ADULT THERAPEUTIC CLINICAL TRIALS PROGRAM FOR AIDS Release Date: July 29, 1998 RFA: AI-98-013 P.T. National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: September 11, 1998 Pre-application Conference Date: September 18, 1998 Application Receipt Date: January 15, 1999 PURPOSE The Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID) announces the availability of a Request for Applications (RFA) to conduct adult HIV/AIDS clinical research. The purpose of this RFA is to solicit applications from institutions interested in establishing cooperative clinical trials groups to plan and direct therapeutics research. The awardees will have the capacity to conduct all phases of clinical trials in patients with early infection to advanced disease. The awardees will have the capability and expertise to address high priority research questions on the treatment and pathogenesis of HIV disease and its sequelae. The scope of activities will range from pathogenesis studies requiring in depth laboratory support to large, long term studies to evaluate clinical management strategies. 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 RFA, Adult Therapeutic Clinical Trials Program for AIDS, is related to the priority area of HIV infection. 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 institutions, such as universities, colleges, hospitals, units of State and local governments, and eligible agencies of the Federal government. An institution may submit multiple applications if different Principal Investigators are named, and there is no overlap of resources including participant patient populations. Foreign institutions are not eligible to apply as primary grantees, however, foreign institutions may participate as part of a domestic application. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. Applicants may choose to propose a research agenda either broad in scope or narrow in scope, such as a limited number of long-term studies (See Research Objectives). An applicant proposing to form an Adult Therapeutics Clinical Trials Group (see DEFINITIONS below) will coordinate the submission of an integrated package of applications that includes: (i) One Coordinating and Research Operations Center (CORC) [Core Application], (ii) One Statistical and Data Management Center (SDMC), and (iii) Clinical Site applications. An applicant may choose to use a single Coordinating Center (CC), which combines the functions of a CORC and a SDMC for operational, statistical, and data management support. The number of clinical site applications should be based on the scope of proposed research activities and on the scientific expertise to accomplish the proposed research agenda. An applicant proposing to form a Group must be capable of maintaining a minimum annual patient census of 2000 participants. Potential clinical site applicants are urged to formally affiliate with a Group applicant, although independent clinical site applications for possible later linkage with a Group will be accepted. MECHANISM OF SUPPORT The administrative and funding mechanism used to undertake 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. Details of the responsibilities, relationships, and governance of the research funded under cooperative agreement(s) are discussed in the section Terms and Conditions of Award. The total project period for an application submitted in response to this RFA may not exceed five years. The NIAID has not determined whether and how this solicitation will be continued beyond the present RFA. FUNDS AVAILABLE The estimated total funds (direct and indirect costs) available for the first year of support for awards made under this RFA will be $95 million for all Groups. The intention of the NIAID is to fund more than one Group, and to ensure that the Groups funded, in aggregate, address the research scope and objectives in this RFA. If sufficient meritorious applications are not received to achieve this goal, a portion of the funds will be withheld and an additional solicitation(s) will be released. The usual PHS policies governing grants administration and management will apply. Although this program is provided for in the financial plans of the NIAID, awards pursuant to this RFA are contingent upon the availability of funds for this purpose, and the receipt of a sufficient number of applications of high scientific merit. Funding beyond the first and subsequent years of the grant will be contingent upon satisfactory progress during the preceding years and availability of funds for this purpose. DEFINITIONS Clinical Site - A clinical unit that is a member of a cooperative network of institutions comprising the Group. A clinical site may be organized as a single main unit or a consortium including subunits under the leadership of one Principal Investigator at the main site. Coordinating and Operations Research Center (CORC) - The CORC is the central Group office and Operations Center with the Group Leader as the Principal Investigator. The CORC coordinates all aspect of the Group"s activities. Coordinating Center (CC) - A combination of the CORC and the Statistical and Data Management Center (SDMC - see below) into one organization under a single Principal Investigator. Data and Safety Monitoring Board (DSMB) - The DSMB is an independent panel of experts established by NIAID and charged with the responsibility of monitoring the progress of trials, the safety of participants, and the efficacy of treatments being tested. The DSMB also makes recommendations to NIAID concerning continuation, termination or modification of the studies based on observed beneficial or adverse effects of any of the interventions under study. This panel is funded separately by NIAID. Division of AIDS (DAIDS) - The Division within the NIAID that has the primary responsibility for basic and clinical research on HIV/AIDS. Executive/Steering Committee - The Executive/Steering Committee, established and chaired by the Group Leader, represents the main governing body of a Group. This committee is responsible for the conduct and overall activities of the Group. (See "SPECIAL REQUIREMENTS - TERMS AND CONDITIONS OF AWARD: I. Awardee Rights and Responsibilities" below.) Group - A cooperative network of institutions conducting therapeutic clinical trials under a common research agenda. A Group is comprised of clinical sites, the CORC and SDMC or the CC (a combined CORC and SDMC). Group Leader - The Group Leader is responsible for overall coordination of all Group activities both scientifically and administratively, and serves as the Principal Investigator for the CORC or CC award. Operations Center - The Operations Center is a unit within the CORC or CC that has responsibility for the administrative and fiscal management of the Group. Project 2000 Research Agenda - A document prepared by the DAIDS defining the scope of the research objectives described in this RFA. Subunit - A subunit is a clinical site supported under the fiscal and managerial direction of a main clinical site. Subunits may be established by the Principal Investigator of a main unit to support the scientific agenda and/or accrual goals. All subunits are subject to the same policies and procedures mandated by Federal regulations, DAIDS and NIAID policies, and the bylaws of the Group. Statistical and Data Management Center (SDMC) - The SDMC is the component of the Group that is responsible for statistical leadership of the Group research agenda, the statistical aspects of study design and analysis, and management of the clinical and laboratory database. Therapeutics Research Program (TRP) - The TRP is a program within the DAIDS that is responsible for the scientific, administrative, and operational management of the clinical therapeutic research programs funded by the Division. RESEARCH OBJECTIVES Background Therapeutics research sponsored by the NIAID has had dramatic impact on our understanding of the pathogenesis, and clinical management of HIV infection over the last decade. Studies conducted by the NIAID therapeutics research groups have defined international guidelines for the treatment of primary HIV infection, associated opportunistic infections, and prophylactic regimens for these secondary infections. More recent studies demonstrate that combination therapies of antiretrovirals, including potent protease inhibitors, can suppress HIV viral load to undetectable levels in many infected individuals. In spite of these advances: (i) latent virus persists in some tissue reservoirs, (ii) some patients do not achieve adequate viral suppression, (iii) the regimens are complex and adherence is an issue, (iv) long term durability and effect of these combination therapies on clinical progression is not known, (v) optimal use of these antiretrovirals has not been established, and (vi) consequences of emerging resistance on opportunistic pathogens and other complications have not been defined. Research Scope and Objectives The objective of this RFA is to establish a comprehensive program with the expertise to address these key issues, and incorporate the latest findings in HIV biology into clinical research. This will require a broad range of capabilities from small focused laboratory intense proof of concept studies to large, long term clinical trials in HIV infected populations. This research program will support a broad range of clinical trials research. Relevant areas include, but are not limited to, the following scientific needs and considerations: o new and more durable approaches to reduce viral replication and tissue burden to a minimum, including evaluation of new drugs and intervention strategies, and strategies targeted to latent HIV reservoirs and drug-resistant viruses o study designs to evaluate the long-term effects of antiretroviral therapies on the quality of life, morbidity, and mortality, and to evaluate medical management strategies that include: when to start, when to switch, and the criteria for drug selection in studies that address therapeutic and pathogenesis questions throughout the course of HIV disease from initial acute infection through advanced disease o evaluation of new strategies for enhanced reconstitution of immune responses to HIV and OIs, and evaluation of antiretroviral therapies on the success of immune-based interventions (e.g. use of vaccines to enhance HIV and OI specific immune responses) o new approaches to determine the degree of, and durability of immune restoration by potent antiretrovirals, and to identify the critical immune defects leading to development of specific opportunistic infections (OIs), and neurologic complications of HIV infection o evaluation of novel agents and regimens to treat and prevent opportunistic complications of HIV infection, particularly for individuals who do not respond to or fail antiretroviral therapy o development of more acceptable regimens that will result in better adherence and compliance SPECIAL REQUIREMENTS Terms and Conditions of Award The following terms and conditions will be referenced in the award statement, and provided to the Principal Investigator and to the institutional official at the time of award. These special Terms of Award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR part 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. The administrative and funding instrument used for this program is the cooperative agreement (U01), an "assistance" mechanism. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the research will be shared among the awardees and the NIAID Scientific Coordinator. I. Awardee Rights and Responsibilities Awardees will have primary responsibility for defining the research objectives, approaches and details of the projects within the guidelines of the RFA, and for performing the scientific activity. Awardees have primary responsibility as described below. A. Coordinating and Research Operations Center (CORC) or Coordinating Center (CC) 1) Research Agenda - The Principal Investigator (Group Leader) of the CORC or CC will be responsible for developing, implementing, monitoring, and updating the Group research agenda. 2) Bylaws/Operating Procedures - The Group Leader will be responsible for ensuring that there are well-documented policies, procedures, and Bylaws to guide all aspects of the cooperative group activities, and operations. 3) Executive/Steering Committee - An Executive/Steering Committee will be established as the main governing body of the group. The committee will be chaired by the Group Leader, and will include the Principal Investigator of the SDMC and the Director of the CORC"s Operations Center, and the DAIDS TRP Associate Director (or designee), one community representative, and at least one clinical site Principal Investigator. 4) Administrative Support - The CORC will be responsible for coordinating, administrating, and supporting all research activities at the direction of the Group Leader or designee. These activities include but are not limited to: (i) protocol development, distribution and training, (ii) administrative support for the Group Leader, scientific leadership, committees, and meeting coordination, (iii) maintenance of Group administrative records and archives, and (iv) fiscal management and oversight of the Group resources. 5) Protocol Development - The group will initiate protocol development only when there is sufficient commitment among the membership to expeditiously develop the protocol, complete accrual, analyze, and publish the research results. There must be clear procedures for designating members of protocol teams, and selecting units for limited site studies. The Group must develop a mechanism to monitor the progress of studies throughout all stages and provide status reports to DAIDS on a mutually agreed upon schedule. Early notification that a study is being considered must be provided to DAIDS to allow for comment on the scientific objectives relative to other NIAID/NIH research programs. Prior to implementation, all protocols must be submitted to DAIDS for approval based on safety, ethics, and consistency with other NIH sponsored research. DAIDS will communicate all decisions, in writing, to the Group. 6) Laboratories - The Group Leader will be responsible for establishing a laboratory network for virology, immunology, pharmacology, and other specialties in support of the research agenda. Funds will be awarded to the CORC for laboratory support. The Group Leader will: (i) identify the number, type and resources needed, and (ii) develop and implement a mechanism to evaluate performance, assess resource allocation, and redistribute funds as necessary. 7) Study Oversight - The group leadership will establish procedures to: (i) assure adequate protection of the rights and safety of subjects involved in the research, (ii) guarantee the quality and integrity of the resulting data, (iii) maintain accurate and timely information on each study, and (iv) provide interim study summaries to the DAIDS Data Safety and Monitoring Board as requested. This oversight must include compliance with all Federal regulations, and DAIDS/NIH policies and procedures. 8) Federally Mandated Regulatory Requirements - The group must be in compliance with all Federal regulations, and NIH policies applying to the conduct of research involving human subjects. These include, but are not limited to, Title 21 CFR 50, 56, 312, and Title 45 CFR 46. 9) Reporting Requirements - Administrative: The Group Leader will submit periodic reports to DAIDS on a mutually agreed upon schedule. The reports will include, for example, lists of investigators and other key personnel, all affiliated sites, protocol abstracts and tracking data, patient accrual and demographics, and publication information. Performance: The Executive/Steering Committee will establish procedures for evaluating the performance of all Group components and provide DAIDS with reports. Procedures will include processes for the addition or elimination of clinical sites or laboratories, redistribution of resources among components based on performance measures such as patient accrual/retention, data quality and scientific contribution. The process will include procedures for recommending to DAIDS adjustments to institutional budgets based on performance. Annual Report: The Group Leader will submit to DAIDS an annual report summarizing group activities, accomplishments, performance evaluations and future directions. 10) Publication of Data - Prompt and timely presentation and publication of major findings is essential and requires acknowledgment of NIAID support. Prior to the submission of manuscripts for publication a copy must be provided to DAIDS. The awardee retains the rights to the data consistent with current HHS, PHS, and NIH policies, however, DAIDS under this cooperative agreement will have access to all data and may periodically review it. 11) National Meetings - The Group is expected to hold at least one national meeting a year in the Washington, DC metropolitan area. They may choose to meet jointly with other clinical trials groups. Responsibility for logistics, scientific content, and fiscal support will be with the sponsoring group or groups. 12) Conflict of Interest - The Group will develop and implement a Conflict of Interest Policy (COI), acceptable to the NIAID, addressing any COI that may occur through financial interest or other associations between members of the Group and the private sector. 13) Discretionary Funds - The CORC will maintain and manage a discretionary fund that will be expended through procedures consistent with the Bylaws. The funds may be used for either scientific or operational needs such as, but not limited to, the addition of new clinical or laboratory sites, funding of innovative pilot studies, outsourcing laboratory work or supplementing superior performers. 14) Community Representation - The Group will develop and implement a plan for community representation in Group activities. The plan should address how the representatives" inclusion will make a substantive contribution to the overall success of the Group. 15) Demographic Diversity - The Group must have plans in place to ensure overall demographic diversity of the study participants and plans for incorporating new, minority and women investigators into the Group"s activities. 16) Collaboration - The Group will have a plan in place that details how it will interact with other NIH sponsored AIDS clinical research groups including mechanisms to integrate and complement the scientific agendas of other NIH Institutes to address specific HIV problems. B. Statistical and Data Management Center (SDMC) 1) Study Design, Conduct, Analyses, and Publications - The SDMC will be responsible for: (i) statistical leadership for the Group research agenda, (ii) performing interim analyses of safety and efficacy for protocol teams and DAIDS, (iii) generating executive summaries of near-final study results for use by the protocol team, DAIDS, and collaborators, (iv) conducting final analyses and participating on publication writing teams, (v) performing cross-protocol or cross study analyses utilizing data from multiple sources within and external to the Group, (vi) producing study monitoring reports for the Group and DAIDS, (vii) conducting analyses and summaries for annual and interim reports for DAIDS sponsored Investigational New Drug Applications, and (viii) developing innovative clinical trial designs and analysis methodologies consistent with the Group research agenda. 2) Data Management The Statistical and Data Management Center will: (i) provide central registration and randomization for all study subjects, (ii) develop case report forms and standardized criteria for clinical endpoint verification, (iii) design and implement systems for the efficient tracking and transfer of clinical, and laboratory data (including quality assurance and specimen tracking) to the central database, (iv) provide data management training to the clinical sites, laboratories, and the DAIDS Clinical Site Monitoring Contractor, (v) provide CRF notebooks to collaborators, (v) provide for central storage, security, processing and retrieval of study results, and (vi) prepare selected public access databases. 3) Collaborations - When collaborating with other clinical study Groups, procedures of conduct will be determined by the Associate Director, Therapeutics Research Program (TRP) and the leadership of each participating Group. Generally, the procedures of the lead Group will be followed. 4) Management - The SDMC must have a management plan and agree to abide by the Bylaws of the Group. C. Coordinating Center The Terms of Award for the CORC and SDMC presented above will be merged into a single set of Terms for applicants choosing to use a Coordinating Center. D. Clinical Sites 1) Clinical Site Responsibilities - Each clinical unit must agree to accept, and abide by the Bylaws of the Group, the research priorities for the scientific agenda, and accept the performance standards established by the Group. DAIDS sponsored clinical research can not be initiated at any performance site until a Site Establishment Plan is approved by DAIDS. 2) Laboratory - Clinical site laboratory capabilities will be determined by the Group leadership. The responsibilities of clinical site laboratories will be defined by the Group Leader and should include: (i) processing clinical specimens, (ii) shipping of specimens to designated laboratories or repositories, and (iii) performance of standard testing and other protocol mandated testing as designated by the Group Leader. 3) Investigational Drug Management - Investigators performing clinical studies sponsored by the NIAID must comply with all Federal regulations for investigational agents, and with DAIDS Standard Operating Procedures, and Pharmacy Guidelines and Procedures. 4) Quality Management - Clinical sites must establish a quality management plan to assess the accuracy and completeness of all research records, and operating procedures. These plans are subject to approval by DAIDS for both the main site and any subsites. 5) Site Monitoring - Clinical sites shall cooperate with the DAIDS Clinical Site Monitoring contractor, and other federally supported site monitoring staff who will inspect records to assure compliance with all federal regulations, and NIH policies on patient safety, and data completeness and accuracy. 6) Participation of New Investigators, Women and, Minorities - Clinical units will establish procedures, and opportunities to ensure the participation of new investigators, especially women, and racial/ethnic minorities, in all aspects of the research effort. 7) Community Advisory Boards (CAB) - All units must establish a CAB representative of the HIV infected community of the catchment area. The unit should have plans that demonstrate how the CAB will be included in the activities to substantively contribute to the success of the unit. Funds requested in the application must be made available to the CAB for reimbursement of reasonable expenses including representation at the annual Group meeting(s). II. NIAID Responsibilities The NIAID will have substantial scientific programmatic involvement during the conduct of this research activity, through technical assistance, advice, and coordination. The role of DAIDS staff described in these Terms is to assist and facilitate. Communication will be primarily with the Group Leader and the scientific leadership. However, DAIDS will interact with the Principal Investigators of any affiliated institution as needed. The following are specific responsibilities of DAIDS staff in terms of interventional clinical research, and the NIAID"s role as a INDA sponsor as defined in 21 CFR Part 312. 1) Scientific Role in NIAID Sponsored Clinical Research - The Associate Director, TRP or designee will: (i) serve as a source of information on related research of other investigators or Groups, and (ii) work closely with the Executive/Steering Committee to assure that the research efforts are consistent with the NIAID priorities for HIV clinical research, and complement those of other NIAID and NIH programs. The DAIDS will serve as the liaison between pharmaceutical companies, the FDA, and the Group. 2) DAIDS Role in Protocol Development - In order for a clinical study to be initiated, the protocol must be approved by the chair of the DAIDS Clinical Science Review Committee (CSRC). Once notified that a study is under consideration, the CSRC will evaluate the proposal relative to: (i) the NIAID priorities for HIV clinical research and other NIAID/NIH related research, (ii) subject safety, (iii) compliance with Federal regulations, (iv) study oversight and monitoring, and (v) feasibility of timely completion. The Associate Director, TRP will return comments and recommendations to the Group within 30 days after review. A DAIDS pharmacist will participate on the protocol team, consult on the pharmaceutical aspects of protocol development and will interact with pharmaceutical companies to ensure product availability. If a protocol is disapproved, DAIDS will not provide study agents or permit expenditure of NIAID funds. 3) DAIDS Involvement in IND Applications - The DAIDS will have the option to cross-file or independently file an INDA for study agents evaluated in Group studies. The Chief, Pharmaceutical and Regulatory Affairs Branch (PRAB) will advise the investigators on specific regulatory requirements for INDA sponsorship. 4) Clinical Trials Agreements (CTA) - When a pharmaceutical collaborator provides a study agent to DAIDS, a CTA will be negotiated describing respective responsibilities and rights. The agreement will include, but is not limited to, INDA sponsorship, safety and data monitoring, and access to data. The Group Leader generally will be consulted on the terms prior to the execution of the CTA. Pharmaceutical collaborators generally request that patentable inventions discovered through the studies are brought to their attention, and the company has rights of first refusal provided that the collaborator has rights to the background patent. Investigators will be required to agree to these terms. 5) DAIDS Role During Study Conduct - A DAIDS Medical Officer will monitor the safety and efficacy of the intervention(s) for ongoing studies, and will be provided with interim and final reports. When a collaborating institution or research group sponsors a protocol, their medical representatives will conduct monitoring activities. 6) DAIDS Role in Protocol Closure - The Associate Director, TRP will monitor the progress of the studies by reviewing reports submitted to DAIDS through a Data Safety and Monitoring Board, and through regular meetings with the Group Leadership. DAIDS may find it necessary to terminate an ongoing study for any of the following reasons: (i) risk to subject safety, (ii) the scientific question is no longer relevant or the objectives will not be answered, (iii) slow accrual, or (iv) the objectives of the study have been met. 7) Access to Data - The Associate Director, TRP or designated DAIDS contractor will have access to all data generated under this cooperative agreement, and may review the data as recorded on the case report forms or in the central database. Data must be available for external checking against the original source documentation as required by federal regulations. The awardees will retain the primary rights to the data consistent with HHS, PHS, and NIH policies. The DAIDS has an external Clinical Site Monitoring Contract to evaluate good clinical research practice, regulatory compliance, accurate protocol implementation, internal quality management, and test product accountability. The monitoring contractor will visit performance sites quarterly or as needed to review selected protocols, provide training on protocol conduct, review internal QM plans, audit pharmacies, and document error resolution. The DAIDS may provide public access to selected data sets generated with the use of public funds within a reasonable time after the primary analysis and publication. 8) Laboratory Quality Assessment The DAIDS will provide through its contract resources support for laboratory quality assessment. Management of the contract will reside with DAIDS. Scientific and technical oversight of these contracts will be provided by DAIDS in collaboration with Group investigators, and the Chief, Drug Development and Clinical Sciences Branch. 9) SAE Reporting - In order to provide for consistent adverse experience reporting across clinical trials groups, DAIDS has established policies and procedures delineated in the Serious AE Reporting Manual. Groups, in collaboration with DAIDS, will have the responsibility for ongoing maintenance of the modified ICD-9 system for classifying and coding the types of adverse experiences reported. 10) DAIDS as a Resource for Performance Evaluation - The performance of all Group components will be reviewed annually by the Associate Director, TRP using the comprehensive annual progress report, and site monitoring reports provided to DAIDS by its contractor. The Chief, Clinical Research Management Branch, and the Chief of the Drug Discovery and Clinical Sciences Branch, TRP will assist the Group in developing evaluation instruments. Substandard data, insufficient subject accrual or retention, inadequate progress in fulfilling the research agenda, non-compliance with federal regulations or these Terms of Award may result in a reduction in budget, withholding of support or termination of award. If the Group Leader proposes to redirect resources among affiliated member awards, DAIDS concurrence is required. III. Collaborative Responsibilities 1) Group Governance - The Group Leader will establish an Executive/Steering Committee as the central decision making body for the Group. The Committee will include the DAIDS TRP Associate Director (or designee) as a voting member. A Chairperson, other than the DAIDS Official, will be elected by the Group membership as defined in the Bylaws. 2) Coordination - To facilitate the overall coordination and integration of the NIAID HIV/AIDS therapeutics research agenda, the Associate Director, TRP will establish forums for sharing information, plans, and establishing collaborations, generally around scientific gaps in the overall national effort, emerging scientific needs or unique opportunities. The forum(s) will be convened at a minimum annually. 3) Annual Review - A subcommittee of the AIDS Research Advisory Committee (ARAC), supplemented by ad hoc members as needed, will review the progress and research priorities of the aggregate HIV therapeutic clinical trials system of the NIH annually. It will provide advice to DAIDS, NIAID, and OAR on overall intergroup coordination, and identify research gaps that are not being addressed by the individual Groups. On an annual basis the leadership of each clinical trials Group will meet with the subcommittee of the ARAC to present and discuss their annual reports. DAIDS will coordinate these meetings, and will be represented on the subcommittee, and will be responsible for implementing recommendations as appropriate and necessary. IV. Arbitration Any disagreement that may arise on scientific or programmatic matters (within the scope of the award) between award recipients and the NIAID may be brought to arbitration. An arbitration panel will be composed of three members: one selected by the Executive/Steering Committee (with the NIAID member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by the NIAID, and the third member with expertise in the relevant area, selected by the first two members to review any scientific or programmatic issue that is significantly restricting progress. While the decisions of the Arbitration Panel are binding, these special arbitration procedures will in no way affect the awardee"s right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, subpart D, and HHS regulations at 45 CFR Part 16. Cooperative agreements are subject to the administrative requirements outlined in OMB circulars A-102 and A-110. All pertinent HHS, PHS, and NIH grant regulations, policies and procedures, with particular emphasis on PHS regulations at 42 CFR Part 52 and HHS regulations at 45 CFR Part 74, are applicable. These special terms and conditions pertaining to the scope and nature of the interaction between the NIAID and the investigators will be incorporated in the Notice of Grant Award. However, these terms will be in addition to, not in lieu of, the customary programmatic and financial negotiations that occur in the administration of cooperative agreements. 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, compelling rationale, and justification are provided 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 "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research", published in the Federal Register of March 28, 1994 (FR 59 14508- 14513) and the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, which is available via the WWW. at: NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and which is available at the following URL address: For the purpose of this RFA adults are defined as persons 13 years of age and older. The NIH has other programs for HIV clinical research in children under 13 years of age. Investigators may obtain copies from these sources or from Dr. Frederick Batzold (listed in INQUIRIES below) who may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective Group applicants are asked to submit a letter of intent by September 11, 1998 that includes a descriptive title of the overall proposed research, the name, address and telephone number of the Principal Investigator, affiliated institutions and the lead investigators, and the number and title of this RFA. Applicants affiliated with a Group need not submit a letter of intent, however, independent clinical sites unaffiliated with a Group are asked to submit a letter of intent. 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 allows NIAID staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Peter Jackson at the address listed under INQUIRIES. APPLICATION PROCEDURES Pre-Application Meeting On September 18, 1998, there will be a one-day meeting in the Washington, DC metropolitan area to provide potential applicants with background information and to answer questions from potential applicants. Details for the meeting and a summary of the results of this meeting that will include NIAID responses to all questions raised by attendees at the meeting will be available upon request and via an NIAID Internet site. Applications. Applications are to be submitted on the grant application form PHS 398 (rev. 5/95). Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email: Application kits also may be obtained electronically via the WWW at: For purposes of identification and processing, item 2 on the face page of the application must be marked "YES" and the RFA number "AI-98-013" and the words "Adult Therapeutic Clinical Trials Program for AIDS" must be entered on the face page. Application packages or independent clinical site applications must be received by January 15, 1999. Applications that are not received on the receipt date or do not conform with the instructions contained in Form PHS 398 (rev. 5/95) Application Kit (as modified in, and superseded by, the special instructions below, for the purposes of this RFA), will be judged non-responsive and will be returned to the applicant. The RFA label available 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. If the application submitted in response to this RFA is substantially similar to a grant application already submitted to the NIH for review, that has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will essentially identical applications be reviewed by different review committees. Therefore, an application that is essentially identical to one that has already been reviewed cannot be submitted in response to this RFA. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. It is highly recommended that the appropriate NIAID program contact (See program contacts under INQUIRIES) be consulted before submitting the letter of intent and during the early stages of preparation of the application. Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, single-sided copies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional exact copies of the grant application and five sets of any appendix material must be sent to Dr. Peter Jackson 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 conducting the proposed research. If so, a letter of agreement from either the GCRC Program Director or Principal Investigator should be included with the application. SPECIAL INSTRUCTIONS APPLICATION PACKAGE A Principal Investigator who proposes to form a Group and assume the role as Group Leader is responsible for coordinating the preparation of a package that will include the following applications: One (1) Coordinating and Research Operations Center, One (1) Statistical and Data Management Center, and One (1) proposal for each individual Clinical Site [The number of clinical sites should be based on the scope of the research agenda]. If the Group Leader chooses to use a Coordinating Center for both operational and statistical and data management support, a single application should be submitted for both components. For all applications: A complete PHS Form 398 (revised 5/95) must be submitted. On Page 2 (Key Personnel) all professional personnel and their institutional affiliations for the project must be listed including those with no requested salary support. Each Biographical Sketch (limited to two pages) and Other Support pages should be listed at the end of the application with the Principal Investigator first followed by other key personnel in alphabetical order. The use of tables, diagrams, organizational and flow charts is strongly encouraged. Key information submitted as appendices should be clearly referenced in the Research Plan Section. Information submitted as appendices should be limited to essential materials in support of the application, summaries or examples of information are encouraged. Letters of support that do not formally commit to contributions to the program should not be included. A. Core Application [Coordinating and Operations Research Center (CORC)] The Research Plan (Items a-d) is not subject to the page limitations in the PHS Form 398. This section of the application should not exceed 300 Pages. The Research Plan should address the following: 1) Comprehensive Research Agenda including the research priorities, key leadership, criteria for affiliated clinical sites, and the criteria for the selection and expertise of the proposed laboratories 2) Comprehensive Management Plan that addresses: a) Bylaws for governance including the election of Group Leadership and committee membership b) Operational plans for the delegation of authorities, decision making, and fiscal management c) Performance evaluation plans and standards for participating institutions including corrective measures 3) Outreach Plan to ensure the inclusion of women, minorities and community representatives in all aspect of the proposed research and Group activities. 4) Procedures for protocol development, implementation, and oversight, committee management, and fiscal management. CORC budget requests must be related to, and justified by, the scope of activities proposed in the research agenda. A composite budget should be included, followed by individual budgets. At a minimum the budget request should include four categories: (i) Operations Center, (ii) administrative support for the Group Leader, scientific committees and annual meetings, (iii) laboratories, and (iv) discretionary funds not to exceed 3% of the total cost budget request. B. Statistical and Data Management Center (SDMC) The Research Plan (items a-d) is not subject to the page limitations in the PHS Form 398. This section of the application should not exceed 150 Pages. The Research Plan should address the following: 1) Statistical expertise that complements the Group research agenda proposed in the Core application. 2) Innovative approaches to clinical trials methodology. 3) Data management expertise including: database design and procedures for managing both clinical and laboratory data, and plans for evaluating new methodologies for data transmission and systems design. 4) Operational, procedural and overall management plans for the SDMC. The SDMC budget request must be related to the scope of activities proposed in the research agenda. C. Coordinating Center (CC) Applicants proposing an agenda of limited focus, for example, may chose to combine the activities of a CORC and SDMC into a single coordinating center. The Research Plan for the CC is not subject to the page limitations in the PHS Form 398, item a-d. Since a CC is composed of a CORC and SMDC, this section should not exceed 450 Pages. The CC application should address all the areas described for the separate CORC and SDMC applications described above. D. Clinical Sites The Research Plan (items a-d) for Clinical Site application is subject to the 25 Page limitation. The Research Plan Section should address the following: 1) Clinical sites named in the Core Application should describe site expertise, and past accomplishments in HIV clinical research and how they will contribute to the Group research agenda. Independent clinical site applications should describe site expertise and past accomplishment in HIV clinical research and how they will contribute to the Project 2000 research objectives. 2) Operational/Management Plan including subject accrual potential, quality management, and regulatory compliance. 3) Outreach Plan to assure the inclusion of women and minorities in all aspects of site activities including patient recruitment and site staffing. 4) Plan for establishing and supporting a Community Advisory Board (CAB) representative of the catchment area. Clinical site budget requests should be based on, (i) the scope of work proposed, (ii) the projected number of new subject accruals, and (iii) on-going commitments to subjects for incumbent applicants. Clinical site applicants named in the Core Application should use the resource allocation criteria developed by the Group Leadership. Independent clinical site applicants should use the projected patient census as the basis for budget development. All clinical sites must include a budget request to support CAB activities including representation at the annual Group meeting(s). REVIEW CONSIDERATIONS GENERAL CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the NIH Center for Scientific Review, and by NIAID staff for responsiveness, those judged to be incomplete or non-responsive will be returned to the applicant without review. Applications that are complete and responsive to this RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIAID. The second level of review will be provided by the National Advisory Allergy and Infectious Diseases Council. REVIEW CRITERIA The criteria to be used in the evaluation of applications in response to this RFA are listed below. A. Core Application (Coordinating and Operations Research Center) 1) Qualifications and experience of the Group Leader and the named Scientific Leadership in the design, implementation, and management of multicenter HIV clinical research. 2) Significance of the research agenda in addressing innovative approaches to HIV clinical research priorities. 3) Quality of the management plan to set/redirect priorities, initiate studies, and govern Group activities. Existing groups should present information on past performance including enforcement of Group standards. New Group applicants should present a plan for evaluating performance and ensuring compliance with the standards of the group. 4) Qualifications and experience of the CORC"s Operations Center Director and staff, and the administrative management plan. 5) Adequacy of the criteria and standards that were used for inclusion of affiliated clinical sites, the criteria that were used for the selection and expertise of the laboratories (any prior experience and/or supporting data should be included). 6) Adequacy of (i) proposed performance standards, (ii) the process for performance evaluation, and (3) resource reallocation for all Group components 7) Adequacy of the plan for the inclusion of women, minorities, and community representation in Group activities. B. Statistical and Data Management Center 1) Qualifications and experience of the Principal Investigator and staff in providing statistical and data management expertise for multicenter clinical studies including the development of innovative trial designs, and analyses consistent with the Group research agenda. 2) Quality of the plan for both clinical and laboratory database designs, data collection, cross-study analyses, security, and site specific training. 3) Quality of the plan to evaluate new technologies and data collection procedures. C. Applications proposing to use a single Coordinating Center for both operational and statistical/data management support will be evaluated on the combined criteria described above for the Core (CORC) and SDMC applications D. Clinical Sites 1) Qualifications and experience of the Principal Investigator, the staff, and clinical laboratories in conducting HIV clinical trials, and for sites included in a Core Application the ability to contribute to the Group research agenda. 2) Quality of the site management plan for conducting research studies including data management, and regulatory compliance. 3) Ability to accrue and retain a demographically diverse patient population representative of the catchment area consistent with accrual projections. 4) Adequacy of the plans to involve community representatives in all aspects of site activities. The initial review group will also examine: (i) the appropriateness of the proposed project budget and duration, (ii) the adequacy of plans to include both genders and minorities and their subgroups, and children as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects, (iii) the provisions for the protection of human and animal subjects, and (iv) the safety of the research environment. AWARD CRITERIA Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program balance, and the availability of funds. The earliest anticipated date of award is January 1, 2000. 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 (research scope and eligibility) issues and the Pre-Application Conference to: Frederick Batzold, Ph.D. Clinical Research Management Branch National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 2B27 Bethesda, MD 20892-7620 (For express mail or courier use 20852) Telephone: (301) 402-0143 FAX: (301) 480-4582 Email: Direct inquiries regarding review issues and special instructions for application preparation, address the letter of intent, and mail two copies of the application and five sets of appendices to: Peter Jackson, Ph.D. Scientific Review Program National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4C10 Bethesda, MD 20892-7610 (For express mail or courier use 20852) Telephone: (301) 496-8426 FAX: (301) 402-2638 Email: Direct inquiries regarding fiscal matters to: Ms. Ann Devine Grants Management Branch National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4B23 Bethesda, MD 20892-7610 (For express mail or courier us 20852) Telephone: (301) 496-5601 Fax: (301) 480-3780 Email: SCHEDULE Letter of intent receipt date: September 11, 1998 Pre-application Conference date: September 18, 1998 Application receipt date: January 15, 1999 Scientific review date: May 1999 Advisory Council date: September 2, 1999 Earliest award date: January 1, 2000 AUTHORITY AND REGULATIONS This program is supported under authorization of the Public Health Service Act, Sec. 301 (c), Public Law 78-410, as amended. The Catalogue of Federal Domestic Assistance Citations are Sec. 93.856, Microbiology and Infectious Diseases Research, and No. 93.855 - Immunology, Allergy, and Transplantation Research. Awards will be 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 review. The Public Health Service 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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