HEPATOTOXICITY CLINICAL RESEARCH NETWORK RELEASE DATE: July 12, 2002 (see amendment NOT-DK-02-007) RFA: RFA-DK-02-033 National Institute of Diabetes and Digestive and Kidney Diseases, NIDDK (http://www.niddk.nih.gov/) LETTER OF INTENT RECEIPT DATE: October 11, 2002 APPLICATION RECEIPT DATE: November 13, 2002 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Organization of the Hepatotoxicity Clinical Research Network 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 Required Federal Citations PURPOSE OF THIS RFA The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites applications for the establishment of a Clinical Research Network that will focus upon the elucidation of the clinical features and pathogenesis of drug and toxin-induced liver injury, a common cause of acute liver disease, morbidity and mortality. Drug and toxin-induced liver injury can be mild and transient, resulting merely in a transient elevation in serum aminotransferase levels, but also can be severe, protracted and even life-threatening, resulting in acute liver failure. Most severe adverse hepatic toxic reactions are unpredictable, idiosyncratic and uncommon. In addition, attribution of the hepatic injury to the medication can be unclear and complicated by the presence other possible causes of liver disease. Liver injury from drugs is often not predicted by pre-clinical testing in laboratory animals and most medications that cause severe liver disease in humans cause little or no hepatic injury in animals. Furthermore, the increasing use of complementary and alternative medicines (CAM) has led to additional cases of toxin-induced liver disease that are often more challenging and confusing to evaluate. Complementary medications often consist of mixtures of herbs and other active compounds that may not be well characterized or studied. These features make diagnosis of drug and toxin-induced liver injury difficult and analysis of the causes of hepatotoxicity limited. Yet drug-induced liver disease is becoming an increasing important problem in medicine. With an increasing proportion of the U.S. population taking medications as well as CAM therapies, the clinical burden of hepatotoxicity is only going to worsen. Hepatotoxicity is the single, most common adverse drug reaction that leads to drug withdrawal and or refusal of approval by the Food and Drug Administration (FDA). Such withdrawals or refusals have enormous financial implications for the pharmaceutical industry and can result in the loss of availability of an effective therapy because of a rare occurrence of toxicity in a small proportion of patients who take the medication. The intent of this Request for Applications (RFA) is to establish and maintain the infrastructure required for a Hepatotoxicity Clinical Research Network consisting of a group of interactive Clinical Centers (CCs) and a Data Coordinating Center (DCC). The primary objective of the Hepatotoxicity Clinical Research Network is to develop standardized instruments to identify and fully characterize bona fide cases of drug, CAM and toxin- induced liver injury to allow for analysis of the epidemiology and clinical spectrum of hepatotoxicity and to obtain biological samples for study of the pathogenesis of hepatotoxicity using biochemical, serological and genetic techniques. The recent development of powerful methods of genetic analysis and pharmacogenomics promises to provide important insights into the mechanisms of drug actions and drug toxicities. These techniques requires the availability of carefully defined cases of liver injury to both create and test hypothesis on metabolic pathways that predispose to liver injury. This initiative will expand our understanding of the mechanisms of drug and toxin- induced liver injury and provide the basis for more effective and safe medical therapies. This is a one-time solicitation to support a feasibility phase of a Hepatotoxicity Clinical Research Network for 3 years. RESEARCH OBJECTIVES A. Background Adverse drug reactions (ADRs) are an increasingly important clinical problem in medicine. ADRs are estimated to cause more than 100,000 deaths per year in the United States and, therefore, rank among the ten most common causes of death.Up to 5% of all hospital admissions may be attributable to ADRs. Increased length of stay in hospital due to ADRs by two days can cost as much as $2500 per patient. Drug-induced liver injury has been the most common type of ADR that has lead to drug withdrawal or refusal of approval by the FDA. In surveys of acute liver failure in the United States, drug-induced hepatotoxicity is the single leading cause. The cause of acute liver injury due to medications, CAM therapies and toxins is often unknown, but in many situations genetic predisposition appears to play a leading role. The role of inheritable variations in predisposing to ADRs was shown by the correlation between drug responses and inherited deficiencies of metabolic enzymes such as pseudocholinesterase (butyrylcholinesterase) and glucose-6-phosphate dehydrogenase (G6PD).Genetic polymorphisms (variants alleles present at least in 1% of the normal population) are a source of genetic variation to drug responses. Although the study of drug-induced liver abnormalities has centered on the involvement of pharmacokinetic factors (absorption, distribution, metabolism and excretion) there is increasing evidence that genetic variation in drug targets (pharmacodynamic factors: receptors, channels, enzymes, immune factors) might also predispose to hepatotoxicity. In addition, environmental factors such as disease, alcohol, smoking and diet might also be significant sources of variability, interacting with genetic factors. Thus, predisposition to hepatotoxicity is likely to be multi-factorial, involving genes that interact with environmental factors. In a similar fashion to complex diseases, heterogeneity of gene variants may also interact to give rise to a similar pattern of injury. These factors of pathogenesis, coupled with the absence of predictable animal models, the lack of specific diagnostic tests, the inaccuracies of scoring scales for drug-induced liver toxicity and the unpredictable, idiosyncratic nature of most drug-induced liver toxicity, has hampered the systematic analysis and study of hepatotoxicity. To begin to analyze the pathogenesis and genetic basis of drug and toxin-induced liver disease, it is first important to have unambiguously characterized cases of hepatotoxicity (phenotype) and carefully selected control subjects. Collection of well defined cases of hepatotoxicity are needed to engage in genetic profiling to establish phenotype-genotype correlations which might predict drug and toxin-induced hepatic injury. To address these issues and to determine the feasibility of prospectively collecting cases of drug, CAM and toxin-induced liver toxicity, a Hepatotoxicity Clinical Research Network is proposed. The primary objective of the Network is to develop operational diagnostic criteria, causality assessment instruments and strategies to identify and collect well defined cases of toxin-induced liver injury in a prospective manner that will permit careful collection of clinical information as well as serum, DNA and tissue/samples for biochemical, pharmacological and genetic analyses. B. Research Scope The objective of this RFA is to establish a Hepatotoxicity Clinical Research Network that will accelerate advances in the understanding and prevention of drug, CAM and toxin-induced liver toxicities. This RFA will fund the development of a protocol and study design and a feasibility phase of the implementation of the study. The Network will have two phases. The first phase will be the development of working definitions for drug-induced liver toxicity, diagnostic algorithms, a causality assessment protocol or instrument, an overall study design to identify cases, a manual of operations for clinical data and specimen collection, and an adequate patient consent form. This phase will extend for up to 12 months from the award start date and will conclude when there is a full-scale study design, data collection forms, a manual of operations and patient consent forms that have been approved by local Institutional Review Boards. The second phase will start with the implementation of the operating procedures and enrollment of patients and control subjects and the capture of data and samples. This phase will last for 24 months. During this phase, patients will be identified and studied, data collected and serum, DNA and tissue specimens collected. During this phase the NIDDK will assess the progress of the primary objectives of the Network and if appropriate, a second RFA will be issued to continue the Hepatotoxicity Clinical Research Network in a fully operational form, with proposals to initiate the genetic profiling studies aimed to determine the role of genetic variability in drug, CAM and toxin- induced liver toxicity. As the Network accumulates clinical information it would provide the preliminary data and background for further investigator-initiated research in both clinical and laboratory areas of interest by providing reagents, specimens or opportunities to assess hypotheses on the pathogenesis, prevention or treatment of drug, CAM and toxin-induced hepatotoxicity. The Network can also provide a focus of learning in hepatotoxicity and serve as a regional and national clinical resource for advice on hepatotoxicity. ORGANIZATION OF THE HEPATOTOXICITY CLINICAL RESEARCH NETWORK The Network will consist of a data coordinating center (DCC) and as many as four to five clinical centers (CC) to collect cases of drug induced liver toxicities and appropriate controls in a standardized and prospective manner. The Hepatotoxicity Clinical Research Network will be a cooperative network of up to five CCs and one DCC. CCs will be responsible for proposing protocols for patient and control identification and accrual, definition of hepatotoxicity, causality assessment and 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 Hepatotoxicity 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 Steering Committee and other standing committees. It is anticipated that the NIDDK Biosample Repository (http://www.niddk.nih.gov/fund/repository/repository.htm) will be used as the specimen repository for the Network. This repository is not part of this RFA and will be funded independently. Study Governance A Steering Committee will be the main governing body of the Hepatotoxicity 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 with assistance from the DCC. The logistics and agenda of subsequent meetings will be determined by the Steering Committee and arranged by the DCC. By the end of the second meeting of the Committee, the NIDDK will name a study Chairperson from one of the CCs to oversee and guide Steering Committee activities. The Steering Committee will meet as often as three to four times during the first 12 months of the study, and two to three times yearly 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 Hepatotoxicity 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. Other subcommittees of the Steering Committee will be established as necessary. For example, a Genetic Profiling Committee with additional expert advice could be formed to assess the different genome screening strategies and proposed a method suitable for future implementation. A Publications Committee would be helpful to facilitate the process for authorship selection and to supervise preparation of manuscripts. Clinical protocols must be approved by local Institutional Review Boards and the Hepatotoxicity Clinical Research Network Steering Committee before initiation. The Hepatotoxicity Clinical Research Network investigators will be 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 Hepatotoxicity Clinical Research Network Database. Any specific collaboration involving the resources of the Hepatotoxicity Clinical Research Network will require approval by the Steering Committee. MECHANISM OF SUPPORT The NIH (U01)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" The total project period for applications submitted in response to this RFA will be three years. This RFA is a one-time solicitation. Although not co-sponsoring this RFA, other Institutes with interest in the research area discussed in this RFA are the National Institute of General Medical Sciences (NIGMS) and the National Institute of Environmental Health Sciences (NIEHS). The NIGMS Pharmacogenetics Research Network (PGRN) wants to interact cooperatively with this program, which complements the aims of the PGRN. NIGMS will encourage deposition of biological samples into an NIDDK Tissue Repository where this is feasible and matches the protocols developed here, for the study of mechanisms of hepatotoxicity. The institute invites those considering submissions to this RFA for the Hepatotoxicity Clinical Research Network to consider developing collaborative connections with the PGRN research sites listed at www.nigms.nih.gov/pharmacogenetics, where significant expertise and resources are devoted to research into drug biotransformation and the therapeutic actions of drugs, with a goal of uncovering clinically significant variation in those pathways. Applicants are encouraged to exchange information, definitions, and standards with the Pharmacogenetics and Pharmacogenomics Knowledge Base, PharmGKB, for the ultimate purpose of making robust correlations between genotypes and phenotypes. The anticipated award date is July 1, 2003. This RFA uses just-in-time concepts. FUNDS AVAILABLE A maximum of five 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 $400,000 direct costs (no more than $600,000 total costs) per year. The amount awarded to each CC per year will vary between $200,000 to $250,000 direct costs (no more than $350,000 total costs) per year. The total costs for the Network will be limited to $2.25 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. Funds to support a NIDDK Tissue/sample repository center will be provided independently of this RFA. 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 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. INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS 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 gastroenterology, hepatology, internal medicine, pediatrics, epidemiology, toxicology, clinical pharmacology, public health and clinical database management. A DCC will be a part of this Hepatotoxicity 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. SPECIAL REQUIREMENTS A. 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 those outlined in 45 CFR Parts 74 and 92, 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 study. Thus, the awardee is expected to work cooperatively with Clinical Centers and sponsoring organizations in a multicenter study and oversee the implementation of and adherence to a common protocol, as well as assure quality control of the data collected. 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 substantial involvement by the Project Scientist is above and beyond the normal program stewardship and monitoring provided by the Program Official who is assigned to administer the award. 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 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 must 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, 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. It is anticipated that the NIDDK Biosample Repository will be used as the specimen repository for the Network. 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 subject to appeal in accordance with the PHS regulations at 42 CFR part 50, Subpart D and HHS regulation at 45 CFR part 16, or the rights of NIDDK under applicable statutes, regulations and terms of the award. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Jose Serrano M.D., Ph.D. Director, Liver, Biliary and Pancreas Programs Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases 2 Democracy Plaza, Room 657, MSC 5450 BETHESDA MD 20892-5450 Phone 301 594-8871 FAX 301 480-8300 E-mail: js362q@nih.gov For Courier service use: 6707 Democracy Blvd, Room 657 BETHESDA MD 20817 o Direct your questions about peer review issues to: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Blvd. Room 752, MSC 5452 Bethesda, MD 20892-5452 Telephone:(301) 594-8897 FAX:(301) 480-3505 Email: fc15y@nih.gov o Direct your questions about financial or grants management matters to: Ms. Donita Marconi Grants Management Specialist Division of Extramural Affairs, NIDDK 6707 Democracy Blvd. Room 710, MSC 5456 Bethesda, MD 20892-5456 Telephone:(301) 594-8860 FAX:(301) 480-3504 Email: dm150h@nih.gov LETTER OF INTENT Prospective applicants are requested 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 plan for a technical assistance workshop, 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, and should be sent to: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Blvd. Room 752, MSC 5452 Bethesda, MD 20892-5452 Telephone:(301) 594-8897 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 https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. 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: https://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, NIDDK 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Applications must be received by the application receipt date listed in the heading of the RFA. If an application is received after that date, it will be returned to the applicant without review. Supplemental documents containing significant revision or additions will not be accepted, unless applicants are notified by the Scientific Review Administrator. 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. B. Application Requirements 1. Clinical Center and Data Coordinating Center Applications Applicants must describe plans to accommodate the stated program requirements, criteria, and staff involvement. Applicants must describe plans to achieve the RESEARCH OBJECTIVES and SPECIAL REQUIREMENTS stated in this RFA. In addition, applicants should 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 cooperatively by the Steering Committee. The research plan should follow the instructions in the PHS 398 application form (https://grants.nih.gov/grants/funding/phs398/phs398.html). Applications may not exceed 25 pages for sections a - d, excluding appendices, which may contain copies of pertinent forms or examples of correspondence useful for required tasks. 2. Clinical Center Applications o Each CC within the Network should propose a plan for identifying and characterizing cases of drug-induced liver disease in a prospective and defined fashion. The plan should demonstrate knowledge of hepatotoxicity and its pathogenesis. o The application should define how patients will be screened and identified, how hepatotoxicity will be defined, a basis for developing diagnostic criteria and an algorithm to define and grade causality between the drugs(s), CAM therapies or toxins and the hepatotoxic event. o A strategy to identify and recruit appropriate clinical controls, should be discussed. If necessary, strategies to reach out to physicians in the community for the identification and recruitment of patients and controls should be proposed. o The CC principal investigator should define an overall structure for the hepatotoxicity network database and outline features and clinical information that should be included in the common database of patients and controls. The plans should include a justification for the necessary information to be accrued on patients. The PI should indicate how many patients meeting proposed criteria are likely to be identified at his/her CC and provide any historical data on cases of hepatotoxicity seen at their institution between September 1, 2001 and August 31 2002. The research plan should follow the instructions in the PHS 398 application form (revised 5/01, https://grants.nih.gov/grants/forms.htm. o The CC principal investigator should propose an informed consent which explains the collection, use and storage of samples suitable for current and future genetic analysis. The Office of Human Subjects Research (OHSR), NIH has developed points to consider in the development of informed consent documents that include the collection and research use of human biological materials http://www.hhs.gov/ohrp/humansubjects/guidance/reposit.htm. The proposed consent form will be considered in the elaboration of the final informed consent form. o The CC principal investigator might propose effective genetic profiling strategies and the samples needed for the identification of genetic variations associated to hepatotoxicity events. To promote development of a collaborative program, the issues discussed below need to be addressed in each application for a CC within the Hepatotoxicity Clinical Research Network. o Qualifications and experience. Applicants for CCs should provide information on their experience with the diagnosis and clinical management of acute drug-induced liver diseases. o Study population. CC applicants should discuss the number of patients with possible drug-induced, CAM therapy-associated or toxin-induced liver toxicities seen and followed at the center who might be eligible to enroll. Inclusion of all eligible candidates is expected. 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 the 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. Documentation with letters of support are needed in any consortium arrangement. 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 should be included with the application. o Willingness to participate in a Hepatotoxicity 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. 3. Applications for a DCC: A separate complete application is required from institutions applying to be the DCC for the Hepatotoxicity Clinical Research Network. Applicants for the DCC component are not required to be a Clinical Center within the study, though applicants for Clinical Centers sites may also submit an application to be the DCC. The Data Coordinating Center, collects, organizes and maintains all the clinical information (clinical data, laboratory and other diagnostics). The Database should be accurate, stable, and comprehensive. The Database must be flexible, adaptable, and responsive to the changing needs of the scientific community. The interface must be simple and easy to understand while the output should allow easy access to different levels of information. This output should include Web-based links to other databases to facilitate the rapid exploration of additional information. Applicants must address the following responsibilities of the DCC: o Participation in the design of the final protocol and development of the manual of operation, data collection forms, and questionnaires, o Development and implementation of systems for communication among Steering Committee members, and among study sites, o Data collection, editing, processing, analysis, and reporting, o Monitoring of adherence to the protocol and of data quality, o Establishment of procedures that insure the safety and confidentiality of all records The following specific criteria should be addressed:. o Qualifications and experience. The applicant for a DCC must demonstrate experience in the area of in coordinating multi-center clinical 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 or toxicities is not required, but the applicant may wish to include a hepatologist with expertise in the area of hepatotoxicity in the application as a key collaborator and advisor. o Study design and management. DCC applications should discuss the applicant"s familiarity and experience with various aspects of study design that would be important in developing clinical studies, for example: eligibility criteria, 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 and plans for statistical analysis. o The applicant for the DCC should delineate how serum, DNA and tissue specimens will be handled. 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 NIDDK Biosample Repository (http://www.niddk.nih.gov/fund/repository/repository.htm) will be used as the specimen repository for the Network and its funding is not included in this RFA. Estimated shipping and handling costs of $25,000 for specimens should be included in the budget of DCC. o The application should discuss strategies for the future acquisition of genetic profiling data to be incorporated in the centralized Database and the annotation methods used to perform computational analyses and extraction of information from the literature regarding the clinical events as well as include information on genes, cDNAs, SNPs protein sequences. C. Budget and Related Issues Applicants should 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 should adequately correspond to the scope of research proposed. Applications for CCs: CCs should consider the following additional issues regarding budgets. The underlying concept of the Hepatotoxicity Clinical Research Network is that a core effort is essential to maintain the infrastructure required to perform screening identification and characterization of bona fide cases of drug-induced liver toxicity, possibly from several regional institutions. 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 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 twenty percent effort for the investigator (principal and any co-investigators), fifty percent effort for a clinical coordinator and a small percent effort for other key personnel (assistants, secretary) to collect core study data. Tasks conducted by these personnel include study recruitment, data entry, specimen shipment and quality control. Equipment costs, such as computers for data-entry and printers, should be included. Include travel costs for two people to attend three one and one-half day Hepatotoxicity Clinical Research Network Steering Committee meetings a year in Bethesda, MD (three to four in the first year). 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 the hepatotoxicity diagnostic criteria. This amount should be placed in the patient enrollment category. Patient care costs may be escalated at three percent for future years. Once the CC has been awarded and the Hepatotoxicity Clinical Research Network Steering Committee members have been selected, a common diagnostic protocol will be established and funds will be allocated to CC on a per patient enrolled basis. 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 Clinical Center in the Network to implement the protocols are $350,000 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 enrollment costs. Estimated protocol implementation costs for Year 1 should be based per patient for conducting each protocol. The budget for each diagnostic protocol should be developed on a cost per patient basis and include all direct and any applicable facilities and administrative costs. Laboratory tests should be part of the per patient cost of conducting a protocol. 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 diagnostic algorithm approved by the Hepatotoxicity 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 Hepatotoxicity Clinical Research Network awards will be subject to administrative review annually. DCC Budget: Applicants for the DCC should prepare budgets for three 12-month periods (not to exceed600,000 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 Hepatotoxicity Clinical Research Network to be developed. The DCC will be subject to administrative review annually. APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW. PEER REVIEW PROCESS Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIDDK in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o 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 NDDK National Advisory Council. REVIEW CRITERIA A. Criteria for CCs and for DCC 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 the application address the problem outlined in the RFA. 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 will be developed collaboratively by the Steering Committee, 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)? Does the Principal Investigator have experience in working collaboratively to carry out a clinical study or standard protocol? Is the Investigator willing to work cooperatively on the Steering Committee to develop and follow a unified protocol? 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? B. 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. 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 repository. 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 Hepatotoxicity 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. C. Review of DCC applicants also will be based on the following: Considerations for the review of applications for the DCC for the Hepatotoxicity 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 Evaluation of the comprehensiveness, stability, adaptability and accessibility of the database. The schema used by the database should be described along with the capacity of the database to expand to accommodate an increase in database entries and information. o Evaluation of plans for a user support service to provide consultation and technical assistance in the use of the database. o Evaluation of the plans for future inclusion of genetic information (genes, cDNAs, SNPs protein sequences) and annotation. Annotation methods should include computational analyses and extraction of information from the literature o Plans to coordinate with related databases, including agreeing on controlled vocabularies and common data exchange formats. The output should include links to information in related databases. 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 Hepatotoxicity 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 Hepatotoxicity 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 CCs and the NIDDK. o Facilities, equipment, and organizational structure to effectively coordinate the Hepatotoxicity Research Network activities. 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. Applicants are encouraged to submit and describe their own ideas on how best to meet the goals of the Hepatotoxicity 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 Hepatotoxicity Research Network and with the NIDDK Project Scientist. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: October 11, 2002 Application Receipt Date: November 13, 2002 Peer Review Date: March 2003 Council Review: May 2003 Earliest Anticipated Start Date: July 2003 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 Hepatotoxicity Research Network a reasonable likelihood. o Availability of funds 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: https://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 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), a complete copy of the updated Guidelines are available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research, updated racial and ethnic categories in compliance with the new OMB standards, clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398, and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH- defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at https://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 https://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 https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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, Clinical Research Network in Drug induced liver toxicity is related to the priority areas of Medical Product Safety. 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. 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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