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HUMAN PANCREATIC ISLET CELL RESOURCES (ICRs) Release Date: January 3, 2001 RFA: RFA-RR-01-002 National Center for Research Resources (http://www.ncrr.nih.gov) National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov) Juvenile Diabetes Research Foundation International (http://www.jdf.org) Letter of Intent Receipt Date: February 8, 2001 Application Receipt Date: March 21, 2001 PURPOSE Recent publications reported that some patients with Type I diabetes mellitus have achieved long-term independence from exogenous insulin after receiving human pancreatic islet cell transplants. To expand this observation and, ultimately, bring such therapies into practice, the National Center for Research Resources (NCRR) together with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Juvenile Diabetes Research Foundation International (JDRFI) invites applications from institutions to establish Islet Cell Resources (ICRs) for the isolation, purification, characterization of human pancreatic islet cells for transplantation into diabetic patients. In addition, this Request for Applications (RFA) will establish a separate Administrative and Bioinformatics Coordinating Center (ABCC) to coordinate the ICRs’ activities. Establishment of up to six ICRs in a wide geographic distribution across the United States is planned. These centers would be responsible for the procurement of whole pancreata, isolation and quality control of islet cell preparations, and distribution of islets for approved research or clinical protocols. They would also perform research and development to improve isolation techniques, cellular viability and function, and shipping procedures. Organizations whose applications receive a favorable initial review will be evaluated, subsequently, for compliance with the Food and Drug Administration (FDA) Good Manufacturing Practice (GMP) guidelines relevant to Phase I cell therapy trials. This entails that each ICR successfully complete a site visit performed by an outside team of inspectors who qualified to evaluate such compliance. This evaluation will be a condition of grant award. ABCC applicants will compete separately under this RFA to coordinate ICRs’ activities, organize their meetings, and correlate data that reflect the efficacy of both the methods used to prepare islets and the assays to predict functionality and clinical outcome. The ABCC will also manage the relevant laboratory and clinical data generated through the activities of the ICRs . While the ABCC may be located within the same institution as one of the selected ICRs, the director of the ABCC must remain independent of that ICR and any other ICR to both preserve the integrity of the studies and avoid any perceived or real conflict of interest. ELIGIBILITY REQUIREMENTS Applications for the ICR portion of this RFA may be submitted by domestic not-for-profit organizations, public and private organizations, such as universities, colleges, hospitals, laboratories, units of state and local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible to receive awards under this solicitation. However, under exceptional circumstances, a foreign component critical to an ICR may be included as a part of the program. Applications for the ABCC portion of this RFA may be submitted by domestic for-profit and not-for-profit organizations, public and private organizations, such as universities, colleges, hospitals, laboratories, units of state and local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible to receive awards under this solicitation. Individual members of racial and/or ethnic minority groups, 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. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be the cooperative agreement (U42), an assistance mechanism rather than an acquisition mechanism, in which substantial NIH scientific and/or programmatic involvement with the awardees is anticipated during performance of the activity. Under a cooperative agreement, the NIH supports and/or stimulates the recipients’ activities by working in partnership with the awardee, without assuming the direction of, prime responsibility for, or dominance in the activities. Responsibilities for the project as a whole reside with the awardees, although specific tasks and activities are shared among the awardees and the NIH Institutes and Centers (ICs). Details of the responsibilities, relationships, and governance of studies funded under a cooperative agreement are discussed later in this document under the section entitled “Terms and Conditions of the Award.” The anticipated award date is September 2001. The total project period for an application submitted in response to this RFA may not exceed five years. Although this RFA is currently anticipated to be a one-time solicitation, if it is determined that there is a sufficient, continuing need, NCRR will invite competitive new and/or competitive continuation cooperative agreement applications for review in accord with the procedures described in REVIEW CONSIDERATIONS. FUNDS AVAILABLE Up to six awards for ICRs and one award for an ABCC will be made under this RFA. Over their five-year duration, the awards made to these ICRs would reach a total of up to ~$11million (direct costs) while the total award to the single ABCC would be up to $3.5 million (direct costs) to support their infrastructure . The NIDDK and JDRFI will provide additional financial support based on the number of islet cell preparations made annually by each of the awardees. Because the nature and scope of the efforts proposed in response to this RFA may vary, it is anticipated that the size of an award will vary between ICRs in all years. Although the financial plans of the NCRR, NIDDK and JDRFI (hereafter termed Funding Entities) 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 appropriate 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. It is not known if new or competing renewal applications will be accepted or if this RFA will be reissued. RESEARCH OBJECTIVES Background Diabetes mellitus affects approximately 16 million people in the United States. Individuals with Type I diabetes have lost their ability to manufacture sufficient amounts of insulin due to autoimmune destruction of the insulin-producing beta cells that are grouped with other types of secretory cells within the “islets of Langerhans” of the pancreas. While injection of exogenous insulin has long been the standard treatment for patients with Type I diabetes, transplantation of human islet cells may be an alternative. However, the recovery of functional pancreatic islets is a complex procedure and needs to be optimized. Several aspects of the process may be critical: the clinical status of the donor before removal of the pancreas, surgical procedures involved in its excision, the enzymatic dispersal of the pancreatic components, the transplantation procedure and the recipient’s immunosuppression remain to be optimized. Selection of appropriate recipients for islet transplantation requires characterization of the target population with particular attention to their response to insulin therapy. Reports from the Diabetes Control and Complications Trial (DCCT) suggest that intensive treatment regimens that achieve tight control of blood glucose can significantly reduce the onset and progression of resultant complications in individuals with Type I diabetes. However, some diabetic patients practicing tight control experience lability of blood glucose levels in response to changes in health status, diet, exercise, or insulin dose. Because even small changes in their daily regimen may interfere with glucose control, these diabetic patients are said to be "brittle". For this subpopulation, insulin therapy is life saving, but may lead to frequent adverse events such as severe hypoglycemia. Islet cell transplantation could provide significant benefits to brittle diabetics for whom effective regulation by insulin therapy is difficult. Objectives and Scope The objectives of this RFA are to 1) establish ICRs to optimize the isolation procedures to obtain high yields of functional islet cells and to provide well-characterized islet cells for transplantation into type 1 diabetic patients, 2) distribute islet cells to investigators for clinical or basic research, and 3) develop isolation procedures that result in maximal islet cell function upon transplantation. ICR applicants should describe plans to establish collaborations with clinical programs that have experience in transplanting human islet cells and wish to optimize such protocols. The ICR research plan should include proposals to: 1) create and/or participate in a network of ICRs to recruit and evaluate pancreas donors, 2) obtain human pancreata; 3) distribute islets to both clinical and basic science researchers; 4) ensure quality control of islet cell isolation and provide a scientific basis for their use in transplantation or basic research; 5) determine the physiologic and genomic components that are correlated with longevity, function and portability of pancreatic islets; 6) facilitate approved transplantation protocols and correlate consequent clinical responses with characteristics of the islets provided. The ABCC will 1) be responsible for the organization and conduct of Steering Committee meetings whose agendas would include protocol review and evaluation of progress; 2) collect data, organize and analyze the methods and assays used to produce islet cells and correlate these data with post-transplant islet cell function; 3) correlate clinical trial data such as patient and donor demographics and baseline assessments, and relevant laboratory and clinical data that result from the use of the islets generated. The ABCC will maintain the database into which all ICRs and collaborating institutions will deposit their data for subsequent analysis. Respondents to the ABCC portion of this RFA should also address issues such as data storage, archiving, retrieval, analysis and data mining, quality control issues, security, and information transfer in the application. The research plan should follow the instructions in the PHS 398 application form (rev. 4/98, http://grants.nih.gov/grants/forms.htm). Program Structure Each ICR should be an identifiable organizational unit formed either within a single institution or with a collaborating institution. The expertise and technologies relevant to this RFA should reside within the ICR, providing a multidisciplinary structure that can coordinate activities between basic science investigators and clinicians to translate basic research discoveries into clinical applications. The ICR will facilitate research by providing laboratory-based and clinical investigators with access to technology and equipment needed for islet cell research that leads to implementation of practical transplantation protocols. These may include current Good Manufacturing Practice (cGMP) suites, Good Laboratory Practice (GLP) isolation procedures, microarray technology, and cell sorters. Applicants must have demonstrated significant research expertise in islet cell transplantation and have facilities within its institution that would enhance its productivity. While each ICR may not have a Training Program specifically designed to advance islet cell transplantation therapy, the institution may wish to use this opportunity to educate other investigators about relevant scientific and ethical issues. The ABCC will serve the administrative functions common to the ICRs, house the bioinformatics core, maintain the consolidated database, provide administrative oversight of the Steering Committee and coordinate ICR activities such as complex assays and unique technologies that would best be housed in a generally accessible, single core. While an institution may apply for both the ABCC and ICR cooperative agreements, applications for the ABCC award should be submitted separately from that of the ICR to enable each to be judged on its own merits. If a single institution does apply for both agreements, the independence of the ABCC from the ICR must be clearly described in a manner that documents the absence of a conflict of interest. An application for the ABCC award should include a plan that describes its proposed function, its resources and how it would facilitate ICR interactions. A Steering Committee will be responsible for scientific oversight and development of collaborative interactions among the ICRs, an example of such being shared research on islet cell isolation procedures. A representative and an alternate from each ICR must be designated to serve on the Steering Committee and must recuse themselves from discussion of any application submitted by individuals affiliated with their home institution. Each ICR must agree to provide pancreatic islets only to investigators whose protocols, either basic or clinical, have received favorable review by the Steering Committee and comply with the current goals of the Funding Entities. Applicants are strongly encouraged to identify a clinical research facility within their institution to facilitate islet cell transplantation. The clinical facility personnel should help to maintain quality assurance and compliance of the various aspects of the protocols. Specialized Resource Facilities and Services Advanced resources are required to develop pre-clinical data and implement clinical studies on cell therapies. Applicants should document the availability of existing laboratories, unique assays, and cell preparation facilities. Clinical activities, either within the applicant’s own institution or collaborating institution, that would to assist the awardee in achieving the goals outlined within this RFA should also be described. Each ICR application must include a description of all the proposed core components of the types cited above, and how they would relate to the ICR and other awardees. For those applications that are in the funding range, a committee of representatives from the Funding Entities will determine which will be selected as common cores to avoid unnecessary duplication of effort among all the ICRs. NIH-supported investigators from both within and outside of the ICRs would be eligible to submit a request for a service that any of the ICR cores provide. The Steering Committee would review the requests based on their scientific merit. Subsequently, the Funding Entities would consider these requests with regard to the scientific review, program relevance and availability of funds and set priorities based on these factors. Funds would be awarded to the core facility to offset the cost of these common services. An ICR application should, at minimum, address: o Experience of key personnel o Pre-clinical research experience o Clinical research experience and collaborations in islet cell transplantation o Core resources and plans for sharing these resources among ICRs o Human Subjects issues o Data Safety Monitoring Plan o Steering Committee function o Interaction with the ABCC An ABCC application should, at minimum, address: o Experience of key personnel o Experience in coordinating multi-center research programs o Biostatistical and bioinformatics experience and plans o Existing computer facilities o Coordination of core resources among ICRs o Human Subjects issues o Data Safety Monitoring Plan o Proposed Steering Committee function o Interaction with the ICRs SPECIAL REQUIREMENTS The cooperative agreement (U42) will require collaboration among the NCRR Program Coordinator, the NIDDK Program Officer, the JDRFI Representative, and the Directors of each ICR in order to assure efficiency and progress toward the stated goals of this RFA. Plans to develop these synergistic relationships should be addressed in each application. The following terms and conditions will be incorporated into the award statement and provided to the ICR Director as well as the institutional official at the time of award. Terms and Conditions of Award These special Terms and Conditions 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, and other HHS, PHS, and NIH Grant Administration policy statements. 1. Awardee Rights and Responsibilities Each ICR Director will plan and detail the functions of the requisite laboratories and cell isolation facilities and retain primary responsibility for the performance of these activities. The Directors and associates must agree to participate as members of the ICR Steering Committee. The ICR Directors will recommend outside experts to balance the composition and size of the Steering Committee to both provide requisite expertise and guarantee that the entire number of NIH representatives does not exceed 40 percent of the total membership. Each member, including the outside experts, will have one vote on matters discussed at the Steering Committee meeting. The ABCC Director and the ICR Directors, in cooperation with the other Steering Committee members, will be responsible for developing the details of the ICR operating policies and documents, including the definition of objectives, protocols, implementation, and interaction to establish a clinical islet cell resource program that is responsive, efficient, and ethical. The ABCC Director will assist the Chairperson of the ICR Steering Committee in organizing Steering Committee meetings. The ABCC will be responsible for administrative matters related to Steering Committee meetings, including preparing agendas, writing and distributing minutes, communicating with outside investigators and the lay public and receiving applications for ICR services from investigators. In addition, the ABCC will maintain close contact with the ICRs, the NCRR Program Coordinator, NIDDK Program Officer and JDRFI representative. It will assist in coordinating the research programs and core resources among the ICRs, provide biostatistical and bioinformatics support to the ICRs, maintain current and relevant databases, arrange appropriate advertising and publicity for the ICRs upon approval by the Steering Committee and prepare a comprehensive annual report for the program in a timely fashion. The Funding Entities will establish rules governing the selection and tenure of the Chairperson and any outside experts for the Steering Committee. The Chairperson of the Steering Committee, the ABCC Director and each ICR Director must present updates of their activities at each meeting that will be held either by telephone conference call or in the metropolitan Washington D.C. area. The ABCC will be responsible for all administrative aspects of the Steering Committee meetings. Individual ICR Directors and the ABCC Director will be responsible for submission of their Annual Progress Reports and other reports to NCRR in compliance with NIH and other Federal Guidelines. 2. I/C Staff Responsibilities One Health Scientist Administrator from the NCRR will be designated to serve as the NCRR Program Coordinator of this cooperative agreement. This individual will assist in coordinating the activities of the awardees and in facilitating exchange of information between them and the Funding Entities. The NCRR Program Coordinator, one Program Officer from NIDDK and one representative from JDRFI will serve on the Steering Committee. NCRR, NIDDK and JDRFI will also designate individuals who will serve as their respective alternates to the Steering Committee. In consultation with the awardees, these individuals and their alternates may convene workshops or sponsor seminars within existing meetings to update the Directors on advances in cell transplantation and immune modulation. As members of the Steering Committee, the NCRR Program Coordinator and NIDDK Program Officer and JDRFI Representative participate in all meetings and assist in developing operating policies and procedures but do not to direct the activities of the ICRs. They also serve as liaisons between the Steering Committee and the NIH and as information resources on research activities in cell transplantation and diabetes mellitus and may further facilitate activities by organizing meetings of groups having specific expertise in areas that could augment the research activities described in this RFA. NCRR and NIDDK reserve the right to terminate or modify each ICR award in the event of (a) failure to develop, implement or maintain mutually acceptable basic and clinical research protocols, (b) substantial shortfall in efficiency, data reporting, quality control, or other such major breach in islet cell production, laboratory studies or clinical protocols, (c) substantive changes in an agreed-upon protocol with which the Funding Entities cannot concur, (d) ethical issues, (e) lack of compliance with FDA GMP guidelines 18 months after issuance of the initial Notice of Grant Award or (f) significant non-compliance with other relevant Federal guidelines. 3. Collaborative Responsibilities The Steering Committee coordinates and facilitates the activities supported by this cooperative agreement. The members of the Steering Committee will establish the policies and operating procedures of both itself and the ICRs and will be described within a Policy and Procedure Document. The Document will also detail requirements for basic and clinical research protocols to use ICR- generated islets including quality control, quality assurance, testing procedures, human subjects protection, conflict of interest, and intellectual property and regulatory issues as they evolve throughout the duration of the studies. The Steering Committee will also make provisions for an arbitration panel as described below. Criteria for accession and discontinuance of use of the ICR facility will also be delineated. The Director of each Funding Entity will review and must approve these ICR guidelines prior to their implementation. The Steering Committee will meet three times during the first year of the awards and semi-annually, thereafter. ICR Directors are also responsible for formulating consistent policies for dealing with recurring situations that require coordinated action at Steering Committee meetings. Data and Safety Monitoring Board All clinical protocols supported by ICR resources must engage a Data and Safety Monitoring Board (DSMB), which will provide overall monitoring of interim data and safety issues. The DSMBs should be assembled by the institutions or funding organizations that sponsor those clinical protocols. The ICRs will not develop an independent DSMB but should present a data safety monitoring plan in their applications. Intellectual Property The Bayh-Dole Act is implemented through Department of Commerce regulations 37 CFR 401. These regulations define terms, parties, responsibilities, prescribe the order of disposition of rights, prescribe a chronology of reporting requirements, and delineate the basis for and extent of government actions to retain rights. The patent rights clauses are found at 37 CFR Part 401.14 and are accessible from the Interagency Edison web page, www.iedison.gov . ICR awardees will have primary rights to their data developed under these awards, subject to Government rights of access consistent with current Federal policies. Database Information developed as a result of ICR activities will be held in a central database by the ABCC. Such data, which will include, for example, laboratory procedures, methods of data analysis and reports, will be made available to the ICR Directors, NCRR Program Coordinator, NIDDK Program Officer and JDRFI Representative. The database will not be distributed to the public until the relevant studies have been completed and only with the concurrence of the Steering Committee. The database must be designed to protect patient identity and ensure the privacy of their medical and genetic data. Publication Awardees are encouraged to publish and to publicly release and disseminate results, data and other information developed by this cooperative agreement. Such documents, written by an individual ICR or by a consortium of ICRs, may be published only after approval by the Steering Committee. However, during or within three years beyond the end date of the project support period, 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 Funding Entities and in accordance with the stipulations within this document. Arbitration Any disagreement that may arise between award recipients and the Funding Entities on scientific or programmatic matters may be brought to arbitration. A panel of external consultants will be created, and convened as needed, to resolve any irreconcilable differences of opinion related to such matters. The panel will include one member selected by the ICR Directors, one member selected by the Funding Entities, and a third member chosen by the other two members of the arbitration panel. These special arbitration procedures in no way affect an awardee's right to appeal an adverse determination in accordance with PHS regulations at 42 CFR part 50, subpart D and HHS regulations at 45 CFR part 16. Applicants should anticipate probable areas of conflict and put forward an arbitration plan in their applications. LETTERS OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed application, 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 neither required nor binding, and does not enter into the review of a subsequent application, its contents allow NCRR staff to estimate the potential review workload and plan the review. The letter of intent is to be faxed, e-mailed, or mailed to John Meyer, Ph.D. at the address listed under INQUIRIES by February 8, 2001. APPLICATION PROCEDURES The research grant application form 398 (rev. 4/98) is to be used in applying for the cooperative agreement described in this RFA. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, Two Rockledge Centre, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: grantsinfo@nih.gov. Application kits are also available on the Internet at: http://grants.nih.gov/grants/funding/phs398/forms_toc.html An applicant may apply for designation as either an ICR or the ABCC. If an institution wishes to apply for both an ICR and ABCC award, separate applications must be submitted for each with special attention to the issues of conflict of interest described below. Material to Include in the ICR Application An application to establish an ICR should be submitted by the proposed Director who will be responsible for organizing and maintaining the ICR research program. A clear description of the plans for communication, interaction, collaboration and sharing among investigators within and between each ICR should be included. Each proposed ICR Director should also propose procedures for handling day-to-day issues, both administrative and scientific. The ICR Director should have the responsibility for oversight and coordination of all projects or components involving that ICR, whether or not they occur at his/her institution. Support for at least 0.25 FTE will be provided for the position of ICR Director. Provision will be made for partial support for a qualified investigator(s) to assist in the direction of the ICR and additional support for individuals to perform technical procedures. The application should detail how this would be accomplished through the inclusion of diabetologists, transplant surgeons and immunologists who are active in clinical research. The ICR application should provide and justify an estimate of the cost of producing islets cell per transplant recipient and per basic research protocol. In addition, each ICR must describe any clinical core either at its own institution or collaborating institution that would participate with the ICR in islet cell transplant projects. Each application must also describe the institutional oversight procedures to be employed and must clearly outline the proposed administrative and organizational structure of their ICR, including integration, collaborative arrangements, and roles for key investigators from all institutions involved with the ICR. The applicant must also state willingness to participate in the Steering Committee that will integrate the activities of the ICRs and agree to abide by its governance. Description of Proposed Resources Applicants to this RFA should consider the points below as examples of relevant information to include in the application. These are examples only and should not be construed as being required or limiting. Applicants are encouraged to address these and/or other points pertinent to the objectives of the RFA. ICR Harvesting o Describe the existing physical facility for isolation and assay of islet cells and the operational guidelines under which GLP is assured and islet cells are produced under cGMP conditions. o Describe plans for procurement of pancreata, including any relevant contracts and consortia agreements. Estimate the number of pancreata available to the proposed ICR annually for islet isolation. This would include all sources, including local transplantation networks. The basis upon which this estimate is made should be documented and presented and accompanied by letters of agreement from the organizations and institutions that will provide pancreata to the ICR. If transplantation of whole pancreas is performed at the applicant's institution, cite the number of whole pancreata that have been transplanted annually for the past five years. Describe the rationale employed when deciding whether the providing organization will allocate a pancreas to either a whole organ transplantation or islet cell transplantation protocol. o Recommend inclusion and exclusion criteria for pancreas donors and pancreata that will be used for islet cell transplantation. Describe the clinical setting with suggested physiological and pharmaceutical interventions to maintain the donors until excision of the pancreas has been completed. o Estimate the cost and identify the funding source(s) in place to obtain each pancreas. Provide an estimate of the number of pancreata that must be harvested to fully transplant one recipient. Isolation o Describe in detail the method planned to isolate islets from whole human pancreata. o Describe quality control (QC) and quality assurance (QA) provisions made at interim points in the procedure and for the final product. o Describe plans to optimize the isolation of islets for clinical and basic research. o To comply with the intent of cGMP, isolation of islet cells should follow a set of current, scientifically sound methods, practices or principles that are implemented and documented during product development and production to ensure the consistent production of islet cells that can be administered safely and with consistent purity and functional capacity. Describe elements of cGMP that would be used in the isolation of islet cells, such as: a) facility design to control operations; b) adequate documentation/records; c) production and process controls; d) quality control/assurance; e) validation; f) equipment and reagents that are calibrated/qualified; g) personnel that are trained and certified; h) traceability; and i) environmental monitoring. It is expected that each ICR will be capable of FDA certification for cGMP, initially to support Phase I trials, and subsequently, Phase II clinical trials. o Describe final product specifications for islet cell preparations, such as: a) presence of non-islet cells; b) absence of infectious agents; and c) sterility. Describe the specifications that will certify that islet cells are suitable for use by investigators at a recipient institution. o Cite QC and QA assay measurements obtained from prior islet cell isolations. List the clinical measurements and end points used to determine islet cell functionality if they were transplanted into animals or humans. Describe variations in isolation technique that are known to affect islet cell sterility, viability or function. o Describe measures to maintain sterility, viability, and function of islet cells that are distributed to investigators at both ICR and non- ICR locations. Distribution o Propose how the Steering Committee should prioritize investigators’ requests for islet cells, for both clinical and basic research protocols, and how islet cells should be allocated between ICR and non- ICR institutions, acknowledging that the Steering Committee will establish the procedures employed. o Describe research plans to determine if isolated islet cells can be shipped to sites outside of the ICR institution. o Provide the research study plans through which the harvesting, maintenance and shipping of human islet cells will be optimized for future clinical protocols. o The duration of time between harvest and transplantation is an important determinant of subsequent islet cell function. Describe means by which this would be minimized within the ICR. o Describe a) product containers; b) closures; c) labeling; d) sterility precautions; and e) packaging and handling procedures that will be employed enroute to the transplantation facility. Transplantation o Describe the location of the ICR relative to the location of the on- site transplantation facility. o Cite prior local experience or collaborations with other investigators in the transplantation of islet cells. If the applicant has had no prior experience with islet transplantation, an investigator at the applicant's institution with experience in the field should be named, with a letter describing that experience, proposed contribution and intention to collaborate with the ICR on protocols involving islet cell transplantation. o Define the inclusion and exclusion criteria for type 1 diabetic candidates for islet cell transplantation. o Describe pre-transplant medical testing and follow-up of diabetic patients that are eligible for islet cell transplantation. Identify the funding source(s) to support these tests. o Propose the process by which islet cells are prepared and infused into the recipient. o Describe the tests to assess the function of transplanted islet cells in vivo and define a data analysis plan to compare pre-transplant and post-transplant test results. Identify the source of funds to support such follow up. o Describe the post-transplant monitoring plan. How will a transplant be deemed successful? What criteria will determine if an additional transplant is necessary? Protocol development o Describe the approach for further protocol development, optimization and implementation of islet cell transplantation within the ICR network. o Identify all existing and planned sources of peer-reviewed funding that to be used in support of research studies relevant to this RFA. Administrative and bioinformatics coordinating center (ABCC) o Each application for the ABCC award must propose the procedures to administer the ICR Program, identify functions common to all ICRs that will be facilitated, describe the procedures that will maintain a current database and manage an intranet web site. Only one ABCC will be selected based upon peer-review of these proposals. o Convey an understanding of the scientific, statistical, logistical, and technical issues underlying multi-center studies, including those relating to islet cell isolation and islet cell transplantation. o Describe the qualifications of the applicant to take a leadership role in the area of study design, statistics, logistics, data acquisition and management, patient confidentiality, handling of laboratory specimens, quality control, data analysis, and network coordination. o Address the expertise, training and experience of the investigators and staff, including the administrative abilities of the principal investigator, co-investigators, and their time planned to devote to coordinate the ICRs. This should specifically include relevant experience in operating a “coordinating center” of the kind described in this RFA. o Provide a plan to acquire, transfer, manage, analyze and monitor basic laboratory information and clinical data generated through the use of ICR resources. o Propose a process to coordinate the activities of all of the ICRs and those of Steering Committee. Include the administrative, supervisory, and collaborative arrangements for achieving the goals of the program, and a willingness to cooperate with the ICRs and Funding Entities. o Describe the facilities, equipment, and organizational structure currently available to coordinate ICR basic and clinical research activities. o Describe how assay and disbursement data will be tracked for each lot of islet cells. o Outline the procedure to collate and analyze data from ongoing clinical and basic research studies that have either been approved by the Steering Committee or use ICR resources. o What data management services will be provided to the ICRs? o Provide a description of the statistical support for protocol design and analyses of completed protocols. o Describe the plan to interact with the DSMBs that are responsible for oversight of the clinical protocols that utilize ICR resources. o Propose how timely reports will be made to DSMBs, the Steering Committee, the Funding Entities and other relevant oversight and regulatory bodies. o Detail how privacy and security of all patient information as well as access by controlled authorization will be ensured. o Describe how investigators would be assisted in the preparation of abstracts and manuscripts and how they would be tracked. o Justify the proposed budget and personnel requested. Since human somatic cell transplantation involves the administration of materials of biological products, it is regulated by the Center for Biologics Evaluation and Research (CBER), FDA. IND applications are filed concerning clinical use of such products. Respondents to this RFA should convey their familiarity with such requirements for clinical, pre-clinical and animal studies. CBER has prepared documents relevant to this RFA that include: o “Points to Consider in Human Somatic Cell Therapy” (1991) o “Points to Consider in the Production and Testing of New Drugs and Biologicals Produced by Recombinant DNA Technology” (1985) o “Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals” (1987) o “Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use” (1987) o “Points to Consider in the Collection, Processing, and Testing of Ex- Vivo Activated Mononuclear Leukocytes for Administration to Humans” (1989) Copies of Points to Consider documents are available from: The Division of Congressional and Public Affairs CBER HFM-12 1401 Rockville Pike, Suite 200 N Rockville, MD 20852-1448 Telephone: (301) 594-0830 CBER staff members are also available to respond to questions at (301) 594-0830. BUDGET AND RELATED ISSUES Applicants should complete the budget information as directed in the PHS 398 application form. Allowable costs In order to fully achieve the goal of this initiative, up to six ICRs are proposed for support. The award will provide up to $300,000 per year in direct costs for each ICR. An award of up to $700,000 direct costs will be awarded annually to the ABCC for support of administrative and bioinformatics activities. During the course of the project period, it is anticipated that technologies such as islet cell isolation and shipping, transplantation techniques, and immune suppression will improve and the proposed protocols may change. Accordingly, it is expected that the investigators will adjust their scientific projects to accommodate such changes. During the course of the award, the Steering Committee will meet at least semi-annually and workshops to review new developments in the field will be held periodically. Applications should present five budget periods of 12 months each that provide adequate budget justification for all applicable direct and F&A; costs. An estimate of personnel costs needs, including the principal investigators, other professional and support staff must be included. A minimum effort of 0.25 FTE is required for the ABCC Director and each ICR director and sub-project principal investigators. Estimates of travel costs to Steering Committee and Data Committee meetings as well as a statement that indicates a willingness to participate in these meetings must also be included. Applicants submitting an ABCC application requesting $500,000 or more in direct costs for any year must obtain approval from NCRR program staff listed in INQUIRIES before submitting the application. The applicant must identify, in the cover letter that is sent with the application, the NCRR staff member who agreed to accept assignment of the application. Non-Allowable Costs: The grant award for this RFA may not be used to pay for patient care costs. Such costs include, but are not limited to: a) transportation and hospital care for organ donors; b) transportation, testing and monitoring of potential islet cell transplantation recipients; and d) inpatient or outpatient costs related to islet cell transplantation or other clinical studies using such preparations. APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. 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. Line 1 should indicate whether the application is for an award as an ICR or ABCC. In addition the RFA title and number must be typed on line 2 of the face page of the application form. Submit a signed, typewritten original of the application, including the Checklist, and two signed photocopies, in one package to: Center for Scientific Review National Institutes of Health Two Rockledge Centre, Room 1040-MSC7710 6701 Rockledge Drive Bethesda, MD 20892-7710 (or Bethesda, MD 20817 if express mail or courier service is used) At the time of submission, three additional copies of the application must be sent to the Deputy Director, Office of Review, NCRR, at the address listed under INQUIRIES. Applications must be received by March 21, 2001. If an application is received after this date it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of an application already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the Center for Scientific Review and for responsiveness by NCRR in collaboration with NIDDK. Applications that are incomplete or non- responsive will be returned to the applicant without further consideration. Applications must adhere to the page limitations and Special Application Requirements noted under the section APPLICATION PROCEDURES above to be considered responsive. 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 Office of Review, NCRR in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and may 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 Advisory Research Resources Council, and the NIDDK Advisory Council. Review Criteria The goals of NIH-supported research are to advance understanding of biological systems, improve the control of disease, and enhance the health of humankind. The scientific and technical merits of the proposed activities and the organizational plans for participating in this cooperative agreement and the extent to which they address the overall goals and objectives of the RFA will be reviewed. Reviewers will be asked to provide written comments on the ICR applications for: o Responsiveness and innovative approaches to Major objectives of this RFA; o Quality of the pre-clinical data and experience in translating them into clinical protocols; o Plans to integrate institutional projects with shared cores and to make cores and resources available to other ICRs and NIH-supported investigators; o Prior experience in organizing and oversight of multi-centered basic and translational research studies and plans to extend this to the ICRs; o Adequacy of laboratory and ancillary facilities and equipment; o Evidence of institutional support; o Experience in the field of human islet cell research and cellular transplantation research; o Adequacy of the process design, methods, and analyses to be used; o Letters of planned or existing collaboration from clinical researchers who will perform pre- and post-transplantation studies using ICR-generated islet cells; The ABCC applicants will be evaluated on the basis of: o Responsiveness and innovative approaches to the major objectives of this RFA; o Experience in the coordination and oversight of relevant, multi- center trials; o Planned organization, oversight and administration of the ICR Program; o Qualifications of personnel; o Availability of computer technologies and equipment suitable for ICR oversight; o Letters of reference from principal investigators who have participated in multi-center basic research or clinical research trial overseen by the ABCC applicant. Both the ICR and ABCC applications will also be evaluated with regard to the likelihood that they will function in a synergistic manner and interact well with the other proposed components . Appropriateness of their proposed budgets will also be considered. In addition to the above criteria, in accordance with NIH policy, all applications will be reviewed with respect to the following: o The adequacy of plans to include, recruit and retain both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. o The training course(s) taken by key personnel addressing the protection of human subjects must be included in the application. For this purpose, key personnel are defined as individuals who design or conduct clinical research protocols. o A discussion of data safety monitoring must also accompany the application. Schedule Letter of Intent Receipt Date: February 8, 2001 Application Receipt Date: March 21, 2001 Peer Review Date: May-June, 2001 Council Review: September 13-14, 2001 Anticipated Award Date: September 2001 AWARD CRITERIA Factors that will be considered in making awards include: a) the scientific merit of the proposed program as determined by peer review, the multi-disciplinary nature of the proposed studies, and the quality of the response to the requirements stated in this RFA; b) relevance to the overall programmatic balance and priorities of NCRR and NIDDK and sufficient compatibility of features proposed in the research plan and qualifications of the investigators to make a collaborative program within the ICRs a reasonable likelihood; and c) the availability of funds. The earliest anticipated date of award is September 2001. Some consideration will also be given to geographic diversity. The award will be subject to administrative review by NCRR and NIDDK staff upon receipt of each annual non-competitive renewal application. INQUIRIES Inquiries concerning this RFA are encouraged. We welcome the opportunity to clarify any issues or respond to questions from potential applicants. Direct inquiries regarding programmatic issues to: Richard Knazek, M.D. Medical Officer Clinical Research Area National Center for Research Resources One Rockledge Centre, Room 6030 6705 Rockledge Drive, MSC 7965 Bethesda, MD 20892-7965 Telephone: (301) 435-0792 FAX: (301) 480-3661 Email: richardk@ncrr.nih.gov Direct inquiries regarding review issues to: John Meyer, Ph.D. Deputy Director, Office of Review National Center for Research Resources One Rockledge Centre, Room 6018 6705 Rockledge Drive, MSC 7965 Bethesda, MD 20892-7965 Telephone: (301) 435-0806 FAX: (301) 480-3660 Email: meyerj@ncrr.nih.gov Direct inquiries regarding fiscal matters to: Ms. Mary Niemiec Section Grants Management Officer Office of Grants Management National Center for Research Resources One Rockledge Centre, Room 6086 6705 Rockledge Drive, MSC 7965 Bethesda, MD 20892-7965 Telephone: (301) 435-0844 FAX: (301) 480-3777 Email: maryn@ncrr.nih.gov 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. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to all priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. 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 NIH, unless there are clear and compelling 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. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.333. Awards are made under authorization of the Public Health Service Act, Titles III and IV, Sections 301, 479, and 480, as amended, Public Laws 78-410 and 99-158, 42 U.S.C. 241, 287, and 287a, as amended, and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CRF Part 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 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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