Full Text AI-92-10 PEDIATRIC AIDS CLINICAL TRIALS PROGRAM NIH GUIDE, Volume 21, Number 39, October 30, 1992 RFA: AI-92-10 P.T. 34, AA Keywords: AIDS Children (Patients) Clinical Trial National Institute Of Allergy And Infectious Diseases Letter of Intent Receipt Date: November 13, 1992 Preapplication Meeting Date: December 7, 1992 Application Receipt Date: January 21, 1993 PURPOSE The purpose of this Request for Applications (RFA) is to recompete the Pediatric AIDS Clinical Trials Program in order to further stimulate pediatric AIDS research. This program, initiated in 1988, is supported by the Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID). The Program is designed to provide a distinct scientific emphasis on HIV disease in children and a focus for addressing therapeutic research issues related to this population. The RFA calls for an emphasis on the development and evaluation of pediatric therapeutic research in three major areas, namely: (1) interruption of perinatal transmission of HIV, (2) antiretroviral therapy, and (3) therapy and prophylaxis against opportunistic infection in HIV disease. The target populations include: infants (0 to 12 months of age), children (13 months to 12 years of age), and adolescents (13 through 18 years of age). 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 Trial Program, is related to the priority area of HIV infection. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No 017-001-00474-0) or through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic, 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. Applications from minority individuals and women are encouraged. Existing pediatric AIDS Clinical Trial Units (ACTUs), pediatric components of adult ACTUs, as well as new applicants are invited to apply. MECHANISM OF SUPPORT Awards funded under this RFA will be supported through National Institutes of Health (NIH) Cooperative Agreements (U01). Assistance provided through the cooperative agreement differs from the traditional research grant in that the Government component (NIAID) anticipates substantial programmatic involvement during the performance of the award. The nature of staff participation is described under, Special Requirements: Terms and Conditions for Award. All policies and requirements that govern the grants programs of the PHS and the NIH apply to these cooperative agreements. This RFA is a one-time solicitation with a specified deadline for receipt of applications. Reissuance of this initiative is uncertain. If by the end of the third year of award the NIAID has not announced an intention to reissue the RFA, awardees who plan to apply for continuing support should contact NIAID program officials for advice on how to recompete. FUNDS AVAILABLE Approximately $23,000,000, total costs, will be available for the first year funding. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit and availability of funds. Approximately 10-14 pediatric ACTUs will be funded under this RFA. Awards will be made for a total project period of four years. The anticipated earliest award date is September 1, 1993. Funding beyond the first and subsequent years of the award will be contingent upon satisfactory performance during the preceding years, including meeting research objectives and patient accrual targets, and the continuing availability of funds for this purpose. RESEARCH OBJECTIVES The Pediatric AIDS Clinical Trials Program is a component of the NIAID-supported AIDS Clinical Trials Group (ACTG). The ACTG is composed of the AIDS Clinical Trials Units (ACTUs), the Statistical and Data Analysis Center (SDAC), and the DAIDS Treatment and Clinical Research Programs (See Appendix I, "Structure and Functions of the ACTG"). In addition, further information about the ACTG is contained in the Operations Manual ["Organization, Policies, and Procedures of the AIDS Clinical Trials Group" (ACTG)], which is available by calling Ms. Kym Adams in the ACTG Operations Office at (301) 230-3150. The Pediatric AIDS Clinical Trials Program consists of NIAID-funded Pediatric ACTUs, Pediatric components of Adult ACTUs, and pediatric units supported by the National Institute of Child Health and Human Development (NICHD) which participate in ACTG research. Appendix II contains a listing of all the clinical trials sites of this program. The primary research objectives of this Program are to evaluate the pharmacokinetics, safety, tolerance, and efficacy of agents in order to: o reduce the rate of perinatal transmission of HIV; o develop effective antiretroviral treatment of primary HIV infection; and o develop effective treatment and prophylaxis of opportunistic infections (OIs). These research aims will be addressed through a multi-center clinical trials network in which Principal Investigators (PI) work collectively (as a group) and cooperatively with NIAID staff to devise and implement the most appropriate studies for these objectives. Special Requirements Terms And Conditions Of Award o Terms and Conditions of Award o Awardee Rights and Responsibilities o Awardees must conduct clinical trials that focus on the three research areas list above. At least 25 new patients per year must be accrued onto pediatric protocols. The majority of the pediatric protocols include patients to ages 17 or 18. Included may be individuals classified as adolescents. Perinatal studies are unique in the multi-disciplinary involvement and cooperation required for their conduct. For these studies, awardees must provide coordinated obstetrical research, care, and outreach. Most current and future pediatric research protocols require multiple neurodevelopmental tests. Thus awardees must also perform neuropsychological and neurological testing as clinical endpoints of required studies. o In addition to the 25 patients mentioned above, awardees who have a particular interest in unique aspects of research on adolescents will implement specific studies designed to focus on this population. Institutions with a special interest in neurological and neuropsychological testing will conduct studies of new and efficient methods that could be used as measures of effectiveness in clinical trials of antivirals. o Pediatric ACTU investigators will be responsible for the overall conduct of the research including developing concept sheets for studies, protocol development, the accrual and retention of study patients, production of high quality data, and the timely dissemination of the research results. o ACTU performance in each budget period will determine the base budget award, release of increments of the base budget, and the amount of incentive funding awarded during that budget period. Accordingly, the PI will submit interim progress reports, due at the end of five months after the beginning of the budget period. The NIAID will provide information thatwhich includes accrual data, site monitoring site visit reports and other performance factors for each ACTU. Awardee institutions will be asked to provide budgetary expenditures for the period of performance and a brief summary of clinical research to date. The level of support in future award years will be contingent upon performance. Inadequately justified performance, such as not meeting minimum accrual goals without justification or poor quality of data during a budget period may result in reduction of future year awards or withholding of support. o The PI and other key pediatric ACTU personnel will be required to attend regularly scheduled ACTG meetings in the Washington, DC area (or at a site designated by NIAID). The meetings will occur approximately three times per year. Awardees must be willing to participate in these activities and are expected to include such plans in their budget requests. o Investigators may form a Pediatric clinical trial unit through consortium arrangements with other institutions or health care agencies. They will be designated as subunits. The goals of such arrangements are to: (1) to contribute substantially to the capability of the awardee institution for providing the necessary ancillary support services, including outreach, for recruiting and retaining pediatric patients on clinical trials; (2) provide access to patient populations (e.g., infants and children of minority and substance abusing women, disenfranchised youth) not well represented at the Main Unit; and (3) provide special clinical or scientific expertise not available at the Main Unit. Ultimate financial and scientific responsibility for subunits would reside with the main unit of the ACTU. o National Institute of Allergy and Infectious Diseases Rights, Responsibilities, and Authorities The role of NIAID staff will be to facilitate and not to direct ACTG activities. The terms described in this section are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations in 45 CFR Part 74, and other HHS, PHS, and NIH grant administration policy statements. o The following support can be anticipated from the Treatment Research Operations Program (TROP) and the Clinical Research Program (CRP), which share responsibility for administering the major portion of NIAID-sponsored ACTG research. o The Associate Directors of TROP and CRP, will assist the ACTG Executive Committee in establishing the scientific priorities of the ACTG. o The Chief, Pediatric Medicine Branch, CRP will assist in pediatric protocol development including assisting the Chief, Clinical Research Management Branch, TROP with review of protocols and advice on effectiveness and appropriate utilization of resources. o The Chief, Clinical Research Management Branch, TROP, will assist in promoting the timely implementation and completion of those clinical trials designated as priority studies by the ACTG Executive Committee and the NIAID, and provide technical advice and assistance. o The Associate Director, TROP, as a member of the ACTG Executive Committee, will facilitate the early termination of a protocol for reasons such asinsufficient accrual, patient safety and noncompliance with 45 CFR Part 46, inconclusive results, when it has been determined that further accrual will not add information of scientific value, when the emergence of new information makes the study question less relevant, when program objectives have been met, or when the limitations on the program budget require that ACTG funds be re-directed to higher priority areas. o The Associate Director, TROP, will coordinate activities among other areas of NIH-sponsored research and assist in dissemination of results of clinical trials to the scientific and medical communities. o The Chief, Operations and Data Management Branch, TROP, will assist in providing operational and data management support. The NIAID will serve as the sponsor for Investigational New Drug (IND) Applications required for conducting studies of new agents under evaluation by the ACTG, provide updated information on the safety and efficacy of investigational new agents supplied to ACTUs under an IND Application sponsored by the NIAID (Note: NIAID will not provide investigational agents or guarantee expenditure of NIAID funds for a study after requesting termination of the study). o The Chief, Pharmaceutical and Regulatory Affairs Branch, TROP, will conduct on-site visits to monitor the conduct of studies involving the use of investigational agents, compliance with regulations for Institutional Review Board (IRB) approval and informed consent (compliance with 45 CFR 46), accuracy of data recording, completeness of reporting adverse drug reactions, and quality control (including periodic audits for quality assurance, investigational drug handling, and drug accountability). o The Chief, Clinical Research Management Branch, TROP, will conduct on-site visits to review progress of the research, and issues concerning administrative, technical, and fiscal management. Fiscal Management - Clinical base funding consists of those resources required to maintain an infrastructure and ancillary services sufficient to accrue a projected minimum number of new patients each year. Clinical base funding includes costs for personnel, supplies/equipment, patient care, laboratory support for protocol- mandated assays, ancillary services, and administrative costs. Clinical base funding to ACTUs will be administered in the following manner: the majority of clinical base funding will be released at the beginning of the budget year. At mid- period, the performance of the unit will be assessed by NIAID staff, using accrual, quality of data, and other measures of performance. This assessment will be based on an Interim Progress Report submitted by the PI. If unit performance is satisfactory, the remaining increment of funding will be released. In the event of unsatisfactory ACTU performance (e.g., failure to meet accrual goals, poor data quality etc.), the remaining funds will be reduced or withheld. Continued inadequately justified, poor performance during the remaining months of the budget period may result in reduction of clinical core funding for the following budget period or interruption of support. The NIAID may set aside a portion of the total ACTG budget each year for Incentive Funding. These funds will be used to support activities such as: (1) funding of NIAID/ACTG designated high priority protocols not anticipated at the beginning of the budget period; (2) increasing focus on a scientific area during a budget year for which resource needs exceed the funding of the individual ACTUs; (3) funding to supplement costs incurred as a result of substantial uncompensated participation by investigators in ACTG activities (e.g., travel or other program work, such as a chair of an ACTG scientific committee). o For activities described herein that require approval by NIAID staff during performance of this cooperative agreement (e.g., protocol review and approval, early termination of a protocol, reports intended for inclusion in IND applications and clinical brochures, distribution of investigational agents from the government, etc.), the NIAID will establish an arbitration process to resolve major differences of opinion. An arbitration panel, composed of one pediatric ACTU designee, one NIAID designee, and a third designee with expertise in the relevant area and chosen by the other two will be formed to review any scientific or administrative issue and to recommend an appropriate course of action to the Director, DAIDS. In the event the NIAID is the holder of the IND, any action taken by the NIAID under its responsibility for the safety of the trial would not be subject to arbitration. The arbitration process in no way affects the right of an award recipient to appeal an action in accordance with PHS regulations in 42 CFR Part 50, Subpart D, and HHS regulations in 45 CFR, Part 16. o Cooperative Rights and Responsibilities Shared rights and responsibilities of awardee institutions and the NIAID can be summarized as follows o ACTU - The scientific investigators at the ACTUs, through scientific committees and the Executive Committee, with assistance from TROP and CRP, develop a scientific agenda, set priorities for clinical trials, and initiate the development of protocols. The majority of ideas for clinical trials are initiated by ACTU investigators. Most Phase III protocols are open to participation by any ACTU. Phase I/Phase II protocols are usually conducted at a limited number of ACTUs. o Protocol Development - Ideas for individual studies may be introduced from any source, although most come from ACTU investigators. Proposed studies are summarized in the form of a "concept sheet", which includes the study's rationale, objectives, design, eligibility criteria, treatment regimen, sample size estimates, and cost impact projections. The concept sheets are reviewed by TROP and CRP staff members comprising a Clinical Trials Review Committee (CTRC). The appropriate Scientific Core Committees and the Executive Committee review, approve, and prioritize concept sheets. Approved concept sheets are developed into protocols by a team composed of a protocol chair (an ACTU investigator); TROP and CRP representatives; an SDAC statistician; an Operations Office representative; and immunologist, virologist, pharmacologist, as required. Because most ACTG clinical trials are conducted under an IND held by the DAIDS/NIAID, regulatory requirements mandate review and approval of protocols by the NIAID CTRC prior to their initiation. After FDA approval of the final protocol it is opened for enrollment. Once a protocol has been activated, the protocol chair is responsible for its ongoing performance and is expected to take the lead in dissemination of study results, including publication of results. o ACTG meetings- Meetings of the entire ACTG are held up to three times a year. The primary purpose of these meetings is to bring the ACTG together to review the work of the scientific and resource committees. This includes a review of the scientific agendas set forth by the committees of the group, scientific plenary sessions covering topics at the leading edge of HIV research, updates on protocols, and workshops dealing with the conduct of ACTG studies and operations. Invited guests from the FDA, the NIH, and pharmaceutical industry also participate in these meetings as do representatives from the Community Constituency Group (which includes HIV infected persons) and other interested parties. The ACTG has a committee structure consisting of scientific committees, resource committees, and the Executive Committee. The scientific committees form the scientific nucleus of the ACTG. Each committee has a chair, vice chair, core member, and additional members with relevant expertise and interest in the committee's research area. Each committee has approximately 1-2 representatives from TROP and CRP, 10-15 investigators, an HIV-infected person or advocate, and a representative of the FDA. The role of each Scientific Committee, together with TROP and CRP, and the Executive Committee, is to develop a research agenda and establish research priorities in a particular scientific area and continually reassess those priorities relative to new research opportunities; and to evaluate the conduct and status of active studies. In addition to providing general expertise, the Immunology, Virology, and Pharmacology Committees also have responsibility for developing and recommending laboratory quality assurance policies in the areas of flow cytometry, viral assays, marker evaluation, and pharmacological assays. The Committees meet during each ACTG meeting. In addition, committees meet and/or are in contact at times other than ACTG meetings. Resource Committees were formed to provide technical expertise and practical advice to the ACTG. There are three ACTG Resource Committees: Site and Data Management, Patient Care, and the Community Constituency Group. The Executive Committee, in consultation with TROP and CRP, develops general ACTG policies concerning committee structure and membership, committee operations, publications, access to data, interim data monitoring, and agendas for the group meetings. In addition, the Executive Committee, with assistance from TROP and scientific committees, and establishes scientific priorities for the ACTG. The majority of the members of the Executive Committee are ACTU investigators. Representatives from TROP and CRP, persons from the Community Constituency Group (including HIV infected individuals), and the SDAC also sit on the Executive Committee. Access to Data, Ownership of Data, and Publication Policies In addition to the reporting requirements currently in existence for awardees of traditional NIH research project grants, the following apply: o Reports of data generated by the ACTG or any of its member pediatric ACTUs that are required for the NIAID to fulfill its role as sponsor of an investigational agent (data required for inclusion in IND Applications, Clinical Brochures, and similar documents, as well as periodic reports to the FDA and other regulatory agencies) must be submitted by the PI upon request of the Chief, Pharmaceutical and Regulatory Affairs Branch, TROP to the Operations Office. The latter provides the services necessary to establish and maintain a system for receipt and review of new concepts and systems to coordinate activities related to implementation of ACTG studies. o The NIAID will have access to all data generated under this cooperative agreement and will periodically review the progress reports. Information obtained from the data may be used by NIAID for the preparation of internal reports on ACTG activities or safety monitoring of protocols. However, the awardees will retain rights to the data (see below). Publication of findings is the responsibility of the investigators in accordance with the publication policies established jointly by the ACTG investigators and the Associate Director, TROP. Publication or oral presentation of work performed under this agreement is the responsibility of the PI and will require appropriate acknowledgement of NIAID support. o ACTG member institutions will generate clinical trial data that will be submitted to the Statistical Data and Analysis Center (SDAC). In most cases, these institutional data will represent only a small subset of the total database for a given clinical trial and therefore, will have limited scientific value. The investigators, with the assistance of the Associate Director, TROP, will establish policies limiting publication of such institutional data. These institutional data will remain the property of the awardee from which they originated, even following submission to the SDAC. o The entire database for a particular trial will usually come from more than one institution. Although the data are physically located at the SDAC, the use and publication of the data will be governed by policies established by the ACTG investigators and the Associate Director, TROP. The Associate Director, TROP, and the Associate Director, CRP, will have access to the data and will require periodic special reports of data generated by the ACTG or any of its members as described above. However, publication or oral presentation is the responsibility of the ACTG investigators, who must follow the publication policies established by the ACTG. o In the event of a collaboration with a pharmaceutical company for the evaluation by the ACTG of an investigational agent, a memorandum of understanding among the Associate Director, TROP, participating pediatric ACTU Principal Investigators and the company will set forth the details providing for access by the company to necessary data. FAILURE TO ABIDE BY THESE TERMS OF AWARD MAY RESULT IN WITHHOLDING OF FUNDS BY NIAID. o STUDY POPULATIONS: SPECIAL INSTRUCTIONS FOR INCLUSION OF WOMEN AND MINORITIES IN CLINICALRESEARCH POPULATIONS NIH policy is that applicants for NIH clinical research grants and cooperative agreements will be required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group, together with a rationale for its choice. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information should be included in the form PHS 398 in the Research Plan and summarized in Item 5, Human Subjects. Applicants/offerors are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of U.S. racial/ethnic minority populations (i.e., Native Americans, including American Indians or Alaskan Natives, Asian/Pacific Islanders, African Americans, Hispanics/Latinos). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects applies to ACTUs and subunits. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women and minorities in the study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. STRUCTURE AND COMPOSITION OF THE APPLICATION I. COMPONENTS OF THE RESEARCH PLAN FOR ACCRUAL OF AT LEAST 25 PATIENTS Part A Pediatric Clinical Trials Unit (REQUIRED) o Proficiency in Pediatric Clinical Trials o Required Study Areas o Optional Studies o Administrative and Organizational Structure o Facilities o Outreach/Recruitment o Ancillary Care/Linkages o Data Management o Pharmacy o Immunophenotyping Part B Laboratory Support o Virology (REQUIRED) o Immunology (OPTIONAL) o Pharmacology (OPTIONAL) Part C Developmental Research Component (ALL OPTIONAL) o Virology o Immunology o Neuropsychological Assessment PART A - PEDIATRIC CLINICAL TRIALS UNIT IN PLACE OF ITEMS 1 - 4 OF THE RESEARCH PLAN (FORM 398), PLEASE ADDRESS THE FOLLOWING AREAS: o PROFICIENCY IN CONDUCT OF PEDIATRIC CLINICAL TRIALS (5 page limit) Applicants are required to describe their clinical proficiency (past performance) in the conduct of clinical trials. o Describe the nature of previous pediatric clinical trials experience. Applicants proposing optional studies (e.g., adolescent or neuropsychological assessment studies) may elect to describe proficiency in these areas under Section 3 below and only reference those studies here. o Describe the level of scientific participation in pediatric clinical studies (e.g., protocol design, oversight, analysis of data, etc). Current ACTG participants (hereafter called incumbents) should include participation in Pediatric ACTU (or equivalent) activities such as: chairing or participating on committees, chairing protocol development/selection, submitting concept sheets, performing laboratory tests and assays for collaborative efforts, and serving on working groups. [For applications from incumbents, copies of Institutional Evaluation reports will be provided to the reviewers. Incumbents may describe circumstances or factors that might have affected the site's performance and attainment of research objectives]. o REQUIRED STUDY AREAS (5 page limit for each study area) Applicants should describe a plan for clinical research in EACH of the following areas: PERINATAL TRANSMISSION OF HIV, ANTIRETROVIRALS, AND OIs. o Describe the plan for participation in the three study areas as indicated in the following table (e.g., antiretroviral studies should focus on phases I/II/III, combination therapies and immune based therapies, etc.). Using a table like the one below, provide an estimate of how the total number of patients accrued in the first year will be distributed among these studies. Phase 1 Phase 2 Phase 3 Comb. I. Based Perinatal x x Anti-HIV x x x x x x x Total o For each of these three areas (perinatal transmission, antiretrovirals, opportunistic infections) the research plan should describe the: o nature of the proposed studies, including the conduct of obstetrical research in the perinatal transmission studies; o special scientific expertise of key investigators. The clinical trials research capability and experience of each participating obstetrician must be included in the perinatal studies; o demographic features of potential study population; o other unique features the proposed site might offer to the pediatric ACTG effort; and o nature, organization and relationship of the pediatric unit vis-a-vis the obstetrical/prenatal care site which will provide care to mothers and infants who will participate in perinatal studies. Applicants must include a description of plans for the transition of women from perinatal infection protocols into regular adult protocols (e.g., linkages with an adult ACTU or HIV service within the same institution, or with an adult ACTU or subunit in some other institution). o OPTIONAL STUDIES o ADOLESCENTS (5 page limit) Applicants having special expertise and interest in HIV INFECTION IN ADOLESCENTS may submit plans describing their past proficiency and proposed research for studies on this population. Adolescents enrolled under this optional area may NOT be counted toward the 25 minimum number per year required for enrollment on pediatric protocols. PROFICIENCY o Describe the nature of past experience in the conduct of clinical trials research involving adolescent patients. The plan should include: o seropositivity rates, numbers of adolescent patients seen at applicant institution, and the number of new adolescent patients expected to be enrolled. o arrangements to be implemented at patient care sites, half-way homes, drug treatment centers, etc. to provide outreach to HIV-infected adolescents in order to increase accrual (see "Guidelines for Establishment of Subunits" in ppendix III). Letters of agreement in support of subunit or other formal arrangements must be included. o Incumbents who received supplemental funding for adolescent research in 1991 should present a summary of progress to date. PROPOSED STUDY AREAS Describe the types of clinical studies proposed for research on adolescents. o NEUROPSYCHOLOGICAL ASSESSMENT (5 page limit) PROFICIENCY Applicants having special expertise and interest in conducting neuropsychological assessment and neurological testing may submit plans for research in this area. PROPOSED STUDY AREAS Applicants should describe: o any past experience in the conduct of neuropsychological and neurological test batteries as measures of clinical endpoints; o the types of studies proposed for research on pediatric patients participating in ACTG studies. Include scientific expertise of each investigator (neuropsychologist, neurodevelopmentalist, etc.). o ADMINISTRATIVE AND ORGANIZATIONAL STRUCTURE (8 page limit) Describe the administrative and organizational features that will be implemented to support clinical studies in the required and optional research areas. The description should address the following areas: o organization - describe the proposed administrative and organizational structure of the clinical trials unit; state whether the clinical trials unit will be an integral part of the patient care activities of the institution or constituted as a separate research unit. o personnel - describe the qualifications and responsibilities of key administrative personnel. Describe the type, number, qualifications and responsibilities of any other personnel who might assist in the conduct of the studies, e.g., physicians or other health care personnel, and institution-supported administrative personnel. o FACILITIES (2 -3 page limit) Describe the facilities available for performing ACTU studies and delivering comprehensive care. The description should include facilities for: o outpatient and inpatient studies at the main pediatric ACTU and any subunits; and o patient care (e.g., where study subjects would receive care primary health care, obstetrical, pediatric, etc.) o OUTREACH/RECRUITMENT (5 page limit, plus supporting letters) Provide a clear, concise plan for outreach to and recruitment of pediatric patients, pregnant women, and adolescent patients, if applicable. Emphasis must be placed on the enrollment of women from high-risk groups (e.g., racial/ethnic minorities, especially Blacks and Hispanics, drug abusers, partners of drug abusers, etc). A pregnant woman enrolled in perinatal studies will count as one enrollee. Document the capability to enroll a MINIMUM OF 25 NEW PATIENTS INTO PEDIATRIC PROTOCOLS/YEAR. This minimum number is required in order to qualify as a prospective clinical trials unit. Each applicant must describe the o demographic features of pediatric patients and pregnant women in the catchment area, including number of AIDS cases, HIV seroprevalence data, sex, race/ethnicity, and risk transmission categories. If available, include a categorization of HIV status (P0, P1, etc.) for pediatric patients currently being seen or anticipated. o primary source of study subjects (i.e., inpatient or outpatient units providing primary care, consultative services, HIV testing sites, referrals from community-based physicians or agencies, or other). If utilizing referral sources, the policies and procedures for communication, outreach, follow-up by research staff or primary care provider, and transfer of care back to primary care provider upon completion of study must be provided; o staff commitment for outreach and recruitment (e.g., paraprofessionals [ex-drug users, etc], and outreach workers, social workers, psychologists/ counselors). Describe the responsibilities of each. Culturally sensitive individuals representative of the target population(s) must be included among staff. o outreach to infants, children, adolescents and pregnant females or HIV infected mothers. If applicable, letters of agreement with other institutions should be provided; o for new applicants, provide past records of clinical trials or data from inpatient or clinic records showing number of patients under care (or projected) and an estimation of percentage suitable for Pediatric ACTG studies. o ANCILLARY CARE/LINKAGES (5 page limit) Describe the mechanisms in place to deliver ancillary health care in order to facilitate participation of pediatric patients in research. o Describe how ancillary care (e.g., language interpretation, child care, patient transportation to/from the research center, etc) will be provided to pediatric patients and their families. Provide evidence of commitment to the provision of personnel (e.g., social workers, paraprofessionals, patient advocates, etc) who counsel patients, especially mothers and adolescents, in dealing with issues which may impact on their participation in clinical trials. Culturally sensitive individuals representative of the target population(s) must be included among staff. o Linkages - to increase the collaborative provision of health care and multidisciplinary services at the community level and to establish interaction between the ACTU, the community, and community-based organizations, the following support linkages are either REQUIRED or strongly ENCOURAGED. Letters of agreement in support of these linkages as well as definitive plans to operate the linkages must be provided o Community Advisory Board [REQUIRED]. A Community Advisory Board (CAB) must be established at each site. The CAB serves as a bridge between the ACTU and the community. Describe the specific role and relationship of the CAB to the research and operations of the applicant institution. Specify the composition of the CAB, including AIDS-related expertise of participants, functions performed for the ACTU, and proposed meeting schedule. Inclusion of women and minorities is required; their participation on the CAB should be reflective of the demographics of HIV-infected persons in the catchment area. o National Institute of Child Health and Human Development (NICHD) [REQUIRED]. Applications from institutions where there are NICHD funded sites will be required to include a letter of agreement between the NICHD unit and the proposed ACTU. Included in the letter should be: screening/ recruitment procedures for HIV-infected children; whether facilities are shared; whether both sites are or will be participating in ACTG protocols, and if so, how assignment to ACTG protocols is or will be made. Ordinarily, an applicants may not receive funding simultaneously from more that one NIH institute (e.g., NIAID and NICHD) to participate in ACTG protocols. [See Appendix II for a listing of NICHD sites.] o National Hemophilia Foundation (NHF). [REQUIRED] Applicants who participate in the NIAID sponsored Hemophilia Contract Program may respond to this RFA. However, if successful, the applicant may not receive duplicate support for the same type of work from both agencies. Applicants wishing to establish an ACTU within the same institution as an NHF site will be required to include a letter of agreement from the Principal Investigator of the NHF site in which the relationship between the two sites is described. The following items should be included: screening/recruitment procedures for HIV-infected children; whether facilities are shared; whether both sites are (or will be) participating in ACTG protocols, and if so, how assignments to ACTG protocols are (or will be) made. [See Appendix II for a listing of NHF sites.] o General Clinical Research Center (GCRC) [ENCOURAGED]. Applicants from institutions which have a GCRC funded by the National Center for Research Resources (NCRR) may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC Program Director or the Principal Investigator should be included with the application. o Health Resources and Service Administration (HRSA) Pediatric AIDS Demonstration Project [ENCOURAGED]. Applicants are encouraged to establish linkage with a HRSA funded pediatric project if one is located within the same region is encouraged and a letter of agreement and a plan describing the relationship should be included. [A listing of HRSA Pediatric AIDS Demonstration Projects may be found in the Appendix IV]. o National Institute on Drug Abuse (NIDA) Treatment and Research Centers [ENCOURAGED]. In order to increase the number of HIV-infected drug users in ACTG protocols. Applicants are encouraged to establish linkages with NIDA Treatment and Research Centers located in the same community. In the event that there is not a NIDA center in the catchment area, applicants may establish linkage with drug treatment centers. [A listing of the NIDA Treatment and Research Centers may be found in Appendix V]. o Applicants are strongly encouraged to form other linkages, including but not limited to: community-based organizations that serve children at increased risk for HIV infection, designated State AIDS Centers, the NCI lymphoma network, and community-based AIDS clinics. A letter of agreement for each linkage should be included with the application. o DATA MANAGEMENT PLAN (5 page limit) Describe a plan for managing the clinical trials data from both inpatient and outpatient studies: i.e., collection, entry, maintenance, monitoring, storage, and transmission. The manner in which clinical sites interact with the Statistical and Data Analysis Center (SDAC) is described in Appendix I, F.1. The scope of data management activities are reflected in the recommended guidelines for personnel that are listed in Appendix VI. o The plan should take into account that Federal Regulations require the retention of research records for investigational drugs for two years after a marketing application is approved for the drug. If an application for the drug is not approved, the records must be retained for two years following discontinuation of shipment and delivery of the drug and after FDA has been notified. o The plan should include the following o documentation of the expertise and duties of the data manager regarding PC hardware, software and DOS, and oversight/supervision; o description of procedures for o completion of the forms required for patient study visits; (the estimated time from patient visit to completion of data entry should be noted) o transcription of laboratory data from lab slips to data forms in preparation for data entry; o data entry into the ACTG PC-based distributed data entry system in a timely fashion; o establishment/maintenance of a filing system for patient charts and completed data forms, and procedures for ensuring the security of these files; o description of procedures for educating and training staff on the above protocol-related issues; o provision of adequate resources with respect to both staff and PC hardware and software to accomplish these responsibilities. NOTE: a list of computer equipment that will be required for a clinical trials unit is located in Appendix VII. Funds to purchase required equipment may be requested as part of the application, with adequate justification; o a plan for establishing on-site quality assurance procedures to ensure the accuracy and completeness of all research records and compliance with Federal Regulation regarding clinical trials (e.g., Institutional Review Board approval and informed consent process); and o mechanisms for interacting with SDAC. o PHARMACY PLAN (5 page limit, plus supporting letters) Applications must provide a pharmacy plan which addresses the development and maintenance of the investigational drug control systems for the proposed ACTU, and if applicable, any subunit sites (see below). o The pharmacy plan must include the guidelines set out in the ACTG Pharmacy Manual (available upon request from the ACTG Operations Office, 301- 230-3150) and FDA regulations involving the use of investigational drugs. These guidelines include the following: o technical procedures for control of drug ordering; o procedures for dispensing drugs; o procedures for accountability of drug inventory; and o drug storage requirements. Letter(s) of agreement in support of the plan(s) from pharmacy personnel at participating institutions should be included. o The plan must include provision of adequate pharmacy staff for the proposed ACTU and complete discussion of duties and responsibilities. Guidelines for levels of pharmacy staff based on projected accrual are included on the form, "PEDIATRIC ACTU BASE BUDGET", under Appendix VI. o IMMUNOPHENOTYPING, Required (3 page limit, plus supporting letters) Applicants must be able to perform the following flow cytometric immunophenotyping measurements at the proposed ACTU. These measurements were established by the Immunology Core Committee of the ACTG. The laboratory must have the capability to perform two- and three-color flow cytometric immunophenotyping on whole blood samples using a laser-based instrument on a minimum annual number of 500 samples. Minimum required immunophenotypes include: CD4, CD8, CD3, CD19, CD45, and CD14. Other phenotypes (e.g. CD25, CD38, CD45RA, CD45RO, DR, CD56, CD16, etc.) may be required in the context of ACTG protocols. (The use of existing ACTG -certified laboratories in the same community, whenever possible, is strongly encouraged. For example, an applicant from an institution where there is an adult ACTU laboratory should use the adult laboratory rather than establish a new one.) For the analysis of ACTG specimens, awardee laboratories shall be required to adhere to methodologic guidelines set forth by the DAIDS Flow Cytometry Advisory Committee and to participate in the DAIDS immunophenotyping quality assessment program. The narrative description should contain the following: o description of the technical and analytic methodologies used in the laboratory for the enumeration of immunophenotypes o description of the flow cytometer(s) o the laboratory's reference range(s) for adult and pediatric populations o qualifications and experience of key laboratorypersonnel o description of internal Quality Control/Quality Assurance (QC/QA) program o involvement in external QC/QA and/or proficiency testing programs o breakdown of costs (e.g., personnel, supplies, etc.), including costs for shipping and processing specimens if these tests are to be performed off- site. PART B - LABORATORY SUPPORT FOR CLINICAL TRIALS A major goal of the ACTG is to maintain the capability to address all aspects of clinical drug evaluation. To meet this goal, the ACTG must acquire a depth of laboratory capability concentrated in pediatric ACTUs in order to address questions that are unique to the conduct of HIV clinical trials in children and pregnant women. The DAIDS intends to fund pediatric ACTUs with resources to support virology, immunology and pharmacology as required in the context of ACTG pediatric trials. The Laboratory Support for Clinical Trials components are: Virology, REQUIRED Immunology, OPTIONAL Pharmacology, OPTIONAL o VIROLOGY, REQUIRED (10 page limit, plus supporting letters) Each applicant must submit a plan describing a capability to perform and/or obtain (via collaboration) virology laboratory services as required for evaluation of patients enrolled in ACTG pediatric clinical trials. Budgets should reflect the costs for performing and/or obtaining virologic testing for patients to be enrolled at the applicant ACTU. Applicants are instructed not to duplicate the costs for required virology testing within the clinical base funding. Applicants proposing to perform any virologic testing on-site must include, as part of their plan, detailed descriptions of: o the laboratory equipment and facilities relating to conduct of virology; o all relevant methodologies, such as o procedures for culturing HIV from clinical samples (PBMC & plasma); o procedures for performing HIV p24 antigen determinations; o procedures for performing antiviral drug resistance (susceptibility) assays; o procedures for performing HIV DNA & RNA PCR; and o intralaboratory QC/QA procedures. Applicants proposing to have virologic testing performed by off-site collaborators must include, as part of their plan, detailed descriptions of all relevant methodologies (as described above). In addition, for each virologic test, applicants must provide the name(s) and address(es) of the collaborating investigator(s) performing the test, as well as appropriate documentation (e.g. letters of agreement) to substantiate the collaborative arrangement. The use of existing ACTG-certified laboratories in the same community, whenever possible, is strongly encouraged. All applicants must include, as part of their plan, a detailed description of their proposed procedures for the storage of specimens and maintenance of specimen inventories. Applicants and/or collaborators approved to perform virologic testing in support of ACTG pediatric clinical trials (i.e. on-site and off- site laboratories) shall be required to: o use the DataWorks software for data transmission; o participate in the DAIDS virology QA program; o adhere to ACTG Virology Committee consensus protocols. Applicants approved to perform on-site virologic testing may be required to provide specified virology laboratory services to other sites on a fee-for-service basis. o IMMUNOLOGY, Optional (10 page limit, plus supporting letters) The primary objective of this component is to establish a capability, within pediatric ACTUs, to evaluate the impact of experimental immune-based therapies (e.g. active immunization, passive immunization, ex-vivo expansion of cellular effectors, cytokine therapy, modulation of cytokines, general immune modulators, and genetic therapies) on host immune function. To support the evaluation of immune-based therapeutic strategies, applicants shall describe their capability to develop and perform immunologic assays, such as o HIV-specific cellular immunity (e.g. cytotoxic T cells, proliferative responses, etc.); o HIV-specific humoral immunity (e.g. neutralizing antibody, binding antibody, etc.); o non-HIV specific antigen responses (e.g. anti-tetanus), mitogen-induced proliferative responses); o markers of immune activation (activation antigen expression, cytokine production, etc.); o specific immune responses to opportunistic pathogens. Applicants awarded funding for this component shall be required to: o adhere to consensus protocols developed by the ACTG Immunology Committee o participate in DAIDS-sponsored quality assessment program(s) (QA) for immunology. Also, awardees may be required to perform fee-for- service protocol-mandated immunology testing on samples obtained from patients at other ACTUs. Budgets should reflect the costs to perform the protocol-mandated immunologic assays (a-e above) for patients at the applicant ACTU. Applicants for this component are instructed not to duplicate these immunology costs within the clinical base funding. Applicants not seeking funding for this component shall include the costs of protocol-mandated immunology testing in the clinical base funding. Applicants who seek but are not awarded funds for this component shall have their clinical base funding adjusted to provide support to include the costs of protocol-mandated immunology testing. o PHARMACOLOGY, Optional (10 page limit, plus supporting letters) ACTU Pharmacology laboratories will perform protocol-mandated measurement of drug levels in clinical samples. Applicants should demonstrate a capability to conduct therapeutic drug level monitoring using a variety of methodologies. New technologies will also be implemented as pharmacologic detection procedures improve and/or require evaluation. Applicants should describe and document o procedures to conduct pharmacokinetic analyses of agents utilized in the treatment of HIV infection and the opportunistic infections associated with AIDS in children; o capability to perform a minimum number of 500- 1000 drug level determinations per year for an experimental agent such as a nucleoside analog; o capability to develop new pharmacological assays by describing past experience in developing and evaluating new clinically relevant techniques; o intralaboratory QC/QA procedures and participation and performance in any external QA programs. Applicants awarded funding for this component shall be required to o adhere to consensus protocols developed by the ACTG Pharmacology Committee o participate in DAIDS-sponsored QA program(s) for pharmacology. Awardees may be required to perform fee-for- service protocol-mandated pharmacology testing on samples obtained from patients at other ACTUs. Budgets should reflect the costs to perform protocol-mandated pharmacologic assays for patients at the applicant ACTU. Applicants seeking funding for this component are instructed not to duplicate the costs for B.3 pharmacologic testing within the clinical base funding. Applicants not seeking funding for this component shall include in their clinical core budget the source and costs of protocol-mandated pharmacologic testing. Applicants who seek but are not awarded funds for this component shall have their clinical base funding adjusted to provide support to include the costs of protocol-mandated pharmacologic testing. PART C - DEVELOPMENTAL RESEARCH Access to clinical samples from patients with detailed medical histories provides a unique resource to support developmental research leading to improved diagnosis, monitoring and treatment of individuals with HIV infection. The primary objective of the developmental research funding is to stimulate investigators to answer clinically relevant questions utilizing pediatric patient specimens generated under ACTG protocols. Emphasis in these studies should be on specific scientific inquiries which make the best use of resources available through ACTG sites and that address the highest priority questions that arise from the performance of AIDS clinical trials in children. Research permitted within the developmental research areas may be broad in scope but must be of high clinical relevance. The Developmental Research components are Developmental Virology, OPTIONAL Developmental Immunology, OPTIONAL Developmental Neuropsychological Assessment, OPTIONAL o DEVELOPMENTAL VIROLOGY RESEARCH, OPTIONAL (10 page limit) Developmental Virology Research projects are encouraged in, but are not limited to, the following areas o identification and validation of virologic markers (e.g. viral phenotypes and/or genotypes) correlating with perinatal transmission, clinical disease progression and/or treatment effects in children; o quantitative determination of viral burden and infectivity of HIV virions or cell-associated virus in bodily fluids/tissues and their correlation with perinatal transmission as well as clinical parameters of HIV infection in children; o development of improved methodologies to screen for antiviral drug resistance and to design and evaluate strategies to counteract drug resistance in children; o characterization of mechanisms of resistance, stability and virulence of drug resistant phenotypes, including development of propagation procedures for optimal cultivation of drug resistant isolates from potentially heterogeneous viral populations. Where applicable, applicants should describe the capability to develop novel assays for virologic markers, describing past experience in developing and evaluating new clinically relevant laboratory techniques. o DEVELOPMENTAL IMMUNOLOGY RESEARCH, OPTIONAL (10 page limit) Developmental Immunology Research projects are encouraged in, but are not limited to, the following areas o maternal immunologic parameters and their association with risk of perinatal transmission and disease progression in children; o immune cell phenotypic/functional characteristics (e.g. HIV-specific CTLs, HIV- specific humoral responses, HIV or other antigen- specific proliferation, cytokine production, etc.) and their relationship to clinical disease progression in children; o mechanisms of immune activation and/or immune cell depletion and their relationship to clinical disease progression in children; o evaluation of the immune response to AIDS- associated opportunistic pathogens; o evaluation of the immune response to therapeutic agents. o DEVELOPMENTAL NEUROPSYCHOLOGICAL ASSESSMENT RESEARCH, OPTIONAL (10 page limit) Developmental neuropsychological research projects are encouraged in, but are not limited to, the following areas: o identification of specific early markers of neurologic or neuropsychologic deterioration in patients enrolled in ACTG pediatric protocols; o development and validation of "mini" neurologic or neuropsychologic screening exams in relation to more comprehensive neurologic or neuropsychologic "gold standard" evaluations; o assessment of the correlation of neuroimaging, or neurologic laboratory studies with neurologic or neuropsychologic findings; o assessment of critical sociodemographic confounders which need to be gathered in ACTG pediatric clinical trials and controlled for in analyses of study drug effects on neuropsychologic outcomes; o development of monitoring mechanisms to ensure timeliness and quality of pediatric neurologic and neuropsychologic data gathered in ACTG pediatric protocols. II. ORGANIZATION OF THE APPLICATION All applications must be submitted on the Form PHS 398 (rev. 9/91). The application should be assembled and paginated as one complete document. A separate narrative and itemized budget with justifications must be prepared for each component for which support is requested. GENERAL INSTRUCTIONS FOR PREPARING THE APPLICATION FOR PARTS A, B, AND C Page 1 of PHS 398 Complete items 1-18 as instructed. Please note that this should be page one for the entire application and that all succeeding pages should be numbered consecutively. Items 7 & 8: The budget requested should represent the TOTAL budget of the entire application including Clinical Base Budget (PART A), Laboratory Support (PART B) and Developmental Research (PART C). Item 7 should indicate the total costs for the first year of support (item 7a should tally with the total figure indicated at the bottom of PHS form page 4) and item 8 should indicate the total costs for all four years of support (item 8a should tally with the corresponding figure at the bottom of PHS form page 5.) Item 9: All performance sites whether receiving support or not should be listed. Page 2 of PHS 398 The abstract should contain a brief summary of the proposed work and objectives for the application. Under "Key Personnel Engaged on Project" list the Principal Investigator of the ACTU and the Program Director of each component. Page 3 of PHS 398 Prepare a detailed Table of Contents that will allow reviewers to readily locate specific information for each component. Pages 4 and 5 of PHS 398 INDIVIDUAL BUDGET PAGES FOR EACH COMPONENT: a detailed 12-month budget with justifications (use page 4 of PHS Form 398) with an corresponding four-year summary budget page (use PHS Form page 5) must be prepared for EACH component applied for and for which support is requested. If there is an unusual item requested in one of the future years which had not been requested in the first year, e.g., an item of equipment requested in the second or third year, this item must have a detailed justification. FOR MORE DETAILED INSTRUCTIONS ON THE BUDGET SEE ITEM III, "BUDGET REQUIREMENTS", BELOW. Pages 6 and 7 of PHS 398 Prepare biographical sketches and information on Other Support for all professional personnel participating in the pediatric ACTU for whom support is requested. The biographical sketches and information on other support should be placed at the end of the application, with the Principal Investigator first, followed by other key professional personnel in alphabetical order, appropriately numbered and referenced in the Table of Contents. III. BUDGET REQUIREMENTS All applicants for pediatric ACTUs must apply for the Pediatric Clinical Trials Unit (PART A) and Laboratory Support for Virology (PART B.1). Laboratory Support for Immunology (PART B.2), Pharmacology (PART B.3) and the Developmental Research Components (PART C) are OPTIONAL. An award for any laboratory component is contingent on receiving an award for Part A. Laboratory Support/Developmental Research (PARTS B AND C) Applicants applying for PARTS B and C, who are employed by institutions that have adult ACTU laboratories could use the adult unit to perform the laboratory work in PARTS B and C. The funds for laboratory support will be awarded to and administered by the Pediatric ACTU. Applicants for Developmental Research in Virology (C.1) and Immunology (C.2) must apply for and receive an award for virology and immunology (PART B.1 and B.2) respectively to be eligible for Developmental Research awards (PART C) in these disciplines. COMPOSITE FIRST YEAR BUDGET: Using page 4 of the application prepare a composite budget for the first 12 month budget period. The Composite Budget should include the subtotals from the individual detailed budgets for the first 12-month budget period for each component part in the application: Part A, Part B1, as well as any (optional) component portion of Part B or C for which funds are being requested. Justification for budget elements should be presented in each individual component budget rather than with the Composite Budget. NOTE: FOR EACH INDIVIDUAL FIRST YEAR BUDGET PAGE (I) PREPARED FOR A GIVEN COMPONENT, A CORRESPONDING FOUR-YEAR SUMMARY BUDGET (II) SHOULD ALSO BE PREPARED. PAGE 4 OF PHS FORM 398 SHOULD BE USED FOR ALL "A" BUDGETS. PAGE 5 OF PHS FORM 398 SHOULD BE USED FOR ALL "B" BUDGETS. FOR EXAMPLE: o (I) 12 MONTH BUDGET FOR PART A o (II) FOUR YEAR SUMMARY BUDGET FOR PART A o (I) 12 MONTH BUDGET FOR PART B1 o (II) FOUR YEAR SUMMARY BUDGET FOR PART B1 o (I) 12 MONTH BUDGET FOR EACH COMPONENT OF PART B BESIDES B1 FOR WHICH SUPPORT IS BEING REQUESTED o (II) FOUR YEAR SUMMARY BUDGET FOR EACH COMPONENT OF PART B BESIDES B1 FOR WHICH SUPPORT IS BEING REQUESTED o (I) 12 MONTH BUDGET FOR EACH COMPONENT OF PART C FOR WHICH SUPPORT IS BEING REQUESTED o (II) FOUR YEAR SUMMARY BUDGET FOR EACH COMPONENT OF PART C FOR WHICH SUPPORT IS BEING REQUESTED o (I) COMPOSITE 12 MONTH BUDGET: TOTAL OF ALL (I)S ABOVE o (II) TOTAL SUMMARY FOUR YEAR BUDGET: TOTAL OF ALL (II)S ABOVE ALL BUDGET PAGES MUST BE PLACED FOLLOWING PAGE 3 OF THE OVERALL APPLICATION, WITH THE OVERALL BUDGETS BEING FIRST, FOLLOWED BY THE BUDGETS FOR PART A, THEN B1, AND SO ON. THESE BUDGET PAGES SHOULD BE NUMBERED CONSECUTIVELY AND BE APPROPRIATELY REFERENCED IN THE "TABLE OF CONTENTS." EACH BUDGET PAGE MUST HAVE THE APPROPRIATE TITLE CORRESPONDING WITH THE TITLE OF THE PROJECT OR COMPONENT, IN THE UPPER MARGIN OF THE PAGE. A SUMMARY TOTAL BUDGET: (personnel, equipment, supplies etc) for all four years of requested support should be presented using page 5. The total budget for all future years of requested support is a composite of the individual FOUR-YEAR budgets of each component. Justification for the budget elements should be presented in the individual components. PREPARATION OF BUDGETS FOR PARTS A, B, AND C PART A: CLINICAL BASE BUDGET That portion of the ACTU budget specifically related to patient care is called Clinical Base Budget. It will include the resources required to accrue a projected number of new patients on an annual basis. Clinical Base Budget should include Protocol Specific Costs: All resources necessary for the study of a projected number of patients on ACTG protocols for the duration of the protocol. This may be multi-year funding if the duration of the study is greater than one year. Costs Not Directly Related to a Specific Protocol: ancillary services and outreach efforts necessary for the recruitment and retention of patients; screening costs for the identification of eligible study participants; costs associated with performing flow cytometry (CD4, CD8, etc); and administrative costs. Clinical budgets will be constructed by relating the cost of performing a protocol to the projected number of patients to be accrued. These costs will represent the major portion of the clinical base budget. CONSTRUCTION OF THE CLINICAL BASE BUDGET FOR PART A (PHS Form 398 Page 4): Guidelines for developing base budgets for pediatric units may be found in under Appendix VII, "Pediatric ACTU Base Budget". Base budgets will provide support for the supplies, equipment, patient care cost and ancillary services, and personnel necessary for conducting pediatric clinical trials. Personnel - Support for specialized personnel essential to studies in neurological assessment and for obstetrical and perinatal services should be included in the base budget. In the ACTG, statistical support is provided by SDAC and thus statisticians will not be supported under this RFA. Patient Care - Include the projected costs for performing clinical laboratory tests and charges for in- patient care that will be required by clinical trials protocols. The amount requested should be justified based on the number of patients the ACTU projects to accrue annually. Additional information: Appendix VIII contains a list of patient care laboratory procedures which has been itemized to reflect the clinical laboratory tests necessary for conducting the study. Applicants are required to provide the costs for performing these tests at their institution. If multiple clinical performance sites are proposed in the application which have significantly different costs, the applicant may provide individual laboratory costings for each site. These costs should be attached as an APPENDIX to the application. This information will be used by the Initial Review Group to evaluate the reasonableness of patient care costs being requested. Equipment - Computer equipment and accessories may be requested if justified. See Appendix VI for required equipment. Supplies - Clinical, administrative, pharmacy, and those supplies necessary for performing flow cytometry should be included. Travel - Limited to a total of 24 trips annually to ACTG meetings. Travel funds for personnel listed in Parts B and C should be requested in those component budgets. Scientific meetings are limited to $2000/year and foreign travel, if applicable, to $3000/year. INCUMBENT APPLICANTS Renewal applications from incumbents should include a SEPARATE detailed budget to cover the protocol specific costs of continuing patients that are projected to be on study as of 9/93. This budget should be entitled, "Component A - Continuing Patients" and should include all costs required for the currently enrolled patients to complete the protocol. At the time an award is made this request may be negotiated to adjust for the actual number of patients on study. PART B- LABORATORY SUPPORT BUDGET Using the format in the Form PHS 398, a detailed budget for the first year and for all four years of support must be prepared for each laboratory component for which you are applying. It is nticipated that Laboratory Support awards (Part B) will not exceed $ 200,000 direct costs per year per laboratory. PART C- DEVELOPMENTAL RESEARCH BUDGET As with Part B above, a detailed 12-month budget and a summary four-year budget must be prepared for each developmental research project proposed, following the instructions in Form PHS 398. It is anticipated and that developmental research awards (Part C) will not exceed $100,000 direct costs annually per component. Applicants may apply for more than one optional component. Each project under Laboratory Support and Developmental Research components will be REVIEWED INDEPENDENTLY and should contain sufficient information and detail to assure a thorough review. SPECIAL INSTRUCTIONS: PART B.1 SAMPLE OPTIONS for Laboratory Support for Virology (B.1) o Perform all protocol-mandated virological tests on site (HIV p24, HIV culture (PBMC, plasma), antiviral drug resistance assay, PCR, etc.). o Perform protocol-mandated HIV p24 antigen assays and HIV PBMC cultures on site and collaborate with another (off-site) ACTG virology laboratory to obtain the remaining tests on a fee- for-service basis. o Arrange for all protocol-mandated virologic assays to be performed by another ACTG virology laboratory (off-site) on a fee-for-service basis. Construction of a Detailed Budget for PART B.1 The budget justification for Part B.1 must contain the estimated number of samples to be evaluated annually (based only on samples from patients enrolled at the applicant ACTU) for each test and the total estimated cost/test. Sample budget justifications referring to possible options A, B, and C above o All necessary personnel, equipment, supplies, etc. should be included. o All necessary personnel, equipment, supplies etc. should be included for the HIV p24 antigen assays and HIV PBMC cultures. The costs of processing (personnel and supplies) and shipping the remaining samples to other laboratories should also be included. The total costs for those tests that will be performed on a fee-for-service basis should be included in the Other Expenses category of the budget. o The costs of processing (personnel and supplies) and shipping the samples should be included. The total costs for all tests to be performed on a fee-for-service basis should be included in the Other Expenses category of the budget. SPECIAL INSTRUCTIONS: PART B.2, B.3, AND PART C Follow the instructions in PHS 398 starting with the preparation of the Detailed Budget. If information (facilities available, procedures for handling and disposing of HIV infected material etc.) has been presented in a prior component of the application, it may be cross referenced in a subsequent component. LETTER OF INTENT Prospective applicants are asked to submit by November 13, a letter of intent (maximum of three pages) that includes a descriptive title of the overall proposed research, the components that will be included, the name and institution of the Principal Investigator and a brief description of the research proposed for each component in which participation is planned. Names of prospective co-investigators and other key personnel should be included. The letter of intent is requested in order to provide an indication of the number and scope of applications to be reviewed and to promote early interactions between applicants and NIAID staff. 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 should be sent to Ms. Tina Johnson, M.A. (SEE INQUIRIES BELOW) APPLICATION PROCEDURES Pre-application Meeting - In order to provide a forum during which prospective applicants may obtain additional information, further clarification and assistance, a Preapplication Meeting will be held on December 7, 1992 in Bethesda, MD. The meeting date and location will also be announced in the NIH Guide for Grants and Contracts. In addition, Ms. Johnson may be called at (301) 496-8214 after November 6, 1992 to obtain specific information about the meeting. Application Preparation and Submission - The research grant application form PHS-398 (rev 9/91) must be used in applying. These forms are available at most institutional business offices or from: Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, (301) 496- 7441. It is important to follow the instructions for preparing the application as described in both the PHS 398 form and in this RFA. Failure to do so will result in an application with insufficient information for appropriate scientific review. For purposes of identification and processing, the RFA number, RFA 92-AI-10, and title,"PEDIATRIC AIDS CLINICAL TRIALS UNITS", should be typed on line 2 of the face page of the application form and the "YES" box should be marked. Designate the PHS component as NIAID/DAIDS/TROP. The RFA label available in the 9/91 revision of the PHS-398 application form should be affixed to the bottom of the face page of the application. 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 the review. Submit a signed, typewritten original of the application, and three (3) exact, single-sided photocopies (including the Appendices), in one package to DIVISION OF RESEARCH GRANTS Westwood Building, Room 240 National Institute of Health Bethesda, MD 20892 AT THE TIME OF SUBMISSION, TWO (2) ADDITIONAL COPIES OF THE APPLICATION INCLUDING APPENDICES, EACH CLEARLY MARKED REGARDING THE COMPONENT OF THE APPLICATION TO WHICH THE APPENDIX PERTAINS, MUST ALSO BE SENT DIRECTLY TO Dianne Tingley, Ph.D. Chief, AIDS Research Review Section Scientific Review Branch, NIAID National Institutes of Health Solar Building, Room 4C16 6003 Executive Boulevard Bethesda, MD 20892 Applicants who wish to use express mail or courier service should substitute Rockville, MD 20852 for the city, state, zip. The deadline for receipt of applications is January 6, 1993. Applications received after this date will be considered as nonresponsive to this RFA and returned without review. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by the DRG staff for completeness and by the NIAID staff for responsiveness. Incomplete applications and those judged to be unresponsive to the RFA will be returned to the applicant without further consideration. Examples that will result in the application being considered nonresponsive include, but are not limited to: 1) failure to address all required items of the Pediatric ACTU component and 2) submission of optional components that are not presented as separate narratives with separate budgets. Those applications that are complete and responsive to triage by a Special Review Committee (SRC) to determine their scientific merit relative to other applications received in response to this RFA. The NIH will administratively withdraw from competition those applications judged to be noncompetitive and notify the applicants and the institutional business officials. Those applications judged to be competitive will undergo further evaluation for scientific merit by a Special Review Committee consisting primarily of non-Federal scientific experts. To the extent possible, members of the committee that conducted the triage will also serve on this committee. The second level review will be provided by the National Advisory Allergy and Infectious Diseases Council. LABORATORY SUPPORT AND DEVELOPMENTAL RESEARCH Applications for Laboratory Support and Developmental Research will undergo the same dual review process and considerations as applications for Part A. These applications will be evaluated independently from the evaluation of Part A. REVIEW CRITERIA The following factors will be considered in the scientific and technical review of Pediatric AIDS Clinical Trials Review, PART A: o Past clinical trials experience in conducting research on perinatal transmission of HIV, antiretroviral therapy, and treatment of OIs including the ability to recruit and retain study participants, especially members of underrepresented group; o Adequacy of scientific understanding of the problem as evidenced by the plan for proposed studies of interruption of perinatal transmission of HIV (e.g., phase I,II,III, combination therapy, and immune-based therapy); antiretroviral therapy (e.g., phase II/III); and treatment and prophylaxis of OIs (e.g., phase I, pharmacokinetics); o The qualifications and expertise of the Principal Investigator and key personnel in the area of perinatal transmission, antiretrovirals, and OIs as required by this RFA, and their past experience in conducting clinical trials; o Quality of a plan for the transfer of mothers from maternal/infant protocols into adult protocols; o Adequacy of the organizational structure, including the relationship between the pediatric clinical trials unit and the parent institution and other consortium arrangements, necessary to support pediatric clinical studies of antiretrovirals, OIs, and prevention of perinatal transmission; o Adequacy of the physical facilities available for performing both outpatient and inpatient pediatric and perinatal studies; o Strength of the administrative experience of the Principal Investigator and key staff, including past experience, in conducting all types and phases of clinical trials; o Inclusion among staff of culturally sensitive individuals representative of, or experienced and sensitive to the needs of, the targeted population(s); o Strength of the outreach/recruitment plan for enrollment of pediatric patients, adolescents, and pregnant women. Special emphasis should be placed on women who are minority members, or abuse drugs, or are partners of drug abusers; o Quality of the plan for provision of ancillary care (including commitment to provision of staff and linkages with state and federal agencies) to increase accrual of HIV-infected pediatric, adolescent, and pregnant female patients; o Adequacy of the data management plan; o Quality of the pharmacy plan; and o Laboratory capability with respect to immunophenotyping for standard of care tests. For optional studies on adolescents and neuropsychological and neurologic testing o Quality of the plan for studies of adolescents; o Quality of the plan describing past experience in studies of neuropsychological testing; o Adequacy of scientific understanding of the problem as evidenced by the plan for proposed studies for neuropsychological assessment research; o The qualifications and expertise of the designated investigator(s) and key personnel in the area of neuropsychological assessment as emphasized by the program and their past experience in conducting this type of research; Laboratory Support for Clinical Trials (PART B) The following factors will be considered in the scientific and technical review of the applications for Virology, Immunology, and Pharmacology Laboratory Support components: o Evidence of appreciation of the depth and scope of scientific issues involved; o Prior participation or experience in relevant quality control programs; o Adequacy of the proposed procedures for receipt, storage and handling of samples from other sites, and for timely reporting of data; o Qualifications, expertise, experience and time commitment of the Principal Investigator and key personnel; and o Adequacy of the available resources and facilities. Developmental Research (PART C) The following factors will be considered in the scientific and technical review of the applications for Developmental Virology, Developmental Immunology and Developmental Neuropsychological Assessment research o Originality and uniqueness of proposed research; o Relevance of the proposed research to the clinical objectives of the ACTG; o Availability of required clinical samples (where applicable; o Qualifications, expertise, experience and time; commitment of the Principal Investigator and key personnel; and o Adequacy of the available resources. CONDITIONS FOR AWARD Although the predominant criteria for funding priorities will be the scientific merit and technical proficiency of Part A of the application (Parts B and C will be evaluated independently however, award considerations will be contingent upon receipt of a Part A award, see page 33) as judged by peer review, after the applications have been approved by the NIAID Advisory Council, staff reserves the right to give consideration to the following factors in the final selection of applications to be funded: (1) inclusion of populations currently underrepresented in clinical trials; (2) HIV prevalence/geographic distribution; (3) cost effectiveness of conducting clinical trials; (4) the overall capacity of funded institutions to carry out the research objectives of the group (see Research Objectives, page 5); and (5) the quality of past performance. INQUIRIES Written or telephone inquiries concerning this RFA are encouraged. The following NIAID staff will be available to answer questions regarding the preparation of the application in response to this RFA. Direct inquiries concerning the programmatic aspects of this RFA to Tina Johnson, M.A. CRMB/DAIDS National Institute of Allergy and Infectious Diseases Solar Building, Room 2A09 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-8214 Direct inquiries regarding review aspects and requirements in the application to Dianne Tingley, Ph.D. Scientific Review Branch National Institute of Allergy and Infectious Diseases Solar Building, Room 4C16 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-8214 Direct inquiries pertaining to budget issues to Ms. Mary Kirker Deputy Chief, Grants Management Branch National Institute of Allergy and Infectious Diseases Solar Building, Room 4B22 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-7075 For express mail or courier service, please send to: Rockville, MD 20852 SCHEDULE Letter of intent receipt date: November 13, 1992 Pre-application meeting date: December 7, 1992 Application Receipt Date: January 21, 1993 Special Review Committee: March 1993 NIAID Advisory Council Review: June 1993 Anticipated Award Date: September 1, 1993 AUTHORITY 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. Awards are under authorization of the Public Health Service Act, Title IV, Part A, Public Law 78-410 as amended, and administered under PHS grant policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12371 or Health Systems Agency Review. .
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