ADOLESCENT MEDICINE TRIALS NETWORK FOR HIV/AIDS INTERVENTIONS Release Date: February 14, 2000 RFA: HD-00-002 (Reissued, see RFA-HD-04-025) National Institute of Child Health and Human Development National Institute on Alcohol Abuse and Alcoholism National Institute on Drug Abuse National Institute of Mental Health Pre-Application Conference: March 25, 2000 Letter of Intent Receipt Date: April 15, 2000 Application Receipt Date: July 11, 2000 PURPOSE The Adolescent Medicine HIV/AIDS Research Network (1994-2001) has been the only national study of the emerging epidemic in teens infected through sex or injecting-drug behaviors. The information derived from this network will be able to inform the nation’s adolescent-specific HIV/AIDS scientific agenda to improve the prevention of HIV infection and the medical treatment of HIV- positive teens. The National Institute of Child Health and Human Development (NICHD), in partnership with the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH), now intends to support a research network infrastructure with the capacity for behavioral, microbicidal, prophylactic, therapeutic, and vaccine trials to take full advantage of the results of the detailed observational and laboratory-intensive studies of the Adolescent Medicine HIV/AIDS Research Network. The primary mission of the Adolescent Medicine Trials Network (ATN) for HIV/AIDS Interventions will be to conduct research, both independently and in collaboration with existing research networks such as the HIV Prevention Trials Network (HPTN), HIV Vaccine Trials Network (HVTN), the Pediatric and Adult AIDS Clinical Trials Groups (PACTG, AACTG), the Community Programs for Clinical Research on AIDS (CPCRA), and others, on promising behavioral, microbicidal, prophylactic, therapeutic, and vaccine modalities in HIV- infected and HIV-at-risk adolescents, ages 12 through 24 years. It is anticipated that 25 percent or less of the ATN research will be generated independently, with the remainder conducted in collaboration with other existing networks. The 25 percent independent, internal ATN research activities are expected to focus on short-term studies (e.g., pathogenic mechanisms, pilot or feasibility studies) in order to generate preliminary data in support of collaborative protocol development either with NIH-funded research networks or independent investigators through RO1 funding mechanisms. Seventy-five percent of the research activities of the ATN will focus on collaboration with other networks or investigators to implement the ATN research agenda. The ATN will bring expertise and resources to collaborative protocol development that will ensure feasible and acceptable study design as well as experience in recruiting and retaining this unique population. For the purposes of collaborative research, ATN resources will support the site- specific and negotiated subject-specific costs entailed in collaborative research activities, and will not duplicate but draw upon the regulatory, drug repository, laboratory, forms design, database management, and statistical capacity available in the NIH-funded research networks that choose to collaborate with the ATN. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA) is related to one or more of the priority areas. Potential applicants may obtain "Healthy People 2010" at http://odphp.osophs.dhhs.gov/pubs/hp2000/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible to apply for these grants. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) cooperative research project grant (UO1) mechanism. The U01 is a cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity reside with the awardees for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among awardees and the NIH staff collaborators. FUNDS AVAILABLE The NICHD intends to commit approximately $5.8 million, the NIDA approximately $750,000, the NIMH approximately $350,000, and the NIAAA approximately $300,000 in total costs (including direct and facilities and administrative costs) in FY 2001 to fund one leadership group grant, one data and operations center grant, and 18-20 trials unit grants in response to this RFA. An applicant for the leadership group may request a project period of up to five years and a budget for direct costs of up to $775,000 in the first year, excluding indirect costs on consortium arrangements, and including discretionary funds of $250,000. An applicant for the data and operations center may request a project period of up to five years and a budget for direct costs of up to $450,000 in the first year, excluding indirect costs on consortium arrangements. An applicant for a trials unit may request a project period of up to five years and a budget for direct costs of up to $120,000 in the first year. Although the financial plans of the NICHD, NIAAA, NIDA, and NIMH provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. RESEARCH OBJECTIVES Background Cases of HIV infection continue to rise in adolescents and young adults. There were 586 cases in 13-19 year olds and 1,605 cases in 20-24 year olds reported to the Centers for Disease Control and Prevention (CDC) in 1997 by those states reporting HIV infection. One year later, new HIV diagnoses reported in these two age categories were 727 and 1,999, respectively. In the 13-19 year old group, 62 percent were female; and in the 20-24 year old group, 43 percent were female. The majority of all reported new HIV infections are in minority populations; 62 percent in the 13-24 age group are of African American or Hispanic origin. The primary transmission for reported AIDS cases has always been sexual in adolescent females and became predominantly male-to-male sexual transmission in adolescent males in 1995. Thus, the picture of the expanding adolescent HIV epidemic based on incident reports to the CDC is one that is increasingly female, minority, and sexually-transmitted through heterosexual activity in females and homosexual activity in males. At the same time, increasing numbers of children who had been infected perinatally are surviving to adolescence. Clinical research for HIV-infected youth has been hampered by the disproportionately small number of the estimated HIV-seropositive youth who are identified and successfully linked to health care. Consequently, there exists no broad-based clinical research infrastructure for HIV-infected adolescents with their particular challenges and unique management demands that is comparable to those established to address adult and pediatric HIV-infected populations. Behavioral interventions that incorporate adolescent-specific skill-building programs that take into account differing levels of adolescent cognitive functioning need to be tested. Primary prevention efforts that combine STI (sexually-transmitted infection) treatment-, barrier method-, and microbicide- approaches specific to adolescents need to be explored. Additional work is needed on understanding the maturation of the mucosal immune response in adolescents to inform mucosal vaccine development. In anticipation of the availability of a preventive HIV vaccine, preparedness studies examining acceptability and feasibility of a preventive HIV vaccine initiative are required. Such studies also should explore the unique ethical considerations inherent in vaccine program implementation, particularly in disenfranchised or emancipated youth. HIV-infected youth now are appearing in health care in increasing numbers so the timing is right for assessing why and how prior prevention strategies and programs failed. Studying the particular constellation of risk that led to HIV infection in seropositive adolescents may produce insights into targeting strategies toward subpopulations at increased risk. Further study also is required into what factors constituted barriers to the effective utilization of preventive programs in the already-infected population. Information on the manifestation and progression of HIV disease, critical to the development and evaluation of a therapeutic agenda, has been established. The effect of early, aggressive therapy needs to be studied, as well as additional inquiry into the full immunologic potential of adolescents and methods for enhancing their HIV-specific cellular immune response. Alternatively, study is required into the effect of delaying treatment when clinical parameters exhibit no apparent damage and the probability of drug adherence is low. Special attention is needed for perinatally-infected adolescents who experience all of the sociobehavioral difficulties of their sexually-infected peers, but also face unique clinical management problems given multiple drug regimen failures in their treatment past. All HIV-infected youth are faced with the social and physical developmental challenges of puberty which make coming to terms with chronic illness, complex drug regimens, and disclosure to peers an intensely more complicated endeavor. The consequences of HIV infection for adolescents is a profoundly understudied area demanding attention. There are few adolescent-specific studies to develop strategies to improve treatment adherence, and to prevent or minimize the negative physical, psychological, cognitive, and social consequences of HIV infection, particularly during the critical developmental periods of adolescence. The manifestations of HIV infection in both vertically and horizontally infected adolescents need to be evaluated specific to HIV pathogenesis, the potential for immune recovery, and the effect of HIV on pubertal development. The long-term consequences of the newer drug therapies with demonstrated metabolic effects administered to adolescents during periods of pronounced growth and sexual maturation also are unknown and require study. As these more effective antiretroviral agents are used more widely in youth, the resulting improved survival may permit the emergence of HIV-induced malignancies, particularly those resulting from co-infection with human papillomavirus (HPV) or Hepatitis B (HBV). Scope of Research This initiative calls for a broad array of supporting and direct intervention studies aimed at the primary, secondary, and tertiary prevention of HIV infection in adolescents and young adults at each trials unit in the network. The application should present an implementation plan to address the research objectives outlined in the 1999 Office of AIDS Research Report on NIH- sponsored Pediatric and Adolescent HIV Infection Research (http://www.nih.gov/od/oar/public/public.htm). Primary prevention studies address behavioral, physical, and/or chemical efforts to interrupt HIV transmission in uninfected populations. These include, but are not limited to, interventions focused on one or more of the following modalities: o assessment of acceptability and feasibility of preventive vaccine initiatives in adolescent and young adults; o evaluation of models of disseminating HIV prevention information and access to health care; o adolescent-specific skill-building efforts related to responsible sexual relationships, avoidance of alcohol and substance abuse, effective condom use, and microbicide use; Secondary prevention studies examine behavioral, nutritional, and/or pharmacologic/therapeutic interventions in order to preserve health in HIV- infected populations. These include, but are not limited to: o evaluation of community methods of identifying HIV-positive youth and linking them to health care; o clinical evaluation of therapies to exploit the immunologic resilience of recently-infected youth; o clinical trials to study both the efficacy and long-term safety of current and new antiretroviral agents; o management trials to study newer drug schedules in order to simplify regimens; o the evaluation of programs designed to promote antiretroviral drug adherence in youth. Tertiary prevention studies evaluate strategies to restore ill HIV-positive adolescents and young people to full or better function. These studies include, but are not limited to: o the effective management of adolescents presenting very ill, as well as the management of adolescents with dwindling therapeutic options; o the assessment of the impact of both HIV infection and its therapy on the life-decisions of young adults with respect to relationships, education, employment, and child-bearing with the development of theory-based interventions. Studies on all three levels should be multidisciplinary collaborations to address the complexity of the population. Organizational Components The Adolescent Medicine Trials Network (ATN) for HIV/AIDS Interventions will consist of the Adolescent Medicine Leadership Group (AMLG), a Data and Operations Center (DOC), and Adolescent Medicine Trials Units (AMTUs). Ancillary groups include the Study Coordinator Group and the Community Advisory Board. Governance and coordination will be provided by an Executive Committee, comprising the Principal Investigator and Chair, the Vice Chair, and the Project Director of the AMLG, the Principal Investigator and Project Director of the DOC, the Chair and Vice Chair representatives elected by and from among the Principal Investigators of the AMTUs, and the NICHD staff science collaborator. (Other NIH staff science collaborators will serve as non-voting members of the Executive Committee, and two representatives of the study coordinators at the AMTUs and the staff person of the Community Advisory Board may serve as non-voting ad hoc members.) Research Responsibilities The Principal Investigator (PI) of the Adolescent Medicine Leadership Group (AMLG) is responsible for assembling the necessary multidisciplinary team of established investigators from within and outside of the PI’s home institution to set the research agenda for the network, and clearly outline the priority areas, plans, processes, and timelines for achieving the implementation of the proposed agenda. The proposed research agenda should address the full spectrum of trials included in the purpose for establishing the ATN (viz. behavioral, microbicidal, prophylactic, therapeutic, and vaccine trials). The AMLG establishes and maintains collaborative relationships with other research networks in order to implement the full research agenda. The Adolescent Medicine Data and Operations Center (DOC) has the responsibility to provide the ATN’s infrastructure and organizational support, staff and site training, quality assurance procedures, the operation and integrity of the managerial database, ATN study development and support, and analytic capacity. The Adolescent Medicine Trials Units (AMTUs) have the responsibility of ATN subject recruitment, retention, and safety through their capacity to provide a wide array of adolescent-specific services by multidisciplinary clinical staffs in well-established adolescent medicine, HIV-care experienced clinical sites. The AMTUs enroll and monitor subjects in a central managerial database, and provide guidance and counsel on the acceptability and feasibility of proposed network research. SPECIAL REQUIREMENTS Special Application Requirements for each organizational component (the Adolescent Medicine Leadership Group, the Data and Operations Center, and the Adolescent Medicine Trials Units) are provided under APPLICATION PROCEDURES. 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 the award. These terms are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Part 74 and 92, and other HHS and NIH grant administration policies. Business management aspects of these awards will be administered by the NICHD Grants Management Office in accordance with HHS and NIH Grant Administration policies. It is envisioned at this time that all awarded funds will be administered by the NICHD Grants Management Office. The cooperative agreement funding mechanism will require collaboration among the NICHD representative(s), the Leadership Group Principal Investigator, the Data and Operations Center Principal Investigator, and the Principal Investigators of the Trials Units. NICHD will assist in coordinating the activities of the ATN as defined below and will facilitate the exchange of information. 1. The Primary Rights and Responsibilities of the Awardees are as follows: All awardees are required to submit annual progress reports to the co- sponsoring institutes providing study and site performance information as stipulated by the institutes. o Adolescent Medicine Leadership Group (AMLG) The AMLG will consist of the Principal Investigator, the AMLG project director, and the collaborating investigators identified in the successful application, and the NIH staff science collaborators. The Principal Investigator of the AMLG will serve as chair of the group. A vice-chair will be elected by the AMLG. The AMLG project director will coordinate the activities of the AMLG at the direction of its officers. The AMLG will have the primary responsibility for defining the research agenda and its implementation in the network, and initiating and maintaining collaboration with other NIH-funded HIV-related research networks within the guidelines of this RFA. Specifically, the AMLG will: Devise ATN policies and procedures for elected terms of office and voting procedures, protocol development and review, authorship and publication, collaboration, site and, where indicated, laboratory monitoring, repository requirements, and related issues and submit to the ATN Executive Committee for approval; Provide for effective communication within the ATN; Retain the primary responsibility for defining and prioritizing the research agenda and submitting the agenda to the ATN Executive Committee for approval; Evaluate the most efficient and scientifically sound mechanisms for developing the research agenda, deciding if the specific agenda items are best pursued independently in the ATN, given resources, or in collaboration with existing research networks; Specify the required elements of the managerial database and collaborate with the DOC in managerial database design; subjects will be recruited into the network on the basis of willingness to consider trial participation and a simple managerial database will permit immediate calculation of available and eligible subjects for any study proposed for implementation in the network; Commit to the development of preventive and therapeutic adolescent-focused studies that take into account the needs and capacities of this special youth population, and the scientific and medical interests and capabilities of the AMTU Principal Investigators; Coordinate ATN collaboration with investigators with funding from sources other than NIH-funded networks. These investigators may include but are not limited to individuals with RO1 funding; Interact, coordinate, and, where indicated, contract with immunology and virology laboratories participating or willing to participate in NIH-supported quality assurance programs in order to provide the ATN with necessary laboratory support for independent ATN studies; Contact the leadership of NIH-supported or other prevention and clinical trials networks, including but not limited to the Adult and Pediatric AIDS Clinical Trials Groups, the HIV Prevention Trials Network, and the HIV Vaccine Trials Network, to inform them of the ATN’s goals, objectives, and organizational structure; Develop in collaboration with these leadership groups formal liaison mechanisms to facilitate interaction and communication on an ongoing basis for the purpose of early involvement in protocol design to address the key scientific and clinical questions in the adolescent population per se or in populations which include adolescents; Consult and interact with NIH-supported or other prevention and clinical trials networks in the design or adaptation of existing trials to meet the needs and characteristics of adolescent populations in order to implement these trials in subjects available in the ATN; Assume responsibility for communication and liaison with existing networks to inform scientific working group chairs of the issues which the ATN would like to see pursued in clinical, behavioral, and prevention research; negotiate shared study costs; and to define and resolve key logistical issues (e.g. data collection and transfer, drug repository and regulatory requirements) which must be addressed to facilitate adolescent enrollment in collaboratively developed research protocols; Recommend the implementation of independent or collaborative research to the Executive Committee when two-thirds of the AMLG members approve the research concept; Identify, with the assistance of the NICHD staff, resources within the ATN to support subject recruitment, enrollment, retention, data collection, specimen shipping, and negotiated protocol monitoring costs for ATN-approved protocols and recommend to NICHD the use of funds for such support; Retain custody of and have primary rights to the data developed from independent research under these awards, during the life of the award and two years subsequent to its termination, subject to government rights of access consistent with current HHS and NIH policies; Negotiate any ATN rights to data and authorship with executive bodies of collaborating networks; Participate in regular conference calls and attend AMLG meetings to be held at least semi-annually. o Data and Operations Center The Data and Operations Center (DOC) will consist of the Principal Investigator, DOC project director, and staff deemed necessary to carry out the mission of the DOC. The DOC project director will coordinate the activities of the DOC at the direction of the principal investigator. The DOC will: Collaboratively plan and conduct AMLG and ATN meetings; Interact with the AMLG on managerial database design and monitoring issues; Provide methodologic and analytic support to the development of independent research projects, design the corresponding data collection forms and database(s), maintain the database(s) and supply the required analytic capacity; Supervise all data collection procedures by the AMTUs, arranging for combined efforts when indicated by regulatory demands of collaborative research; Provide for the most efficient transfer of study data generated by collaborative research either by maintenance of all necessary study-associated database(s) with their electronic transfer or arranging for on-site data entry at the AMTUs; Provide training, including the development and updating of study manuals of operation, to all AMTU site personnel related to acceptable quality control and quality assurance procedures at the sites as well as protocol-training where indicated; Provide periodic on-site monitoring to the AMTUs for those studies being performed at a particular site; Recruit and support the Community Advisory Board (CAB) staff person who will act as a liaison between the CAB members and the ATN, and provide logistical support to any CAB-associated meetings; Participate in regular conference calls and attend AMLG meetings to be held at least semi-annually. o The Adolescent Medicine Trials Unit (AMTU) Group The AMTU Group will consist of the Principal Investigators of the AMTU grants, awarded on the basis of past accomplishment in conducting adolescent clinical research and future capacity to participate effectively in implementing ATN study protocols. The AMTU Group will have a chair and vice chair elected from among and by the AMTU Principal Investigators. Specifically, the AMTU Principal Investigators will: Have primary responsibility for the implementation of the ATN managerial database and ATN-approved study protocols, where feasible, the recruitment and monitoring of study participants, associated data collection, and study- associated quality control measures at the clinical site; these activities may be coordinated by the site study coordinator at the direction of the Principal Investigator; Obtain Institutional Review Board (IRB) approval of all ATN study protocols implemented locally and comply with both IRB and ATN policies and procedures; Provide counsel and advice to the ATN Executive Committee through its elected representatives on the feasibility of proposed research, implementation strategies, and subsequent data collection as well as information on their own perceptions of needed intervention evaluations; Recruit two youths to serve as community representatives, one as the primary representative and the other as an alternate, who both shall be between the ages of 16 and 21 at the time of recruitment and participate in the ATN Community Advisory Board; With consultation from the Study Coordinators Group, formulate the format and procedures for input to the ATN from the Community Advisory Board; Have the opportunity to generate, either unilaterally or in collaboration with AMLG investigators, clinical research proposals for submission to the AMLG for review; Participate in conference calls and attend ATN meetings to be held at least semi-annually. 2. NIH Staff Science Collaborator Involvement Staff Science Collaborators will represent each of the institutes co- sponsoring the RFA. The science collaborators will: Facilitate the exchange of information between the AMLG and other existing research networks to support collaborative efforts; Participate in the Executive Committee that oversees the establishment and maintenance of the ATN and its progress in achieving program goals; Assist the Executive Committee in monitoring the progress of ongoing studies, including field data collection, standardization of methods across study sites, and adherence to protocol and quality control measures; Assist the AMLG in the selection of research topics, and the development or review of protocols for specific studies and interventions; Arrange, when necessary, for the external peer review of the protocols, clearing these studies for implementation; Assist the AMLG in identifying ATN resources required for the successful implementation of collaboratively developed research protocols; Assist in data analyses, interpretation, and publication of study results; Assist in identifying the need to terminate or curtail the study (or an individual award) in the event of nonparticipation in the committee/group activities, substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breach of protocol, or substantive protocol changes without prior approval from program or the ATN Executive Committee. 3. Collaborative Responsibilities: The Executive Committee The Executive Committee is the main governing body of the ATN. The Committee is composed of the Chair, Vice Chair, and Project Director of the AMLG; the Principal Investigator and Project Director of the DOC; the Chair and Vice Chair of the AMTU Group; and the NICHD staff science collaborator. Other NIH science collaborators are non-voting members. The Chair and Vice Chair of the Study Coordinators Group and the CAB Staff Person are non-voting and ad hoc members of the Executive Committee. A quorum must exist for Executive Committee action; a quorum consists of five voting members. Voting members will have one vote each, and motions will carry with a simple majority. The Chair of the AMLG will also chair the Executive Committee. The Vice Chair of the Executive Committee will be elected by the entire committee from among the committee members; none of the NIH science collaborators are eligible to serve as Chair or Vice Chair of the Executive Committee. The Executive Committee will: Assist the AMLG in the identification of adolescent HIV/AIDS research issues; Approve the direction of the research effort, and facilitate the conduct and monitoring of the studies; Approve the ATN policies and procedures developed by the AMLG; Approve the research agenda specific to its feasibility, clinical relevance, and implications as well as advise on the development of implementation strategies; Approve use of discretionary funds as recommended by the AMLG; Establish timelines for the completion of tasks and monitor progress; Oversee site participation and performance, informing the appropriate program managers. 4. Arbitration Process The specific terms and conditions above and the details of arbitration procedures below pertaining to the scope and nature of the interaction among NIH and participating sites will be incorporated into the notice of grant award. These procedures will be in addition to the customary programmatic and financial negotiations that occur in the administration of grants. Arbitration procedures will be invoked only when agreement cannot be reached on programmatic issues that may arise between awardee(s) and the science collaborator(s) after the award has been made. In that event, an arbitration panel will be composed of three members-- one selected by the Executive Committee (with the NICHD science collaborator not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by the NIH program officers, and a third member selected by the two prior selected members. The decision of the arbitration panel by majority vote will be binding. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS Regulations at 42 CFR Part 50, Subpart D and HHS Regulation at 45 CFR Part 16. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which was published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, and is available at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of this RFA. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NICHD staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Audrey Smith Rogers at the address listed under INQUIRIES, below, by April 15, 2000. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research, on the web at http://grants.nih.gov/grants/funding/phs398/phs398.html and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, E-mail: Grantsinfo@nih.gov. Application Preparation All instructions accompanying Form 398 (rev. 4/98) should be followed, except for those items modified by the following special instructions: On line 2 of the face page of the application, applications must clearly indicate the component applied for, specifying either Adolescent Medicine Leadership Group or Adolescent Medicine Data and Operations Center or Adolescent Medicine Trials Unit. If an institution intends to apply for more than one component of the Adolescent Medicine Trials Network for HIV/AIDS Interventions, the institution must submit a separate application for each component. The names of key personnel involved in each application, regardless of whether salary support is requested, should be listed on Form Page 2 of the application and described in the narrative Budget Justification, with their specific responsibilities in support of the research effort outlined and percent time specified. Alphabetized Biographical Sketches for key personnel (limited to two pages each) should follow the budget justification. o Specific Application Requirements for Adolescent Medicine Leadership Group (AMLG) An application for the AMLG is submitted by an institution on behalf of the Principal Investigator of the AMLG who should propose a research agenda for the ATN in the application, clearly outlining the priority areas in depth, discussing plans, processes, and timelines for achieving the implementation of the proposed agenda, and assembling the necessary multidisciplinary team of established investigators from within and outside of the PI’s home institution. Disciplines required to be represented on the AMLG include HIV virology, immunology, mucosal immunology, endocrinology, adolescent medicine, and adolescent behavior. Other disciplines should be included as required to support the proposed research agenda (e.g., infectious disease, gynecology, pharmacology). The proposed research agenda should address the full spectrum of trials listed in the NICHD’s purpose for establishing the ATN (viz. behavioral, microbicidal, prophylactic, therapeutic, and vaccine trials). Evidence of potential collaborative relationships with existing research networks should be provided. Applicants are encouraged to consider, in particular, relationships with research networks such as the Prevention Trials Network (PTN), Vaccine Trials Network (VTN), the Pediatric and Adult AIDS Clinical Trials Groups (PACTG, AACTG), and the Community Programs for Clinical Research on AIDS (CPCRA). The budget for the AMLG should include, at a minimum, salary and administrative support for the AMLG and the committees of the ATN, and travel to one three-day AMLG meeting and two three-day ATN meetings per year. The AMLG PI should also request a discretionary budget in this application; one-quarter to be used for funding innovative pilot studies, and supplementing the budgets of collaborating institutions undertaking resource-intensive pilot studies, and three-quarters in reserve to accommodate non-routine, protocol- mandated requirements (e.g., specimen shipping costs) on an as-needed basis. Requests for discretionary funds may not exceed $250,000 direct costs in the first year of the study. Similar requests may be made in subsequent years of the project period. The application must describe the review procedures that will guide the Executive Committee in distributing discretionary funds. o Specific Application Requirements for Adolescent Medicine Data and Operations Center (DOC) An application for the DOC is submitted by an institution on behalf of the Principal Investigator of the DOC who should propose an infrastructure and organizational support plan for the ATN in the application, clearly outlining the mechanisms proposed for staff and site training, quality assurance procedures, the operation and integrity of the managerial database, ATN study development and support, and analytic capacity. These responsibilities should be presented with plans, processes, and timelines. The DOC applicant should be able to respond flexibly to the changing needs of the ATN as the project unfolds, adding and deleting staff as the requirements dictate. The application should reflect an understanding of these processes. An application for the DOC must provide evidence of data management capabilities by describing standard operating procedures that address: (1) plans for managerial database design and administration; (2) plans for data collection, management, analysis, and data quality control for internal pilot studies; and (3) plans for providing an electronic mail system to participants of the ATN. The budget for the DOC should include, at a minimum, salary and administrative support for the PI, Project Director, and staff required for first study year responsibilities (managerial database and AMTU training and set-up), and travel to one three-day AMLG meeting and two three-day ATN meetings per year. The DOC budget should also include a funding request for Community Advisory Board (CAB) staff support and travel of CAB representatives (one from each AMTU) to one annual meeting. o Specific Application Requirements for Adolescent Medicine Trials Unit (AMTUs) An application for an AMTU is submitted by an institution on behalf of the Principal Investigator of the AMTU who should present evidence of the following in the application: (1) personal expertise, experience, and capacity to contribute to the implementation of the ATN research agenda as outlined in the duties of AMTU PIs; (2) an interdisciplinary health team providing a wide array of adolescent-specific clinical services on site; (3) successful past research participation, with documentation of recruitment and retention rates; (4) the availability of experienced study coordinator(s); (5) clinic and health department numerical and rate data attesting to the presence of adolescents and youth between the ages of 12 and 24 years, with HIV infection rates or rates of high-risk behavioral activity in the clinic catchment area; and (6) ability to recruit and retain at least 75 HIV-positive youth and at least 125 HIV-negative but HIV-at-risk youth in the target age range. Outreach plans and existing liaisons with other community organizations to access these youth should be described in detail, as well as documentation of past performance in these areas. Applications should describe the applicant’s clinical research organization and should include plans, information, and documentation that describe the site’s ability to accomplish the work successfully. The budget for an AMTU should include salary support for the Principal Investigator, study coordinator(s), outreach/recruiting workers, and support staff; all with appropriate justification. Local laboratory costs for the managerial database elements and screening costs for intervention trial participation should be included. Costs for travel to two two-day ATN meetings for the PI and primary study coordinator, communications, supplies, equipment, and subject reimbursement and compensation should be included. Submission Procedures The RFA label available in the PHS 398 (rev. 4/98) application form must be attached to the bottom of the face page of the application and must display the RFA number HD-00-002. A sample RFA label is available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Please note that this is in pdf format. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application should be sent to: Director Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5E03, MSC 7510 Bethesda, MD 20892-7510 Rockville, MD 20852 (for express/courier service) Applications must be received by July 11, 2000. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NICHD. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NICHD, in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second-level review by the National Advisory Councils of the co- sponsoring institutes.. Review Criteria Specific Review Criteria for Adolescent Medicine Leadership Group (AMLG) 1. Significance o Adequacy of the proposed plans to address the intervention research agenda outlined in the Office of AIDS Research 1999 Status Report on NIH-sponsored Pediatric and Adolescent Research (http://www.nih.gov/od/oar/public/public.htm); o Adequacy and breadth of understanding of existing adolescent HIV-related research; o Adequacy and appropriateness of the proposed ranking of research priorities in the application; o Evidence that the proposed research agenda reflects the changing context of adolescent HIV infection in the United States. 2. Approach o Adequacy of the plan for collaborative research and demonstration of current and proposed linkages with other research groups; o Strength and adequacy of the overall management plans, including plans for effective communication among ATN components and collaborators; o Adequacy of the plans for ATN policy development; o Adequacy of plans to assure the appropriate protection of the rights and safety of subjects involved in clinical investigations; o Adequacy of the review plans and procedures that will guide the Executive Committee in distributing discretionary funds. 3. Innovation o Evidence that the research agenda addresses innovative approaches to the development and clinical evaluation of interventions in adolescents and youth. 4. Investigators o Adequacy of qualifications, research experience, and time commitment of the AMLG PI; o Adequacy of the qualifications and research experience of the proposed scientific leadership, including previous experience or working knowledge of recent HIV adolescent-specific research findings; o Adequacy of the proposed resources and personnel for administering the ATN. Specific Review Criteria for Adolescent Medicine Data and Operations Center (DOC) 1. Significance o Quality of the scientific contribution to the ATN research agenda; o Quality of the operational contribution to the ATN research agenda. 2. Approach o Adequacy of site set-up and staff training plans; o Adequacy of the plans for supporting a managerial database in order to generate potential subjects available for proposed or planned studies; o Flexibility of plans to respond to the changing analytic needs of the ATN. o Adequacy of the plans to guarantee the quality and integrity of collected data; o Adequacy of plans to maintain accurate and timely information on the progress of studies and site performance. 3. Innovation o Demonstration of innovative analytic approaches to evaluating clinical research data. 4. Investigators o Adequacy of the qualifications and research experience of the management and analytic team; o Adequacy of previous experience with design, administration, management, and coordination of multi-center clinical studies or trials. o Adequacy of the proposed resources and personnel for supporting the ATN. Specific Review Criteria for Adolescent Medicine Trials Unit (AMTUs) 1. Significance o Quality of the scientific contribution to the ATN research agenda; o Quality of the operational contribution to the ATN research agenda. 2. Approach o Availability of the relevant populations for HIV intervention studies, including a demonstration of the site’s capacity to recruit and retain at least 75 HIV-positive and at least 125 HIV-negative but HIV-at-risk youth in the target age range; o Strength and adequacy of plans and mechanisms for subject recruitment and retention, including plans to extend HIV testing and health care options to hard-to-reach youth populations (viz. run-away and throw-away youth, homeless and street youth populations) and plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research; o Strength and adequacy of the site’s management and communication plan; o Adequacy of plans for implementing multiple intervention trials, including the ability to expand; o Adequacy of plans for community outreach and collaboration, as well as community representation in ATN research 3. Innovation o Evidence that the proposed contribution will provide innovative approaches to the identification, linkage to health care, and engagement in research of at-risk youth; o Evidence that the proposed plans will produce innovative strategies for recruiting and retaining youth in research studies. 4. Investigators o Adequacy of professional qualifications and research experience of the PI; o Adequacy of the research experience of the PI and study coordinator in multi-center clinical research networks; o Adequacy of committee and analytic team experience of the PI in demonstrating an understanding of basic study design and data collection practices. 5. Environment o Evidence of the required expertise, experience, and capacity to carry out the aims of the ATN research agenda; o Evidence of a well-established and -managed health care delivery system provided by a multidisciplinary care team with the full scope of adolescent- specific services available on-site; o Evidence that the clinical settings for adolescents and youth have a comfortable, drop-in atmosphere with attention to group and individual counseling and support. In addition to the above criteria, in accordance with NIH policy, all applications also will be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects also will be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. The initial review group also will examine the provisions for the protection of human subjects and the safety of the research environment. SCHEDULE Pre-application Meeting: March 25, 2000 Marriott Crystal Gateway Hotel 1700 Jefferson Davis Highway Arlington VA 22202 9-10 a.m., Salon G Letter of Intent Receipt Date: April 15, 2000 Application Receipt Date: July 11, 2000 Peer Review Date: October 2000 Council Review: January 25-26, 2001 Earliest Anticipated Start Date: January 27, 2001 AWARD CRITERIA Criteria that will be used to make award decisions include scientific and technical merit, as determined by peer review; availability of funds; and programmatic priorities. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Audrey Smith Rogers, Ph.D. Pediatric, Adolescent, and Maternal AIDS Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B11, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6873 FAX: (301) 496-8678 E-mail: ar44n@nih.gov Anne Willoughby, M.D., M.P.H. (Administrative issues) Pediatric, Adolescent, and Maternal AIDS Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B11, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 402-0699 FAX: (301) 496-8678 E-mail: aw55g@nih.gov Direct inquiries regarding fiscal matters to: Ms. Mary Daley Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1305 FAX: (301) 402-0915 Email: md74u@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.865. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act, as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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