ADULT TO ADULT LIVING DONOR LIVER TRANSPLANTATION COHORT STUDY Release Date: July 9, 2001 RFA: RFA-DK-02-010 Update: The following update relating to this announcement has been issued: December 12, 2008 - This RFA has been reissued as (RFA-DK-09-003). National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov/) Letter of Intent Receipt Date: October 16, 2001 Application Receipt Date: November 28, 2001 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites cooperative agreement applications for clinical and coordinating centers to conduct a Living Donor Liver Transplantation (LDLT) Cohort Study among adults awaiting transplantation. The primary goal of this study will be to provide valuable information on the outcomes of LDLT. This information is needed to aid decisions made by physicians, patients, and potential donors. Adult to adult LDLT is a relatively new procedure increasingly used at major transplantation centers. Too few cases are performed at any one center and approaches to the patient and donor are too diverse across centers to provide reliable and generalizable information on donor and recipient outcomes from individual centers. The objective of this Request for Applications (RFA) is to establish and maintain the infrastructure required to accrue and follow sufficient numbers of patients being considered for and undergoing LDLT to provide generalizable data from adequately powered studies. Up to 8 Transplantation Centers (TCs) and a Data Coordinating Center (DCC) will be necessary to meet this objective. This is a one-time solicitation to support a Clinical Research Consortium for 7 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. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and nonprofit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign applications will not be accepted. 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 cooperative agreements awarded under this RFA. Among the disciplines and expertise that may be appropriate for this program are hepatology, transplantation, ethics, epidemiology, radiology, pharmacology, clinical psychology, psychiatry, and clinical database management. A DCC will be a part of the LDLT Cohort Study. In order to ensure that data analysis is done independently of data acquisition, the DCC cannot have the same Principal Investigator as a TC. Within the study consortium an institution may apply for both a TC and the DCC, but each must have separate principal investigators and submit a separate application with a specific plan of how the independent operation of each unit of the TC and DCC will be maintained. Only TCs that are currently conducting adult to adult LDLT may apply. To be eligible, a TC must have performed a minimum of 10 adult to adult LDLT during the 18 months prior to October 16, 2002. MECHANISM OF SUPPORT This RFA will use the NIH cooperative clinical research (U01) award mechanism of support, an “assistance” mechanism (rather than as “acquisition” mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients’ activity by involvement in the activity and otherwise working jointly with the award recipients in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships and governance of the study to be funded under cooperative agreements are discussed below under Terms and Conditions of Award. The total project period for an application submitted in response to this RFA may not exceed 7 years. Applicants from institutions which have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is 7/01/02. FUNDS AVAILABLE The NIDDK intends to commit approximately $2 million in FY 2002 in total costs (Direct plus Facilities and Administrative (F & A) costs) to fund as many as 8 TCs and 1 DCC in response to this RFA. A TC applicant may request a project period of up to 7 years and a budget for total costs (direct plus F & A) of up to $160,000 per year. A DCC applicant may request a project period of up to 7 years and a budget for total costs (direct plus F & A) of up to $750,000 per year. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. 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. At this time, it is not known if this RFA will be reissued. RESEARCH OBJECTIVES A. Background Over the last 20 years liver transplantation has become the standard of care and the only cure for end stage liver disease. Its success has led to over 4,000 transplants performed yearly. But there are at least 17,000 patients on the transplantation list awaiting cadaveric liver donation. As the waiting list has expanded, waiting time has also grown. As a result, patient mortality has increased while awaiting transplantation and patients are often critically ill by the time of transplantation. Among possible remedies, living donor transplantation has become widely accepted for pediatric transplantation. Adult-to- adult LDLT is a more challenging procedure and of potentially greater risk to the donor because of the larger portion of liver that is required. Right lobe adult-to-adult LDLT is a recently developed procedure, but several hundred have already been performed in the United States. Although still a small number relative to the several thousand adult cadaveric liver transplants performed annually, LDLT has the potential for changing the face of liver transplantation. Not only does LDLT avoid the lengthening waiting period for a cadaveric transplant, it greatly reduces the ischemic period of the transplanted organ, allows more time for evaluation of the donor, and changes the operation from an emergency into a scheduled procedure. In the special situation of hepatocellular carcinoma (HCC), early LDLT might improve survival among patients whose better liver function gives them a lower priority for cadaveric liver under current criteria. The major disadvantage of LDLT is that it is a difficult and potentially fatal operation for the donor. It also provides the recipient with a smaller portion of liver than would have been received with cadaveric transplantation. Although many questions remain about LDLT, the pressure of the waiting list has drawn many centers to consider implementing it. As was noted at a November 2000 NIH workshop on adult LDLT, more than 20 centers in the United States are currently performing the procedure and at least as many are considering beginning it in the next year. As LDLT becomes more frequently used, a number of research issues need to be addressed through a prospective, multi-center, cooperative effort among centers performing the procedure. B. Research Scope The goal of this RFA is to select a Data Coordinating Center (DCC) and as many as eight Transplantation Centers (TC) to participate in planning and implementing a multi-center cohort study on adult living donor liver transplantation. The research objectives of the LDLT Cohort Study concern factors that influence the outcomes of adult to adult LDLT. Recruited into this longitudinal cohort study would be adult patients and potential donors being considered for LDLT. Recipients and their donors would be followed for sufficient time to determine outcomes related to LDLT. These outcomes will be compared with those of appropriate comparison groups. One such comparison group might be transplant candidates who are evaluated for but do not receive LDLT. Another group might be patients not evaluated for LDLT, but who have the same diagnosis, severity of illness and other clinically significant features as patients who undergo LDLT. Regardless of the specific criteria for selecting a comparison group, the primary objective concerns comparison of morbidity and mortality of patients who receive LDLT with a group or groups of patients with similar illnesses and prognosis. A critical question to answer with this information is how do the outcomes of LDLT compare with those of cadaveric transplantation. Transplant physicians need this information on outcomes to advise patients and prospective donors. Therefore, sufficient patient and donor pairs will be recruited to determine whether recipients of LDLT have substantially different survival than non-LDLT recipients. A large number of donors and recipients from several geographically distributed institutions will be necessary to reliably determine if outcomes are different with the two approaches. Among other questions that could be addressed in the LDLT Cohort Study would be the following: What are the immediate as well as long-term risks for the donor? Is long-term liver function preserved for the donor? What is the effect of donation on the donor’s quality of life? What are the financial and psycho-social effects on the donor? What is the minimal size of the donor organ? How does the amount of fat in a donor liver affect outcomes? What are the optimal operative procedures? Can biliary tract and other surgical complications be minimized among donors and recipients? Do costs differ substantially for LDLT and cadaveric transplantation? Do donor factors such as age, sex, and whether the donor is a first degree relative affect recipient outcomes and the need for immunosuppression? Can accurate markers of hepatic regeneration be identified? Is disease recurrence affected by LDLT? What is the impact of LDLT on a center’s waiting time? What is the optimal pre-operative preparation to prevent disease recurrence, rejection, and other morbidity? These study questions 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. Applicants may also suggest and justify other study designs. At least 250 adult to adult LDLT recipients and at least as many candidates who do not receive LDLT will need to be recruited prospectively and followed to determine if there are appreciable differences in mortality and graft loss between the two groups. The ability to recruit all or nearly all of a TC’s LDLTs is important in order to meet the required study size and to ensure unbiased results. Participating centers would also be expected to pool outcome data on patients that have already undergone LDLT to provide preliminary information on the study’s major questions. All projects must be completed within 7 years (84 months). STUDY ORGANIZATION The LDLT Cohort Study will be a cooperative consortium of up to eight TCs and one DCC. TCs will be responsible for proposing data to be collected for the database and protocols, participating in their overall development, patient recruitment, evaluation, and treatment, conducting the research, and disseminating research findings. All individual TCs will be required to participate in a cooperative and interactive manner with one another and with the DCC in all aspects of the LDLT Cohort Study. The DCC will support development of a database of clinical information, serum and tissue samples, and protocols, 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 (if needed), 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. A. Study Governance A Steering Committee will be the main governing body of the LDLT Cohort Study. At a minimum, the Steering Committee will be composed of the principal investigators of each TC in the Consortium, 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 TCs to oversee and guide Steering Committee activities. The Steering Committee will meet three to six times during the first 12 months of the study, and two to four times per year thereafter. All major scientific decisions will be determined by a majority vote of the Steering Committee. Each TC, the DCC, and the NIDDK Project Scientist will have one vote. The Steering Committee will have primary responsibility for the general organization of the study, 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. Protocol topics will be proposed and prioritized by the Steering Committee. For each protocol, one TC 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 TCs. 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. If experimental protocols are implemented, an independent Data and Safety Monitoring Board will be established by the NIDDK to review protocols and monitor patient safety and performance of the resulting studies. 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 TCs, 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 TCs must be willing to pursue this funding arrangement for each new protocol conducted. Clinical protocols must be approved by local institutional review boards and, as appropriate, the LDLT Cohort Study Data and Safety Monitoring Board before initiation. The exact number of protocols supported in the seven-year program will depend on the nature and extent of the investigations proposed by the Steering Committee. A database will be developed to support epidemiological studies and other clinical studies. Planning may be done for large clinical trials that would be submitted as separate R01s if further funding is necessary. The LDLT Cohort Study 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 LDLT Cohort Study. Any specific collaboration involving the resources of the LDLT Cohort Study will require approval by the Steering Committee. B. Study Phases During the first 9 months, investigators will develop the protocol with IRB and other approvals obtained by the end of the first year (Phase 1). Recruitment of donor-recipient pairs and controls will take place between approximately 1 year to 4 years (Phase 2) with patient follow- up for an additional 2 years (Phase 3). Lengthy follow-up is needed to compare outcomes with recipients who receive cadaveric liver transplantation, which may occur long after initial evaluation. Study analysis and close out would occur during the final year (Phase 4). All projects must be completed within the seven-year duration of this research program. Parallel to the development of the protocol will be development of a study of outcomes of patients who had previously undergone LDLT at the TCs. Initial data compilation on these patients would be expected within 18 months of the beginning of the study with analysis to follow over the following 2 years. SPECIAL REQUIREMENTS A. Participation in a Collaborative Program To promote the development of a collaborative program among the awardees, the applicant should present evidence of experience in working cooperatively with other Clinical and Data Coordinating Centers and of ability to follow common protocols that are collaboratively developed. 1. TCs will be expected to communicate with the DCC and the NIDDK Project Scientist on a regular basis. All TCs in the LDLT cohort study must agree to implement the protocols and manual of operations that will be developed cooperatively during planning stage and agree to electronically transmit all study data in a timely fashion to the DCC for combination and analysis. An explicit statement of willingness to participate in a collaborative program should be included in the application. 2. The DCC will be involved in collaborations with NIDDK and the TCs during all phases of the trial. Thus, the applicant is expected to demonstrate experience in working cooperatively with Clinical Centers and sponsoring organizations in multicenter clinical studies and in overseeing the implementation of and adherence to a common protocol, as well as assuring quality control of the data collected. In addition to organizing and attending regular meetings, the DCC will be expected to maintain close communications with the NIDDK Project Scientist and the Principal Investigators of the TCs. B.Terms and Conditions of Award The administrative and funding instrument used for this program is a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient"s activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NIDDK Project Scientists. The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator(s) as well as the institutional official at the time of award. These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92, the NIH Grant Policy statement. 1. Awardee Rights and Responsibilities o The awardees 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, if necessary, by the Data and Safety Monitoring Board. o 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. o The DCC will be involved in collaborations with the NIDDK and the TCs 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 DCC will be expected to maintain close communications with the NIDDK Project Scientist and the Principal Investigators of the TCs. o 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. o Support or other involvement of industry or any other third party in any study performed by the Consortium-- e.g., participation by the third party, involvement of project resources or citing the name of the project or the NIDDK support, or special access to project results, data, findings or resources -- may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification to, and concurrence by, NIDDK. o 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 The Steering Committee, composed of each of the Principal Investigators of the DCC and the TCs, and the NIDDK Project Scientist, 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, study protocols, 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). Subcommittees will be established on topics such as ancillary studies, publications and presentations, quality control, recruitment, protocol adherence, among others. Each TC 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 TCs 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 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. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS. It is the policy of NIH 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. The LDLT cohort study is limited to adult donors and patients. The NIDDK has determined that the adult to adult LDLT Cohort Study does not require inclusion of children for the following reasons: Adult to child LDLT is a well established procedure, the risks are substantially less for the donor and the recipient, and the surgical procedures are quite different. For example, the right lobe of the liver is typically transplanted to adults and the left lobe to children. A number of the research questions of importance to the proposed study have either been addressed in children or are not as pressing in children as in adults. Investigators may also obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. DATA AND SAFETY MONITORING IN CLINICAL TRIALS Applicants are directed to the full text of the NIH Policies regarding Data and Safety Monitoring and Reporting of Adverse Events that are found in the NIH Guide for Grants and Contracts Announcements at the following web sites: http://grants.nih.gov/grants/guide/notice-files/not98-084.html, http://grants.nih.gov/grants/guide/notice-files/not99-107.html, http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html All applicants receiving an award under this RFA must comply with the NIH policy cited in these NIH Announcements and any other data safety and monitoring requirements found elsewhere in this RFA. The following is a brief summary of the Data and Safety Monitoring and Adverse Event Reporting Requirements: Data and Safety Monitoring is required for every clinical trial. Monitoring must be performed on a regular basis and the conclusions of the monitoring reported to the extramural Program Director. If the LDLT cohort study includes experimental protocols or clinical trials, the DSM plan will be established at the time the protocol is developed and must be approved by both the Institutional Review Board (IRB) and the NIH and be in place before the protocol/trial begins. If the protocol will be developed during the research funded under this RFA, a general description of the data and safety monitoring plan must be submitted as part of the proposal and will be reviewed by the initial review group. If the protocol has been developed and is included as part of the submitted proposal, the complete and specific data and safety monitoring plan must be submitted as part of the proposal. Monitoring plans, at a minimum, must include the prompt reporting of adverse events to the IRB, Food and Drug Administration and the NIH. The frequency of reporting of the conclusions of the monitoring activities should also be described in the plan. The overall elements of each plan may vary depending on the size and complexity of the trial. Examples of monitoring activities to be considered are described in the NIH Policy for Data and Safety Monitoring at http://grants.nih.gov/grants/guide/notice-files/not98-084.html. 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. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. LETTER OF INTENT Prospective applicants are asked to submit, by 10/16/2001, 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, 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 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) Telephone: (301) 594-8885 FAX: (301) 480-3505 APPLICATION PROCEDURES A. Submission Instructions The research grant application form PHS 398 is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-435-0714, email: GrantsInfo@nih.gov. The RFA label available in the PHS 398 application form must be affixed to the bottom of the face page of the application and must display the RFA number. 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. 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 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. Transplantation 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 (http://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. Transplantation Center Applications (a) Core Study To meet the objectives of the study, each TC applicant should propose a research plan that includes the structure of a database and an information core that they believe should be collected on all participants that are prospectively enrolled: potential and actual donors, LDLT patients and non-LDLT control patients. Justification for core data elements should be provided. Core elements for the separate retrospective data collection should also be provided and discussed. Comparison of the proposed amount and quality of information gathered retrospectively and prospectively would be appropriate. Discussion of the pros and cons of various non-LDLT comparison groups should be provided. Applicants must document that they have performed at least 10 adult to adult LDLTs within 18 months prior to October 16, 2001. Applicants should provide a projection of the number of adult patients expected to receive either cadaveric or living donor transplants in the first year of the study. Assurance of institutional support will be critical. TC applicants should provide evidence of their success in recruitment and retention of liver transplant patients into research protocols. (b) Clinical Research Protocols Each TC applicant should also propose two clinical research protocols as models that could be used within the suggested recruitment guidelines. Within the 25 page application limit, a guideline for the clinical research protocols is two pages for each. The protocols should demonstrate knowledge of the diseases and experience in treating and following patients undergoing living donor and cadaveric liver transplantation. Each protocol should require sufficient subjects to necessitate the use of a consortium with multi-center participation. Applicants should indicate knowledge of the number of patients required for each study based on sample size calculations. At least one protocol must focus on improvement of recipient outcomes. For each of the two clinical research 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 across relevant sex, ethnic, and age groups and assurances of the applicant"s access to the patient populations. In both the core and clinical research proposals it is important to indicate appropriate objective measures of primary and secondary outcome. The TC principal investigators are encouraged to explore, within the context of their proposed protocols, new technologies to monitor issues of clinical significance to donors and recipients. Funding for the relevant technology should be presently available for each clinical research protocol proposed. The TC principal investigator should indicate for each clinical research protocol how many patients meeting proposed criteria are available in his/her TC and how many will be required from the entire Consortium (all of the TCs). In the discussion of outcome measures, it will be important to indicate appropriate objective measures of primary and secondary outcome. The TC principal investigators are encouraged to explore, within the context of their proposed protocols, new technologies to monitor disease progression and response to therapy. To promote development of a collaborative program, the issues discussed below need to be addressed in each application for a TC within the LDLT Cohort Study Consortium. This material is in addition to the submission of a research plan, as described in the section entitled Research Scope. (c) The following specific criteria should be addressed: o Qualifications and experience. Applicants for TCs must demonstrate experience and expertise to conduct clinical studies in LDLT. o Study population. TCs must discuss the number of adult patients that have thus far been evaluated as well as transplanted using living donors. The number of patients at the center that might be eligible to enroll in protocols must be discussed. The applicant for a TC in the Consortium must include a description of the pool of previous as well as future potential study participants by sex, age categories, and ethnic/racial distribution, as well as recruitment source. It is important for TCs to demonstrate a willingness and ability to recruit all recipients and their living donors into the core study. Applicants for a TC 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 LDLT Cohort Study. The principal investigator should state his/her general support of collaborative research and interaction with the NIDDK, the other TCs, and the DCC through the Consortium 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. TCs 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. 2. Data Coordinating Center Applications A separate complete application is required from institutions applying to be the DCC for the LDLT Cohort Study. Applicants for the DCC component are not required to be a transplantation site within the study, though applicants for transplantation sites may also submit an application to be the DCC. Applicants must address the following responsibilities of the DCC: 1) participation in the design of the final protocol and development of the manual of operation, data collection forms, and questionnaires, 2) development and implementation of systems for communication among Steering Committee members, and among study sites, 3) data collection, editing, processing, analysis, and reporting, 4) monitoring of adherence to the protocol and of data quality, and 5) establishment of procedures that insure the safety and confidentiality of all records. Data management and quality control procedures must be detailed. Methods for assuring privacy and maintaining confidentiality should be included. There must be a data and safety management plan. Applicants must state their plans for the reporting of results that examine differences in treatment effects across these subgroups (see section, “Inclusion of Women and Minorities in “Research Involving Human Subjects”). 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 is not required, but the applicant may wish to include a transplantation surgeon or hepatologist 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 Data and Safety Monitoring Boards. o Sample size calculations should be provided for the prospective core component between LDLT patients and possible control groups based on reasonable assumptions of mortality and graft loss of transplant candidates at large U.S. transplantation centers. 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 beyond those required for clinical care will be budgeted as a part of the per patient costs of each TC. 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. o The applicant should describe the functions of a blood and tissue repository in the context of the design presented in this RFA. Included should be a discussion of shipping of biological specimens in a clinical setting, as well as the handling and tracking of specimens. This repository will be established during the planning phase. BUDGET INSTRUCTIONS Applicants should complete the budget information as directed in the PHS 398 application form. The applicants shall not submit budget information in modular format and cost projections should adequately correspond to the scope of research proposed. 1. Transplanation Center Applications TCs should consider the following additional issues regarding budgets. The underlying concept of the LDLT Cohort Study is that a core effort is essential to maintain the infrastructure and essential data collection. Therefore, individual TCs should submit requests a budget to maintain these core features. It is anticipated that this Core Budget will cover a minimum ten percent effort for the investigators (principal and any co-investigators), and a small percent effort for other key personnel 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 three people to attend three one and one-half day LDLT Cohort Study meetings a year in Bethesda, MD (six 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 TC will be provided funds for implementation of protocols. The precise number of protocols conducted will be determined by the LDLT Cohort Study Steering Committee and will depend on availability of funds. It is anticipated that during the first year, two to four protocols will be developed for implementation at the start of recruitment. Allowable total costs for each TC (core costs, costs per patient to conduct the protocols, and indirect costs) will vary. However, the maximum total costs for each Consortium to implement the protocols (including TCs and DCC and Specimen Core) are $200,000 per year. The TCs are requested to present the following information: o For each year, each TC should include the core budget costs and costs to conduct protocols. Estimated protocol implementation costs for Year 2 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. A guideline is to devote between one-third and one-half of resources in Phase 2 to clinical research protocols and between one half and two-thirds of resources to the core prospective and retrospective data collection. 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 TC to conduct the proposed study or trial, and not for the entire LDLT Cohort Study. The yearly budget for each TC should include the number of patients available for the proposed protocol at that TC. 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 LDLT Cohort Study Steering Committee and will be funded through a per patient basis (capitation) funding mechanism. The individual TCs will be expected to project patient enrollment for a specific protocol during a specified time frame, continuation and level of funding for each TC will be based on actual recruitment and overall performance. The LDLT Cohort Study awards will be subject to administrative review annually. 2. Data Coordinating Center Applications Applicants for the DCC should prepare budgets for seven 12-month periods (not to exceed $750,000 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 LDLT Cohort Study 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 as well as the cost of meeting three times/year in Bethesda (six times the first year). Approximately $30,000 for the whole 7 years should be budgeted for managing the Data and Safety Monitoring Board. 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. The DCC is expected to maintain a blood and tissue repository to be established during the planning stage of the LDLT Cohort Study. Cost for shipping specimens from the TCs will be covered by the DCC. REVIEW CONSIDERATIONS Applications must be received by November 28, 2001. If an application is received after that date, it will be returned to the applicant without review. 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, all applications will 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 A. Criteria for TCs and for DCC All applications will be reviewed according to the criteria listed below. The 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: The application should address the problem outlined in the RFA. The application should demonstrate how the study will advance scientific and/or medical knowledge. o Approach: The adequacy of the proposed conceptual framework, design, methods, and analyses. Potential problem areas and consideration of alternative tactics should be acknowledged Because the final protocol study design(s) 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: The applicant should demonstrate how the project challenges existing paradigms or develops new methodologies or technologies. o Investigator: The investigator should be appropriately trained and well suited to carry out this work. The proposed study should be appropriate to the experience level of the principal investigator and other researchers (if any). There should be evidence of prior experience in working collaboratively to carry out a clinical study or standard protocol as well as evidence of willingness to work cooperatively on the Steering Committee to develop and follow a unified protocol. o Environment: The environment in which the work will be done should contribute to the probability of success. The proposed protocol should take advantage of unique features of the scientific environment and employ useful collaborative arrangements. There should be evidence of institutional support. 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. B. Review of TC applicants also will be based on the following specific criteria: o Evidence of successful experience in recruitment and retention of research subjects in multicenter clinical studies, and particularly experience in the recruitment and retention of patients evaluated for liver transplantation. Commitment to recruiting all eligible recipient-donor pairs and documentation of access to an adequate patient population from which to recruit at least 10 eligible recipient-donor pairs per year and. o The extent that the two clinical research studies proposed by the applicant will result in information that will further our understanding and management of LDLT patients or of transplantation or liver disease in general. o Cogency of the discussion of appropriate controls for LDLT recipients. o 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 Evidence of prior experience in working collaboratively in carrying out a developed study protocol. Evidence of willingness to work cooperatively in this study. o Demonstrated knowledge of clinical and epidemiological aspects of liver transplantation and specifically LDLT, including management of donors and recipients both pre- and post-operatively. o Collaborations between TCs within the LDLT Cohort Study: For those applicants that propose collaborative efforts between two groups to form a single TC, 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 specific criteria: o Demonstration of the plans for exercising appropriate leadership in matters of study design, fostering cooperative relationships, data acquisition, data management, and data analysis. o Demonstrated ability to identify, enlist, recruit and coordinate the efforts of a central Blood/Tissue repository. o Experience in and understanding of the scientific, statistical, logistical, and technical issues underlying multi-center studies. o Understanding of issues related to management of liver disease and to organ transplantation. o The administrative, supervisory, and collaborative arrangements for achieving the goals of the program, including willingness to cooperate with the principal investigators of the TCs and the NIDDK. o Plans for determining the sample sizes necessary for the prospective core study and proposed statistical analyses of outcomes. o Adequate assurances that personnel have experience in utilizing procedures that insure the safety and confidentiality of medical records. SCHEDULE Letter of Intent Receipt Date: October 16, 2001 Application Receipt Date: November 28, 2001 Peer Review Date: March 2002 Council Review: May 2002 Earliest Anticipated Start Date: June 2002 AWARD CRITERIA Award criteria that will be used to make award decisions include: o The quality of response to the special requirements stated in this RFA. o Scientific merit as determined by peer review, o Availability of funds, o Programmatic priorities. o Geographic diversity o A demonstrated ability to conduct a successful program in adult LDLT o A demonstrated willingness on the part of the investigators to work as part of the LDLT Cohort Study and with the NIDDK Project Scientist. o Program balance, including, in this instance, sufficient compatibility of features to make a successful collaborative program a reasonable likelihood. 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: James Everhart, M.D., M.P.H. Division of Digestive Diseases and Nutrition, NIDDK Two Democracy Plaza Rm. 655 6707 DEMOCRACY BOULEVARD MSC 5450 BETHESDA MD 20892-5450 Telephone: (301) 594-8878 FAX: (301) 480-8300 E-mail: email@example.com Direct inquiries regarding review matters to: Francisco Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities, NIDDK Room 752 6707 Democracy Blvd. MSC 5452 Bethesda, MD 20892-5452 Telephone: (301) 594-8897 FAX: (301) 480-3505 Email: firstname.lastname@example.org Direct inquiries regarding fiscal matters to: Ms. Sharon Bourque Senior Grants Management Specialist Division of Extramural Affairs, NIDDK 6707 Democracy Blvd. Room 719, MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-8846 FAX: (301) 480-3504 Email: email@example.com AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.848. Awards are 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 NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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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