Full Text AI-96-001 PEDIATRIC AIDS CLINICAL TRIALS GROUP NIH GUIDE, Volume 25, Number 4, February 16, 1996 RFA: AI-96-001 P.T. 34 Keywords: Clinical Trial AIDS Children (Patients) National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: March 27, 1996 Application Receipt Date: June 11, 1996 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 establish a multisite Pediatric AIDS Clinical Trials Group (PACTG). The purpose of this RFA is to solicit applications from institutions interested in participating in a cooperative group to plan, direct, and conduct Phase I, II, and III clinical trials. These clinical trials will address high priority research questions on the treatment and prevention of human immunodeficiency virus (HIV) disease and its sequelae. The focus will be on: (1) treatment of primary HIV disease, (2) interventions designed to prevent perinatal transmission of HIV, and (3) prophylaxis and treatment of opportunistic infections. Modalities of intervention may include, but are not limited to: (1) drugs or combinations, (2) active and/or passive immune based therapies, (3) immunomodulators, and (4) gene transfer techniques. The initiative targets HIV infected and perinatally exposed infants, HIV infected children, HIV infected pregnant women at risk of transmitting HIV to the infant, and HIV infected adolescents, when therapeutic research questions specific for this age group are identified. 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, Pediatric AIDS Clinical Trials Group, relates to the priority area of pediatric 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 202/783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic institutions, public and private organizations (for-profit and non- profit), such as universities, colleges, hospitals, laboratories, units of State and local government, and eligible agencies of the Federal government. Foreign organizations are not eligible to apply. Racial/ethnic minorities, women, and persons with disabilities are encouraged to apply. The PACTG will consist of: (1) ONE COORDINATING AND OPERATIONS CENTER (CORC), (2) 18-25 PEDIATRIC AIDS CLINICAL TRIALS UNITS (PACTUS), and (3) ONE STATISTICAL AND DATA MANAGEMENT CENTER (SDMC). Applicants applying for more than one award must submit a separate application for each category. Each applicant for a CORC award is responsible for identifying, in the body of the application, the SDMC with which it proposes to work and must coordinate the preparation of the application with them. Accordingly, each applicant for the SDMC award is expected to identify the CORC applicant with which it plans to work and must ensure that the applications are coordinated. Each applicant for a PACTU award must identify, in a cover letter and in the body of the application, the CORC with which it proposes to collaborate. PACTU applicants must be able to meet the minimum annual recruitment standards as described in this RFA under "C. APPLICATION PREPARATION; 2. Pediatric AIDS Clinical Trials Unit Application; Accrual Potential." Each CORC applicant should demonstrate the capability to develop and manage a comprehensive multicenter research program comprising a comprehensive research agenda, scientific and managerial leadership, laboratories to support the research agenda, organizational and governance structure, and an Operations Office. Upon the formation of the PACTG, the group will annually accrue 200 or more HIV positive (HIV+) children who have not been previously enrolled on PACTG protocols and 300 HIV+ pregnant women. This enrollment is exclusive of the subjects accrued to pediatric and perinatal clinical trials funded by the National Institute of Child Health and Human Development (NICHD). NICHD-funded institutions participate, at all levels, in the collaborating group of institutions comprising the PACTG. It is anticipated that the NICHD sites will contribute an additional 100 HIV+ children who have not been previously enrolled on PACTG protocols and an additional 150 HIV+ pregnant women. MECHANISM OF SUPPORT The administrative and funding instrument to be used for these awards will be the cooperative agreement (U01). The cooperative agreement is an assistance mechanism in which substantial NIAID scientific and programmatic involvement is anticipated during performance of the activity. Under the cooperative agreement, the NIAID's purpose is to support and encourage the recipients' activities by working jointly with the awardees in a partner role, but not to assume direction, prime responsibility, or dominance. Details of the responsibilities, relationships, and governance of the studies to be funded are described under the section entitled, SPECIAL REQUIREMENTS, "Terms and Conditions of Award." The total project period for each award may not exceed four years. The anticipated award date is March 1, 1997. It is anticipated that the award for the CORC will be approximately $ 5,000,000 to 8,000,000 total costs per year. The awards for the PACTUs will be approximately $ 18,000,000 to 21,000,000 total costs per year for 18-25 PACTUs; and the Statistical and Data Management Center award will be approximately $ 3,000,000 to 5,000,000 total costs per year. Because the nature and scope of the research proposed in response to this initiative may vary, it is anticipated that the size of individual awards will vary. This RFA is a renewal of the ongoing PACTG Program. Reissuance of this RFA is uncertain. If it is determined that there is sufficient programmatic need for continuing, the NIAID will invite applications for competitive renewal of this program. FUNDS AVAILABLE The NIAID plans to fund one CORC, 18 to 25 PACTUs, and one SDMC. Approximately $30,000,000 total costs is expected to be available for the first year of support under this RFA. The number of awards to be made is dependent on the receipt of a sufficient number of applications of high scientific merit and the availability of funds. Funding beyond the level awarded in the first year will be contingent upon the continued availability of funds for this purpose and the continued progress of the PACTG. RESEARCH OBJECTIVES A. Background HIV disease is now the seventh leading cause of death in the United States (U.S.) for children between one and fourteen years of age. Approximately 6500 HIV+ women deliver children annually in the U.S., and currently 1000-2000 of these children will be infected with HIV. The World Health Organization estimates that by the year 2000, approximately 10,000,000 children worldwide will have been infected with HIV, nearly all by perinatal transmission of the virus. The HIV epidemic in children follows the epidemic in women. It is a major health problem in urban centers where an increasing number of racial/ethnic minorities, women, and injection drug users are being infected. In addition, the epidemic is growing in rural areas where access to appropriate health care and research protocols is extremely difficult because of logistical problems. The goal of NIAID's research on pediatric HIV disease is to identify and support the development of improved interventions to prevent and treat HIV infection and its sequelae in infants, children, and adolescents. Considerable progress has been made in initial therapy of HIV disease with antiretrovirals, prophylaxis of Pneumocystis carinii pneumonia (PCP), and the dramatic reduction in the risk of perinatal transmission of HIV achieved by the administration of the ACTG Protocol 076 regimen. [Note: This regimen is the current standard of care, using zidovudine (ZDV) for the prevention of perinatal transmission.] Current antiretroviral regimens produce short-term improvements in quality of life, but little improvement in survival. The development of resistance results in current regimens becoming ineffective. Therapy for many common opportunistic infections requires the use of multiple drugs, many of which are toxic or only available for parenteral use. Many drugs in use or under investigation for adults are not available in a pediatric formulation, and the current available regimen for prevention of perinatal transmission is expensive, difficult to administer, and not completely effective. The relatively small number of newly infected HIV+ children in the U.S. imposes limitations on the design and conduct of clinical trials in this country. For example, a Phase III efficacy trial of antiretroviral agents might require 800 subjects, which is about one half the annual number of new pediatric cases projected by the Centers for Disease Control and Prevention. As the ACTG Protocol 076 and other preventive regimens become routinely used, this number could fall to approximately 600 new cases per year. Therefore, because of this possible decrease in numbers, pediatric clinical trials must be carefully designed and targeted to address high priority questions with the potential for major gains in therapeutic effect. Similarly, it is important to design these trials to obtain the maximum information about mechanisms of action and disease pathogenesis. Successful conduct of such trials requires the efforts of a large multicenter clinical trials organization. Limitations on the number of HIV+ pregnant women lead to similar conclusions with regard to trials designed to prevent perinatal transmission of HIV. B. Definitions Advanced Technology Laboratory (ATL) - The ATLs are central laboratories that enable the PACTG to implement state-of-the-art assays and technologies that are essential for the completion of the scientific agenda, as defined in the PACTG CORC Application. In addition to the performance of these assays for the group, these laboratories may investigate the feasibility, validity, and standardization of the assays and techniques. The ATLs are not intended to conduct basic research directed at finding new assays. Awards for ATLs will be made through the PACTG CORC and will provide support for protocol related studies only. Collaborating Institution - A collaborating institution of the PACTG may be either the CORC, the Statistical and Data Management Center, or a PACTU. Cooperative Agreement - A cooperative agreement is an assistance mechanism in which substantial NIAID programmatic involvement with the recipient is anticipated during performance of the planned activity. Coordinating and Operations Center (CORC) - The CORC is the central group, consisting of the Group leadership (Group Leader and Executive/Steering Committee) and Operations Office. This group coordinates all aspects of the PACTG and has oversight for the ATLs. Data and Safety Monitoring Board (DSMB) - The DSMB is an independent group 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 trials 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 the PACTG. This committee will be responsible for the conduct and overall activities of the PACTG. (Refer to "SPECIAL REQUIREMENTS; B. Awardee Rights and Responsibilities" in the RFA.) Group Leader - The Group Leader is responsible for the leadership and coordination of all PACTG activities both scientifically and administratively, and serves as the Principal Investigator for the CORC award. The Group Leader may also be associated with a PACTU. NICHD Site - NICHD sites are funded by the National Institute of Child Health and Human Development to conduct AIDS clinical trials research in children and pregnant women. These institutions participate, at all levels, in the collaborating group of institutions comprising the PACTG. The NICHD sites and investigators are selected, funded, monitored, and evaluated by NICHD or its contractor. Operations Office - The Operations Office is a unit within the CORC that will take responsibility for coordinating PACTG administrative activities. Participant Subunit - A subunit is an institution supported under the fiscal and managerial umbrella of a PACTU. Subunits may be established 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 PACTG. Pediatric AIDS Clinical Trials Group (PACTG) - The PACTG is a collaborative network of institutions comprised of the CORC, PACTUs, and the SDMC. This group conducts all phases of clinical trials and laboratory studies. The PACTG consists of experienced investigators in multiple disciplines (e.g., pediatrics, infectious diseases, virology, immunology, clinical pharmacology, neurology, neuropsychology, obstetrics and gynecology, and biostatistics). Clinical investigators and sites supported by the NICHD will participate in the PACTG under an agreement between NICHD and NIAID. Pediatric AIDS Clinical Trials Unit (PACTU) - A PACTU is a clinical site that is a member of the collaborating group of institutions comprising the PACTG. A PACTU may be organized as a main clinical site or a main site and several subunits under the leadership of one Principal Investigator. Statistical and Data Management Center (SDMC) - The SDMC is the component of the PACTG that is responsible to the Group leadership for the statistical aspects of study design and analysis and management of the PACTG database. Therapeutics Research Program (TRP) - The TRP is 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. Research Goals and Scope The primary goals of the PACTG are to evaluate in Phase I, II, and III clinical trials: 1) innovative interventions for the prevention of perinatal transmission of HIV, and 2) innovative therapeutic strategies and interventions for HIV infection and its complications in infants and children. The structure for the group, as defined in this RFA, is intended to strengthen coordination between the PACTG research agenda and understanding in the basic sciences in order to increase understanding of the pathogenesis and complications of pediatric HIV disease and perinatal transmission. This structure will also allow the PACTG to exploit the most recent developments in the biology of HIV and its transmission, and to develop more effective treatments and interventions while enhancing knowledge of the pathogenesis of HIV disease, its complications, and its transmission. The NIAID HIV/AIDS Research Agenda comprehensively documents the Institute's major scientific programs, priorities, and plans in the following scientific areas: pathogenesis, epidemiology and natural history, therapeutics research and development, vaccine research and development, and pediatric disease. The agenda forms the basis for NIAID's scientific planning, program management and evaluation, and communications about the scope and nature of NIAID's efforts in HIV research. The PACTG will play a crucial role in helping to fulfill the goals and priorities delineated in the Pediatric Section of the NIAID's HIV/AIDS Research Agenda. For this reason, it is important that the PACTG identify (by gender and minority status for individuals who choose to be identified) its leadership, advisory boards, and committees. The PACTG will focus on those parts of the Pediatric Section related to the treatment and prevention of pediatric HIV and its complications. Copies of the Pediatric Section of the NIAID HIV/AIDS Research Agenda are available from program staff listed under INQUIRIES. The Group Leadership will identify the highest priority research questions from the major therapeutic areas, and develop a comprehensive clinical trials agenda consistent with the NIAID HIV/AIDS Pediatric Research Agenda. The PACTG will be responsible for developing a prioritized plan to address the research questions in the NIAID HIV/AIDS Research Agenda. Specific areas of the NIAID HIV/AIDS Research Agenda are summarized below: Prevention of Perinatal Transmission of HIV - Nearly all new cases of pediatric HIV infection are due to perinatal transmission. The ZDV regimen developed by the PACTG in ACTG Protocol 076 has demonstrated that perinatal transmission of HIV can be significantly reduced. Additional ongoing trials are investigating the use of HIV hyperimmune globulin (HIVIG) and other agents. Because the ZDV regimen from ACTG Protocol 076 is complex, costly, and likely to be ineffective in patients with resistant HIV, there is a need to develop shorter, more effective, and less expensive regimens. Insights into the mechanisms and biology of perinatal transmission of HIV are emerging from ongoing natural history studies and will be developed as ACTG Protocol 076 comes to a close. These insights should permit the rational design of new regimens. These regimens may involve more effective combinations of antiretroviral agents, passive and/or active immunotherapy, and obstetrical interventions or combinations of the above. Specific goals should include the following: 1. Development of new antiretroviral agents, or combinations of agents, and other modalities for prevention of perinatal transmission (including all necessary Phase I and Phase II trials) in pregnant women and infants for the rational design of efficacy regimens. Recognizing the international nature of the problem, and the limited capacity in the U.S. for the conduct of multiple efficacy trials, the PACTG might undertake research in Phase I and II trials to initially evaluate regimens which could undergo further evaluation in overseas trials funded through other mechanisms by NIAID or other domestic and foreign agencies. 2. Design and conduct efficacy trials of promising regimens for the prevention of perinatal transmission with the goal of improving upon currently available treatments by simplifying them or increasing efficacy. Increased efficacy, low cost, low potential toxicity, and the potential for worldwide use are desirable characteristics of new regimens. 3. Design clinical intervention trials in perinatal transmission to provide as much information as possible regarding the biology of transmission as well as the reasons for success or failure of the intervention being studied. 4. When appropriate, conduct long-term follow-up studies of infants born to mothers who participated in perinatal transmission trials to evaluate potential long term adverse consequences of the therapies. Similarly, conduct appropriate studies in women who participated in perinatal transmission trials to evaluate consequences of the therapies. 5. Determine, if possible, clinical and laboratory markers useful for deciding what regimen, if any, is appropriate for pregnant women who are HIV+. This will require careful thought when designing future efficacy trials. Primary Therapy of HIV Disease in Pediatrics - Considerable progress has been made in the development of antiretroviral drugs for the primary therapy of HIV disease in children. ZDV, ddI, ddC, and d4T have all been extensively evaluated in children. Combinations of agents designed to improve efficacy and impair development of resistance are underway. As new agents become available, it is vital that necessary information becomes available to allow for the safe and rational use of these agents in children as rapidly as possible. New information regarding the pathogenesis of HIV disease suggests that significant events which ultimately damage the immune system occur within the first weeks after the initial infection. Since the time of acquisition of infection can be well defined in some children who acquire HIV by perinatal transmission, the opportunity exists to evaluate effective antiretroviral therapy beginning at or before the time of infection. The PACTG should focus on: 1. Initiation of clinical trials of new agents or combinations in therapeutic regimens for children, in parallel with research for adults, if possible. Emphasize rapid implementation of Phase I/II trials designed to establish tolerable doses, pharmacokinetics and preliminary anti-viral activity of new agents, combination therapy, and novel approaches (e.g., gene transfer methods). 2. Development and initiation of protocols to study the effect of interventions given immediately after delivery in order to answer questions about treatment during acute infection. Such trials should be designed to relate treatment to the pathogenesis of the disease. 3. Production of the necessary information for labeling of new agents for children using minimal information required by FDA rules. 4. The conduct of Phase III efficacy trials when the possibility exists to make improvements over currently available therapy, or when pediatric specific disease questions cannot be answered in adult populations. 5. Utilization of data from completed trials, such as ACTG Protocol 152, to study the impact of the development of resistance to antiretroviral agents retrospectively. When practical assays are available, design prospective studies to evaluate whether change in therapy, triggered by resistance or other markers, results in clinical benefit. 6. The development of protocols suitable for subjects for whom standard regimens are no longer effective. Prevention and Treatment of Opportunistic Infections - The incidence of various opportunistic infections in children differs from that in adults. Serious bacterial infections play an important role. While toxoplasmosis is seen less frequently than other infections, PCP and Cytomegalovirus (CMV) occur as primary disease rather than latent infection. Some important illnesses (e.g., measles) may occur before primary immunization has taken place and cause significant mortality in children with symptomatic HIV infection. In general, agents used to treat opportunistic infections in adults are effective in children, but suitable formulations and knowledge of the pharmacokinetics are lacking. Therefore research related to opportunistic infections should focus on: 1. Evaluation of pharmacokinetic and pharmacodynamic properties of agents known to be effective so that rational use in pediatric subjects is possible. 2. Development of a suitable alternative to trimethoprim/sulfa for prophylaxis of PCP in children. 3. Evaluation of the safety, tolerance, and interactions of oral agents for the treatment and prevention of Mycobacterium avium intracellulare (MAI) and CMV infections in children. 4. Evaluation of the pharmacokinetics of agents effective against multi-drug resistant (MDR) tuberculosis when they become available. 5. Evaluation of the immunogenicity and effectiveness of childhood vaccines in HIV infected children when the results of the studies are likely to have a significant impact on the care and well being of children. 6. Evaluation of new agents, as they become available, for pharmacokinetics and safety in children for the treatment of enteric pathogens. Immune Based Therapy - The pathogenesis of HIV involves destruction of components of the host immune system. In addition, there is ample evidence that immune mechanisms can play a role in controlling HIV. Thus, evaluations of immune based therapies may increase our understanding of the pathogenesis of HIV disease, and may prove useful in the treatment and prevention of pediatric HIV disease. PACTG activities should focus on: 1. Evaluation of active and passive immunization in children, using HIVIG, monoclonal antibodies, and vaccines. These modalities may play a role both in treatment of HIV and in the prevention of perinatal transmission. 2. Evaluation of the ability of cytokines to modulate favorably the course of HIV disease in children. 3. Support of innovative cell transfer studies, particularly the use of cord blood for immune reconstitution and as a substrate for gene therapy. Adolescents - Adolescents are an increasingly important population affected by HIV. Not only are an increasing number of new HIV infections in adolescents occurring through sexual contact or injection drug use, but some perinatally infected children are living into their teens. The PACTG should support research directed at specific questions related to the pharmacokinetic, pharmacodynamics, and interactions of drugs which might be expected to differ in the adolescent population. In general, the PACTG should include adolescents in therapeutic protocols when their inclusion would enhance the ability to answer the scientific questions addressed in the protocols. Often, treatment protocols designed for adults are more appropriate for subjects in their teens and the group is encouraged to refer adolescents to other trials or make arrangements to have appropriate trials available at their sites. Nutrition and other Supportive Care - Nutrition and other supportive care play an important role in the overall health of children with HIV. The PACTG should address scientific questions relating to nutrition and supportive care through clinical trials. Long Term Follow-up - As treatments improve over the years, an increasing number of children will be living longer while receiving various combinations of antiretroviral agents and other drugs or treatments. It is expected that some of these regimens may have long term toxicities which would influence decisions about their use. The PACTG should develop and maintain a long term follow-up protocol that will monitor subjects over an extended period of time for the purpose of identifying such problems. Other - The above items are not meant to be limiting. The PACTG may propose clinical trials outside those mentioned provided they address important scientific questions which may provide information that will improve treatment or prevention of pediatric HIV disease and its complications. SPECIAL REQUIREMENTS 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 terms are in addition to, 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 the cooperative agreement concept, the dominant role and prime responsibility for the planned activity resides with the awardees for the PACTG. Specific tasks and activities in carrying out the activity will be shared among the awardees, DAIDS staff and its contractors. The cooperative agreement funding mechanism will require collaboration between: the DAIDS Associate Director of the TRP, the Group Leader of the PACTG, and the Principal Investigator of the SDMC. The DAIDS will assist in coordinating the activities of the PACTG 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, performing the scientific activity, and agreeing to accept close coordination, cooperation, and participation of NIAID staff in those aspects described below. 1. Responsibilities of the Coordinating and Operations Center (CORC) a. Research Agenda - The Principal Investigator (Group Leader) of the CORC, in collaboration with other investigators constituting the key scientific and managerial leadership, will be responsible for developing, implementing, monitoring, and updating the PACTG scientific clinical trials research agenda consistent with the research goals and priorities of the NIAID's HIV/AIDS Research Agenda, Pediatric HIV Disease Section. These research goals will be reviewed on a mutually agreed upon schedule with DAIDS staff. b. Bylaws/Operating Procedures - The Group Leader will be responsible for ensuring that there are well-documented and clearly defined policies, operating procedures, and bylaws guiding all aspects of PACTG activities. c. Executive/Steering Committee - An Executive/Steering Committee will be established by the PACTG as the main governing body of the group. The committee will be chaired by the Group Leader. The composition must include the Principal Investigator of the SDMC and at least one member from each of the following: DAIDS staff, the community, NICHD staff, PACTG sites, and NICHD sites. d. Protocol Development - The PACTG will initiate development of each protocol only when there is sufficient commitment among the Principal Investigators and other scientific leaders within the group to proceed expeditiously to write the protocol, complete accrual, and analyze and publish the study results. Early notification that the PACTG 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. The PACTG must have clear procedures for designating members of protocol teams and selecting sites for limited-site trials. The PACTG must develop a mechanism to monitor progress, from study initiation through publication, and provide status reports to the DAIDS, on each study, in a format and on a schedule mutually agreed upon. e. Protocol Submission - Prior to implementation of a clinical trial, the PACTG leadership must submit a final draft protocol to DAIDS for review and approval based on consistency with the NIAID HIV/ AIDS Research Agenda and overlap with other NIAID clinical trial programs. DAIDS will communicate all decisions, in writing, to the PACTG; it will be the PACTG's responsibility to disseminate this information to investigators and others as appropriate. f. Administrative Support - The Operations Office, within the CORC, 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: (i) protocol development and distribution; (ii) administrative support for the Group Leader and scientific leadership of the PACTG and all committees; (iii) coordination of protocol specific training; (iv) assembly, review, and submission of regulatory documents to the Pharmaceutical and Regulatory Affairs Branch (PRAB) for registration of sites to conduct clinical trials; (v) maintenance of group administrative records and archives; (vi) coordination of efforts with DAIDS regarding one annual national group meeting to be held in the Washington D.C. metropolitan area in collaboration with the Adult ACTG; and (vii) preparation of administrative and scientific reports (in conjunction with the group's SDMC.) g. Advanced Technology Laboratories (ATLs) - The Group Leader, in consultation with the Executive/Steering Committee of the PACTG, will be responsible for identifying and justifying ATLs with expertise in virology, immunology, and pharmacology which are required to support the PACTG research agenda. Using funds awarded to the CORC, the Executive/Steering Committee will: (i) identify and justify the number of suitable ATLs; (ii) propose a plan for the competitive selection of the ATLs; (iii) determine appropriate distribution of resources; (iv) develop and justify a mechanism to monitor laboratory performance; and (v) propose a plan to periodically assess allocation of funds. h. Laboratory Quality Assurance and Data Management - All virology, immunology, and pharmacology laboratories supported through the PACTG must adhere to technical and analytic guidelines set forth by the scientific leadership of the PACTG. All laboratories must participate in quality assurance programs supported by DAIDS and overseen jointly with the PACTG. In addition, all PACTG-supported laboratories must utilize a common laboratory data management system for specimen tracking and data transmission as designated by DAIDS. i. Study Oversight Responsibility - The PACTG leadership must establish procedures to: (i) assure adequate protection of the rights and safety of subjects involved in its clinical investigations; (ii) guarantee the quality and integrity of resulting data; and (iii) maintain accurate and timely information on the progress of each study. This oversight must include compliance with all Federal regulations and NIH policies and procedures. j. Federally Mandated Regulatory Requirements - The PACTG must be in compliance with all Federal regulations and NIH policies which apply 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 PACTG must be able to demonstrate that: (i) each institution conducting PACTG trials has a current, approved Assurance Number on file with the NIH Office for Protection from Research Risks (OPRR); (ii) each protocol and informed consent is approved by the responsible Institutional Review Board (IRB) prior to subject entry; (iii) each investigator has supplied a completed (including curriculum vitae) FDA 1572 to DAIDS for each protocol conducted at each site; and (iv) each subject (or legal representative) gives written informed consent prior to entry on study. The PACTG must assure timely reporting of all serious and unexpected toxicities and adverse experiences to DAIDS in accordance with DAIDS established policy and procedures delineated in the "ACTG Adverse Experience Reporting Manual." k. Reporting Requirements - The PACTG will submit to the DAIDS requisite information in order to meet administrative, oversight, and regulatory needs. Administrative - To facilitate DAIDS compliance with reporting obligations, the PACTG Group Leader, working through the Operations Office and SDMC, will submit various administrative information to DAIDS. Types of information will include address lists of investigators and other key contacts, protocol abstracts, tracking data, participating sites, accrual and demographic data, and publication information. Some information will be required weekly, some less often. Submission by electronic means, wherever possible, is preferred. Performance - The PACTG Executive/Steering Committee will establish procedures for regularly evaluating performance of the PACTUs, Operations Office, and the SDMC. Procedures will include a process for the addition, reduction, expansion, or removal of PACTUs and subunits based on scientific contributions/protocol participation; observance of protocol requirements; data management/quality; and subject accrual and retention. This mechanism will include a procedure for recommending to DAIDS an adjustment of institutional funds based on the level of contribution and performance. The PACTG Group Leader will submit to the DAIDS an annual progress report summarizing the data on protocol performance by the PACTG as a whole and by each participating clinical unit. These reports will include at a minimum: (i) subject accrual and retention rates; (ii) subject demographics; (iii) timeliness and completeness of all data, including adverse events; (iv) timeliness of IRB approvals of new protocol versions; (v) completeness and quality of laboratory data; and (vi) scientific contributions, including publications. These data should be compiled across all studies and by protocol, as appropriate. Regulatory - Reporting requirements will be in agreement with Federal regulations and NIAID procedures for clinical trials. Prior to the date specified, the PACTG Group Leader will submit to the DAIDS data summary reports that are required of Investigational New Drug (IND) sponsors to by the Food and Drug Administration (FDA). The PACTG 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 PACTG. l. Publication of Data - Prompt and timely presentation and publication in the scientific literature of major findings is essential. Publications or oral presentations of work performed under this cooperative agreement will require acknowledgement of NIAID support and NICHD support when NICHD-funded sites participated. Prior to the submission of manuscripts for publication, the PACTG will provide a preprint to the DAIDS. 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. m. Interaction with DAIDS - The PACTG Group Leader will meet with the Associate Director, TRP on a mutually agreed upon schedule. The purpose of the meetings will be as follows: to discuss research progress, establish priorities, and plan future activities; and to meet with investigators representing other NIAID clinical trials programs to ensure coordination of research agendas. Additional meetings between DAIDS and the PACTG Group Leader may be held as needed. n. National Meetings - It is expected that the PACTG will hold two national meetings per year, at least one of which will be held in conjunction with the Adult ACTG in the Washington, D.C. metropolitan area. Portions of these meetings are open to the public. Upon award of this cooperative agreement, responsibility for both logistical support and scientific content of meetings, for other than the one combined national meeting in the Washington, D.C. area, will transfer to the PACTG Operations Office. DAIDS will continue to provide logistical support (e.g., contracting with local hotels and vendors, providing on-site registration, and audio visual support) through a contractor, for the combined ACTG group meetings. The PACTG will be responsible for developing and coordinating the scientific agenda for its portion of the joint meeting. o. Conflict of Interest - The PACTG will develop, establish, monitor and enforce a Conflict of Interest (COI) Policy, acceptable to NIAID, addressing and resolving any conflict of interest issues that may arise through financial ties between members of the PACTG and the private sector. A report on the PACTG's activities regarding COI issues will be part of the biannual review. p. Discretionary Fund - The Operations Office will maintain and manage a Discretionary Fund. These funds will be expended only upon approval by the Executive/Steering committee. 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 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. q. Inclusion of NICHD Sites - Under an agreement between NICHD and NIAID, clinical sites funded by NICHD participate fully in the activities of the PACTG. The CORC and the SDMC must accommodate the continued participation of the NICHD sites in the PACTG. The NICHD funds a network of sites and a data coordinating center that collects data from the NICHD sites and electronically transmits those data to the PACTG SDMC. NIAID and NICHD program staff will assist in this requirement. NICHD investigators will be expected to conduct research and contribute to the pediatric effort according to standards set for NIAID units; however, the NICHD or its contractor will evaluate NICHD site performance. r. Participation of New Investigators, Women, and Minorities - The CORC will establish and implement strategies to ensure the participation of new investigators, especially women and racial/ethnic minorities, in all levels of the PACTG research effort. 2. Responsibilities of Pediatric AIDS Clinical Trials Units (PACTUs) a. Clinical Studies - Each PACTU must agree to conduct clinical trials according to the priorities and performance goals established by the PACTG and according to the PACTG bylaws. PACTUs must have the capability to recruit and retain yearly a minimum of 10 new (never before enrolled on a PACTG trial) HIV-infected children (including adolescents); and if planning to participate in perinatal transmission trials, PACTUs must recruit and retain yearly a minimum of 15 additional HIV+ pregnant women. Each PACTU will identify, enroll, and retain HIV infected infants, children and pregnant women who are representative of the catchment area. PACTUs must agree to include members of the community in the planning and dissemination of information about clinical trials. b. Routine Laboratory Assays - The CORC will identify the virology, immunology, and pharmacology capabilities, if any, that will be carried out at the PACTUs. Each PACTU must have the capability to perform on site or obtain (via collaboration or purchase) protocol- specific laboratory services, as required by the CORC. Use of existing DAIDS-certified laboratories in the same community, whenever possible, is strongly encouraged. Laboratories performing protocol- mandated tests will be required to participate in DAIDS laboratory quality assurance programs. c. Quality Assurance: Investigational Drug Management -Investigators performing trials under NIAID cooperative agreements must comply with the requirements listed in the DAIDS Standard Operating Procedures and Pharmacy Guidelines and Instructions for ACTG. Investigators must follow all Federal regulations for investigational agents. [Note: The pharmacy manual provides guidance on storage, dispensing, and accountability of investigational agents.] As part of site registration, each clinical unit must complete a DAIDS pharmacy plan that must be approved for compliance with FDA and DAIDS requirements. Upon approval by PRAB, each site may participate in DAIDS sponsored trials. Sites must also register for each protocol sponsored under a NIAID IND by submitting appropriate regulatory documents to the PRAB, DAIDS. These documents will be verified complete and accurate by the PACTG. Once a site is registered by PRAB for a protocol, drug will be supplied by the NIAID Clinical Research Products Management Center, and subjects can be enrolled. d. Quality Assurance: Internal Data Quality Control - Each PACTU must establish an internal quality assurance program to assess the quality of its research records. The plan must be approved by and consistent with the quality control policies developed by the PACTG. These policies should include, but are not limited to, quality control measures for collection, reporting and recording of data. Each PACTU's internal audit plan should apply to the main unit as well as any subunits. e. Quality Assurance: External Data Quality Control - Each PACTU must cooperate with NIAID Clinical Site Monitoring contractor and other appropriate Federally supported site monitoring staff who may inspect records to assure site compliance with all Federal regulations and NIH policies with respect to subjects' safety, data completeness and accuracy. f. Participation of New Investigators, Women, and Minorities - Each PACTU will establish procedures to ensure the participation of new investigators, especially women and racial/ethnic minorities, in all aspects of the PACTG research effort. 3. Statistical and Data Management Center Responsibilities a. Study Design, Conduct, Analysis and Publication - The statistical staff will be responsible for the following: (i) providing statistical scientific leadership for the PACTG and collaborating institutions and organizations; (ii) collaborating at all stages of protocol development and implementation; (iii) performing timely interim analyses of safety and efficacy results for review by protocol teams and/or the DAIDS DSMB; (iv) performing final analyses for publication, participating in the writing of scientific papers and publishing study results in conjunction with other protocol team members; (v) producing timely study monitoring reports, deliverable to the Group Leader and the Associate Director, TRP; (vi) conducting secondary analyses of PACTG data to improve the planning, design, conduct and interpretation of PACTG trials; and (vii) preparing summary tables and data analyses for use in IND annual and interim submissions to the NIAID, FDA, and the DSMB. b. Data Management - The data management staff will: (i) provide central registration and randomization of subjects on all studies; (ii) develop case report forms; (iii) develop standardized criteria for verification of clinical endpoints; (iv) 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; (v) in conjunction with the Laboratory Data Management System contractor and the NIAID AIDS Specimen Repository, facilitate the tracking and identification of laboratory specimens and the merger of laboratory test results with subject clinical data; (vi) provide for centralized storage, security, processing, and retrieval of study results; (vii) provide limited online access for PACTUs to their own blinded data in the central database; (viii) prepare selected, significant public access datasets, with adequate documentation, deliverable to a location designated by DAIDS; (ix) provide for an electronic mail system, capable of exchanging messages through the Internet, to facilitate communication among PACTUs, other PACTG components, and DAIDS; (x) provide data management training of the clinical unit staff and DAIDS Clinical Site Monitoring contractor in the areas of form completion and use of the e-mail system and clinical methodology; and (xi) develop reports detailing site performance in data management, deliverable to the Group Leader and the Associate Director, TRP. The data management staff must function in accordance with policies and bylaws of the PACTG. c. Collaboration - When collaborating with any other clinical trial groups, the PACTG will agree to follow procedures of conduct as determined by the Associate Director, TRP in consultation with the leadership of each clinical trials group. Normally, one group will be given the lead responsibility by DAIDS and its procedures and policies will be followed by all other collaborators. In addition, the SDMC will receive and record adverse experience reports from the PACTG and collaborating institutions and report these events to DAIDS; the SDMC will be required to provide registration and randomization of subjects for, and accept data from, any organization funded by NIAID and NICHD to participate in PACTG trials. For planning purposes, NICHD will contribute approximately 30 percent of the group activity. Oversight of the performance of NIAID and NICHD funded institutions will be the responsibility of the respective institutions. d. Participation of Women and Minorities - The SDMC will establish procedures to ensure the participation of women and racial/ethnic minorities in all levels of the PACTG research effort. 4. NIAID Staff Responsibilities The NIAID will have substantial scientific/programmatic involvement during the conduct of this activity, through technical assistance, advice, and coordination. Through its own funding mechanism, NICHD staff will share in these responsibilities. The role of the DAIDS staff, as described throughout these terms of cooperation, is to assist and facilitate, not to direct the research activities. Communication and interaction will occur primarily with the Group Leader and the scientific leadership of the PACTG. DAIDS will interact directly with the Principal Investigators of any collaborating institutions and the SDMC as needed. Following are specific responsibilities of DAIDS staff in terms of investigational drug research and the Division's role as a drug sponsor as defined in 21 CFR Part 312. This project is a part of NIAID's larger program of therapeutics research. a. Scientific Role of DAIDS in NIAID-Supported Clinical Research - The Associate Director, TRP and/or designated staff will work closely with the PACTG Executive/Steering Committee to assure that the research efforts of the PACTG are consistent with the NIAID agenda for pediatric HIV-related clinical research and are complementary to those of the other clinical trials mechanisms supported by DAIDS. 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 study 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 PACTG investigators. b. DAIDS Role in Protocol Review and Development - In order for a clinical trial to be initiated by the PACTG, the study proposal must be mutually approved by the PACTG and the DAIDS Clinical Science Review Committee (CSRC), chaired by the Assistant Director, TRP, DAIDS. The NICHD scientific program staff also participate on the CSRC deliberations concerning PACTG trials. Once notified that a trial is under serious consideration within the PACTG, DAIDS will evaluate the priority of the proposed trial in relation to: (i) the NIAID HIV/AIDS Therapeutic Research Agenda and other NIAID trials; (ii) the likelihood of timely completion; (iii) subject safety; (iv) compliance with Federal regulatory requirements; (v) plans for interim monitoring of results; and (vi) resource requirements. TRP staff will estimate the costs associated with the protocol. The Assistant Director, TRP will return comments and recommendations in writing to the PACTG within 30 days. In addition, DAIDS pharmacists will participate on PACTG protocol teams, consulting on available dosage forms and placebos. They also will interact with pharmaceutical companies to ensure adequate and timely supply of products. In the event a protocol is disapproved, the Assistant Director, TRP will work with the PACTG Executive/Steering Committee to resolve specific concerns and ensure consistency between the research interests, abilities and priorities of the PACTG 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 PACTG 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. c. DAIDS Role During Protocol Conduct - For ongoing clinical trials, a DAIDS Medical Officer will monitor the safety and efficacy of the treatment being evaluated. NICHD may also assign a medical officer to protocol teams. 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. In instances where a collaborating institute or organization is the sponsor of a protocol, their medical officer and medical monitor will assume the lead. d. DAIDS Role in Protocol Closure - The Associate Director, TRP and/or designated staff will monitor the progress of PACTG trials by reviewing reports periodically submitted to DAIDS, through the Data and Safety Monitoring Board which consists of experts from several disciplines, and through regular meetings with PACTG leadership. DAIDS may deem it necessary to deny access to further investigational drug supplies and deny the expenditure of additional NIAID funds if any of the following reasons apply: (i) risk of subject safety; (ii) scientific question no longer relevant; (iii) slow accrual, or (iv) 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. e. Access to Data - The Chief, Coordinating Centers Branch (CCB) and/or designated monitoring contractor staff will have access to all data generated under the cooperative agreements to be funded through this RFA 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 PACTG. 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 Clinical Site Monitoring contractor will visit PACTUs 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. f. 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 PACTG, 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 PACTG Group Leader normally will 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. Company collaborators generally request that patentable inventions made by PACTU staff during the conduct of clinical trials be brought to the company's attention and that the company be given rights of first refusal to these inventions, provided that the company owns the background patents to such inventions. PACTUs will be required to agree to these requests through a mechanism established by NIAID. g. Laboratory Quality Assurance and Data Management - The DAIDS will provide the PACTG with contractual support for virology, immunology, and pharmacology laboratory quality assurance services. Administrative and fiduciary aspects of contract management will be the responsibility of DAIDS. Responsibility for the scientific and technical oversight for these quality assurance programs shall reside within the DAIDS Drug Development and Clinical Sciences Branch (DDCSB) and will be carried out in conjunction with advisory groups comprised of ACTG and other investigators working in a cooperative manner. The DAIDS will provide the PACTG 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. Similar to the quality assurance programs, the oversight and responsibility for the laboratory data management system shall reside within the DAIDS CCB, in conjunction with an advisory group comprised of ACTG and other investigators working in a cooperative manner. h. 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 PACTG 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. i. DAIDS Review of PACTG Compliance with Federally Mandated Regulatory Requirements - The Chief, PRAB will advise the PACTG regarding mechanisms to meet FDA regulations for DAIDS-sponsored studies involving investigational agents, and OPRR regulations. For DAIDS- sponsored trials with investigational agents, the DAIDS has established an external Clinical Site Monitoring Contract to document good clinical research practices, including regulatory compliance, proper protocol implementation, and test agent accountability. 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 Adult 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. However, when differences exist that are not found within the Adult ACTG, the PACTG will provide input into coding and classification of adverse experience reporting for pediatric populations. This will require collaboration with staff from the DAIDS and other trials groups. j. DAIDS as a Resource for Site Evaluation - The Chief, Clinical Site Management Branch (CSMB) will assist the PACTG in developing criteria to evaluate the performance of the collaborating institutions. The Chief, CSMB will provide data on the cost of the PACTG's research activities, including protocol specific costs. k. Review of Performance - The performance of the PACTG as a whole and that of the individual institutions will be reviewed at least annually by the Associate Director, TRP. The basis of the review will be information provided in annual progress reports, evaluations of site performance conducted by the Executive/Steering Committee, and clinical site monitoring reports provided to DAIDS by its contractor. Substandard data management/quality, insufficient subject accrual and retention, 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. l. DAIDS Review of Quality Control and Study Monitoring Procedures - The Chief, PRAB will periodically conduct a review of the PACTG sites for the reliability of and compliance with clinical and regulatory systems, and will advise on the same. 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. Tina Johnson (see "INQUIRIES") who may also provide relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by March 27, 1996, a letter of intent that includes a descriptive title of the proposed application (Pediatric ACTG CORC, Pediatric ACTU, or Pediatric 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 PACTU and SDMC applicants, the identity of the CORC with which the applicant plans to affiliate, if known. 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 PACTG CORC awards will be used by DAIDS program staff to refer unaffiliated potential applicants for PACTUs to potential PACTG CORCs. 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. (See "INQUIRIES".) APPLICATION PROCEDURES Applications must be submitted on the standard research grant application form PHS 398 (rev. 5/95). Applications kits are available at most institutional offices of sponsored research and may be obtained from the Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: girg@drgpo.drg.nih.gov. 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. For purposes of identification and processing, item 2 on the face page of the application must be marked "YES" and the RFA number and the words "Pediatric ACTG - COORDINATING AND OPERATIONS CENTER" or "Pediatric ACTG - ACTU or "Pediatric ACTG - STATISTICAL AND DATA MANAGEMENT CENTER," as appropriate, must be typed in. If applying for more than one type of award, each application must be submitted separately. Submit a signed, typewritten original of the application, including the Checklist, and three signed exact photocopies. Each application for the CORC, Statistical and Data Management Center, and each PACTU must be submitted separately to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional 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 6003 Executive Boulevard, Room 4C10 MSC 7610 Bethesda, MD 20892-7610 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-8426 FAX: (301) 402-2638 Email: pj8v@nih.gov The deadline for the receipt of applications is June 11, 1996. Applications received after this date will be considered 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 the PACTG It is the responsibility of potential applicants for the PACTG CORC award, Pediatric ACTU awards, and Statistical and Data Management Center award as components of a PACTG to identify themselves to each other and to establish affiliations. In addition to the standard communication channels among investigators, the NIAID will facilitate the formation of the PACTG by: (1) providing the identity of potential CORC applicants to unaffiliated potential ACTU applicants, and the names of unaffiliated potential ACTU applicants to potential PACTG CORC applicants based on the letters of intent; and (2) holding a pre-application meeting on March 20, 1996. B. Pre-Application Meeting - March 20, 1996 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. At the Pre-Application Meeting, all CORC applicants will be asked to submit a scientific agenda and laboratory requirements to DAIDS. This information will be distributed to all potential applicants for a PACTU to assist them in their response. Subsequent to submission of this information, CORC applicants will transmit any changes to the scientific agenda to DAIDS. DAIDS will distribute the changes to all potential applicants. For further information contact Dr. Tina Johnson. (See "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 copies of any materials that are distributed. C. Application Preparation All applications must be submitted on the form PHS 398 (rev. 5/95). Successful applications for each PACTG component (CORC, SDMC, and PACTUs) 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. On page 11 of the PHS 398 application brochure, in the section entitled PERSONNEL, it is imperative that all applicants list ALL individuals and their institutions participating in the scientific execution of the project in the specified format, 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. A key feature of this RFA is that it requires a CORC application to be submitted by a Group Leader/Principal Investigator of the PACTG CORC. All pediatric ACTUs seeking membership in a collaborative group must submit a separate application identifying the CORC to which they are seeking membership. The Statistical and Data Management Center application must be submitted separately, and must also identify the CORC with which it will affiliate. The use of tables (e.g., accrual and protocol type), diagrams, and organization and flow charts is strongly encouraged throughout the preparation of all applications. In summary, applications in response to this RFA must include, but are not limited to, the minimum requirements: 1. Pediatric Coordinating and Operations Center (CORC) Application The CORC application is not subject to the page limitations as stated in the form PHS 398. However, the entire Research Plan must be limited to 100 pages. When preparing your application, use the topics listed below as a guide for writing the research plan in lieu of items a-d listed on pages 16-17 of the PHS 398 application brochure. However, the "Gender and Minority Inclusion for Research Involving Human Subjects" and (e) "Human Subjects" must be included in the Research Plan. Research Plan and Scientific Agenda- The application should discuss the process by which the Group Leader will identify the scientific leadership required to produce a comprehensive research agenda on behalf of a PACTG, the research agenda, and identification of the scientific and managerial leadership required for the Group to effectively and efficiently carry out its research plan. The research plan must clearly identify the priority areas. The applicant must demonstrate, in the preparation of the research plan, linkage with the SDMC application. For established committees (e.g., Executive /Steering Committee) include a gender and minority status for individuals who choose to be self identified. Operations and Management - The application should provide well- documented, clearly defined policies, operating procedures (e.g., protocol development, review, initiation, conduct and closure, data collection, and publication etc.), and bylaws (e.g., delineating the requirements and expectations of collaborating institutions, membership criteria and process for new site consideration by the PACTG, standards of performance, and procedures for removing institutions due to poor performance) guiding all aspects of PACTG activities. In addition to a discussion of the support needed for the Operations Office, each CORC application should include a plan and a budget, developed by the Group Leader, for administrative/managerial support. The CORC applicant and the SDMC applicant must show evidence of ongoing cooperation in the preparation of their applications. Operations Office Procedures - The application must describe the steps that the Group Leader will take to ensure internal and external communication between the Operations Office and the CORC, the PACTUs, and collaborating institutions (e.g., SDMC and DAIDS). Outreach - The application must describe the mechanisms and procedures that will be put in place for monitoring outreach and accrual efforts at the individual PACTUs. Plan and Budget for ATLs - A narrative and budget request for establishing central ATLs must be included in this application. Potential ATLs must not be mentioned by institution or site name in any application materials or supporting documents. 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 PACTG research agenda. Discretionary Funding - The Group Leader may also request a discretionary budget in this application that will be used to: fund innovative pilot studies, supplement the budgets of collaborating institutions undertaking resource intensive studies, 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 $1,500,000 total costs per year. The application must describe how the funds will be used, what review procedures will guide the Executive/Steering Committee for distributing the funds, and what criteria will be used for distribution of funds. Plan for Enrolling Women Completing Perinatal Protocols Into Adult Studies - The application must describe a plan for facilitating and monitoring the referral of post-perinatal study subjects into adult protocols. Budget - As a part of the proposed detailed overall first year budget and summary budgets for future years, the applicant must show evidence of collaboration with SDMC personnel on the preparation of the SDMC workscope and budget. Additionally, the applicant should identify the annual budgets for the following four categories of activities: (a) administrative support for the Group Leader (b) the Operations Office; and, within the Operations Office, (i) the Advanced Technology Laboratories (ii) the Discretionary Funds and (iii) support for the scientific leadership. 2. Pediatric AIDS Clinical Trials Unit Application Each application requesting support as a PACTU is subject to the page limitations (25 pages) for the Research Plan. When preparing your application, use the topics listed below as a guide for writing the research plan in lieu of items a-d listed on pages 16-17 of the PHS 398 application brochure. However, the "Gender and Minority Inclusion for Research Involving Human Subjects" and (e) "Human Subjects" must be included in the Research Plan. Appendices should be limited to no more than 30 pages. Applications exceeding the page limitation will be returned to the applicant. Principal Investigator and Coordinating and Operations Center (CORC) Affiliate - The application for the PACTU must name a Principal Investigator who would be responsible for clinical research. A PACTU applicant may propose association with more than one CORC by submitting a separate cover letter and a separate application for each affiliate. Ability to Contribute to the Scientific Agenda - Each PACTU applicant must demonstrate an ability to enroll adequate numbers of subjects and contribute to the scientific agendas of all CORC applicants with whom it proposes to affiliate. Demonstrated Clinical Trials Capabilities and Expertise -Each PACTU application must describe the following: (a) expertise of key staff and nature of proposed scientific contributions, consistent with the PACTG research agenda described in the CORC application; (b) evidence of past accomplishments relative to multi-center pediatric/perinatal clinical trials (especially in infectious diseases), including a break-down of accrual by protocol and by year [Note: performance data of incumbent applicants for FY 95 and 96 will be provided to reviewers.]; (c) organizational structure and responsibilities of key personnel; (d) procedures and mechanisms for facilitating the referral and enrollment of women from perinatal trials into adult studies; (e) procedures for the protection of human subjects; (f) internal quality assurance programs for regulatory compliance and data management; and (g) plans to ensure the participation of new investigators, women, and racial/ethnic minorities at all levels of the scientific and managerial activities of the PACTU. Ability to Provide Protocol Mandated Laboratory Capability -The CORC will mandate to its affiliated sites what laboratory needs each site should be prepared to provide. Accrual Potential - As a measure of patient accrual potential into the PACTG, each applicant must provide evidence of the ability to enroll yearly a minimum of 10 new (never before enrolled on a PACTG trial) HIV-infected children (including adolescents), and if planning to participate in perinatal transmission trials, a minimum of an additional 15 HIV+ pregnant women in such studies. Applicants employing the standard of care regimen (ACTG Protocol 076) should consider its impact on accrual and take this matter into account when projecting potential accrual goals. In addition, each PACTU applicant must provide evidence of the ability to enroll subjects, other than those described above, in trials (e.g., Phase I, OIs, etc) designed to support fully the Pediatric scientific agenda. Thus, the total accrual of HIV infected children at a PACTU will be significantly greater than the accrual of new subjects. Plan for Enrolling Women Completing Perinatal Protocols Into Adult Studies - The application must describe a plan for facilitating the referral of post-perinatal study subjects into adult protocols. Outreach - The application must demonstrate: a) evidence of the ability to outreach to the community and means of assessing success; b) evidence of effective community linkages and plans for involving community representatives in research activities (e.g., Community Advisory Board); and c) an ability to ensure the appropriate inclusion and retention of under-represented populations from within the applicant's catchment area and the populations most affected by HIV and AIDS as evidenced by a breakdown of available subjects by protocol type (e.g., perinatal, OIs, etc). Applicants must make a good faith effort to demonstrate linkage with local Title IV Ryan White sites in order to facilitate their participation in AIDS clinical trials research. Budget - Budget requests from each PACTU applicant must include all activities that will be undertaken at the unit, such as: recruitment and retention of new subjects, routine laboratory testing, costs associated with the follow-up of subjects continuing on PACTG protocols at incumbent applicant institutions, and purchase and maintenance of any hardware and software required. Budget requests from incumbent institutions will be reviewed based on the following information that will be provided to reviewers: site performance over the past two years, annual subject accrual and retention, and types of protocols. Budget justifications must be based on the projected types of studies to be conducted, number of subjects to be accrued, and the number and type of personnel required relative to the above projections. Incumbent applicants proposing to increase accrual significantly over previously documented accrual levels must provide a compelling justification for this increase and explain how it will be accomplished. Historically, the protocol specific mean direct costs per subject per year for PACTG Phase I, Phase I/II, Phase II, and Phase III studies at main units and subunits have been approximately $5,719; $8,787; $10,695; and $5,203 respectively. The mean annual protocol specific costs include: personnel time directed toward patient care (e.g., physicians, nurses, and pharmacists), laboratory costs, and clinical procedures. The mean costs do not include resources devoted to subject recruitment, screening and ancillary services, data management, quality assurance, program administration or supplies. 3. Statistical and Data Management Center Application The SDMC application is not subject to the page limitations as stated in the form PHS 398. However, the Research Plan must be limited to 100 pages. When preparing your application, use the topics listed below as a guide for writing the research plan in lieu of items a-d listed on pages 16-17 of the PHS 398 application brochure. However, the "Gender and Minority Inclusion for Research Involving Human Subjects" and (e) "Human Subjects" must be included in the Research Plan. The workscope and activities proposed by the SDMC must be consistent with the research agenda proposed by the CORC. The SDMC budget must show linkage to the research priorities in the CORC application. Principal Investigator and Coordinating and Operations Center (CORC) Affiliate - The application must designate a Principal Investigator who would be responsible for the SDMC. The applicant must be affiliated with only one CORC application, and the CORC affiliate must be stated in a cover letter and in the application. Statistical Expertise - The application must provide documentation of plans and standard operating procedures for protocol development, timely interim analyses of safety and efficacy, final analyses for publication, and procedures for supplying scientific, administrative and regulatory reports to the Executive/Steering Committee and DAIDS. Samples of protocols should be provided in the appendices to demonstrate experimental design, methods of analysis, and sample size calculations. If the SOPs and protocols are not available, this information should be described in detail in the text of the application. Organizational Structure/Management Plan - The application must include an organizational chart, procedures for communicating with the Operations Office and other collaborating institutions, availability of experienced biostatisticians and other key statistical scientific leadership. The management plan must address areas of responsibility of key personnel. The justification for staffing levels for each category of staff should relate to projected workload in terms of study size, study phase, number, and complexity of protocols. Data Management Capabilities - Each application for a SDMC must provide evidence of data management capabilities by describing SOPs that address: (a) plans for database design and administration; (b) procedures for data collection (including from the NICHD data coordinating center), management, analysis and quality control; (c) plans for developing/maintaining subject registration/randomization systems, centralized storage and retrieval of data; (d) interface with DAIDS laboratory data management contractor for tracking laboratory specimens and merger of laboratory data with clinical data; (e) plans for training site personnel and DAIDS Clinical Site Monitoring contractor; and (f) plans for providing an electronic mail system. The application should describe, in detail, any hardware and software requirements and expectations to be imposed on the PACTUs and other collaborators. REVIEW CONSIDERATIONS A. Review Procedures Upon receipt, applications will be reviewed for completeness by the Division of Research Grants and reviewed for responsiveness by the NIAID staff. 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. The review of the PACTU applications will focus on each unit's ability to contribute to the PACTG scientific agenda, as well as the ability and expertise to conduct Pediatric AIDS clinical trials. Applications will be reviewed for scientific and technical merit by a review committee convened by the Division of Extramural Activities, NIAID. The second level of review will be provided by the National Institute of Allergy and Infectious Diseases Council. B. Review Criteria 1. Pediatric Coordinating and Operations Center (CORC) Application a. Adequacy of the proposed plans to address the research questions in the Pediatric Section of the NIAID HIV/AIDS Research Agenda. Adequacy of the proposed ranking of the research priorities and justifications. b. Adequacy of the qualifications, research experience, and time commitment of the Group Leader. Adequacy of the qualifications and research experience of the proposed scientific leadership, including but not limited to previous experience with design, administration, management, and coordination of multi-center clinical trials. c. Strength of the provided strategies to ensure for overall subject recruitment and retention including subject enrollment into potentially difficult areas or high priority areas of study. Adequacy of the plans to ensure outreach to members of the HIV infected subpopulations. d. Strength and adequacy of the plans for overall PACTG management and operations, including the plans and mechanisms for effective communication among group membership and committees. e. Adequacy of proposed bylaws; procedures for protocol development; and procedures for delegation of responsibilities; plans for performance evaluation; plans to improve performance; and procedures to eliminate inadequate performers. Adequacy of plans for managing discretionary funds. f. Adequacy of plans for establishing, monitoring and enforcing a Conflict of Interest policy. g. Adequacy of the available or proposed resources and personnel for administering the PACTG. Adequacy of Operations Office capabilities in research administration, protocol development, and management of regulatory documents. h. Adequacy of plans to assure that virology, immunology, and pharmacology laboratories supported through the PACTG adhere to guidelines set forth by the scientific leadership of the PACTG. i. Adequacy of the overall plan for the Advanced Technology Laboratories (ATLs) to meet the stated research goals; and appropriateness of the proposed plan and budget for soliciting, reviewing, selecting, monitoring/evaluating, and terminating ATLs, in order to accomplish the research goals and priorities. j. Adequacy of plans for effective communication and collaboration between the NICHD-funded components and NIAID-funded components. k. Adequacy of proposed plan to accomplish mutual, ongoing collaborations between the Operations Office and the SDMC. Adequacy of proposed links between the Coordinating and Operations Center application and budget and the SDMC application and budget. l. Adequacy of plans to: (i) assure adequate protection of the rights and safety of subjects involved in its clinical investigations; (ii) guarantee the quality and integrity of resulting data; and (iii) maintain accurate and timely information on the progress of each study. This oversight must include compliance with all Federal regulations and NIH policies and procedures. m. Strength and adequacy of plans for inclusion of community representation in PACTG research and organizational activities. n. Adequacy and feasibility of plans to foster participation of new investigators, especially women and racial/ethnic minorities, in activities at all levels of the PACTG. 2. Pediatric AIDS Clinical Trials Unit Application a. Adequacy of the qualifications and availability of key personnel to achieve the stated goals of the PACTU. b. Strength of the proposed scientific contributions of the PACTU to the PACTG scientific agenda. Adequacy of the plans for achieving the proposed PACTU scientific contributions. c. Adequacy of information provided concerning the ability of the applicants to recruit and retain yearly a minimum of 10 new (never before enrolled on a PACTG trial) HIV-infected children (including adolescents). Adequacy of information provided concerning the ability of the applicants to recruit and retain yearly a minimum of 15 additional HIV+ pregnant women, if the proposed PACTU plans to participate in perinatal transmission trials. Strength of evidence that the applicants will be able to accrue additional subjects, beyond the minimum enrollment requirement, into PACTG trials to answer the research questions of the multifaceted pediatric scientific agenda. [PACTU applicants employing the ACTG Protocol 076 regimen should consider its impact on accrual and take this factor into account when projecting potential accruals.] Reviewers will consider the prior HIV/AIDS research experience, multi-center trials experience, and/or pediatric/perinatal clinical trials research experience of the applicants and the involved institutions. Reviewers will also consider the applicant's specific plans for recruitment and retention of subjects, including: ability to accrue patients into potentially difficult or high priority research areas; ability to achieve gender and minority representation appropriate to the HIV infected subpopulations within the catchment area; and ability to outreach to the HIV infected subpopulations. d. Adequacy of plans for the involvement of community representatives in the planning and dissemination of information about clinical trials. e. Adequacy of the plans for, and strength of the applicant's prior experience in, collecting and promptly transmitting reliable, data, and in developing and implementing an internal program for data quality assurance, security and confidentiality. f. Adequacy of available facilities and resources to conduct the proposed work. Adequacy of proposed plans to provide or to obtain core laboratory services as required in the Coordinating and Operations Center application. Adequacy of the proposed drug control procedures and plans for pharmacy support. g. Adequacy of plans for management and coordination of PACTU activities, including communication and cooperation with other PACTG components. h. Strength of the proposed plans and the implementation strategies for identifying and involving new, women and minority investigators at all levels of the proposed PACTU. i. Adequacy of plans for the protection of human subjects. 3. Statistical and Data Management Center Application a. Strength of the qualifications, research experience and availability of the proposed program director as well as other biostatisticians and data systems personnel to provide statistical scientific leadership for the design and analysis of multicenter clinical trials. b. Adequacy of the proposed linkage between the workscope of the SDMC and the research agenda priorities proposed in the Coordinating and Operations Center application. The adequacy of the proposed organizational structure of the SDMC to carry out the proposed responsibilities and the adequacy of SDMC budgetary consistency with the priorities presented in the Coordinating and Operations Center application. c. Adequacy of plans for database design, security, confidentiality and administration, and adequacy of proposed procedures and policies for data collection, analysis and quality control. d. Adequacy of plans for developing and maintaining systems for: patient registration/randomization; receiving, recording and reporting of adverse events from the PACTG and collaborating institutions; providing timely interim analyses of safety and efficacy, and final analyses for publication; and supplying scientific, administrative, and regulatory reports to DAIDS. e. Adequacy of the plan for interfacing and collaborating with the DAIDS laboratory data management system contractor for tracking laboratory specimens. Adequacy of the plan for the merger of laboratory data with the clinical database. f. Adequacy of plans for establishing an electronic mail system, capable of exchanging messages through the Internet, for all collaborating PACTG institutions and DAIDS. g. Adequacy of procedures for interacting with the Coordinating and Operations Center's Operations Office, the NICHD, and other clinical trials groups, as needed. h. Adequacy of the plan for training clinical (PACTU) site staff and the DAIDS Clinical Site Monitoring contractor in: forms completion and data management; the use of the e-mail system; and in clinical trials methodology. NOTE: The following section expands upon review criteria for the Protection of Human Subjects and for Gender and Minority Representation. This section applies to all applications responding to this RFA. 1. Adequacy of the proposed means for protecting against adverse effects of the research upon humans, animals or the environment, where such are involved. 2. In clinical studies, if there is inadequate representation of any gender and/or racial/ethnic minorities in a study design AND this affects the potential to answer the scientific question(s) addressed, such inadequacy will be considered deficient in the study design. The deficiency will be reflected in the priority score, unless a convincing justification is provided by the investigator to explain the inadequate representation.[Note: The Group Leadership should take overall responsibility (and state how in its Coordinating and Operation Center application) for ensuring that the overall representation of study population, PACTG-wide, will be appropriately inclusive of under-represented populations. The SDMC should address in its application how it will ensure that the conditions of the new Guidelines for Gender and Minority Representation are met with regard to clinical trials design (e.g., stratifications, sample sizes, levels of statistical significance required according to what is previously known about gender/ethnicity effects), and how it will conduct appropriate analyses of any data collected. PACTU recruitment should reflect the demographics of the catchment area with respect to HIV- infected under-represented minorities.] AWARD CRITERIA The predominant criteria for funding priorities will be the scientific and technical merit of applications in response to this RFA. Consideration will 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; (2) cost- effectiveness of proposed studies; and (3) the ability of the PACTG to cover all points of the scientific agenda. 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: Tina Johnson, Ph.D. Division of AIDS National Institute of Allergy and Infectious Diseases Solar Building, Room 2B31 6003 Executive Boulevard MSC 7620 Bethesda, MD 20892-7620 Telephone: (301) 496-8214 FAX: (301) 480-5703 Email: tj8y@nih.gov Inquiries regarding review criteria and procedures: Peter Jackson, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4C10 6003 Executive Boulevard MSC 7610 Bethesda, MD 20892-7610 Telephone: (301) 496-8426 FAX: (301) 402-2638 Email: pj8v@nih.gov Inquiries regarding fiscal issues to: Carol Alderson Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4B26 6003 Executive Boulevard MSC 7610 Bethesda, MD 20892-7610 Telephone: (301) 402-5937 FAX: (301) 480-3780 Email: ca10h@nih.gov Schedule Letter of Intent Receipt Date: March 27, 1996 Pre-Application Meeting: March 20 , 1996 Application Receipt Date: June 11, 1996 Special Review Committee: October 1996 NIAID Advisory Council: January 23, 1997 Anticipated Award Date: March 1, 1997 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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