering Committee in carrying out the study. The Project Scientist will have one vote for all key study group subcommittees. 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. The NIDDK reserves the right to terminate or curtail the study (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 a) The Steering Committee, composed of each of the Principal Investigators of the DCC and the CCs, the NIDDK Project Scientist, and the Chairman of the Steering Committee, will be the main governing board of the studies. 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 the study results. It will also be responsible for establishing study policies in such areas as access to patient data, ancillary studies, 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 the field of liver diseases who are not participating directly in the study. Subcommittees will be established on topics such as ancillary studies, publications and presentations, quality control, recruitment, protocol adherence, among others. Each Network 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 Washington DC Metropolitan Area. The NIDDK Project Scientist (and the other cited NIDDK 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. 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. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are 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 research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. Under the statute, when an NIH defined Phase III clinical trial is proposed, evidence must be reviewed to show whether or not clinically important sex/gender and/or race/ethnicity differences in the intervention effect are to be expected. This evidence may include, but is not limited to, data derived from prior animal studies, clinical observations, metabolic studies, genetic studies, pharmacology studies, and observational, natural history, epidemiology and other relevant studies. Cost is not an acceptable reason for exclusion of women and minorities from clinical trials. When planning, conducting, and reporting an NIH defined Phase III clinical trial, it must be considered whether, based on prior studies, one of the following three situations apply: that prior studies support the existence of significant differences, that prior studies support no significant differences, and that prior studies neither support nor negate significant differences. The NIDDK believes that prior studies neither strongly support nor negate significant differences in expected intervention effects by sex/gender and/or race/ethnicity. In this case, the NIH Phase III clinical trial will be required to include sufficient and appropriate entry of sex/gender and/or racial/ethnic subgroups, so that valid analysis of the intervention effect in subgroups can be performed. However, the trial will not be required to provide high statistical power for each subgroup. The Research Plan in the application or proposal must include a description of plans to conduct the valid analyses of the intervention effect in subgroups. The final protocol(s) approved by the IRB(s) must include these plans for analysis. The award will require that the results of subset analyses must be reported to NIH in Progress Reports, Competitive Renewal Applications, and in the required Final Progress Report. Inclusion of the results of subset analyses is strongly encouraged in all publication submissions. If the analysis reveals no subset differences, a brief statement to that effect, indicating the subsets analyzed, will suffice. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit, by June 15, 2001, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, whether the application is for a CC or the DCC, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIDDK staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to: Francisco Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Blvd. Room 655, MSC 5452 Bethesda, MD 20892-5452 Telephone: (301) 594-8897 FAX: (301) 480-3505 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov. The PHS 398 application kit is also available on the Internet at http://grants.nih.gov/grants/forms.htm The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. 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 sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Special Instructions for Use in Preparing an Application Applicants must describe plans to accommodate the stated program requirements, criteria, and staff involvement. Applicants must address points discussed in the SPECIAL REQUIREMENTS section of this RFA. Applications for CCs: Each CC within the Network should propose a research plan that includes the structure of a large database as well as two clinical research protocols as models that could be used in the Network environment. The protocols should demonstrate knowledge of the disease and its pathogenesis. Each protocol should require sufficient subjects to necessitate the use of a Network with multicenter participation. Applicants should indicate knowledge of 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) and one a long- term study (one to three years). The research plan should follow the instructions in the PHS 398 application form (revised 4/98, http://grants.nih.gov/grants/forms.htm. For the overall structure and factors that are included in the common database of patients include a justification for necessary information on patients to be included. For each of the two protocols include a description in approximately two pages of the rationale, research aims, outcome measures, and study design. In addition, provide a description of the proposed patient populations with an estimate of the expected distribution of male and female patients, ages, and assurances of the applicant"s access to the patient populations. The CC principal investigator should 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 Network (all of the CCs). In the discussion of outcome measures, it will be important to indicate appropriate objective measures of primary and secondary outcome. The CC principal investigators are encouraged to explore, within the context of their proposed protocols, new technologies to monitor disease progression and response to therapy. Funding for the relevant technology should be presently available for each protocol proposed. It will also be important to include strategies to assure adherence to therapy as part of the protocol. To promote development of a collaborative program, the issues discussed below need to be addressed in each application for a CC within the NASH Clinical Research Network. 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 NASH. This must include documentation of experience in the diagnosis and management of patients with NASH. Of particular importance, is the availability of an expert hepatic pathologist as a collaborator in the CC application. o Study population. CCs must discuss the number of patients with NASH seen and followed at the center who might be eligible to enroll in protocols. Approximately half of the patients enrolled in the NASH Clinical Research Network should be females. Furthermore, inclusion of children is required, although not all Centers can be expected to include a pediatric cohort of patients. The applicant for a CC in the Network must include a description of the pool of potential study participants by sex, age categories, and ethnic/racial distribution, as well as recruitment source. Patient access may be developed by establishing links with other groups outside the CC"s institution. If outside links are proposed, there must be a well described plan to link the individual CCs with community health care providers such as HMOs, clinics, or private practice physicians to ensure adequate numbers patients for clinical studies of therapeutic agents and management strategies. 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 should be included with the application. o Willingness to participate in a NASH Clinical Research Network. The principal investigator should state his/her general support of collaborative research and interaction with the NIDDK, the other CCs, and the DCC through the Network concept. Applicants should discuss their willingness, and that of the institutions involved, to pursue 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 should discuss their capability to participate in a distributed data entry system. o Institutional resources for patient care and follow-up including personnel, space, and special laboratory facilities should be described. 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 liver disease is not required, but the applicant may wish to include a hepatologist or hepatic pathologist in the application as a key collaborator and advisor. o Study design and management. DCC proposals should 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 should also describe their familiarity with model plans for managing the Data and Safety Monitoring Board. Approximately $20,000 for the whole 5 years should be budgeted for managing the Data and Safety Monitoring Board. o The applicant for the DCC should 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. The costs of performing specific laboratory tests will be budgeted as a part of the per patient costs of each CC. The costs of specimen shipment as well as laboratory data acquisition and management will be a part of the budget of the DCC. The DCC does not need to prepare two protocols. Estimated shipping and handling costs of $25,000 for specimens should be included in the budget of DCC. BUDGET AND RELATED ISSUES Applicants should complete the budget information as directed in the PHS 398 application form. Applications for CCs: CCs should consider the following additional issues regarding budgets. The underlying concept of the NASH Clinical Research Network 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 Network. Therefore, individual CCs should submit requests for a CORE BUDGET not to exceed $150,000 total costs per year. It is anticipated that this core budget will cover a minimum ten percent effort for the principal investigator, and a small percent effort for other key personnel (nurse, technician, clinic coordinator, secretary), and travel costs for two people to attend three NASH Clinical Research Network meetings a year in Bethesda, MD. These costs should be justified appropriately in budgets and may be distributed into subcontracts. Escalation is allowed at three percent for future years. 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 NASH Clinical Research Network Steering Committee and will depend on availability of funds. It is anticipated that after the first year, two to four protocols may be active each year. CCs may request PATIENT CARE costs. This amount should be placed in the patient care category. Patient care costs may be escalated at three percent for future years. Allowable total costs for each CC (core costs, costs per patient to conduct the protocols, and indirect costs) will vary. However, the maximum total costs for each Network to implement the protocols (including CCs and DCC and Specimen Core) are $200,000 per year. The CCs are requested to present the following information: o For each year, each CC should include the core budget costs (not to exceed $150,000 total costs) and patient care costs. Estimated protocol implementation costs for Year 1 should be based on the two proposals presented in the applicants research plan. A table should be included showing estimated costs per patient for conducting each protocol. Total cost for implementation of both protocols should not exceed $200,000. The budget for each clinical protocol should be developed on a cost per patient basis and include all direct and any applicable facilities and administrative costs. Costs of drugs or laboratory tests should be part of the per patient cost of conducting a protocol. The clinical protocol should identify the potential source(s) for any drugs or substances that are being considered for clinical protocols that are currently unavailable commercially. Investigators should only prepare budgets for their own CC to conduct the proposed study or trial, and not for the entire NASH Clinical Research Network. The CC should state the total number of patients required by the entire Network to complete each proposed study or trial. The yearly budget for each CC should 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 should be included for each protocol. Note that ongoing annual budgets for protocols will be based on the protocols approved by the NASH Clinical Research Network 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. The NASH Clinical Research Network awards will be subject to administrative review annually. DCC Budget: Applicants for the DCC should prepare budgets for five 12-month periods (not to exceed $900,000 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 should include all costs associated with the organization of all administrative aspects of the NASH Clinical Research Network to be developed and with the initiation of one protocol to be developed and started. For subsequent years, applicants may assume that two to four protocols a year will be active, i.e. either in the protocol development, implementation, or analysis and writing phase. DCC should include costs for managing the Data and Safety Monitoring Board including the cost of meeting three times/year in Bethesda. The DCC will be subject to administrative review annually. It is expected that all protocols will 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. 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 time of submission, two additional copies of the application must be sent to: Francisco Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Blvd. Room 655, MSC 5452 Bethesda, MD 20892-5452 Telephone: (301) 594-8897 FAX: (301) 480-3505 Applications must be received by July 20, 2001. 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 previously reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIDDK in accordance with the review criteria stated below. As part of the initial merit review, a process will be used by the initial review group in which applications receive a written critique and 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, assigned a priority score, and receive a second level review by the National Diabetes and Digestive and Kidney Diseases Advisory Council. REVIEW CRITERIA In the written comments reviewers will be asked to evaluate the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. o Significance: Does this study address an important problem? Is there a need for research in this area? If the aims of the applications are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? o Approach: Are the conceptual framework, design, and methods adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 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. o 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? o 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)? o Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Is there evidence of institutional support and commitment for the proposed program? 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 NASH Clinical Research Network: 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 NASH Clinical Research Network include the following issues: o Understanding of the scientific, statistical, logistical, and technical issues underlying multi-center studies, including issues relating to treatment and management of liver disease, and knowledge necessary to resume a leadership role in the area of study design, statistics, logistics, data acquisition and management, handling of laboratory specimens, quality control, data analysis, and network 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 NASH Clinical Research Network activities. 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 NASH Clinical Research Network. o The administrative, supervisory, and collaborative arrangements for achieving the goals of the program, including willingness to cooperate with the principal investigator of the Administrative Core, the principal investigators of the CCs and the NIDDK. o Facilities, equipment, and organizational structure to effectively coordinate the NASH Clinical Research Network activities in implementing the protocols, providing for specialized laboratory testing, and collecting data. o Appropriateness of the budget for the work proposed. In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o The adequacy of the proposed protection for humans or the environment, to the extent they may be adversely affected by the project proposed in the application. The initial review group will also examine the safety of the research environment. In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. Applicants are encouraged to submit and describe their own ideas on how best to meet the goals of the NASH Clinical Research Network, but they are expected to address issues identified under APPLICATION PROCEDURES of the RFA. Applications will be judged primarily on the scientific quality of the application, however, the scientific merit of the proposed research plan will not be the sole criterion for selection of a CC. Further considerations for the review include: access to patients including children and minority individuals, multi disciplinary nature of the proposed studies, the discussion of considerations relevant to this RFA, and a demonstrated willingness on the part of the investigators to work as part of the NASH Clinical Research Network and with the NIDDK Project Scientist. Schedule Letter of Intent Receipt Date: June 15, 2001 Application Receipt Date: July 20, 2001 Peer Review Date: November 2001 Council Review: February 2002 Earliest Anticipated Start Date: April 2002 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific and technical merit of the application for a Clinical Center or a Data Coordinating Center. o The multi-disciplinary nature of the proposed studies (CC). o Demonstration of expertise to manage, design and coordinate multicenter clinical trials that include handling and storage of laboratory specimens (DCC). o The multi-disciplinary nature of the proposed studies. o The quality of response to the special requirements stated in this RFA. o Relevance to the overall programmatic balance and priorities of the NIDDK and sufficient compatibility of features proposed in the research plan and qualifications of the investigators to make a collaborative program within the NASH Clinical Research Network a reasonable likelihood. o Availability of funds INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Patricia Robuck, Ph.D., M.P.H. Director, Clinical Trials Program Division of Digestive Diseases and Nutrition, NIDDK 6707 Democracy Blvd. Room 675, MSC 5450 Bethesda, MD 20892-5450 Telephone: (301) 594-8879 FAX: (301) 480-8300 Email: robuckp@extra.niddk.nih.gov Direct inquiries regarding review matters to: Francisco Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Blvd. Room 655, MSC 5452 Bethesda, MD 20892-5452 Telephone: (301) 594-8897 FAX: (301) 480-3505 Email: calvof@extra.niddk.nih.gov Direct inquiries regarding fiscal matters to: Ms. Sharon Bourque Grants Management Specialist Division of Extramural Affairs, NIDDK 6707 Democracy Blvd. Room 612, MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-8846 FAX: (301) 480-3504 Email: bourques@extra.niddk.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.848. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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