Full Text AI-94-028 ADULT AIDS CLINICAL TRIALS GROUPS NIH GUIDE, Volume 23, Number 32, August 26, 1994 RFA: AI-94-028 P.T. 34 Keywords: AIDS Clinical Trial National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: September 15, 1994 Application Receipt Date: January 12, 1995 PURPOSE The Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID) invites applications for cooperative agreement (U01) awards from institutions interested in participating in a cooperative group(s) that will perform Phase I, II, and III clinical evaluations of promising new interventions for the treatment of HIV disease, AIDS, and opportunistic diseases resulting from HIV infection including malignancies and neurologic complications. The institutions will conduct multi-center clinical trials involving adult participants. Each group of collaborating institutions awarded cooperative agreements as a result of this competition will be referred to as an Adult AIDS Clinical Trials Group (ACTG). 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), Adult AIDS Clinical Trial Group, 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 "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202/783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic non-profit and for-profit organizations, public and private organizations, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign organizations are not eligible to apply. Applications from minority individuals and women are encouraged; funds are being set-aside for minority institutions (see FUNDS AVAILABLE). Eligible institutions may apply for one or more of the following types of awards: o Adult ACTG Central Group o AIDS Clinical Trials Unit (ACTU) o Statistical and Data Management Center Separate applications must be submitted for each type of award. Each Adult ACTG Central Group applicant must identify a single Statistical and Data Management Center with which it is proposing to work. Each applicant for an ACTU award must identify in a cover letter and in the body of the application the Adult ACTG Central Group with which the applicant ACTU it is proposing to collaborate. Each applicant for a Statistical and Data Management Center must identify both in a cover letter and in the body of the application the Adult ACTG Central Group with which the applicant is proposing to collaborate. (See SPECIAL INSTRUCTIONS FOR THE PREPARATION OF COOPERATIVE AGREEMENT APPLICATIONS, Identification of Potential Applicants and Formation of ACTGs, for further details.) It is the responsibility of potential applicants for an Adult ACTG Central Group award and a Statistical and Data Management Center award, as components of the ACTG, to identify themselves to each other and establish affiliations. The NIAID will facilitate the formation of an ACTG by: (1) identifying potential Adult ACTG Central Group applicants and unaffiliated potential ACTU applicants to each other; and (2) holding a pre-application meeting on September 28, 1994. Each applicant for an Adult ACTG Central Group must demonstrate the ability to recruit and support a minimum capacity of 1,250 new patients per year. Each ACTU applicant must demonstrate the capability to accrue a minimum of 75 new patients per year. It is anticipated that once the AIDS Clinical Trial Units (ACTUs) are selected and the ACTG(s) formed, the combined capacity of the ACTG or ACTGs will allow for accrual of 2,500 to 3,500 new patients per year. MECHANISM OF SUPPORT The administrative and funding instrument to be used for 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 performance of the activity. Under the cooperative agreement, the NIAID purpose is to support and/or stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships and governance of the studies to be funded under these cooperative agreements are discussed later in this document under the section "Terms and Conditions of Award." The total project period for an application submitted in response to the present RFA may not exceed five years. At present, the NIAID is administratively limiting the duration of U01 cooperative agreements to four years; this administrative limitation may change in the future. The anticipated award date is January 1, 1996. Awards and level of support depend on receipt of a sufficient number of applications of high scientific merit. 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. This RFA is a recompetition of an ongoing program (the Adult AIDS Clinical Trials Group [ACTG]). Reissuance of this initiative is uncertain. If it is determined that there is sufficient programmatic need for continuation of this program, the NIAID will invite applications for extension of this program. FUNDS AVAILABLE Approximately $60,000,000 total costs will be available in fiscal year 1996 for the first year of support for awards made under this RFA. Of this total, at least $3.5 million will be reserved exclusively to support meritorious clinical trials units (ACTUs) at minority institutions. In Fiscal Year 1996, the NIAID plans to fund one or two ACTG Central Groups, one Statistical and Data Management Center per Central Group, and 22 to 29 ACTUs. Minority institutions are defined as those that have more than 50 percent minority student enrollment and award an M.D., D.D.S., D.V.M or other doctorate degrees in the health professions. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of individual awards will vary. The level of support will be dependent upon the number of applications of high merit received and the availability of funds. Funding beyond the initial budget period at the level awarded in the first year of support will be contingent on the continued availability of funds for this purpose, and the continued progress of the ACTG. RESEARCH OBJECTIVES A. Background The emergence of the AIDS epidemic in the United States has had a major impact on public health, as well as medical, social, and economic institutions in this country. Within the U.S., over 350,000 persons have developed AIDS and over one million Americans are believed to be infected with HIV-1. In addition, it is estimated that 40,000 adults are newly infected with HIV in the U.S. every year. Particularly hard hit by the epidemic are urban centers, where an increasing number of minorities, women, and injection drug users are being infected. One critical goal of the NIAID in the field of AIDS research is the discovery and development of therapies that will improve the quality and duration of life of HIV-infected individuals. While the interests and mission of the pharmaceutical industry and NIAID overlap in the field of applied therapeutics research and development, NIAID's overall responsibility is to focus on those research opportunities of utmost importance to the public health that are not being addressed elsewhere. Considerable strides have already been made in the clinical development of antiretroviral therapies, as well as for the treatment and prophylaxis of a myriad of opportunistic infections that occur in severely immunosuppressed patients with AIDS. Nonetheless, the impact on survival and clinical disease progression of the existing approved antiretroviral therapies is of limited magnitude and duration. Furthermore, the current treatments for some of the opportunistic infections are not always effective, and breakthrough infections occur despite prophylaxis therapies. It is apparent that clinical investigations of new, innovative interventions are crucial in order to make a significant impact on survival and quality of life of the HIV-infected individual. B. Definitions Adult AIDS Clinical Trials Group (ACTG) - A collaborative group of institutions composed of a Central Group, AIDS Clinical Trials Units (ACTUs), and a Statistical and Data Management Center, which together conduct all phases of clinical trials, and laboratory studies. (see Organization of ACTG for description of all component parts.) Each ACTG consists of experienced investigators in multiple disciplines (e.g. infectious diseases, virology, immunology, clinical pharmacology, oncology, neurology, gynecology, and biostatistics). Advanced Technology Laboratory (ATL) - Additional, central laboratory capabilities that enable the ACTG to investigate the feasibility, validity, standardization and implementation of state-of-the-art assays/technologies related to the scientific agenda. Awards for ATLs are made through the ACTG Central Group award. AIDS Clinical Trials Unit (ACTU) - A clinical site that is a member of the collaborating group of institutions comprising the ACTG. The ACTU is required to participate and enroll patients in clinical trials and conduct or obtain protocol mandated laboratory tests. Collaborating Institution - An institution that is an ACTG awardee either as a Central Group, Statistical and Data Management Center, or an ACTU. Cooperative Agreement - An assistance mechanism in which substantial NIAID programmatic involvement with the recipient is anticipated during performance of the planned activity. Data Safety and Monitoring Board - The Data and Safety Monitoring Board (DSMB) is charged with the responsibility of monitoring performance of the trial, the safety of participants, the efficacy of treatments being tested, and to make recommendations to NIAID concerning the continuation, termination or modification of the trial based on observed beneficial or adverse effects of any of the interventions under study. This panel is funded separately by the NIAID. Division of AIDS (DAIDS) - The division within the NIAID that has the primary responsibility for basic and clinical research on AIDS. Executive/Steering Committee - The main governing body of the ACTG that is established and chaired by the Group Leader. This committee will be responsible for making the ultimate decisions on all scientific and operational issues of the ACTG (See Terms and Conditions of Awards). Group Leader - The individual who directs the development and implementation of the research agenda and the organizational structure and governing procedures that form the basis of ACTG operations. The Group Leader is responsible for the leadership and coordination of all ACTG activities both scientifically and administratively, and serves as the Principal Investigator for the ACTG Central Group award. The Group Leader may also be associated with an ACTU. Operations Office - An administrative unit within the ACTG Central Group that will take responsibility for coordinating ACTG activities, including protocol development and distribution, administrative support for the Group Leader and scientific leadership of the ACTG and of scientific and other committees, training sites and monitors; assembly and submission of documents to DAIDS for registration of sites for individual trials; maintenance of ACTG administrative records and archives; planning of two national meetings per year, at least one of which is held in collaboration with the Pediatric ACTG in the Washington metropolitan region; and, in conjunction with the ACTG Statistical and Data Management Center, preparation of administrative reports of ACTG activities as requested by DAIDS. Participant Subunit - An institution supported through a subcontractual agreement with one of the primary, collaborating institutions. A subunit may be established to support the scientific agenda and/or patient 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 ACTG. Statistical and Data Management Center - The statistical and data management unit that is responsible to the ACTG for the statistical aspects of study design and data analyses and management. Therapeutic Research Program (TRP) - A program within the DAIDS that is responsible for the scientific, administrative, and operational management of clinical therapeutic research programs funded by the division. C. Organization of an ACTG The ACTG Central Group will consist of: o Principal Investigator (ACTG Group Leader) o Key Scientific and Management Leadership o Operations Office o Resources for Advanced Technology Laboratories o Executive/Steering Committee The Statistical and Data Management Center will consist of: o Principal Investigator o Experts in Statistics, Study Design and Analysis o Data Management Resources and Facilities The AIDS Clinical Trials Units (ACTUs) will consist of: o Principal Investigator o Clinical Facilities and Staff o Clinical Laboratory Facilities and Staff o Study Subjects DAIDS staff, DAIDS contractors (such as those for laboratory quality assurance, clinical site monitoring, and management of virology, immunology, and pharmacology laboratory data) and a Data and Safety Monitoring Board will support the efforts of these awardees. (See Terms and Conditions of Award for specific on the roles and responsibilities of each contributing unit.) D. Functions of an ACTG The activities of an ACTG and its component parts awarded under this RFA are delineated below. (See "Terms and Conditions of Award" for further specifications of selected roles and responsibilities of an Adult ACTG Central Group.) Specifically, an ACTG Central Group will be responsible for: 1. Developing, implementing, monitoring, and updating the ACTG's scientific agenda for therapeutic research consistent with the NIAID HIV\AIDS Therapeutic Research Agenda. 2. Provision of the key scientific and managerial leadership required to carry out the ACTG scientific agenda. 3. Identification of a Statistical and Data Management Center responsible for the statistical aspects of study design, and the collection and analysis of data from the clinical trials conducted by the ACTG. 4. Development and management of an Operations Office that will provide the necessary infrastructure and staff to support the ACTG Group Leader in the management and administration of the ACTG. 5. Organizational structures and management mechanisms for effective communication and collaboration among ACTG components including: committee structure, bylaws, procedures for protocol development and modification, performance evaluation, and monitoring of research progress. 6. Identification, selection and management of Advanced Technology Laboratories (ATLs) that will investigate the feasibility, validity, standardization and implementation of state-of-the-art pharmacologic, immunologic and virologic assays/technologies for use in support of the ACTG clinical trials. 7. Criteria and processes for: assessing the performance of ACTG components, including individual ACTUs, subunits, ATLs, the operations office and the statistical and data management center; the addition, reduction, expansion, or removal of ACTUs based on the needs of the scientific agenda and the performance of ACTUs; and the modification of the activities of the ATLs, the operations office and the statistical and data management center. 8. Mechanisms to ensure the involvement and participation of community representatives at all levels of scientific planning and study conduct. 9. Procedures for encouraging the participation in the proposed research of new investigators, women and minorities. Each AIDS Clinical Trials Unit will be expected to perform the following activities. (See "Terms and Conditions of Award" for further specification of selected activities of an Adult ACTU). 1. Participate in single and multi-institutional clinical trials according to the agenda of the ACTG. 2. Perform on site and/or obtain (via collaboration) virology, immunology (including flow cytometry), and pharmacology laboratory services as required for protocol mandated evaluation of patients enrolled in ACTG clinical trials. 3. Identify and recruit HIV-infected patient populations to support patient accrual, with a minimum of 75 new patients per ACTU per year. 4. Enroll and retain ethnically diverse patient populations that are representative of the local community and the population(s) most affected by HIV and AIDS, including women. 5. Provide or have access to gynecological and outreach related resources to assist in evaluating the efficacy of treatments for and to address the needs of women infected with HIV. 6. Obtain input and involve community representation of the populations most affected by HIV and AIDS in the planning, conduct and dissemination of information on clinical trials. 7. Encourage the participation of new investigators, women and minorities in scientific and managerial aspects of the ACTU. 8. Agree to follow the organizational structures and managerial mechanisms of the ACTG. The Statistical and Data Management Center for an ACTG will be responsible for the following activities. (See "Terms and Conditions of Award" for further specifications of selected roles and responsibilities of a Statistical and Data Management Center.) 1. Statistical aspects of study design, data analyses and data management. 2. Development and maintenance of systems for registration and randomization of participating patients into Phase 1, 2, and 3 clinical trials. 3. Centralized storage, security, processing and retrieval of ACTG and ACTU information. 4. Design and implement procedures for the collection, reporting and quality control of data (including standardized case report forms) and for submission of information by the ACTG, the ACTUs and collaborating institutions. 5. Training of clinical site staff and external site monitors (external site monitoring is performed by a DAIDS contractor) in the areas of data management and clinical trials methodology. 6. Receipt, recording, and reporting of adverse experience reports from the ACTUs to DAIDS and the FDA. 7. Analyses for IND annual reports to the FDA, and interim reports for NIAID, FDA, and DSMB review. 8. Agree to follow the organizational structures and managerial mechanisms of the ACTG. E. Objectives and Scope The primary goal of this initiative is to evaluate, in Phase 1, 2, and 3 clinical trials, innovative therapeutic strategies and interventions for HIV infection and its complications. These interventions will be based on emerging knowledge of the biology and potential therapeutic targets of HIV and associated pathogens, the pathogenesis of HIV infection and resulting opportunistic diseases, and factors influencing disease progression and treatment outcome. This initiative is specifically designed to strengthen the coordination of the ACTG research agenda with progress in basic research and it emphasizes the rapid utilization of these discoveries in multi-disciplinary clinical research. The goal is to allow the ACTG to capitalize on the latest insights into the biology of HIV and its associated pathogens and into host-pathogen relationships for the purpose of developing more effective treatments while enhancing knowledge of the pathogenesis of HIV disease and its complications. The NIAID HIV/AIDS Research Agenda comprehensively documents the Institute's major scientific programs, priorities, and plans in each of five broad scientific areas: pathogenesis, epidemiology and natural history, therapeutics research and development, vaccine research and development, and pediatric disease. The Agenda is the basis for NIAID's scientific planning, program management and evaluation, and communication on the scope and nature of the Institute's efforts in HIV research. Through the performance of clinical trials, the ACTG will play a critical role in helping to fulfill the goals and priorities delineated in the Therapeutics Section of the Institute's HIV/AIDS Research Agenda as summarized below. Copies of the Therapeutics Section of the NIAID HIV/AIDS Research Agenda are available from the program staff listed under INQUIRIES. The ACTG Central Group will identify the highest priority research questions from the major therapeutic areas, and develop a comprehensive clinical trials agenda consistent with the HIV/AIDS Therapeutics Research Agenda. The ACTG will be responsible for addressing the major areas in the NIAID's Agenda and establishing areas of emphasis. 1. Primary Disease Therapeutics. Considerable progress has been made in developing, evaluating, and instituting into clinical practice nucleoside analogues that inhibit HIV-1 replication and enhance disease free survival in infected individuals. However, the clinical utility of these agents are of limited duration and magnitude. Therefore, it is crucial to base further progress in primary disease therapeutics on additional knowledge of HIV life cycle and pathogenesis. Innovative approaches should focus on the following: o Development of antiretroviral therapies aimed at interfering with the life cycle of HIV as well as therapeutic strategies to treat the primary disease processes of HIV infection. These approaches should complement the efforts of industry and should be targeted to the entire spectrum of immunodeficiency, from acute infection through the chronic asymptomatic stage, and the stages of AIDS-related complications. o Determination of the clinical implications of the development of resistance of HIV-1 and the role of viral phenotypes. o Identification and validation of surrogate markers both as indicators of biologic activity and as predictors of overall clinical outcome. o Improvements in the therapeutic index of existing and/or approved anti-HIV therapies through the use of novel combinations of agents, alternative dosage schedules, or improved drug formulations, including antiviral and immunomodulators in combination. 2. Immune Based Therapeutics/Immune Reconstitution. The development of immunodeficiency in HIV-1 infection can be evident at its earliest stages, far in advance of clinically apparent disease. The immunodeficiency is relentless in its progression, ultimately leading to opportunistic infections and malignancies. The infected individual generates a myriad of immunological responses to HIV-1, however, it remains unclear which, if any, of these responses is protective. In addition, recent gains in our understanding of HIV pathogenesis have identified many factors contributing to the progressive immunosuppression, including CD4+ T-cell depletion, CD4+ T-cell qualitative dysfunction, loss and dysfunction of T-cell precursor cells and the developmental microenvironment, cytokine dysregulation, abnormal immune activation, apoptosis, and superantigen effects. Therefore, strategies could include the: o Development of immune-based approaches to the treatment of HIV disease and reconstitution of the immune system, e.g., passive and active immunotherapies, cytokines/cytokine modulators, adoptive cell transfer/stem cell therapies, and inhibitors of immune activation. 3. Treatment and Prevention of HIV-Related Opportunistic Infections. The morbidity and mortality caused by the multiple opportunistic infections (OIs) associated with HIV infection are substantial. Several of these pathogens have been associated with other immunocompromised states. However, the frequency and severity of some HIV-related OIs surpasses previous experience. For most OIs, there are only a limited number of agents effective in prophylaxis or treatment, many of which have significant toxicities associated with their use. There are no known effective therapies for some OIs including cryptosporidiosis and the emergence of drug resistance will limit the effectiveness of currently available agents. Support of basic, preclinical and clinical research on HIV-related OI pathogens is viewed as an important role of the NIAID. Innovative strategies may include, but are not limited to: o Develop approaches to provide safe and effective simultaneous prophylaxis against multiple OIs, recognizing that long term utility of these regimens will be dependent on patient acceptability and tolerance. Risks and benefits of widespread prophylaxis, including the development of drug-resistant organisms, pharmacokinetic interactions, and additive toxicity must also be specifically evaluated. o Assess markers for the optimal initiation of prophylaxis. Evaluate new methods for more rapid diagnosis of opportunistic infections, determine drug susceptibility, and evaluate response to therapy, including predictors of relapse. o Evaluate the use of active/passive immunization, cytokine modulation, and other immune based therapies as adjunctive therapies in the management of selected opportunistic infections. o Develop improved agents for the treatment and prevention of HIV-associated CMV, disseminated Mycobacterium avium Complex, enteric pathogens, and azole-resistant candida. o Develop new agents and combinations for the prophylaxis and treatment of disease caused by Mycobacterium tuberculosis infection, including strains that are resistant to standard agent(s). Develop and evaluate regimens, formulations or delivery vehicles that enhance patient compliance through convenience or improved tolerance. o Evaluate the role of OIs, for example CMV, MAI, TB, as cofactors in the progression of HIV-disease. 4. Oncology Treatment Research. Proposed research could focus on development and implementation of a coordinated research agenda in conjunction with the National Cancer Institute that will address the development of better therapeutic strategies to treat Kaposi's sarcoma, lymphoma, CNS lymphoma and human papilloma-virus associated malignancies in HIV-infected individuals. 5. Neurology Treatment Research. Proposed research could focus on development and implementation of a coordinated research agenda with the National Institute of Neurologic Diseases and Stroke that will facilitate the development of therapeutic strategies for the neurologic manifestations of AIDS, including AIDS dementia complex, neuropathy, progressive multifocal leukoencephalopathy, CNS lymphoma, and CMV encephalitis. NOTE: In addition the National Institute of Mental Health is interested in receiving applications, independent of this RFA, that will advance the development of therapeutics for the neuropsychiatric and neuropsychological manifestations associated with HIV infection, including early cognitive impairment, AIDS Dementia Complex, and associated mania, psychosis, depression and anxiety disorders. Methodological studies focused on the identification of markers of disease progression to AIDS-associated cognitive and motor impairment are strongly encouraged. For further information contact Dr. Walter L. Goldschmidts, Office on AIDS, NIMH, (301) 443-7281. 6. Women's Health Treatment Research. Proposed research could focus on development and implementation of a research agenda that will facilitate better understanding and treatment of women's specific health issues of HIV infection, such as drug pharmacokinetics in women, cervical neoplasia, pelvic inflammatory disease and vaginal candidiasis. 7. Pharmacology. Proposed research could focus on development of a research agenda that will define the pharmacokinetics and pharmacodynamics of new drugs and study the interactions of drugs used in combination to treat HIV and opportunistic infections. 8. Methodology for Trials. Using data from group trials increase the understanding of HIV/AIDS and related diseases and improve the design and conduct of trials. SPECIAL REQUIREMENTS In the terms and conditions of award listed below, reference is made to other research programs in AIDS, principally funded through NIAID cooperative agreements and contracts. Information concerning these programs will be discussed at a pre-application meeting scheduled for September 28, 1994. For additional information contact Dr. Frederick H. Batzold at the address listed under INQUIRIES. A. Terms and Conditions of Award The following terms and conditions will be incorporated into the award statement and provided to each Principal Investigator as well as the institutional officials at the time of award. These special Terms of Award are in addition to, and not in lieu of, otherwise applicable Office of Management and Budget (OMB) administrative guidelines, HHS Grant Administration Regulations at 45 CFR part 74 and 92, and other HHS, PHS, and NIH Grants 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 awardees for the ACTG as a whole, although specific tasks and activities in carrying out the study will be shared among the awardees and the NIAID and its contractors. The cooperative agreement funding mechanism will require collaboration between the DAIDS Associate Director of the Therapeutics Research Program (TRP), and the Group Leader(s) of the ACTG(s). The DAIDS will assist in coordinating the activities of the ACTG(s) as defined below and will facilitate the exchange of information. B. Awardee Rights and Responsibilities Awardees 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 NIAID staff in all aspects of scientific and technical management of the project. Specifically, awardees have primary responsibilities as described below. 1. Responsibilities of the ACTG Central Group a. Research Agenda The Principal Investigator (Group Leader) of an ACTG Central Group, in collaboration with other investigators constituting the scientific leadership of the ACTG, is responsible for the development and implementation of a comprehensive clinical trials research agenda, consistent with the research goals and priorities established in NIAID's HIV/AIDS Therapeutic Research Agenda and complementary to the research conducted by the Community Programs for Clinical Research on AIDS (CPCRA), the Division of AIDS Treatment Research Initiative (DATRI), NIAID Division of Intramural Research, and other AIDS clinical trials mechanisms. These research goals will be reviewed and discussed quarterly with DAIDS staff. b. Bylaws/Operating Procedures The Group Leader will be responsible for ensuring that there are well-documented policies and operating procedures guiding all aspects of ACTG activities (e.g., protocol development, review, initiation, conduct, and closure, data collection, publication, etc.) and bylaws delineating the requirements and expectations of collaborating institutions, membership criteria and process for new site consideration by the ACTG, standards of performance, and procedures for removing institutions due to poor performance. c. Executive/Steering Committee The ACTG will establish this governing committee that will be chaired by the Group Leader. At a minimum the committee will include representatives from the Statistical and Data Management Center, the Operations Office, and a member of the community. In addition, there will be one voting member of the committee from the DAIDS Therapeutics Research Program. This committee will be responsible for overseeing all scientific and operational activities of the ACTG including, but not limited to: scientific direction, policies and bylaws, standards of performance, study oversight, evaluation of collaborating institutions, and criteria and review procedures for distributing discretionary funds. d. Protocol Development The ACTG will initiate development of each protocol only when there is sufficient commitment among the principal investigators of clinical units and other scientific leaders to proceed expeditiously to write the protocol, complete accrual, and analyze and publish the study results. Early notification that the ACTG is considering a trial must be provided to the DAIDS to allow for comment on scientific rationale, feasibility, costs, and compatibility with overall NIAID research priorities and activities in other clinical trials programs. The ACTG must have clear procedures for designating members of protocol teams and for selecting sites for limited-site trials. The ACTG must develop a mechanism to actively monitor progress, from initiation through publication, and must provide status reports to the DAIDS on each study, in a format and on a schedule to be mutually agreed upon. e. Administrative Support The Operations Office will be responsible for coordinating, administering, and supporting all research activities at the direction of the Group Leader or designee. These activities include, but are not limited to: protocol development; administrative support of scientific and other committees; assembly, review, and submission of regulatory documents for registration of sites for clinical trials; maintenance of group administrative records and archives; organization/support of, at a minimum, one annual national group meeting in collaboration with the Pediatric ACTG; and in conjunction with the group's Statistical and Data Management Center, preparation of administrative and scientific reports. f. Data Management and Analysis Each ACTG will develop standard procedures to ensure that data collection and management are: (1) adequate for quality control and analysis and (2) as simple as appropriate in order to minimize data collection burden on the part of the clinical sites. g. Protocol Submission Prior to implementation of a clinical trial, the ACTG leadership must submit a final draft to DAIDS for review and approval based on consistency with the NIAID HIV/AIDS Therapeutic Research Agenda and overlap with other NIAID clinical trial programs. DAIDS will communicate all decisions in writing to the ACTG; it will be the ACTG's responsibility to disseminate this information to member investigators and others as appropriate. Implementation may not proceed in the case of disapproval. (See "B. NIAID Staff Responsibilities" below for additional information on the approval and appeal processes.) h. Quality Assurance: Data Management The ACTG's Statistical and Data Management Center will design and implement systems to promote and ensure the quality of clinical trials data. The center will develop quality assurance procedures to be employed by staff at each clinical site and the managers of the central database, including types of manual and computerized procedures and edit checks that will be used to identify and correct data errors, the process that will be used to verify that eligibility criteria have been met, the process that will be used to verify endpoint data, and the average time period that erroneous computerized data will remain on-line before errors are corrected. Procedures will be developed to assure data security and recovery in the event of lost data. i. Quality Assurance: Laboratory Quality Control and Data Management All virology, immunology, and pharmacology laboratories supported through the ACTG (i.e., laboratories performing protocol-mandated testing and Advanced Technology Laboratories) should adhere to methodological and analytic guidelines set forth by the scientific committees of the ACTG. All laboratories must participate in quality assurance programs supported under contract with the DAIDS and overseen jointly with the ACTG (See. "B. NIAID Staff responsibilities"). In addition, all ACTG-supported laboratories should utilize a laboratory data management system for specimen tracking and data transmission provided by a contractor to the DAIDS. j. Advanced Technology Laboratories The Group Leader, in consultation with the Executive/Steering Committee of the ACTG, will be responsible for identifying the centralized advanced technology laboratory capabilities required in virology, immunology and pharmacology to support the ACTG research agenda. With the designated funds awarded to the ACTG Central Group, the Executive/Steering Committee will identify suitable laboratories, determine appropriate distribution of resources, develop a mechanism to monitor laboratory performance and annually assess allocation of the ATL funds. k. Study Oversight Responsibility The ACTG leadership must establish procedures to assure adequate protection of the rights and safety of volunteers involved in its clinical investigations, and for the quality and integrity of these studies and resulting data. This study oversight by the ACTG includes compliance with all Federal regulations and NIAID policies and procedures. The ACTG must also maintain accurate and timely information on the progress of each study it conducts. l. ACTG Compliance with Federal Regulatory Requirements The ACTG 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. The ACTG must be able to demonstrate that each institution conducting ACTG trials has a current, approved Assurance Number on file with the NIH Office for the Prevention of Research Risks (OPRR), that each protocol and informed consent is approved by the responsible Institutional Review Board (IRB) prior to patient entry, that each investigator has a current Food and Drug Administration Form 1572 and curriculum vitae on file at DAIDS, and that each patient (or legal representative) gives written informed consent prior to entry on study. The ACTG must assure timely reporting of all serious and unexpected toxicities to DAIDS in accordance with DAIDS established policy and procedures delineated in the "ACTG Adverse Experience Reporting Manual." m. Reporting Requirements The ACTG Group Leader will submit to the DAIDS an annual progress report summarizing data on protocol performance by the ACTG as a whole and by each participating clinical unit. These reports will include, at a minimum: patient accrual and retention rates; patient demographics; timeliness and completeness of all data, including adverse events; timeliness of IRB approvals of new protocol versions; completeness and quality of laboratory data; and scientific contributions, including publications. These data should be compiled across all studies and by protocol, as appropriate. Reporting requirements will be in agreement with Federal regulations and NIAID procedures. The ACTG Group Leader will submit to the NIAID data summary reports prior to the due dates to the Food and Drug Administration (FDA) required of IND sponsors. At the time of protocol review, for each clinical study DAIDS will identify the types and frequencies of reports needed to monitor the safety and clinical effectiveness of the therapeutic interventions. These reports may include (1) a line listing and summary tables of all serious adverse events submitted as frequently as every two weeks; (2) a report on patient status submitted every two weeks for each Phase I and I/II study; (3) a quarterly and annual report summarizing adverse events and patient status for each protocol, including unblinded analysis for the DAIDS medical monitor with the approval of the Data and Safety Monitoring Board. The ACTG will submit to DAIDS a narrative summary of the data contained in these reports and future plans for each study one month in advance of each IND report's due date. A system for providing such information in a timely manner must be implemented by the ACTG. n. Publication of Data Prompt and timely presentation and publication in the scientific literature of major findings is required. Publications or oral presentations of work done under this cooperative agreement will require acknowledgement of NIAID support to the ACTG. Prior to the submission of manuscripts for publication the ACTG will provide a preprint to the Division of AIDS. Although the awardee will retain custody and primary rights to the data consistent with current HHS, PHS and NIH policies, DAIDS will have access to all data generated under this cooperative agreement and may periodically review it. o. Progress Review The ACTG Executive/Steering Committee will establish procedures for regularly evaluating the performance of its members including data management/quality, accrual of adequate numbers of patients, adherence to requirements for enrolling women and minorities, observance of protocol requirements, scientific contributions/participation, and timely publication of data. This mechanism will include a procedure for recommending to DAIDS an adjustment of institutional funds within the group as appropriate for the level of contribution and performance. p. Interaction with DAIDS The ACTG Group Leader will meet with the Associate Director, TRP quarterly. The purpose of the meeting will alternate as follows: semi-annual meetings will be held to discuss research progress, establish priorities, and plan future activities. Also, semi-annual meetings will be held with investigators representing other NIAID clinical trials programs to ensure coordination of research agendas. Additional meetings between DAIDS and the ACTG Group Leader may be held as needed. q. National Meetings It is expected that an ACTG will hold two national meetings per year, at least one of which is held in conjunction with the Pediatric ACTG and located in the Washington metropolitan area. These meetings will be open to the public. Through calendar year 1996, the DAIDS will provide logistical support for two national meetings (and one smaller meeting of ACTG leadership), e.g., contracting with local hotels and vendors; however, the ACTG will be responsible for organizing the scientific content and format of the meeting. As of 1997, funds will be transferred to the ACTG Operations Office to cover the costs associated with all aspects of meeting planning, including logistics (e.g., hotel, scheduling). r. Conflict of Interest The ACTG will develop, establish, monitor and enforce a Conflict of Interest (COI) Policy, acceptable to NIAID, for addressing and resolving any conflict of interest issues that may arise through financial ties between members of the ACTG and the private sector. A report on the ACTG's activities regarding COI issues will be part of the biannual review. s. Discretionary Fund The Operations Office will maintain and manage a Discretionary Fund. The Executive/Steering Committee will develop criteria and review procedures for allocating discretionary funds, based on scientific and administrative needs and priorities of the group. Appropriate uses may include funding innovative pilot studies, supplementing budgets of collaborating institutions which are undertaking resource intensive studies, facilitating the initiation of large efficacy studies, accommodating non-routine protocol mandated requirements on an as needed basis, and supporting additional clinical or laboratory sites needed by the group. 2. Responsibilities of AIDS Clinical Trials Units (ACTUs) a. Staffing Each ACTU must have experienced physician investigators associated with the project who have demonstrated expertise in multi-center AIDS clinical trials. Adequate staffing must also include nursing, pharmacy, data management and outreach personnel to recruit and screen potential patients, implement clinical research protocols, perform protocol required assessments, dispense investigational agents and appropriately document clinical data, meeting all data reporting requirements. b. Clinical Studies Each ACTU will be required to have the capability to accrue a minimum of 75 patients per year, and develop and implement a community outreach program. All clinical trials conducted at each ACTU must be in compliance with the policies and bylaws of the ACTG. c. Routine Laboratory Assays For those laboratory studies that will not be carried out in centralized ATLs, each ACTU must have the capability to perform and/or obtain (via collaboration) virology, immunology (including flow cytometry) as required for evaluation of patients enrolled in the ACTG's clinical trials. Plans may entail arrangements including both on-site and off-site testing. Applicants proposing to obtain laboratory testing from off-site collaborators (outside of their institution) must provide the appropriate documentation (e.g., letters of agreement) to substantiate the collaborative arrangement. Use of existing DAIDS-certified laboratories in the same community, whenever possible, is strongly encouraged. All laboratories performing protocol mandated tests must participate in relevant laboratory quality assurance programs. d. Quality Assurance: Investigational Drug Management Investigators performing trials under cooperative agreements must be NIAID registered investigators (Form 1572 and curriculum vitae on record with DAIDS) and must comply with requirements described in the DAIDS Standard Operating Procedures. Investigators must comply with the "Pharmacy Guidelines and Instructions for ACTG" for storage, dispensing and accountability of investigational agents and must comply with all Federal regulations for investigational agents. e. Quality Assurance: Internal Quality Control Each ACTU must establish an internal quality control program to assess the quality of its research records, which must be approved by and consistent with the quality control policies developed by the ACTG. These policies should include, but are not limited to, quality control measures for collection, reporting and recording of data. Each ACTU's internal audit plan should apply to the main unit as well as any subunits that might be established in affiliation with it. Each clinical unit must submit a pharmacy plan to the Chief, Pharmaceutical and Regulatory Affairs Branch (PRAB) for approval for compliance with FDA requirements. Upon approval, sites must register for each protocol sponsored under an NIAID IND by submitting a package of regulatory documents. This package will be verified complete and accurate by the ACTG Operations Office. Once a site is registered for a protocol, drug will be supplied by the NIAID Clinical Research Products Management Center, and patients can be enrolled. Each ACTU will be required to cooperate with the DAIDS Clinical Site Monitoring Contractor, which will conduct external site monitoring to assure site compliance with all Federal regulations and NIH policies with respect to patient safety, data completeness and accuracy. 3. Statistical and Data Management Center Responsibilities a. Study Design, Conduct, Analysis and Publication The statistical staff will be responsible for providing statistical scientific leadership for the ACTG; collaborating with other protocol team members in all stages of protocol development and implementation; performing timely interim analyses of safety and efficacy results for review by protocol teams and/or the DAIDS Data and Safety Monitoring Board; performing final analyses for publication, participating in the writing of scientific papers and publish study results in conjunction with other protocol team members; producing timely study monitoring reports, deliverable to the Group Leader and DAIDS; conducting secondary analyses of ACTG data to improve the planning, design, conduct and interpretation of ACTG trials; and summary tables and data analyses for use in IND annual and interim submissions to the FDA and function in accordance with the policies and bylaws of the ACTG. b. Data Management The data management staff will provide for central registration and randomization of patients on all studies; develop case report forms; develop standardized criteria for verification of clinical endpoints; design and implement a system to provide for the efficient transfer of study results from clinical sites to a central database, using either a centralized or distributed data entry approach; in conjunction with the laboratory data management project and the NIAID AIDS Specimen Repository, provide support for tracking and identification of laboratory specimens; provide for processing, storage in a central database and retrieval of study results; provide limited online access for ACTUs to their own blinded data in the central database; prepare selected, significant public access datasets, with adequate documentation, deliverable to a location designated by DAIDS; provide for an electronic mail system, capable of exchanging messages through the Internet, to facilitate communication among clinical sites, other ACTG components, and DAIDS; provide data management training of the clinical unit staff and external site monitors; and develop reports detailing site performance in data management, deliverable to the Group Leader and DAIDS. The data management staff should function in accordance with policies and bylaws of the ACTG. c. Collaboration When circumstances require the ACTG to collaborate with one or more other clinical trial groups (e.g., CPCRA), the ACTG will agree to follow procedures for trial conduct to be determined by DAIDS in consultation with the leadership of each clinical trials group. Normally, one group will be given the lead responsibility by DAIDS and its procedures will be followed by all other collaborators. In addition, the Statistical and Data Management Center will be required to provide registration and randomization of patients for, and accept data from, any organization funded by NIAID to participate in adult ACTG trials, such as the National Hemophilia Foundation. (Oversight for the performance of such organizations will be the responsibility of the NIAID.) Annual patient accrual to ACTG protocols by other programs will not exceed five percent of the total ACTG accrual. 4. NIAID Staff Responsibilities The NIAID 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 role of the DAIDS staff as described throughout these terms of cooperation is to assist and facilitate, but not to direct the research activities. Communication and interaction will occur primarily with the Group Leader and the scientific leadership of the ACTG; however, DAIDS will also interact directly with the Principal Investigator of any of the collaborating institutions as needed. This project is part of a larger program of therapeutics research supported by NIAID. Each of the DAIDS staff listed below has specific responsibilities in terms of investigational drug research and the role of the DAIDS as a drug sponsor as defined in 21 CFR Part 312. a. DAIDS' Scientific Role in NIAID-Supported Clinical Research The Associate Director, TRP and/or designated staff will work closely with the ACTG Executive/Steering Committee to assure that the research efforts of the ACTG are consistent with the NIAID agenda for HIV-related clinical research and are complementary to those of the other clinical trials mechanisms supported by DAIDS, specifically the CPCRA and DATRI. DAIDS will serve as a resource, and will disseminate information regarding promising new agents, therapeutic strategies, or developments. DAIDS staff will advise the clinical investigators, as requested or needed, of results from other trials (e.g., adverse experiences and early terminations) that could influence the design, development, or conduct of clinical trials and will serve as the liaison between the pharmaceutical company representatives, the FDA and the ACTG investigators. b. DAIDS Role in Protocol Review and Development In order for a clinical trial to be initiated by an ACTG, the study proposal must be mutually approved by the ACTG and the DAIDS Clinical Science Review Committee (CSRC), chaired by the Associate Director, TRP, DAIDS. Once notified that a trial is under serious consideration within the ACTG, DAIDS will evaluate the priority of the proposed trial in relation to the NIAID HIV/AIDS Therapeutic Research Agenda, to other NIAID trials, likelihood of timely completion; patient safety; compliance with Federal regulatory requirements; plans for interim monitoring of results; and resource requirements. DAIDS staff will also estimate the costs associated with the protocol. The Associate Director, TRP will return comments and recommendations in writing to the ACTG within 30 days. In addition, DAIDS pharmacists will participate on ACTG protocol teams, consulting on available dosage forms and placebos. They will also interact with pharmaceutical companies to ensure adequate and timely supply of products. In the event a protocol is disapproved, the Associate Director, TRP will work with the ACTG Executive/Steering Committee to resolve specific concerns and ensure consistency between the research interests, abilities and priorities of the ACTG and NIAID. Nonetheless, DAIDS will not provide investigational materials or permit expenditure of NIAID funds for a protocol that has not been approved. Disagreements arising pursuant to protocol approval may be submitted to an arbitration panel for resolution. A panel composed of one ACTG designee, one DAIDS designee, and a third member with HIV/AIDS clinical trials expertise chosen by the other two members will be formed to review the DAIDS decision and recommend an appropriate course of action to the Director, DAIDS. These special arbitration procedures in no way affect the awardee's right to appeal an adverse determination in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. For protocols under a DAIDS IND, DAIDS will be responsible for filing the protocol to the IND. d. DAIDS Role During Protocol Conduct For ongoing clinical trials, DAIDS Medical Officer will monitor the safety and efficacy of the treatment being evaluated. Therefore, interim and final reports on efficacy and toxicity for all sponsored clinical trials will be routinely provided to the DAIDS Medical Officer. In addition, for protocols in which the DAIDS is the IND sponsor, DAIDS will assign medical monitors who will review blinded and unblinded safety and efficacy data with the protocol statistician on behalf of the DAIDS Data and Safety and Monitoring Board to permit appropriate monitoring. e. DAIDS Role in Protocol Closure The Associate Director, TRP and/or designated staff will monitor the progress of ACTG trials by reviewing reports periodically submitted to DAIDS, through the Data and Safety Monitoring Board which consists of experts from several disciplines, and through semi-annual meetings with ACTG leadership. DAIDS may deem it necessary to deny access to further investigational drug supplies and deny the expenditure of additional NIAID funds (except where volunteers are already enrolled) if any of the following reasons apply: (a) risk of patient safety, (b) scientific question no longer relevant, (c) slow accrual, or (d) study will not answer question. Appeal of such a decision by the ACTG would proceed in the same manner as an appeal regarding the disapproval of a protocol prior to opening. f. Access to Data The Chief, Coordinating Centers Branch (CCB) and/or designated monitoring contractor staff will have access to all data generated under these cooperative agreements and may periodically review the data as recorded on case report forms and/or maintained in the central database. Data must be available for external checking against original source documents as required by NIAID policy and Federal regulations relative to the responsibility of DAIDS as an IND sponsor. The awardees will retain custody and primary rights to the data consistent with current HHS, PHS, and NIH policies, including a policy to provide public access to selected, significant data sets generated with the use of public funds, within a reasonable period of time after primary analysis and publication by the ACTG. g. Clinical Trials Agreements It is expected that for most clinical trials, a pharmaceutical company collaborator will provide investigational agents for the trials. In order for the ACTG, DAIDS and the company to understand their respective responsibilities and rights, a Clinical Trials Agreement (CTA) will be negotiated and signed by DAIDS and the company. Important terms of the agreement include IND sponsorship, safety and data monitoring, and access to trial data. Concurrence with the ACTG Group Leader will normally be obtained prior to execution of the final agreement. In general, terms in the CTA covering data access and sharing will conform to policies developed jointly by the group leadership and DAIDS. h. Laboratory Quality Assurance and Data Management The DAIDS will provide the ACTG with contractual support for virology, immunology and pharmacology laboratory quality assurance services. Administrative, fiduciary and other aspects of contract management will be the responsibility of DAIDS. Scientific and technical oversight for these quality assurance programs will be provided by DAIDS in conjunction with advisory groups comprised of ACTG and other investigators, and the Chief, Drug Development and Clinical Sciences Branch working in a cooperative manner. The DAIDS will also provide the ACTG with contractual support for the management of virology, immunology and pharmacology laboratory data. Given the complex nature of these data, the large volume to be collected and the highly technical aspects of its collection, this activity will be supported by its own project, distinct from, but coordinated with, the group's data management system/facility. i. DAIDS Involvement in Investigational New Drug Applications The DAIDS will have the option to cross file or independently file an IND on investigational drugs evaluated in the ACTG clinical trials. The Chief, PRAB will advise investigators of specific requirements and changes in requirements concerning IND sponsorship that the FDA may mandate. Investigators performing trials under cooperative agreements will be expected, in cooperation with the DAIDS, to comply with all FDA regulations associated with investigational drug studies. j. DAIDS Review of ACTG Compliance with Federally Mandated Regulatory Requirements The Chief, PRAB will advise the ACTG regarding mechanisms to meet (1) FDA regulations for DAIDS-sponsored studies involving investigational agents, and (2) the NIH Office for Protection from Research Risks (OPRR) regulations for the protection of human volunteers. For DAIDS-sponsored trials with investigational agents, the DAIDS has established an external DAIDS Clinical Site Monitoring Contract to document good clinical research practices, including regulatory compliance, proper protocol implementation, and test agent accountability. The DAIDS Clinical Site Monitoring contractor will visit ACTUs on a quarterly basis (approximately five days per visit) to review specific priority protocols, train in specific protocols, review, internal quality assurance plans, audit pharmacies, and document error resolution. In order to provide for consistent reporting of adverse experiences across clinical trials groups, DAIDS has established policies and procedures delineated in the "ACTG Adverse Experience Reporting Manual." The ACTG, as the largest of the groups, will have the responsibility for ongoing maintenance of the modified ICD-9 system for classifying and coding the types of adverse experiences reported. This will require collaboration with staff from the DAIDS and other trials groups. k. DAIDS as a Resource for Site Evaluation The Chief, Clinical Site Management Branch (CSMB) will assist the ACTG in developing criteria to evaluate the performance of the collaborating institutions. The Chief, CSMB will also provide ongoing data pertaining to each site's performance as well as data on the cost of the ACTG's research activities, including protocol specific costs. l. Review of Performance The performance of the ACTG as a whole and that of the individual institutions will be reviewed at least annually by the Associate Director, TRP on the basis of information provided in annual progress reports, evaluations of site performance conducted by the Executive\Steering Committee, and site monitoring reports provided to DAIDS by its contractor. Substandard data management/quality, insufficient patient accrual, inadequate progress in executing the research agenda, or noncompliance with the Terms and Conditions of Award may result in a reduction in budget, withholding support, suspension, or termination of award. m. DAIDS Review of Quality Control and Study Monitoring Procedures The Chief, PRAB will periodically conduct a review of the ACTG and its sites for the reliability of and compliance with clinical and regulatory systems, and will advise on the same. STUDY POPULATIONS INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification 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 1003-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women 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. A copy is also available through the NIH Grant Line (data line (301) 402-2221). Investigators may obtain copies from these sources or from Dr. Frederick H. Batzold (see "INQUIRIES") who may also provide relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by September 15, 1994, a letter of intent that includes a descriptive title of the proposed application (Adult ACTG Central Group, Adult ACTU, or Adult ACTG Statistical and Data Management Center); the name, address, and telephone number of the Principal Investigator; the number and title of this RFA; a list of the key investigators and their institution(s); and for Adult ACTU and Statistical and Data Management Center applicants, the identity of the ACTG Central Group with which the applicant plans to affiliate. The letter of intent is requested to provide an indication of the scope and number of applications that will be received and to promote early interaction among potential applicants and between the applicants and NIAID staff. Letters of intent from potential applicants for ACTG Central Group awards will be used by DAIDS program staff to refer unaffiliated potential applicants for ACTUs to potential ACTG Central Groups. The letter of intent does not commit the sender to submit an application, nor is it a requirement for submission of an application. The letter of intent is to be sent to Dr. Peter Jackson at the address listed under INQUIRIES. APPLICATION PROCEDURES Applications are to be submitted on the standard research grant application form PHS 398 (rev. 9/91). For purposes of identification and processing, item 2a on the face page of the application must be marked "YES" and the RFA number and the words "ADULT ACTG - CENTRAL GROUP" or "ADULT ACTG - ACTU" or "ADULT ACTG - STATISTICAL AND DATA MANAGEMENT CENTER", as appropriate must be typed in. The research grant application form PHS 398 (rev. 9/91) must be used in applying. These forms are available at most institutional offices of sponsored research and may be obtained from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone (301) 594-7441. The RFA label in the 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. Submit a signed, typewritten original of the application, including the Checklist, and three signed exact photocopies. Each application for the ACTG Central Group, Statistical and Data Management Center, and each ACTU must be submitted separately. Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies of the application and all five copies of appendices must also be sent to: Peter Jackson, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4C14 6003 Executive Boulevard MSC 7610 Bethesda, MD 20892-7610 Telephone: (301) 496-8426 FAX: (301) 402-2638 The deadline for the receipt of applications is January 12, 1995. Applications received after this date will be considered as non-responsive to this RFA and will be returned without review. Special Instructions for the Preparation of Cooperative Agreement Applications A. Identification of Potential Applicants and Formation of ACTGs It is the responsibility of potential applicants for an ACTG Central Group award, ACTU award, and Statistical and Data Management Center award as components of an ACTG to identify themselves to each other and establish affiliations. In addition to the standard communication channels among investigators, the NIAID will facilitate the formation of an ACTG by: (1) providing the identity of potential ACTG Central Group applicants to unaffiliated potential ACTUs applicants and the names of unaffiliated potential ACTU applicants to potential ACTG Central Group applicants based on the letters of intent; and (2) holding a pre-application meeting on September 28, 1994. B. Pre-Application Meeting - September 28, 1994 The purpose of this meeting, to be held in the Bethesda, MD area, is to provide potential applicants with: (1) additional information about the structures and functions of DAIDS clinical research programs; (2) the opportunity to ask questions and obtain clarifications; and (3) the opportunity to establish affiliations (when these have not already been established). For further information contact: Dr. Frederick H. Batzold at the address listed under INQUIRIES. Potential applicants that request the RFA but are unable to attend the pre-application meeting will be sent a summary of the discussion and any materials that are distributed. C. Application Preparation All applications must be submitted on the form PHS 398 (rev. 9/91). Successful applications for each ACTG component (ACTG Central Group, Statistical and Data Management Center, and ACTUs) will be awarded as separate cooperative agreements to the sponsoring institutions and will include the Terms and Conditions of Award specified in this RFA. Each individual application must contain a Detailed Budget for the First 12-Month Period and a Budget for the Entire Proposed Project Period for Direct Costs. All applications, including that of the ACTG Central Group, the Statistical and Data Management Center, and the ACTUs should describe the scientific and administrative experience of key personnel. On page 2 of the PHS 398 form, in the section entitled PERSONNEL ENGAGED ON PROJECT, it is imperative that all applicants list all individuals and their institutions participating in the scientific execution of the project in the format as specified including those with no requested salary support. All applicants must ensure that the list is complete using as many continuation pages as necessary. Biographical Sketches and Other Support pages should be placed at the end of each individual application with the Principal Investigator first followed by other key personnel in alphabetical order; biographical sketches are limited to two pages each. The key feature of this RFA for the Adult ACTG(s) is that it requires an ACTG Central Group application to be submitted by a Group Leader/Principal Investigator of the ACTG Central Group. All ACTUs seeking membership in a collaborative group must submit a separate application identifying the Central Group to which they are seeking membership. The Statistical and Data Management Center application must be submitted separately, and must also identify the ACTG Central Group with which it is affiliated. In summary, for each ACTG being proposed, applications in response to this RFA must include the following elements: o Adult ACTG Central Group Application o Scientific Agenda and Research Plan Operational/Management Plan Plan/Budget for Advanced Technology Laboratories Outreach Plan Operations Office Procedures o AIDS Clinical Trials Unit Application Principal Investigator Association with One ACTG Central Group Ability to Contribute to the Scientific Agenda Demonstrated Clinical Trials Capabilities and Expertise Ability to Provide Protocol Mandated Laboratory Tests Accrual Potential Demographic Diversity/Community Outreach Plan o Statistical and Data Management Center Application o Principal Investigator Association with One Central Group Ability to Provide Expertise in Statistics and Study Design and Analysis Data Management Capabilities The specific requirements for each application are listed below. 1. Adult ACTG Central Group Application The Group Leader is required to assemble the scientific leadership required to produce a comprehensive research agenda on behalf of an ACTG, and identify the scientific and managerial leadership required for the ACTG to effectively and efficiently carry out its research plan. The ACTG Central Group application is not subject to the page limitations as stated in the form PHS 398. However, the Research Plan (see pages 19 through 23 of the PHS 398 application brochure) must be limited to 250 pages. (Note: the Research Plan includes the scientific agenda, the key scientific and managerial leadership, the organizational and governance structure, the Operations Office procedures, and the plan for establishing ATLs.) The application should be as concise as possible to ensure a thorough review. The use of tables, diagrams, organization and flow charts is strongly encouraged. Suggested format and page limitations for the Central Group Application. Applicants may request reallocation of the page limits from Dr. Frederick H. Batzold (see INQUIRIES). Scientific Agenda and Research Plan: 130 pages including identification of the Group Leader/Principal Investigator, key scientific leadership and a statistical and data management center. Operational/Management Plan: 25 pages including organizational chart, governance structure, plans for establishing bylaws, and key managerial leadership. Advanced Technology Laboratory Plan/Budget: 35 pages Outreach Plan: 10 pages including plans for ensuring access to under-represented populations especially women and minorities, for involving community representatives in ACTG activities. Operations Office Procedures: 50 pages including plans for developing, implementing, and monitoring protocols, and plans for carrying out regulatory responsibilities to the extent possible these plans can be included as appendices. Otherwise, these procedures should be described in detail within the text of the application. In addition to the support needed for the Operations Office, this application should include a budgetary request by the Group Leader for administrative/managerial support. The application should also include a budget request for central ATLs. The total budget request and planned distribution among virology, immunology and pharmacology should be based on the scope of activities proposed directly in support of the ACTG research agenda. The Group Leader may also request a discretionary budget in this application that will be used to fund innovative pilot studies, to supplement the budgets of collaborating institutions, which are undertaking resource intensive studies, to facilitate the initiation of large efficacy studies, accommodate non-routine protocol mandated requirements on an as needed basis, and support any additional clinical or laboratory sites needed by the group. The Discretionary Funds may not exceed $2,000,000 and the application must describe the criteria and review procedures that will be used by the Executive/Steering Committee for distributing these funds. In addition to the proposed detailed overall first year budget and summary budgets for future years, the applicant should identify the annual budgets for the following four categories of activities: (1) administrative support for the Group Leader and scientific leadership of the ACTG; (2) the Operations Office; and, within the Operations Office, (3) the Advanced Technology Laboratories and (4) the Discretionary Funds. 2. Adult AIDS Clinical Trials Unit (ACTU) Each application requesting support as an ACTU is subject to the page limitations (25 pages) for the Research Plan as specified in the Form PHS 398. (Note: the Research Plan should include the information requested below.) Appendices should be limited to no more than 60 pages. Applications exceeding the page limitation will not be provided to the Initial Review Group and will be returned to the applicant. ACTU applicants must specify the ACTG Central Group application with which it is proposing to affiliate. Budget requests for clinical units cannot exceed $1,700,000 in TOTAL COSTS per year for all activities at the unit including recruitment and retention of new patients, protocol mandated virology and immunophenotyping, and costs associated with the follow-up of patients continuing on ACTG protocols at incumbent applicant institutions. Budget justifications must be based on the projected types of studies to be conducted, number of patients to be accrued, and the number and type of personnel required relative to the above projections. Historically, the protocol specific mean costs per patient per year for ACTG Phase I, Phase II, and Phase III studies have been approximately $6,300, $7,500, and $4,300, respectively. The mean annual protocol specific costs include: all personnel time directed toward patient care (e.g., physicians, nurses, and pharmacists), all laboratory costs, and all clinical procedures. The mean costs do not include resources devoted to patient recruitment, screening and ancillary services, data management, quality assurance, program administration or supplies. The ACTU application should include, but is not limited to, the following information: a. Expertise of key staff and nature of proposed scientific contributions, consistent with the ACTG research agenda described in the ACTG Central Group application; b. Evidence of past accomplishments relative to multi-center HIV clinical trials; c. Organizational structure and responsibilities of key personnel; d. Evidence of the ability to accrue a minimum of 75 HIV-infected patients per year; e. Evidence of the ability to enroll and retain ethnically diverse patient populations, and plans to ensure the inclusion of under-represented populations from within the applicant's catchment area and the populations most affected by HIV and AIDS, especially women and minorities (demographic data on the institution's catchment area must be provided); f. Evidence of effective community linkages and plans for involving community representatives in research activities; g. Procedures for the protection of human subjects; h. Internal quality assurance programs for regulatory compliance and data management; i. Experience in conducting protocol mandated virologic and immunologic assays; j. Plans to encourage the participation of new investigator, women, and minorities in the scientific and managerial aspects of the ACTU. 3. Statistical and Data Management Center The application for the Statistical and Data Management Center must be associated with only one ACTG Central Group application, and the ACTG Central Group with which the Center is proposing to affiliate must be stated in a cover letter and in the application. The Statistical and Data Management Center application is not subject to the page limitations as stated in the form PHS 398. However, the Research Plan (see pages 19 through 23 of the PHS 398 application brochure) must be limited to 110 pages. (Note: the Research Plan should include the information requested below.) The application should be as concise as possible to ensure a thorough review. Suggested format and page limitations for the Statistical and Data Management Center: Organizational Structure/Management Plan: 10 pages including organizational chart, procedures for communicating with collaborating institutions, availability of experienced biostatisticians and other key statistical scientific leadership. Statistical Expertise: 30 pages to the extent possible plans and standard operating procedures for providing timely interim analyses of safety and efficacy and final analyses for publication, procedures for supplying scientific, administrative and regulatory reports to the Executive/Steering Committee and DAIDS should be included as appendices. Samples of protocols should also be provided in appendices to demonstrate experimental design, methods of analysis, and sample size calculation. If the SOPs and protocols are not available, this information should be described in detail in the text of the application. Data Management Capabilities: 70 pages SOPs that address plans for database design and administration, procedures for data collection, management, analysis and quality control, plans for developing/maintaining patient registration/ randomization systems, centralized storage and retrieval of data, plans for tracking laboratory specimens, plans for training site personnel and site monitors, and plans for providing an electronic mail system should be included in the appendix. If they are not available they should be described in detail in the text of the application. REVIEW CONSIDERATIONS A. Review Procedures Applications will be reviewed by the Division of Research Grants (DRG) for completeness and by the NIAID staff to determine responsiveness to the RFA. Incomplete or non-responsive applications will be returned to the applicant without further consideration or review. 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 NIAID in accordance with the review criteria stated below. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non- competitive will be withdrawn from further consideration and the Principal Investigator and the official signing for the applicant organization will be notified. A second level of review will be provided by the National Advisory Allergy and Infectious Disease Council. The review will be conducted in two stages. A review panel will review the ACTG Central Group application(s), focusing on the merit of the proposed scientific agenda and the factors that will affect the group's ability to achieve its stated goals and objectives. The review panel also will review the application from the Statistical and Data Management Center associated with each ACTG Central Group application. The review of the ACTU applications will focus on each unit's ability to contribute to the ACTG Central Group's scientific agenda, as well as the ability and expertise to conduct AIDS clinical trials, including accruing 75 or more demographically representative patients/year. B. Review Criteria The basic review criteria for this RFA are the same as those for unsolicited research project grant applications, namely: a. Scientific, technical, or clinical significance and originality of the proposed research; each project will be rated on its own merit. b. Appropriateness and adequacy of the experimental approach and the methodology proposed to carry out the research. c. Qualifications and research experience of the Group Leader and key staff in the area of the proposed research. d. Availability of necessary resources to conduct the research. e. Adequacy of the proposed means for protecting against adverse effects of the research upon humans, animals or the environment, where such are involved. f. In clinical studies, if there is inadequate representation of women and/or minorities in a study design AND this affects the potential to answer the scientific question(s) addressed, such inadequacy will be considered to be a weakness or deficiency in the study design. This weakness will be reflected in the priority score assigned to the project, unless a convincing justification is provided by the investigator to explain the inadequate representation. In addition, applicants are expected to address criteria specific to the objectives of this RFA. These criteria include: 1. ACTG Central Group Application a. Scientific, medical, and technical significance of the proposed research agenda; proposed plan to effectively accomplish the scientific priorities outlined in the Adult ACTG research agenda; and the strategies to integrate the clinical and laboratory activities of the Adult ACTG. b. Adequacy of the proposed plan and budget for Advanced Technology Laboratories to accomplish the research goals and priorities outlined in the Adult ACTG Central Group application. c. Availability, qualifications and research experience of the Group Leader, and named scientific leadership, including but not limited to, previous experience with design, administration and management of multi-center clinical trials. d. Plans for overall group management and operations, including the structure and mechanism for effective communication and collaboration among the group members including committee structure, an outline of proposed bylaws, procedures for protocol development, data analysis, delegation of responsibilities, performance evaluation and monitoring of research progress, and management actions to improve performance or eliminate inadequate performers. e. Plans for effective interaction and coordination among participating institutions, with DAIDS, and with other research groups conducting HIV/AIDS clinical trials. f. Adequacy of the available resources and personnel for administering the group. Evidence of Operations Office capabilities in research administration, protocol development, and management of regulatory documents. g. Adequacy of plans for appropriate inclusion of women and under-represented minority groups in the clinical trials. h. Adequacy of plans for inclusion of community representation in research and organizational activities. i. Adequacy of plans to encourage participation of new investigators, especially women and minorities in activities at all levels of the ACTG. 2. AIDS Clinical Trials Unit Application a. Qualifications of key personnel, and scientific merit of the proposed contributions to the cooperative group consistent with the Adult ACTG Central Group's scientific agenda. b. Experience in multi-center HIV/AIDS clinical trials research. c. Demonstrated experience in conducting or obtaining virologic, immunologic and pharmacologic assays in support of AIDS clinical trials, and adequacy of laboratories internal quality assurance plan. d. Adequacy of available facilities and time availability of the investigators and key personnel. e. Availability of a minimum of 75 patients per year and evidence of the ability to accrue such patients. f. Adequacy of drug control procedures and pharmacist support to ensure appropriate dispensing of study product. g. Adequacy of provisions for the protection of human subjects. h. Previous experience and adequacy of plans for the inclusion of women and minority patients and for participation of new and minority investigators. i. Previous experience and adequacy of plans for involving community representatives in the sites' research activities. 3. Statistical and Data Management Center Application a. Availability of experienced biostatisticians and other key personnel to provide statistical scientific leadership for the design and analysis of multi-center clinical trials. b. Organizational structure, responsibilities, and procedures for communicating with collaborating institutions. c. Plans for database design and administration, and procedures and policies for data collection, management, analysis, and quality control. d. Plans for developing and maintaining systems for patient registration/randomization and for centralized storage, processing, and retrieval of data. e. Procedures for providing timely interim analyses of safety and efficacy and final analyses for publication. f. Procedures for supplying scientific, administrative, and regulatory reports to DAIDS. g. Plan to provide for an electronic mail system for all collaborating ACTG institutions and DAIDS capable of exchanging messages through Internet. h. Evidence of ability to collaborate with one or more other clinical trial groups as needed. i. Plan for tracking laboratory specimens. j. Plan for training clinical (ACTU) site staff and external site monitors in data management and clinical trials methodology. AWARD CRITERIA The predominant criteria for funding priorities will be the scientific and technical merit of applications in response to this RFA. Consideration will also be given to the following factors in the final selection of applications to be funded: (1) inclusion of populations currently under-represented in clinical trials; and (2) cost-effectiveness of proposed studies. Of the total funds available a minimum of $3.5 million will be reserved for awards for ACTUs at minority institutions. INQUIRIES Written and telephone inquiries concerning the objectives and scope of this RFA are strongly encouraged and may be directed to the staff listed below. Requests for the "NIH GUIDELINES FOR INCLUSION OF WOMEN AND MINORITIES AS SUBJECTS IN CLINICAL RESEARCH" and the "NIAID HIV/AIDS Research Agenda" as well as inquiries regarding programmatic issues may be directed to: Frederick H. Batzold, Ph.D. Division of AIDS National Institute of Allergy and Infectious Diseases Solar Building, Room 2A03 6003 Executive Boulevard MSC 7620 Bethesda, MD 20892-7620 Telephone: (301) 496-8214 FAX: (301) 480-5703 Inquiries regarding review criteria and procedures: Peter Jackson, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4C14 6003 Executive Boulevard MSC 7610 Bethesda, MD 20892-7610 Telephone: (301) 496-8426 FAX: (301) 402-2638 Inquiries regarding fiscal issues to: Kathryn Phillips Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4B33 6003 Executive Boulevard MSC 7610 Bethesda, MD 20892-7610 Telephone: (301) 496-7075 FAX: (301) 480-3780 Schedule Letter of Intent Receipt Date: September 15, 1994 Pre-Application Meeting: September 28, 1994 Application Receipt Date: January 12, 1995 Special Review Committee: May 1, 1995 NIAID Advisory Council: September 11, 1995 Anticipated Award Date: January 1, 1996 AUTHORITIES AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, 93.856 - Microbiology and Infectious Diseases Research and 93.855 - Allergy, Immunology and Transplantation Research. Grants are awarded under the authority of the Public Health Service Act, Section 301 (42 USC 241) and administered under the PHS grants policies and Federal Regulations, most specifically at 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of the Executive Order 12372 or Health Systems Agency review. The Public Health Service strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American People. .
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Office of Extramural Research (OER) |
National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892 |
Department of Health and Human Services (HHS) |
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