Full Text DC-96-002 CLINICAL TRIALS COOPERATIVE GROUPS NIH GUIDE, Volume 24, Number 34, September 29, 1995 RFA: DC-96-002 P.T. 34 Keywords: Communicative Disorders, Hearing Communicative Disorders, Speech Clinical Trial National Institute on Deafness and Other Communication Disorders Letter of Intent Receipt Date: November 1, 1995 Application Receipt Date: April 11, 1996 PURPOSE The National Institute on Deafness and Other Communication Disorders (NIDCD) invites applications from organizations, institutions, or groups of institutions that have the capability and resources to organize multicenter cooperative clinical trials of the efficacy of treatment for diseases and disorders of human communication. These consortia, referred to as Cooperative Groups, will plan, implement, conduct, analyze, and disseminate results of clinical studies on the treatment or management of diseases and disorders of hearing, balance, smell, taste, voice, speech or language, or any combination thereof. The goal of these studies will be to evaluate: (1) innovative therapeutic approaches; (2) established but controversial therapeutic approaches; or (3) modifications in existing therapeutic approaches to diseases and disorders affecting the processes involved in human communication. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Clinical Trials Cooperative Groups, is related to the priority area of diabetes and chronic disabling diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001- 00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local government, and eligible agencies of the Federal government. Foreign organizations are not eligible to apply. Domestic applications may not include international components. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT The administrative and funding mechanism to be used to support this program will be the 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 the 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. Details of the responsibilities, relationships, and governance of a study funded under cooperative agreement(s) are discussed later in this document under the section "SPECIAL REQUIREMENTS: B. Terms and Conditions of Award." The total project period for an application submitted in response to this RFA may not exceed five years. The anticipated award date is December 1, 1996. Because the nature and scope of the research studies proposed in response to this RFA may vary, it is anticipated that the sizes of awards will vary also. Awards and level of support will depend on receipt of a sufficient number of applications of high scientific merit. At this time, the NIDCD has not determined whether and how support for the Cooperative Groups will be continued beyond the period specified in the present RFA. FUNDS AVAILABLE The estimated total funds (direct and indirect costs) available for the first year of support for awards under this RFA will be $2,000,000. In Fiscal Year 1997, the NIDCD plans to award up to two Clinical Trials Cooperative Groups. It is anticipated that the size of awards will vary depending on the number of participating institutions and the number of potential study participants. The usual PHS policies governing grants administration and management will apply. Although this program is provided for in the financial plans of the NIDCD, awards pursuant to the RFA are contingent upon the availability of funds for this purpose. Funding in the second and subsequent years of the grant will also be contingent upon satisfactory progress during the preceding years and availability of funds. RESEARCH OBJECTIVES The objective of this RFA is to provide support for clinical trials collaborative groups proposing to access the appropriate populations and to provide the expertise to construct and conduct controlled clinical trials addressing issues in the treatment of diseases and disorders affecting hearing, balance, smell, taste, voice, speech, or language. The primary goal is to evaluate existing and new therapeutic strategies and interventions, based upon emerging knowledge of the biological and other factors influencing disease development and progression and treatment outcome. This initiative is specifically designed to strengthen the coordination of the NIDCD clinical research agenda with progress in basic research, and to emphasize the rapid integration of these discoveries into multidisciplinary clinical research. The primary objectives of the studies include the design and execution of common protocols to determine the efficacy of treatment in a controlled manner for established but controversial therapeutic approaches to the treatment and/or alleviation of diseases and disorders affecting human communication; and innovative therapeutic approaches, including modifications in existing therapeutic approaches. Study Design The Cooperative Group must be able to transform a new research concept into an active protocol; conduct the study within a specified time period; analyze and publish the results in peer-reviewed publications for the benefit of the entire scientific community; integrate findings with current research; and develop subsequent research concepts. The Cooperative Group will identify key questions substantiating the need for specific clinical trials in human communication, and formulate scientific agendas prioritized according to public health need for approval by the NIDCD. The Cooperative Group will secure support for patient care and related costs to enable the proposed trials to run to completion, providing administrative, data management, and statistical support for the planning, implementation, execution, analysis and dissemination of the results of the clinical trials. It will also provide quality assurance monitoring. A separate Data and Safety Monitoring Committee will be established for each clinical trial, responsible for assuring, to the extent possible, the safety of the study participants and to ensure the integrity of the study. In order to ensure a subject population of adequate size for the study, a collaborative effort will be required by participating Clinical Facilities. In this collaborative effort, the Clinical Facilities will follow a uniform study protocol, standardized treatment regimens, and predetermined data collection procedures. It is anticipated that although most studies will be carried out consecutively, some concomitant studies are possible since additional protocols may be developed and implemented throughout the award period. SPECIAL REQUIREMENTS A. Study Organization 1. Executive Policy Board An Executive Policy Board, responsible for establishing policy and procedures and for representation of each participating institution and the awardee organization, will be established to serve as the main governing body of the study. This committee will be responsible for overseeing all scientific and operational activities of the Cooperative Group including, but not limited to, scientific directions; policies and bylaws; standards of performance; study oversight; evaluation of collaborating institutions; and criteria and review procedures for the distribution of funds. The Executive Policy Board will also develop research hypotheses and ensure that individual protocols are prioritized among existing protocols. At a minimum, the Executive Policy Board will be composed of the Cooperative Group Principal Investigator (CGPI) who has scientific responsibility for the project as a whole, including all Cooperative Group-related research activities performed under it; a representative from the Cooperative Group Coordinating Center (see A.5. below); an epidemiologist; the NIDCD Project Scientist; and the Principal Investigator of each Clinical Facility (see A.8. below), whether a single institution or a consortium of institutions. Senior Investigators, responsible for on-site scientific direction and implementation of the protocol at institutions participating in a consortium arrangement, will not be considered as members of the Executive Policy Board. The CGPI must have substantial experience in both the treatment of diseases and disorders affecting human communication, and the design, implementation, and evaluation of clinical trials. Principal Investigators must have knowledge of the diseases and disorders affecting human communication, and experience in the design, implementation, and evaluation of clinical studies or clinical trials. All major scientific and operational decisions will be determined by the Executive Policy Board, with each member having one vote. The Chairperson will be selected by the Executive Policy Board from among the CGPI and Principal Investigators during the first meeting of the Board. The Executive Policy Board will be responsible for organizing and conducting Cooperative Group meetings. Three subcommittees of the Executive Policy Board must be established: (1) a Protocol Writing Subcommittee; (2) a Quality Assurance Subcommittee; and (3) a Publication Subcommittee, described in sections A.2., A.3., and A.4. below, respectively. Additional subcommittees may be established as necessary. 2. Protocol Writing Subcommittee of the Executive Policy Board The Executive Policy Board will establish a Protocol Writing Subcommittee with primary responsibility for developing research designs and protocols. Topics for the protocols will be proposed by the Executive Policy Board. Following NIDCD concept concurrence of protocol hypotheses for public health needs, the protocols will be written by the Protocol Writing Subcommittee, whose membership may be broadened beyond the membership of the Executive Policy Board. Proposed protocols will then proceed forward to the NIDCD for peer review for scientific merit (see A.6 below). Each protocol should include a controlled clinical trial designed to determine the efficacy of innovative therapeutic approaches, established but controversial therapeutic approaches, or modifications in existing therapeutic approaches for diseases and disorders affecting the processes involved in human communication. Each protocol must address randomization of treatment groups and complete and unbiased outcome ascertainment. It is anticipated that additional research hypotheses with subsequent protocol development, in addition to the detailed protocol submitted with this application (see "SPECIAL REQUIREMENTS: C. Minimum Requirements for Application"), may be proposed during the award period. 3. Quality Assurance Subcommittee of the Executive Policy Board The Executive Policy Board will establish a Quality Assurance Subcommittee. For the purposes of this RFA, a quality assurance program is defined as the philosophy, procedures, and methods for generating, collecting, processing, and analyzing data aimed at guaranteeing its reliability and validity. The Quality Assurance Subcommittee will have primary responsibility for monitoring the quality of diagnostic and therapeutic performance of the Clinical Facilities. The monitoring of the Clinical Facilities will include both remote (information questionnaire) and on-site activities. Issues to be considered in monitoring Clinical Facilities include, but are not limited to, status of facilities and equipment; calibration of equipment; patient/study records; proper surgical, laboratory and patient care techniques; adherence to protocol; and forms of therapy. Reports prepared by the Quality Assurance Subcommittee will be provided to the Executive Policy Board and the NIDCD, with copies provided to the Clinical Facility under examination. The Executive Policy Board is responsible for responding to reports of the Quality Assurance Subcommittee and for determining appropriate follow-up actions to recommendations of the Quality Assurance Subcommittee. Responses and actions should be recorded and the report forwarded to the Executive Policy Board, the NIDCD, and the Clinical Facility. Copies will also be provided to the Data and Safety Monitoring Committee upon request, forwarded through the Executive Policy Board (see A.7. below). The membership of the Quality Assurance Subcommittee may be broadened beyond the membership of the Executive Policy Board. 4. Publication Subcommittee of the Executive Policy Board The Publication Subcommittee will have primary responsibility for the establishment of all policies and bylaws regarding Cooperative Group publications, and for writing scientific publications resulting from the Cooperative Group. The Executive Policy Board will approve all policies, bylaws, and products of the Publication Subcommittee, and resolve issues related to scientific content, authorship, and journal selection. All manuscripts must be reviewed and approved by the Executive Policy Board, the Publication Subcommittee, and submitted to the NIDCD Project Scientist. 5. Coordinating Center The Coordinating Center is responsible for providing data management and coordination assistance to the Cooperative Group. The Coordinating Center will have primary responsibility for supporting the Cooperative Group activities and providing operational, data management, analysis and statistical support, and technical services addressing methodological issues. Specifically, the Coordinating Center will: (1) determine patient eligibility and provide subsequent registration; (2) provide randomization; (3) receive consent and data forms and enter the data; and (4) analyze data. The Coordinating Center will be responsible for receiving and processing proposed protocols; tracking ongoing protocol status; preparing and transmitting status reports to the NIDCD; coordinating submission of protocols, consent forms, site registration, local Institutional Review Board approval documents and other information, as appropriate; preparing a list of responsibilities delineating the role of industry, the Cooperative Group, and the NIDCD in each of the trials; and developing manuals of operations. The Coordinating Center will also provide the technical assistance and data management services to the Clinical Facilities with respect to quality control, uniformity of data collection, management of the collective database, and data analysis. The Coordinating Center will also develop monitoring guidelines to ensure compliance with protocols; signing and filing of consent forms; current information for contacting trial participants; status of on-site medical records; local conditions or situations; appropriate storage and dispensation of patient records; agreement of reported data with other available records; observation of standardized interviews; data handling techniques; and training of new personnel. The Coordinating Center maintains data on the performance of the Clinical Facilities, including accrual and delinquent consent and data forms, and regularly reports this information to the Executive Policy Board. Under certain circumstances, it may be appropriate for the Coordinating Center to conduct an on-site visit to a Clinical Facility. Clinical Facilities will submit data to the Coordinating Center. Specific data analyses to be carried out will initially be determined by the Coordinating Center, and the results of those analyses will be delivered to the Executive Policy Board as the group responsible for determining which further analyses should be done, how the results should be interpreted, whether the results should influence ongoing data collection, and how the findings should be disseminated. Monitoring of the Coordinating Center should include review of the timeliness and quality of centralized data analysis and reporting, assistance to the Clinical Facilities, and database errors in treatment allocation, data entry and/or procedures. 6. Protocol Review Each protocol, whether proposed in the application submitted in response to this RFA or proposed at a later date by the awardee, will be subject to peer review for scientific merit by a scientific review committee, to be established and administered by the Scientific Review Branch, Division of Extramural Activities, NIDCD. Hypotheses will be proposed and prioritized by the Executive Policy Board. The hypotheses will be forwarded to the NIDCD for concept concurrence in the light of public health importance and need. Those hypotheses, for which the NIDCD has concurred are an important public health need, will be assigned by the Executive Policy Board to the Protocol Writing Subcommittee for protocol development. Proposed protocols will be forwarded to the NIDCD to be peer reviewed for scientific merit. Upon receipt of a meritorious and approbative evaluation, the protocol may be implemented. Upon receipt of a less favorable evaluation for scientific merit, the protocol will be returned to the CGPI with advice. Protocols will also be subject to review and acceptance by the Data and Safety Monitoring Committee in an advisory capacity only. In summary, protocols will proceed into the implementation stage only following Executive Policy Board prioritization; NIDCD concept concurrence; peer review for scientific merit; advisory review and acceptance by the Data and Safety Monitoring Committee; and NIDCD award of funding. 7. Data and Safety Monitoring Committee A separate Data and Safety Monitoring Committee will ordinarily be established for each protocol. The primary function of the Data and Safety Monitoring Committee is to assure, to the extent possible, the safety of the study participants and to ensure the integrity of the study. The Data and Safety Monitoring Committee will be familiar with the protocol and accept the study concept, propose appropriate analyses, and periodically review data on outcome and safety. It will also review data on such aspects as participant accession, appointments and procedures; forms completion; data quality; losses to follow-up; and other measures of adherence to protocol. The Data and Safety Monitoring Committee will make independent recommendations to NIDCD concerning the continuation, termination, or modification of the trial based on ethical concerns or observed beneficial or adverse effects of any of the interventions under study. Proposed protocols will be subject to review and acceptance by the Data and Safety Monitoring Committee in an advisory capacity. The Committee membership, which must be multidisciplinary and include a biostatistician and a bioethicist, will be entirely independent of the Cooperative Group personnel and funded separately by the NIDCD. All of the voting members should be external to the investigative group, assuring independent assessment and minimizing the chances of biased data collection and ethical conflicts in cases where accumulating data suggest trends. With the exception of selected NIDCD staff and the trial biostatisticians, only voting members of the Data and Safety Monitoring Committee should be made aware of accumulating trial data. Exceptions may be made under circumstances where there are serious adverse events. Nominations for committee membership will be provided by the Cooperative Group; however, authority for membership selection resides solely with the NIDCD. Conflict of interest statements, written and oral and updated over time, will be obtained from all members of the committee. Individuals who have a conflict of interest, as determined by the NIDCD, will be excluded from service on the Data and Safety Monitoring Committee. While an Executive Policy Board member(s) may attend or be requested to attend some parts of a Data and Safety Monitoring Committee meeting, attendance will be denied in closed session when outcome data are discussed. The Data and Safety Monitoring Committee will review progress at least every six months, more frequently if determined necessary. Recommendations and a summary report of the Data and Safety Monitoring Committee's deliberations will be provided to the NIDCD within one week of each review. The NIDCD is responsible for the implementation of any recommendations. The Data and Safety Monitoring Committee will not have enforcement responsibilities. A summary report, which does not contain confidential data, will be prepared by the Data and Safety Monitoring Committee Chair and distributed to its members, the Executive Policy Board, and the NIDCD. 8. Clinical Facilities Clinical Facilities with clinical research capabilities and experience will be responsible for providing an adequate patient base and clinical expertise for the conduct of diverse clinical trials in human communication. Participating Clinical Facilities may be structured as either single institutions or consortia of institutions. Every Clinical Facility, whether a single institution or a consortium of institutions, will designate a Principal Investigator. Additionally, Senior Investigators will be designated from each institution participating in a consortium arrangement. 9. Awardee organization The awardee organization will be responsible for the development, organization and conduct of the Cooperative Group and its required entities, and also for the fiscal resources and operations. B. Terms and Conditions of Award The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator, as well as the institutional official at the time of award. These special Terms and Conditions of Award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, DHHS Grant Administration Regulations at 45 CFR parts 74 and 92, and other DHHS, PHS, and NIH Grant Administration policy statements. The administrative and funding instrument used for this program is the 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 the 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 for the project as a whole, although specific tasks and activities in carrying out the study will be shared between the awardee and the NIDCD Project Scientist. 1. Awardee Rights and Responsibilities The awardee will have primary responsibility for defining the details for the project within the guidelines of the RFA and for performing the scientific activity, and agree to accept close coordination, cooperation, and participation of NIDCD staff in those aspects of scientific and technical management of the project as stated in these terms and conditions. Specifically, the awardee has primary responsibilities as described below: Executive Policy Board Membership and Meeting Attendance The Cooperative Group Principal Investigator (CGPI) and each Principal Investigator will serve as a voting member of the Executive Policy Board and will participate in all scientific decisions. The CGPI and each Principal Investigator (or his/her designee) will be responsible for attending all Executive Policy Board meetings. The Executive Policy Board shall be responsible for determining the frequency of meetings and scheduling the time and location. There must be no less than three meetings during the first 12 months of the study and no less than two per year thereafter. The CGPI and each Principal Investigator (or his/her designee) will be expected to participate in all other Executive Policy Board activities (e.g., conference calls, special subcommittees as needed). Subcommittees of the Executive Policy Board may be established as needed. At a minimum, the Executive Policy Board will establish a Protocol Writing Subcommittee, a Quality Assurance Subcommittee, and a Publication Subcommittee. Protocol Review and Conduct Each protocol will undergo peer review for scientific merit. Protocols will also be subject to review and acceptance by the Data and Safety Monitoring Committee in an advisory capacity only. Upon implementation of a protocol, each Clinical Facility, whether a single institution or a consortium of institutions, will follow the procedures required by the protocol regarding study conduct and monitoring, patient management, data collection and quality control. Data Coordination and Management Each awardee will be responsible, through a Coordinating Center, for ensuring the provision of centralized data management and coordination assistance. The Coordinating Center is responsible for providing all data coordination and management, including quality control and analysis, using procedures and standards determined by the Coordinating Center. Specific analyses to be performed will initially be determined by the Coordinating Center and the results of these analyses will be provided to the Executive Policy Board as the group responsible for determining which further analyses should be done. Additional analyses may be requested by the Executive Policy Board on behalf of any of its Subcommittees or the Data Safety and Monitoring Committee. Under the direction of the Executive Policy Board, the Coordinating Center will provide technical assistance and data management services to the Clinical Facilities with respect to quality control, uniformity of data collection, management of the collective data base, and data analysis and publication. Any post- award changes in the selection of the facility or organization serving as the Coordinating Center will require NIDCD approval. The awardee will retain custody of and have primary rights to all data developed under these awards, subject to Government rights of access consistent with DHHS, PHS, and NIH policies. Data and Safety Monitoring Committee A separate Data and Safety Monitoring Committee will ordinarily be established for each protocol. The Data and Safety Monitoring Committee will make independent recommendations to NIDCD concerning the continuation, termination or modification of the trial based on ethical concerns or observed beneficial or adverse effects of any of the interventions under study. The Committee membership, which must be multidisciplinary and include a biostatistician and a bioethicist, will be entirely independent of the Cooperative Group personnel and funded separately by the NIDCD. Nominations for committee membership will be provided by the Cooperative Group; however, authority for membership selection resides solely with the NIDCD. Conflict of interest statements, both written and oral and updated over time, will be obtained from all members of the committee. Individuals who have been determined by the NIDCD to have a conflict of interest will be excluded from service on the Data and Safety Monitoring Committee. Recommendations and summary reports of Data and Safety Monitoring Committee deliberations will be forwarded to the NIDCD within one week of each review. A summary report, which does not contain confidential data, will be prepared by the Data and Safety Monitoring Committee Chair and distributed to its members, the Executive Policy Board, and the NIDCD. The NIDCD is responsible for the implementation of any recommendations. The Data and Safety Monitoring Committee will not have enforcement responsibilities. Study Materials The Coordinating Center will be responsible for the acquisition and distribution of those study materials involved in the protocol. The Coordinating Center will also arrange for the appropriate approvals (when necessary) from the Food and Drug Administration (FDA) and the Bureau of Biologics (BOB) with respect to the use of investigational drugs. Publication and Presentation of Study Findings Early publication of major findings is encouraged. Review and approval by the Executive Policy Board will be required for all analyses prior to publication or presentation according to criteria that will be developed by the Executive Policy Board. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgement of support by both the Cooperative Group and NIH/NIDCD. Analyses to be performed using the data will be determined and directed by the Executive Policy Board in conjunction with the Coordinating Center. Clinical Facilities wishing to perform analyses of local data must obtain consent of the NIDCD Project Scientist for any such analyses prior to initiation. Monitoring Study Progress The Executive Policy Board, through a Quality Assurance Subcommittee, will establish mechanisms for assessing and evaluating the quality of the diagnostic and therapeutic performance of the Clinical Facilities, whether individual institutions or institutions participating in consortia arrangements. All reports and recommendations will be forwarded from the Quality Assurance Subcommittee to the Executive Policy Board. Organizational Changes Each awardee is responsible for developing a plan for managing organizational changes. These include the changes of the CGPI, Principal or Senior Investigator, affiliate, component, or research facility or organization that is associated with this study. A change in the CGPI, or in any key personnel identified on the Notice of Award, as well as the facility serving as the Coordinating Center, must have the prior written approval of the NIDCD Grants Management Specialist in consultation with the NIDCD Project Scientist. 2. NIDCD Staff Responsibilities The NIDCD will have a staff representative known as the NIDCD Project Scientist. The NIDCD Project Scientist will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination above and beyond normal program stewardship for grants, as described below: The NIDCD Project Scientist will serve as a voting member and attend all Executive Policy Board meetings; will participate in other Board activities (e.g., conference calls, special subcommittees); will serve on Executive Policy Board Subcommittees; will participate in periodic on-site monitoring; will serve as a member of the Protocol Writing Subcommittee and will assist the Subcommittee in protocol development; will attend protocol peer reviews; will serve as a resource in the development of operations manuals; and will serve as a resource to the Quality Assurance Subcommittee of the Executive Policy Board in the development of mechanisms and procedures for monitoring quality of diagnostic and therapeutic performance of the Clinical Facilities. The Government, through the NIDCD Project Scientist, will have access to data generated under this Cooperative Agreement at the end of each clinical trial. The awardee will retain custody of and have primary rights to all data developed under these awards subject to regulations regarding Government rights to access. The NIDCD Project Scientist will review the progress of each Cooperative Group and Clinical Facility through consideration of the annual reports, site visits, patient logs, etc. This review may include, but is not limited to, compliance with the study protocol, meeting patient enrollment targets, adherence to uniform data collection procedures, and the timeliness and quality of data reporting. The NIDCD reserves the right to terminate or curtail the study (or any individual study component at any individual Clinical Facility) in the event of: (1) substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breach of the protocol; (2) substantive changes in the agreed- upon protocol to which the NIDCD does not agree; (3) reaching a major study endpoint substantially before schedule with persuasive statistical significance; or (4) human subject ethical issues that may dictate a termination. 3. Collaborative Responsibilities An Executive Policy Board, responsible for establishing policy and procedures and for representation of each participating institution and the awardee organization, will be established to serve as the main governing body of the study. This committee will have primary responsibility for overseeing all scientific and operational activities of the Cooperative Group. At a minimum, the Executive Policy Board will be composed of the CGPI who has scientific responsibility for the project as a whole, including all Cooperative Group-related research activities included under it; a representative from the Cooperative Group Coordinating Center; an epidemiologist; the NIDCD Project Scientist; and the Principal Investigator of each Clinical Facility, whether a single institution or a consortium of institutions. All major scientific and operational decisions will be determined by the Executive Policy Board, with each member having one vote. The Executive Policy Board will establish three subcommittees. The Protocol Writing Subcommittee will have primary responsibility for the development of research designs and protocols. Hypotheses for the protocols will be proposed by the Executive Policy Board and forwarded to the NIDCD for public health concept concurrence. Following NIDCD concurrence, the protocol will be written by the Protocol Writing Subcommittee. Proposed protocols will then proceed forward to peer review for scientific merit. Upon receipt of peer review approval of the protocol, the protocol may be implemented. Protocols will proceed into the implementation stage only following hypothesis prioritization by the Executive Policy Board; NIDCD concept concurrence; peer review; advisory comment by the Data and Safety Monitoring Committee; and NIDCD award of funding. A Quality Assurance Subcommittee and a Publication Subcommittee will also be established. The Quality Assurance Subcommittee will have primary responsibility for the monitoring of quality of diagnostic and therapeutic performance of the Clinical Facilities. Reports prepared by the Quality Assurance Subcommittee will be available to the Data and Safety Monitoring Committee upon request, forwarded through the Executive Policy Board. The Publication Subcommittee will have primary responsibility for the establishment of all policies and bylaws regarding Cooperative Group publications, and for the writing of scientific publications resulting from the Cooperative Group. The Executive Policy Board will approve all policies, bylaws, and products of the Publication Subcommittee. The Data and Safety Monitoring Committee will have primary responsibility for assuring, to the extent possible, the safety of the study participants and to ensure the integrity of the study. The Data and Safety Monitoring Committee will make independent recommendations to NIDCD concerning the continuation, termination or modification of the trial based on ethical concerns or observed beneficial or adverse effects of any of the interventions under study. The Committee membership, which must be multidisciplinary and include a biostatistician and a bioethicist, will be entirely independent of the Cooperative Group personnel and funded separately by the NIDCD. Reports from the Quality Assurance Subcommittee of the Executive Policy Board will be available to the Data and Safety Monitoring Committee upon request. Once a protocol is initiated, Clinical Facilities, whether individual institutions or consortia of institutions, will be required to accept and implement the protocol and procedures delineated within, including study conduct and monitoring, patient management, data collection and quality control. 4. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award) between award recipients and the NIDCD may be brought to arbitration. An arbitration panel will be composed of three members: one selected by the Executive Policy Board [with the NIDCD Project Scientist not voting] or by the individual awardee in the event of an individual disagreement; a second member selected by the NIDCD; and a third member selected by the two prior members. This special arbitration procedure in no way affects the awardee's rights to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR part 50, subpart D, and DHHS regulation at 45 CFR part 16. 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 subpopulations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some new provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11. Investigators may obtain copies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by November 1, 1995, a letter of intent that includes a descriptive title of the overall proposed research; the name, address and telephone number of the Cooperative Group Principal Investigator; the number and title of this RFA; and a list of the key investigators and their institution(s). Although the letter of intent is not required, is not binding, does not commit the sender to submit an application, and does not enter into the review of subsequent applications, the information that it contains allows NIDCD staff to estimate the potential review work load and to avoid conflicts of interest in the review process. The letter of intent is to be sent to Acting Chief, Scientific Review Branch, at the address listed under INQUIRIES. APPLICATION PROCEDURES Applications are to be submitted on the research grant application form PHS 398 (rev. 5/95). These application forms may be obtained from the applicant institution's office of sponsored research or its equivalent and from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 6701 Rockledge Drive, Room 3034, MSC 7762, Bethesda, MD 20892-7762, telephone (301) 710-0267, email: girg@drgpo.drg.nih.gov. Applications from multicomponent consortia must contain a single face page, an overall budget page, and separate budget pages for each institution involved. Each application in response to this RFA is allowed 35 pages for the overall administrative plan, 4 pages for each of up to five hypotheses for which clinical trials could be designed, and 200 pages for the one protocol proposed in detail. Each application must contain a Detailed Budget for the First 12- Month Period and a Budget for the Entire Proposed Project Period for Direct Costs, including all expected costs for both the Cooperative Group structure and administration and the one research protocol proposed in detail. Biographical sketches are limited to 2 pages each. For additional information, refer to page 14 of the PHS 398 application form. Applications must address the requirements as outlined in the section "SPECIAL REQUIREMENTS: C. Minimum Requirements for Application." It is highly recommended that the applicant organization or the proposed CGPI contact the Acting Chief, Hearing and Balance/Vestibular Sciences Branch of the Division of Human Communication, in the early stages of preparing the application. (See program contact in INQUIRIES below.) Applications must be received by April 11, 1996. All components, subparts and sections of the application must be collated into the application, and the packages sent to the DRG and to the NIDCD must each be complete in themselves. Applications that do not conform to the instructions contained in the PHS 398 (rev. 5/95) application kit, will be judged nonresponsive and will be returned to the applicant. The RFA label in the application form PHS 398 must be affixed to the bottom of the face page. 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. For purposes of identification and processing, item 2 on the face page of the application must be marked "YES" and the RFA number and the words "CLINICAL TRIALS COOPERATIVE GROUP" must be typed in. Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, single-spaced photocopies, in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional exact copies of the grant application and all five sets of appendix material must also be sent to Acting Chief, Scientific Review Branch, at the address listed under INQUIRIES. Applicants from institutions that 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 conduct of the proposed research. If so, a letter of agreement from either the GCRC program director or Principal Investigator should be included with the application. The Division of Research Grants (DRG) 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 DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such applications must include an introduction addressing the previous critique. C. Minimum Requirements for Application To ensure the development of collaboration among the participants of the Cooperative Group, a minimum number of issues must be addressed in the application, as outlined below: 1. The application must contain up to five hypotheses for which clinical trial protocols could be designed to answer high-priority questions in the areas of human communication. A brief scholarly discussion, describing the problem, current knowledge in the problem area, and the experimental approach for its study, should be provided for each of these hypotheses. One of these hypotheses should be further developed and submitted as a protocol prepared in sufficient detail to undergo peer review for scientific merit. The protocol proposed in detail should meet the objectives and scope of this RFA, as well as include a discussion of the rationale for the patient population; the study design, including randomization and ascertainment of outcome; the therapeutic approach(es) selected for study; and an assessment of how anticipated study results can be expected to contribute to improvements in treatment of diseases or disorders affecting hearing, balance, smell, taste, voice, speech, or language, or any combination thereof. The submitted protocol will involve as few or as many of the Clinical Facilities as may be necessary for the recruitment of research subjects to reach significant statistical power. The submitted protocol will undergo peer review for scientific merit as part of the application (see A.6. above) submitted in response to this RFA. 2. The application should include a detailed description of an organizational and administrative structure, which includes the following components: Awardee organization; Executive Policy Board and its Protocol Writing, Quality Assurance, and Publication Subcommittees; Coordinating Center; and the Data and Safety Monitoring Committee. The Clinical Facilities in the Cooperative Group should be briefly discussed, including the reason for their selection. 3. The applicant organization and each participating institution or institution associated with a consortium must document its experience and capacity to recruit and retain pediatric and adult study participants and provide a description of the population currently available for the proposed protocols. 4. The application must identify the single applicant organization that will be legally and financially responsible and accountable for the use and disposition of funds awarded on the basis of this RFA to other institutions, consortia, and/or individual components of the Cooperative Group, and demonstrate availability of personnel and facilities capable of performing and supporting the administrative functions of the Cooperative Group. 5. The application must name a single CGPI who will have scientific responsibility for the project as a whole, including all Cooperative Group-related research activities included under it. The CGPI must have substantial knowledge of: (1) diseases and disorders affecting human communication; and (2) the design, implementation and evaluation of clinical trials. In addition, applications from institutions or consortia of institutions must name a single Principal Investigator or Senior Investigator for each participating institution (other than the applicant organization) who will be responsible for on-site scientific direction and implementation of the protocol. Principal Investigators and Senior Investigators must have knowledge of: (1) diseases and disorders affecting human communication; and (2) the design, implementation and evaluation of clinical trials or clinical studies. 6. The application must name a lead Project Coordinator who has substantial technical/administrative experience in managing patient enrollment, patient follow-up, and multisource data collection for clinical studies. Each participating institution or institution associated with an applicant consortium must also name such a Project Coordinator. 7. The application must provide a clear, concise plan in narrative and diagrammatic form that depicts the interrelationships among the members of the Cooperative Group, its relevant experience/expertise, and the contribution of each to fulfillment of the objectives of this RFA; an organizational chart of the Cooperative Group showing the name, organization, and scientific discipline of the CGPI, Principal Investigators, Senior Investigators and of all key scientific, technical and administrative personnel; and a mechanism for selecting and replacing key professional or technical personnel. 8. The application must provide a plan to assure the maintenance of close cooperation and effective communication among members of the Cooperative Group, whether a single institution or a consortium of institutions, including letters of commitment to this plan from all participating institutions. 9. The application must discuss the capability of the applicant organization and each institution or institution in an applicant consortium to participate and interact effectively in cooperative, multicenter clinical trials. 10. The application must demonstrate that consent is viewed as an ongoing process of communication with the trial participants and provide a plan to assure that the consent form is understandable, written in a language that the patient or family can understand, and be descriptive enough that the protocol and possible side effects can be easily comprehended. For trials involving special populations, such as minorities and children, steps should be taken to ensure that consent is fully informed. 11. The application must include a plan addressing data file integrity. This plan should address data backup, data security, data validation, and the timeliness of data transfer from the Clinical Facilities to the Coordinating Center. The application must also include management strategies to assure patient confidentiality such that individual patients cannot be identified from study data and information available to the public (e.g., birth or death records), while maintaining the ability to track patients for future notification. The application should also specify the time window at which all data and records from the clinical trial will be sealed. 12. The application must include a written commitment to accept the participation and assistance of NIDCD staff in accordance with the guidelines outlined under "B. Terms and Conditions of Award: 2. NIDCD Staff Responsibilities." The application must also include from each Clinical Facility a written commitment to the Cooperative Group and a willingness to serve on the Executive Policy Board and adhere to the decisions reached by that Board, including following the protocol and publication guidelines. 13. All costs required for the project must be included in the application and must be fully justified. Requested budgets should also include travel for Executive Policy Board meetings and any associated Subcommittees. Costs for the Data and Safety Monitoring Committee should not be included in the application. 14. Costs for future protocols, which may be proposed at a later date by the awardee, should be included as part of the future protocol application and be fully justified. Future protocol costs will be paid subject to determination of actual expenses. 15. The costs of patient care must not be included in the application and will not be covered by this RFA. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the NIH Division of Research Grants (DRG) and for responsiveness by NIDCD staff. 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 NIDCD in accordance with NIH peer review procedures. 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 applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Deafness and Other Communication Disorders Advisory Council. Review Criteria Each application will be evaluated for the administrative and organizational structure, the expertise and capabilities of the Coordinating Center, and the scientific merit of the protocol. Applicants are expected to submit and describe their own methods and procedures for meeting the goals of the RFA. In addition, applicants are expected to address the issues identified under "SPECIAL REQUIREMENTS," as well as criteria specific to the objectives of this RFA. The initial review group will assess the technical and scientific merit of the hypotheses, study protocol, and related factors, including: 1. The extent to which the application addresses the goals and objectives of the RFA. 2. The adequacy of the applicant's plans for addressing the special scientific and technical requirements presented in the RFA. 3. The scientific and technical significance, merit and originality of the proposed protocols and their anticipated contributions to the treatment of diseases and disorders affecting hearing, balance, smell, taste, voice, speech, or language, or any combination thereof. 4. Qualifications, experience, and availability of the Cooperative Group in the content area of disorders and diseases of the processes of human communication and clinical trial design, conduct and analysis. 5. Documentation of the availability of adequate patient populations; experience and expertise of the key personnel, including the availability of the necessary Clinical Facilities for the recruitment, retention and follow-up of study participants; and adequacy of ethical and human safety issues, including current IRB approvals and informed consent/assent forms. 6. Adequacy of plans to include both genders and 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. 7. Documentation of the sponsoring organization's or institution's commitment to the Cooperative Group, including support for membership of the proposed Cooperative Group Principal Investigator and Principal Investigators on the Executive Policy Board; willingness to abide by the scientific decisions made via consensus of Executive Policy Board members; and willingness to accept the participation and assistance of NIDCD staff. 8. Adequacy of the proposed plan for coordination and communication within the applicant organization, and with Clinical Facilities and institutions participating in consortia-type arrangements, particularly with respect to multicenter clinical trials. 9. Adequacy of available laboratory and Clinical Facilities, including information on the institution's present patient load, and access to and projections for patient involvement in clinical investigations. 10. The scientific and technical significance and originality of the proposed protocols. 11. Appropriateness of the proposed budget and requested period of support. AWARD CRITERIA Recommendations of the initial review group will receive a second level of review by the National Deafness and Other Communication Disorders Advisory Council for consideration of programmatic needs and priorities. Funding decisions will be made on the basis of scientific and technical merit, program needs and balance, and the availability of funds. INQUIRIES Written and telephone 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: Amy M. Donahue, Ph.D. Division of Human Communication National Institute on Deafness and Other Communication Disorders Executive Plaza South, Suite 400C 6120 Executive Boulevard MSC 7180 Bethesda, MD 20892-7180 Telephone: (301) 402-3458 FAX: (301) 402-6251 Email: Amy_Donahue@nih.gov Direct inquiries regarding review issues, address the letter of intent to, and mail two copies of the application and all five sets of appendices to: Acting Chief, Scientific Review Branch Division of Extramural Activities National Institute on Deafness and Other Communication Disorders Executive Plaza South, Suite 400C 6120 Executive Boulevard MSC 7180 Bethesda, MD 20892-7180 Telephone: (301) 496-8683 FAX: (301) 402-6250 If the package for NIDCD is to be sent via overnight, express mail or courier service, the zip code should be changed to 20852. Direct inquiries regarding fiscal matters to: Grants Management Officer National Institute on Deafness and Other Communication Disorders Executive Plaza South, Suite 400B 6120 Executive Boulevard MSC 7180 Bethesda, MD 20892-7180 Telephone: (301) 402-0909 FAX: (301) 402-1758 Schedule Letter of Intent Receipt Date: November 1, 1995 Application Receipt Date: April 11, 1996 Scientific Review Date: July 1996 Advisory Council Date: October 1996 Earliest Award Date: December 1, 1996 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, No. 93.173. Awards will be made under the authority of the Public Health Service Act, Title III, Section 301 (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR part 52 and 45 CFR part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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