PEDIATRIC CLINICAL TRIALS PROGRAM FOR AIDS Release Date: September 13, 2000 RFA: AI-00-015 National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov/) Letter of Intent Receipt Date: November 15, 2000 Application Receipt Date: March 21, 2001 PURPOSE The Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID) announces the availability of a Request for Applications (RFA) to conduct Pediatric HIV/AIDS clinical research. The purpose of this RFA is to solicit applications from institutions interested in establishing cooperative clinical trials groups to plan and direct pediatric therapeutics and prevention research. The awardees will have the capacity and expertise to conduct all phases of clinical trials involving children, adolescents and pregnant women with all stages of infection. Studies will focus on high priority research questions on the treatment and pathogenesis of HIV disease and its sequelae. The scope of activities will range from studies requiring in-depth laboratory support to research in long-term clinical outcomes. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS led national activity for setting priority areas. This Request for Applications, Pediatric Clinical Trials Programs for AIDS is related to HIV disease. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and not for profit organizations, public and private institutions, 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 as primary grantees, however, foreign institutions may participate as part of a domestic application. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. An applicant proposing to form a Pediatric AIDS Clinical Trials Group (PACTG) will coordinate the submission of an integrated package of applications that includes: (i) One Coordinating and Research Operations Center (CORC) [Core Application], (ii) One Statistical and Data Management Center (SDMC), and (iii) Clinical Site applications. An applicant may choose to use a single Coordinating Center (CC) which combines the functions of a CORC and a SDMC for operational, statistical, and data management support. The number of Clinical Site applications should be based on the scope of proposed research activities and on the scientific expertise to accomplish the proposed research agenda. Potential clinical site applicants are urged to formally affiliate with a Group applicant, although applications will be accepted from independent clinical sites for possible later linkage with the Group. MECHANISM OF SUPPORT The administrative and funding mechanism to be used to undertake this program will be the Cooperative Agreement (U01), an "assistance" mechanism, rather than an "acquisition" mechanism, in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. Details of the responsibilities, relationships, and governance of a study funded under cooperative agreement(s) are discussed under the section Terms and Conditions of Award. The total project period for applications submitted in response to this RFA may not exceed five years. At this time, the NIAID has not determined whether and how this solicitation will be continued beyond the present RFA. FUNDS AVAILABLE The estimated total funds (direct and Facilities and Administrative Cost) available for the first year of support for all awards made under this RFA will be $36 million. In FY 2002 the NIAID plans to fund one (1) Group award. Although this program is provided for in the financial plans of the NIAID, awards pursuant to this RFA are contingent upon the availability of funds for this purpose and the receipt of a sufficient number of applications of high scientific merit. Funding beyond the first and subsequent years of the grant will be contingent upon satisfactory progress during the preceding years and the availability of funds. RESEARCH OBJECTIVES Background Many major advances in the care and prevention of pediatric HIV/AIDS have occurred since the existing PACTG last underwent competitive renewal in 1997. As a consequence, research priorities have rapidly evolved and become much more complex. In the United States and other developed countries, new HIV infections in infants exposed to HIV in utero or neonatally have fallen sharply with the implementation of effective means to prevent mother-to-infant transmission. In contrast to the successes in preventing mother-to-infant transmission of HIV, new infections in high-risk adolescents continue unabated and at an alarming rate. Furthermore, both HIV-infected youth and those at high risk for HIV infection have been difficult populations to reach and engage in long-term health care and research programs. Like HIV-infected adults, HIV-infected children have benefited from dramatic improvements in control of HIV replication and slowing of disease progression resulting form highly active antiretroviral therapy. However, HIV-infected children were heavily pre-treated prior to the advent of highly suppressive antiretroviral regimens and they, their families and clinicians struggle with many questions including: what are the optimum treatment regimens to use?, can more pediatric friendly regimens be developed?, what are the most appropriate doses to use for treatment across the spectrum of pediatric ages?, when is the best time to switch regimens and what tools should be used to guide that decision?, what is the long-term clinical effectiveness of regimens that are currently recommended?, what is the long-term safety of the drugs currently used to combat HIV in children on chronic therapy?, and finally, now that HIV-infected pregnant women and their babies (infected and uninfected) are exposed to a growing number of powerful antiretroviral drugs, what are appropriate antiretroviral doses during pregnancy and what is the short and long-term safety of infants exposed in utero and neonatally to these antiretrovirals? Tragically, the impressive advances which have occurred in prevention of mother-to-infant transmission and treatment of HIV-infected women and children in the United States and other resource-rich nations are unavailable in most resource poor nations where the epidemic is at its worst and continues to accelerate at a staggering rate. The NIH supports a comprehensive biomedical and behavioral research programs to address this complex array of problem. This RFA focuses on the component of that program directed to the research needs of the developed world. Other components such as the HIV Prevention Trials Network (HPTN) and new initiatives to build and support greater basic and clinical research capacity are aimed at the epidemic in the developing world. This RFA also requires collaborations between PACTG investigators and HPTN and other international investigators to facilitate scientific exchange and optimize resource utilization. Research Objectives and Scope The goal of this RFA is to establish a flexible, comprehensive pediatric clinical trials program to address the questions of highest priority in treatment of pediatric and adolescent HIV/AIDS and prevention of mother-to- infant transmission. The focus is on the needs of the epidemic in the U.S. and other developed countries. This RFA seeks to re-focus pediatric HIV research priorities in the following areas: expand and enhance the adolescent research agenda and efforts to engage youth in treatment research opportunities, strengthen and augment long-term follow-up studies of safety and clinical effectiveness, continue pediatric treatment research at approximately the present level of effort, evaluate the safety, pharmacology and activity of new regimens and strategies that may be used in HIV-infected pregnant women. Relevant objectives include, but are not limited to: o Support the development of novel interventions, drugs or biologics, to treat HIV infection in children and adolescents. o Assess the optimal use of and timing of the introduction of therapeutic modalities from acute/early infection through advanced disease o Evaluate the durability of potent antiretroviral regimens in suppressing viral replication and in impacting the developing immune system. o Identify novel therapeutic interventions to preserve or restore immunologic integrity, including studies of safety, toxicity and immunogenicity of experimental therapeutic HIV vaccines in pediatric populations. o Evaluate novel interventions against opportunistic diseases. o Investigate therapeutic interventions to elucidate the pathogenesis of HIV disease. o Support the development of novel strategies to prevent maternal infant transmission of HIV as well as collaborate with other NIH programs to prevent infection of adolescents. o In collaboration with the HIV Vaccine Trials Network (HVTN), evaluate the safety, toxicity and immunogenicity of candidate vaccines to prevent HIV infection in pediatric populations. o Evaluate the long-term safety of antiretroviral therapies in uninfected infants exposed to antiretroviral agents (ARVs) o Evaluate the long-term impact of antiretroviral therapies in infants, children and adolescents treated with ARVs with particular emphasis on lipid abnormalities and other metabolic toxicities. This RFA strongly encourages collaboration with the HPTN, HVTN and other research organizations or sites that are engaged in international research, both for scientific exchange and cross enrichment, and for consideration of international pediatric studies that are both scientifically appropriate and of high priority in both domestic and international settings. SPECIAL REQUIREMENTS TERMS AND CONDITIONS OF AWARD The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator as well as the institutional official at the time of award. The administrative and funding instrument used for this program is cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the research will be shared among the awardees and the NIAID Scientific Coordinator. Cooperative agreements are subject to the administrative requirements outlined in OMB circulars A-102 and A-110. All pertinent HHS, PHS, and NIH grant regulations, policies and procedures, with particular emphasis on PHS regulations at 42 CFR Part 52 and HHS regulations at 45 CFR Part 74 and 92, are applicable. These special terms and conditions pertaining to the scope and nature of the interaction between the NIAID and the investigators will be incorporated in the Notice of Grant Award. However, these terms will be in addition to, not in lieu of, the customary programmatic and financial negotiations that occur in the administration of cooperative agreements. I. Awardee Rights and Responsibilities Awardees will have primary responsibility for defining the research objectives, approaches and details of the projects within the guidelines of the RFA, and for performing the scientific activity. Awardees have primary responsibility as described below. A. Coordinating and Research Operations Center (CORC) or coordinating Center (CC) will be responsible for: 1. Research Agenda - The Principal Investigator (Group Chair) of the CORC or CC will be responsible for developing, implementing, monitoring, and updating the Group research agenda. 2. Bylaws/Operating Procedures - The Group Chair will be responsible for ensuring that there are well-documented policies, procedures, and Bylaws to guide all aspects of the Group activities and operations. 3. Executive/Steering Committee - An Executive/Steering Committee will be established as the main governing body of the Group. The Committee will be chaired by the Group Chair and will include: the Principal Investigator of the SDMC and the Director of the CORC"s Operations Center, and the DAIDS TRP Associate Director (or designee), one community representative, and at least one clinical site Principal Investigator. 4. Administrative Support - The CORC will be responsible for coordinating all research activities at the direction of the Group Chair or designee. These activities include but are not limited to: (i) protocol development and implementation, (ii) administrative support for the Group Chair, scientific leadership, committees, and meeting coordination, (iii) maintenance of Group administrative records and archives, and,(iv) fiscal management and oversight of the Group resources. 5. Protocol Development - The Group will initiate protocol development only when there is sufficient commitment among the membership to expeditiously complete accrual, analyze, and publish the research results. There must be clear procedures for designating members of protocol teams and selecting units for limited site studies. The Group must develop a mechanism to monitor the progress of studies throughout all stages and provide status reports to DAIDS on a mutually agreed upon schedule. Early notification that a study is being considered must be provided to DAIDS to allow for comment on the scientific objectives relative to other NIAID/NIH research programs. Prior to implementation, all protocols must be submitted to DAIDS for approval based on safety, ethics, and consistency with other NIH sponsored research. DAIDS will communicate all decisions, in writing, to the Group. 6. Laboratories - The Group Chair will be responsible for establishing a laboratory network in support of the research agenda. Funds will be awarded to the CORC for laboratory support. The Group Chair will: (i) identify the number, type and resources needed, and (ii) develop and implement a mechanism to evaluate performance, assess resource allocation, and redistribute funds as necessary. 7. Study Oversight - The Group leadership will establish procedures to: (i) ensure adequate protection of the rights and safety of subjects involved in the research, (ii) guarantee the quality and integrity of the resulting data, (iii) maintain accurate and timely information on each study, and (iv) provide interim study summaries to the NIAID Therapeutic Data and Safety Monitoring Board as requested. 8. Federally Mandated Regulatory Requirements - The Group must be in compliance with all Federal regulations, and NIH policies applying to the conduct of research involving human subjects. These include, but are not limited to, Title 21 CFR 50, 56, 312, and Title 45 CFR 46. 9. Reporting Requirements - Administrative: The Group Chair will submit periodic reports to DAIDS on a mutually agreed upon schedule. The reports will include, for example, lists of investigators and other key personnel, all affiliated sites, protocol abstracts, patient accrual and demographics, and publication information. Annual Report: The Group Chair will submit to DAIDS an annual report summarizing group activity, accomplishments, performance evaluations and future directions. 10. Performance Evaluation: The Executive/Steering Committee will establish procedures for evaluating the performance of all Group components and provide DAIDS with annual reports. Procedures will include processes for the addition or elimination of clinical sites or laboratories, redistribution of resources among components based on performance measures such as patient accrual/retention, data quality and scientific contribution. The process will include procedures for recommending to DAIDS annual adjustments to institutional budgets based on performance. 11. Publication of Data - Timely presentation and/or publication of major findings is essential and requires acknowledgment of NIAID support. Prior to the submission of manuscripts for publication, a copy must be provided to DAIDS. The awardee retains the rights to the data consistent with current HHS, PHS, and NIH policies, however, DAIDS under this cooperative agreement will have access to all data and may periodically review it. 12. National Meetings - The Group is expected to hold at least one national meeting a year in the Washington, DC metropolitan area. Responsibility for logistics, scientific content, and fiscal support will be with the sponsoring group. 13. Conflict of Interest - The Group will develop and implement a Conflict of Interest (COI) Policy acceptable to the NIAID, addressing any COI that may occur through financial interest or other associations between members of the Group and the private sector. 14. Discretionary Funds - The CORC will maintain and manage a discretionary fund that must be expended through procedures consistent with the Bylaws. The funds may be used for either scientific or operational needs such as, but not limited to, the addition of new clinical or laboratory sites, funding of innovative pilot studies, outsourcing laboratory work or supplementing superior performers. 15. Community Representation - The Group will develop and implement a plan for community representation in Group activities. The plan should address how the representatives" inclusion will make a substantive contribution to the overall success of the Group. 16. Demographic Diversity - The Group must have plans in place to ensure the overall demographic diversity of study participants and have plans in place for incorporating new, minority and women investigators into the Group"s activities. 17. Collaboration - The Group will have a plan that details how it will interact with other NIAID/NIH-sponsored HIV/AIDS clinical research groups including procedures to integrate and complement the scientific agendas of other NIH Institutes to address specific pediatric HIV priorities. B. Statistical and Data Management Center (SDMC) 1. Study Design, Conduct, Analyses, and Publications - The SDMC will be responsible for: (i) statistical leadership for the Group research agenda, (ii) performing interim analyses of safety and efficacy, (iii) generating executive summaries of study results for use by the protocol team, DAIDS, and collaborators, (iv) conducting final analyses and participating on publication writing teams, (v) performing cross-protocol analyses utilizing data from multiple sources, (vi) producing study monitoring reports for the Group and DAIDS, (vii) conducting analyses and summaries for annual and interim reports for DAIDS-sponsored Investigational New Drug Applications, and (viii) developing innovative clinical trial designs and analysis methodologies consistent with the Group research agenda. 2. Data Management The Statistical and Data Management Center will: (i) provide central registration and randomization for all study subjects, (ii) develop case report forms and standardized criteria for clinical endpoint verification, (iii) design and implement systems for the efficient tracking and transfer of clinical and laboratory data (including quality assurance and specimen tracking) to the central database, (iv) provide data management training to the clinical sites, laboratories, and the DAIDS Clinical Site Monitoring Contractor, (v) provide CRF notebooks to collaborators, (vi) provide for central storage, security, processing and retrieval of study results, and (vii) prepare selected public access databases. 3. Collaborations - When collaborating with other clinical study groups, procedures of conduct will be determined by the Associate Director, Therapeutics Research Program (TRP) and the leadership of each participating Group. Generally, the procedures of the lead Group will be followed. 4. Management - The SDMC must have a management plan and agree to abide by the Bylaws of the Group. C. Coordinating Center The Terms of Award for the CORC and SDMC presented above will be merged into a single set of Terms for applicants choosing to use a Coordinating Center. D. Clinical Sites 1. Clinical Site Responsibilities - Clinical Sites must agree to accept and abide by the Group’s Bylaws, the research priorities, and the performance standards. DAIDS-sponsored clinical research cannot be initiated at any performance site until a Site Establishment Plan is approved by DAIDS. 2. Laboratory - Clinical site laboratory capabilities will be determined by the Group leadership. The responsibilities of clinical site laboratories include: (i) processing and logging of clinical specimens, (ii) shipping of specimens to designated laboratories or repositories, (iii) performance of standard testing and other protocol mandated testing as designated by the Group Chair, (iv) participating in QA programs required by the Group. 3. Investigational Drug Management - Investigators performing clinical studies sponsored by the NIAID must comply with all Federal regulations for investigational agents, and with DAIDS Standard Operating Procedures, and Pharmacy Guidelines and Procedures. 4. Quality Management - Clinical sites must establish a quality management plan to assess the accuracy and completeness of all research records, and operating procedures. 5. Site Monitoring - Clinical sites shall cooperate with the DAIDS Clinical Site Monitoring Contractor, and other federally supported site monitoring staff who will inspect records to ensure compliance with all federal regulations, NIH policies on patient safety, quality management and data completeness and accuracy. 6. Participation of New Investigators, Women and Minorities - Clinical sites will establish procedures, and opportunities to ensure the participation of new investigators, especially women and racial/ethnic minorities, in all aspects of the research effort. 7. Community Advisory Boards (CAB) - All sites must establish a CAB representative of the HIV infected community in the catchment area. The site should have plans that demonstrate how the CAB will be included in the activities to substantively contribute to the success of the unit. Funds requested in the application must be made available to the CAB for reimbursement of reasonable expenses including representation at the annual Group meeting(s). II. NIAID Responsibilities NIAID staff assistance will be provided by the Associate Director, Therapeutics Research Program, who will serve as NIAID"s Scientific Coordinator. The NIAID Scientific Coordinator will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination above and beyond normal program stewardship for grants, as described below. The role of DAIDS staff described in these Terms is to assist and facilitate. Communication will be primarily with the Group Chair and the scientific leadership. However, DAIDS will interact with the Principal Investigators of any affiliated institution as needed. The following are specific responsibilities of DAIDS staff and the NIAID"s role as an IND sponsor as defined in 21 CFR Part 312. 1. Scientific Role in NIAID Sponsored Clinical Research - The Associate Director, TRP or designee will serve as a source of information and work closely with the Executive/Steering Committee to ensure that the research efforts are consistent with the NIAID priorities for HIV clinical research, and complement those of other NIAID and NIH programs. The DAIDS will serve as the liaison between pharmaceutical companies, the FDA, and the Group. 2. DAIDS Role in Protocol Development - In order for a clinical study to be initiated, the protocol must be approved by the chair of the DAIDS Clinical Science Review Committee (CSRC). The CSRC will evaluate the proposal relative to: (i) the NIAID priorities for HIV clinical research, (ii) subject safety, (iii) compliance with Federal regulations, (iv) study oversight and monitoring, and (v) feasibility of timely completion. The Associate Director, TRP will return comments and recommendations to the Group within 30 days after review. A DAIDS pharmacist will participate on the protocol team, consult on the pharmaceutical aspects of protocol development and will interact with pharmaceutical companies to ensure product availability. If a protocol is disapproved, DAIDS will not provide study agents or permit expenditure of NIAID funds. 3. DAIDS Involvement in IND Applications - The DAIDS will have the option to cross-file or independently file an INDA for study agents evaluated in Group studies. The Chief, Regulatory Affairs Branch (RAB) will advise the investigators on specific regulatory requirements for INDA sponsorship. 4. Clinical Trials Agreements (CTA) - When a pharmaceutical collaborator provides a study agent to DAIDS, a CTA will be negotiated describing respective responsibilities and rights. The agreement will include, but is not limited to, INDA sponsorship, safety and data monitoring, and access to data. The Group Chair generally will be consulted on the terms prior to the execution of the CTA. Pharmaceutical collaborators generally request that patentable inventions discovered through the studies are brought to their attention, and the company has rights of first refusal provided that the collaborator has rights to the background patent. Investigators will be required to agree to these terms. 5. DAIDS Role During Study Conduct - A DAIDS Medical Officer will monitor the safety and efficacy of the intervention(s) for ongoing studies, and will be provided with interim and final reports. When a collaborating institution or research group sponsors a protocol, their medical representatives will conduct monitoring activities. 6. DAIDS Role in Protocol Closure - The Associate Director, TRP will monitor the progress of the studies by reviewing reports submitted to DAIDS through a Data and Safety Monitoring Board, and through regular meetings with the Group Leadership. DAIDS may find it necessary to terminate an ongoing study for any of the following reasons: (i) risk to subject safety, (ii) the scientific question is no longer relevant or the objectives will not be met, or (iii) slow accrual. 7. Access to Data - The Associate Director, TRP or designated DAIDS contractor will have access to all data generated under this cooperative agreement, and may review the data as recorded on the case report forms or in the central database. Data must be available for external checking against the original source documentation as required by federal regulations. The awardees will retain the primary rights to the data consistent with HHS, PHS, and NIH policies. The DAIDS has an external Clinical Site Monitoring Contract to evaluate Good Clinical Research Practice, regulatory compliance, accurate protocol implementation, internal quality management, and test product accountability. The monitoring contractor will visit performance sites quarterly or as needed to review selected protocols, provide training on protocol conduct, review internal QM plans, audit pharmacies, and document error resolution. The DAIDS may provide public access to selected data sets generated with the use of public funds within a reasonable time after the primary analysis and publication. 8. Laboratory Quality Assessment - The DAIDS will provide through its contract resources support for laboratory quality assessment. Management of the contracts will reside with DAIDS. Scientific and technical oversight of these contracts will be provided by DAIDS in collaboration with Group investigators, and the Chief, Drug Development and Clinical Sciences Branch. 9. Adverse Event Reporting - In order to provide for consistent adverse experience reporting across clinical trials groups, DAIDS has established policies and procedures delineated in the Serious AE Reporting Manual. Groups, in collaboration with DAIDS, will have the responsibility for ongoing maintenance of the modified ICD-9 system for classifying and coding the types of adverse experiences reported. 10. DAIDS as a Resource for Performance Evaluation - The performance of all Group components will be reviewed annually by the Associate Director, TRP using the comprehensive annual progress report, and site monitoring reports. The Chief, Clinical Research Management Branch, and the Chief of the Drug Discovery and Clinical Sciences Branch, TRP will assist the Group in developing evaluation instruments. Substandard data, insufficient subject accrual or retention, inadequate progress in fulfilling the research agenda, non-compliance with federal regulations or these Terms of Award may result in a reduction in budget, withholding of support, or termination of award. If the Group Chair proposes to redirect resources among affiliated member awards, DAIDS concurrence is required. III. Collaborative Responsibilities Group Governance - The Group Chair will establish an Executive/Steering Committee as the central decision making body for the Group. The Committee will include the DAIDS TRP Associate Director (or designee) as a voting member. A Chairperson, other than the DAIDS Official, will be elected by the Group membership as defined in the Bylaws. IV. ARBITRATION Any disagreement that may arise on scientific or programmatic matters (within the scope of the award) between award recipients and the NIAID may be brought to arbitration. An arbitration panel will be composed of three members: one selected by the Steering Committee or by the individual awardee in the event of an individual disagreement, a second member selected by the NIAID, and the third member with expertise in the relevant area who is selected by the two other members. Together they will review any scientific or programmatic issue that is significantly restricting progress. While the decisions of the Arbitration Panel are binding, these special arbitration procedures will in no way affect the awardee"s right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, subpart D, and HHS regulations at 45 CFR Part 16. STUDY POPULATIONS The study population is limited to HIV infected infants, children, adolescents, and pregnant women. 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 is 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 UPDATED "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at: (http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm). The revisions relate to NIH-defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and which is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators may obtain copies from these sources or from Frederick Batzold listed in INQUIRIES below who may also provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit by November 15, 2000 a letter of intent that includes a descriptive title of the overall proposed research, the name, address and telephone number of the Principal Investigator, and the number and title of this RFA. Although the letter of intent is not required, is not binding, does not commit the sender to submit an application, and does not enter into the review of subsequent applications, the information that it contains allows NIAID staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Peter R. Jackson at the address listed under INQUIRIES. APPLICATION PROCEDURES Pre-Application Meeting There will be a one-day meeting in the Washington, DC metropolitan area to provide potential applicants with background information and to answer questions from potential applicants. For details about the meeting, please contact Dr. Frederick Batzold at the address listed under INQUIRIES or go to the URL listed below. Information about this meeting and a detailed summary that will include NIAID responses to all questions raised by attendees at the meeting, will be available upon request as well as being available via an NIAID Internet site at URL: http://www.niaid.nih.gov/daids/pediatrictrialsrfa.htm Applications Applicants are strongly encouraged to call NIAID program staff with any questions regarding the responsiveness of their proposed project to the goals of this RFA. Applications are to be submitted on the grant application for PHS 398 (4/98). These forms are available at most institutional offices of sponsored research, from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov, and on the internet at http://grants.nih.gov/grants/forms.htm. For purposes of identification and processing, item 2a on the face page of the application must be marked "YES" and the RFA number AI-00-015 and the words "Pediatric Clinical Trials Program for AIDS" must be entered on the face page. Applications must be received by March 21, 2001. Applications not received on the receipt date or not conforming to the instructions contained in PHS 398 (4/98) Application Kit (as modified in, and superseded by, the special instructions below, for the purposes of this RFA), will be judged non- responsive and will be returned to the applicant. The RFA label and line 2 of the application should both indicate the RFA number. The RFA label must be affixed to the bottom of the face page. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. If the application submitted in response to this RFA is substantially similar to a grant application already submitted to the NIH for review, but that has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will essentially identical applications be reviewed by different review committees. Therefore, an application that is essentially identical to one that has already been reviewed cannot be submitted in response to this RFA. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, single-sided 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 Mail or Courier Service) At the time of submission, two additional exact copies of the grant application and five sets of any appendix material must be sent to Dr. Peter Jackson list under Inquiries . Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC Program Director or Principal Investigator should be included with the application. SPECIAL INSTRUCTIONS APPLICATION PACKAGE A Principal Investigator who proposes to form a Group and assume the role as Group Chair is responsible for coordinating the preparation of a package that will include the following applications: One (1) Coordinating and Research Operations Center, One (1) Statistical and Data Management Center, and One (1) proposal for each individual Clinical Site [The number of clinical sites should be based on the scope of the research agenda]. If the Group Chair chooses to use a Coordinating Center for both operational and statistical and data management support, a single application should be submitted for both components. For all applications: A complete PHS Form 398 (4/98) must be submitted. On Page 2 (Key Personnel) all professional personnel and their institutional affiliations for the project must be listed including those with no requested salary support. Each Biographical Sketch (limited to 3 pages) and the Other Support page should be positioned at the end of the application with the Principal Investigator first followed by other key personnel in alphabetical order. The use of tables, diagrams, organizational and flow charts is strongly encouraged. Key information submitted in the appendix should be clearly referenced in the Research Plan Section. Information submitted as appendices should be limited to essential materials in support of the application, summaries or examples of information are encouraged. Letters of support that do not formally commit to contributions to the program should not be included. A. Core Application [Coordinating and Operations Research Center (CORC)] The Research Plan (Items a-d) is not subject to the page limitations in the PHS Form 398. This section of the application should not exceed 300 Pages. Appendices should be limited to 150 pages excluding reprints of publications and Annual Reports. The Research Plan should address the following: 1. Comprehensive Research Agenda including the scientific priorities, key leadership, criteria for affiliated domestic and international clinical sites and laboratories. 2. Comprehensive Management Plan that addresses: o Bylaws for governance including the election of Group Leadership and committee membership. o Operational plans for the delegation of authorities, decision-making, and fiscal management. o Operational plans for the integration of NICHD participating clinical sites. o Performance evaluation plans and standards for participating institutions including corrective measures. o Outreach Plan to ensure the inclusion of women, minorities and community representatives in all aspect of the proposed research and Group activities. o Procedures for protocol development, implementation and oversight, and committee management. o Plan for collaborating with important and relevant HIV treatment or prevention study groups, including but not limited to the: i. Adult ACTG adolescent and women’s health issues (Required). ii. HPTN domestic adolescent agenda and coordination of domestic and international perinatal prevention studies (Required). iii. HVTN perinatal and adolescent preventive vaccine studies (Required). iv. Adolescent Medicine Trial Network adolescent treatment studies (Required). v. Pediatric European Network for Treatment of AIDS (PENTA) - shared pediatric agenda treatment trials (Recommended). o Plan for other potential collaboration with international investigators. CORC budget requests must be related to, and justified by, the scope of activities proposed in the research agenda. A composite budget should be included, followed by individual budgets. At a minimum the budget request should include four categories: (i) Operations Center, (ii) administrative support for the Group Chair, scientific committees and annual meetings, (iii) laboratories, and (iv) discretionary funds not to exceed 15% of the total cost budget request. B. Statistical and Data Management Center (SDMC) The Research Plan (items a-d) is not subject to the page limitations in the PHS Form 398. This section of the application should not exceed 150 Pages. Appendices should not exceed 150 pages excluding reprints of publications. The Research Plan should address the following: 1. Statistical expertise that complements the Group research agenda. 2. Innovative approaches to clinical trials methodology. 3. Data management expertise including: database design and procedures for managing both clinical and laboratory data, and plans for evaluating new methodologies for data transmission and systems design. 4. Operational, procedural and overall management plans for the SDMC. The SDMC budget request must be related to and justified by the scope of activities proposed in the research agenda. C. Coordinating Center (CC) Applicants may choose to combine the activities of a CORC and SDMC into a single Coordinating Center. The Research Plan for the CC is not subject to the page limitations in the PHS Form 398, item a-d. Since a CC is composed of a CORC and SMDC, this section should not exceed 400 Pages. Appendices should not exceed 200 pages excluding reprints of publications and Annual Reports. The CC application should address all the areas included within the CORC and SDMC applications described above. D. Clinical Sites The Research Plan (items a-d) for each Clinical Site application is subject to the 25 page limitation. Appendices should not exceed 50 pages excluding reprints of publication. The Research Plan Section should address the following: 1. Clinical sites named in the Core Application should describe site expertise, and past accomplishments in pediatric HIV clinical research and how the site will contribute to the Group research agenda particularly with regard to recruitment and retention of HIV-infected infants, adolescents, and pregnant women. Independent clinical site applications should describe site expertise and past accomplishments in pediatric HIV clinical research and how the site will contribute to the research objectives in the RFA. 2. Operational/Management Plan including subject accrual potential, quality management, and regulatory compliance. 3. Outreach Plan to assure the inclusion of women and minorities in all aspects of site activities. 4. Plan for establishing and supporting a Community Advisory Board (CAB) representative of the catchment area. Clinical site budget requests should be based on, (i) the scope of work proposed, (ii) the projected number of new subject accruals, and (iii) on- going commitments to subjects for incumbent applicants. Clinical site applicants named in the Core Application should use the resource allocation criteria developed by the Group Leadership. Independent clinical site applicants should use the projected patient census as the basis for budget development. All clinical sites must include a budget request to support CAB activities including representation at the annual Group meeting(s). REVIEW CONSIDERATIONS GENERAL CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the NIH Center for Scientific Review, and by NIAID staff for responsiveness, those judged to be incomplete or non-responsive will be returned to the applicant without review. Applications that are complete and responsive to this RFA will be evaluated for scientific and technical merit by an appropriate peer review group(s) convened by the NIAID. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Advisory Councils of the sponsoring NIH Institutes. The second level of review will be provided by the National Advisory Allergy and Infectious Diseases Council. REVIEW CRITERIA The criteria to be used in the evaluation of applications in response to this RFA are listed below. A. Core Application (Coordinating and Operations Research Center) 1. Qualifications and experience of the Group Chair and the named Scientific Leadership in the design, implementation, and management of multicenter pediatric HIV clinical research. Significance and innovativeness of the research agenda in addressing the objectives of the pediatric agenda. 2. Quality of the management plan to set/redirect priorities, initiate studies, and govern Group activities. 3. Adequacy of past performance of existing Groups including enforcement of Group standards. New Group applicants should present a plan for evaluating performance and ensuring compliance with the standards of the Group. 4. Qualifications and experience of the CORC"s Operations Center Director and staff, and the administrative management plan. 5. Adequacy of the criteria and standards used for inclusion of affiliated clinical sites and laboratories. 6. Adequacy of (i) proposed performance standards, (ii) the process for performance evaluation, and (iii) resource reallocation for all Group components. 7. Adequacy of the plan for the inclusion of women, minorities, and community representation in Group activities. B. Statistical and Data Management Center 1. Qualifications and experience of the Principal Investigator and staff in providing statistical and data management expertise for pediatric HIV therapeutic multicenter clinical studies including the development of innovative trial designs, and analyses consistent with the Group research agenda. 2. Quality of the plan for both clinical and laboratory database designs, data collection, cross-study analyses, database security, and site specific training. 3. Quality of the plan to evaluate new data management technologies and data collection procedures C. Applications proposing to use a single Coordinating Center for both operational and statistical/data management support will be evaluated on the combined criteria described above for the Core (CORC) and SDMC applications. D. Clinical Sites 1. Qualifications and experience of the Principal Investigator and the staff in conducting pediatric HIV clinical trials, and the ability to contribute to the research objectives in the RFA. 2. Quality of the site management plan for conducting research studies including data management, and regulatory compliance. 3. Ability to accrue and retain a demographically diverse patient population representative of the catchment area consistent with accrual projections. 4. Adequacy of the plans to involve community representatives in all aspects of site activities. The initial review group(s) will also examine: (i) the appropriateness of the proposed project budget and duration, (ii) the adequacy of plans to include both genders and minorities and their subgroups where they are included, (iii) the provisions for the protection of human and animal subjects, and (iv) the safety of the research environment. Schedule Letter of intent receipt date: November 15, 2000 Application receipt date: March 21, 2001 Scientific review date: September 2001 Advisory Council date: January 17, 2002 Earliest award date: March 1, 2002 AWARD CRITERIA Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program balance, and the availability of funds. The earliest anticipated date of award is March 1, 2002. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants are welcome. Further information can be found at the World Wide Web site: http://www.niaid.nih.gov/daids/pediatrictrialsrfa.htm Direct inquiries regarding programmatic (research scope and eligibility) issues to: Dr. Frederick Batzold Division of AIDS National Institute of Allergy and Infectious Diseases Room 5154, MSC-7624 6700-B Rockledge Drive Bethesda, MD 20892-7624 Bethesda, MD 20817 (For Express Mail or Courier Service) Telephone: (301) 402-0143 FAX: (301) 480-4582 E-Mail: fb10c@nih.gov Direct inquiries regarding review issues, address the letter of intent to, and mail two copies of the application and all five sets of appendices to: Peter Jackson, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2154, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Bethesda, MD 20817 (For Express Mail or Courier Service) Telephone: (301) 496-8426 FAX: (301) 402-2638 E-Mail: pj8v@nih.gov Direct inquiries regarding fiscal matters to: Ann Devine Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2118, MSC-7614 6700-B Rockledge Drive Bethesda, MD 20892-7614 Bethesda, MD 20817 (For Express Mail or Courier Service) Telephone: (301) 402-5601 Fax: (301) 480-3780 E-mail: ad22x@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalogue of Federal Domestic Assistance No. 93.856(Use appropriate program number. NIAID citations are Sec. 93.856, Microbiology and Infectious Diseases Research, and No. 93.855 - Immunology, Allergy, and Transplantation Research.) 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 Public Health Service strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or, in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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