Ancillary Studies Charter Version 2.0 May 18, 2016 REPRIEVE Clinical Coordinating Center Massachusetts General Hospital 55 Fruit Street, 5 LON207 Boston, MA 02114 617-724-8015 Fax: 617-724-8998 Contents 1.0 Guiding Principles for Ancillary Study Development and Approval .......................... 2 2.0 Summary of the Ancillary Study Review Process, Goals and Requirements for Studies Requiring Collection of Additional Specimens or Tests ......................................... 2 3.0 Investigator Teams ........................................................................................................ 3 3.1 ACTG Investigator Teams ............................................................................................. 3 3.2 Investigator Teams not Primarily Affiliated with the ACTG ........................................ 4 4.0 Submission of Concept Sheet and Criteria for ASC Review ...................................... 4 5.0 Ancillary Study Committee Review and Procedures for EC Approval (See attached flow chart) ................................................................................................................................. 5 6.0 Initial Evaluations of Concept Proposals .................................................................... 5 7.0 Development and Peer Review of Approved Concept Proposals .............................. 5 8.0 Final Approval of Ancillary Study ................................................................................ 6 9.0 Ancillary Databank Studies Proposing the Use of Already Collected Specimens .... 6 10. Data Analysis ................................................................................................................. 7 11.0 Oversight of Approved Ancillary studies .................................................................... 7 12.0 Publication of Ancillary Studies ................................................................................... 8 APPENDIX I. Call for Applications: REPRIEVE Ancillary Studies ......................................... 9 APPENDIX II: REPRIEVE Study Objectives ..........................................................................11 APPENDIX III: Concept Proposal Application .......................................................................12 APPENDIX IV: Ancillary studies proposal review template ................................................15 APPENDIX V Co-enrollment of REPRIEVE participants in single-site, on-site studies with ultimate goal of assessing statin effects on site-specific study endpoints ........................17 VERSION 2.0, MAY 18, 2016 1 1.0 Guiding Principles for Ancillary Study Development and Approval Investigators both within and outside the REPRIEVE trial will be encouraged to develop ancillary and databank studies. Ancillary studies are investigations that are not part of the REPRIEVE main trial, but that propose questions and test hypotheses that are relevant to and further the goals and purposes of REPRIEVE. An ancillary study may require the collection of additional data, e.g. clinical, imaging, biomarkers, genetic and outcome data during the course of the trial. Databank studies may use the findings obtained in the trial that are reformatted or analyzed in a novel fashion. For example, the presence of certain already ascertained patient characteristics and clinical outcomes may be analyzed in an effort to improve risk stratification. It is recognized that well designed ancillary studies, consistent with the goals of REPRIEVE, can leverage the study’s resources to provide critical answers to highly relevant questions for the field. In contrast, ancillary studies that may impede the primary or secondary goals of REPRIEVE, either by burdening patients, study investigators or study sites, jeopardizing the collection of primary and secondary data, or investigating questions not relevant to the scientific goals of REPRIEVE, will not be recommended for approval. In addition, proposals that do not have adequate resources to perform the outlined ancillary studies will not be approved. It is further recognized that REPRIEVE will not be able to furnish significant resources to fund any ancillary study or team and that successful ancillary studies should be able to secure adequate funding through peer review, either through the ACTG, NIH or other funding sources (see Funding in Appendix 1). This charter sets forth basic principles regarding ancillary studies to be requiring the collection of additional data that is not already collected within the REPRIEVE study. Toward the end of the study, proposals seeking to utilize already captured data and stored specimens not being analyzed in REPRIVE will be solicited, and this process is also outlined. 2.0 Summary of the Ancillary Study Review Process, Goals and Requirements for Studies Requiring Collection of Additional Specimens or Tests The REPRIEVE Ancillary Study Committee (ASC) is charged with the review, and recommendation for approval of ancillary studies to the Executive Committee of REPRIEVE, for a final vote. An additional function of the ASC will be to make the EC aware of important new research opportunities, including those proposed by outside investigators for REPRIEVE. These VERSION 2.0, MAY 18, 2016 2 could include additional trials or investigations to be carried out during the current or future funding periods. The Executive Committee (EC), including representatives from NHLBI and DAIDS, will hold the authority to approve any ancillary studies recommended for approval by the ASC. Voting members of the EC will be Drs. Grinspoon, Hoffmann, Douglas, Ribaudo, Currier, Allston-Smith andDesivgne-Nickens. In this process, the EC will take into account logistical and regulatory considerations, including but not limited to scientific merit, advancing the goals of REPRIEVE, feasibility, and potential for peer reviewed funding source. A major purpose of REPRIEVE is to facilitate collaborations between Heart, Lung and Blood (HLB) and HIV experts. Multi-disciplinary scientific partnerships were indeed a key recommendation from the 2012 NHLBI AIDS Working Group. It is anticipated that ancillary study proposals for REPRIEVE may come from investigators within REPRIEVE, the ACTG, and/or investigators who are not affiliated with the trial. Ancillary studies focused on HIV-related cardiovascular disease will be prioritized. Moreover, collaborative proposals that include ACTG REPRIEVE investigators who are enrolling patients will also receive priority. Utilization of the imaging core is encouraged. There will be two pathways for ancillary studies to be forwarded to the ASC for review. 3.0 Investigator Teams 3.1 ACTG Investigator Teams For ACTG investigative teams, initial concept sheet proposals will first be reviewed by the ACTG, and only those concept proposals approved by the ACTG ITSG will be reviewed by the REPRIEVE ASC. It is anticipated that the ACTG will collect concept proposals for review at specific time points early on in the course of REPRIEVE, such that multiple proposals can be reviewed simultaneously through the ACTG, and judged with respect to each other and available resources. In its review, the ACTG will recommend to the protocol investigative team if it feels that the costs of the proposal can be covered by ACTG funds, or if the investigative team will be recommended to apply simultaneously for outside funding sources, for example to the NIH, to support the proposed studies. A limited number of concept proposals judged meritorious by the ACTG ITSG committee, will be forwarded to the ASC for review and ultimately for vote by the EC. The ACTG ITSG includes members who are part of the REPRIEVE protocol team, to ensure that the ITSG discussions and decisions are fully informed. In addition to providing a list of recommended proposals, the ITSG will provide the REPRIEVE ASC a list of proposals not VERSION 2.0, MAY 18, 2016 3 recommended, in order that the REPRIEVE ASC can fairly judge and place into context all submitted proposals, including those from outside the ACTG. 3.2 Investigator Teams not Primarily Affiliated with the ACTG For investigators not primarily affiliated with the ACTG, pursuing independent funding (e.g. NIH, industry), concept proposals should be submitted directly to the REPRIEVE ASC for review. Such proposals may include ACTG investigators in a collaborative role, to further the goals of REPRIEVE, as outlined above. Concept proposals will be reviewed with respect to the criteria outlined below. 4.0 Submission of Concept Sheet and Criteria for ASC Review Investigators wishing to pursue an ancillary study shall submit a 3 page concept sheet to the REPRIEVE ASC (see attached), or to the ACTG ITSG, depending on the nature of the proposed ancillary study and potential funding source, as outlined above. The format includes: Background, Specific Aims/hypotheses, Significance, Methodology, Feasibility and collaboration, Statistical analysis and power calculations, Proposed funding mechanism, Budget, and References (see attached template). The proposed budgets for ancillary studies should include projected costs associated with implementing and monitoring the study (See Funding, Appendix 1). Investigators are encouraged to contact the REPRIEVE DCC and ACTG to obtain realistic estimates for these projections. There is no additional funding in REPRIEVE to support ancillary studies, and thus all proposed studies must detail the sources and amounts of funding adequate to cover the proposed investigation. The following items will be of particular importance to the ASC in evaluating concept proposals: 1. Scientific Importance 2. Feasibility/Impact on Parent Trial 3. Proposed Funding Source/Adequacy of Proposed Budget 4. Potential for Successful External Peer Review 5. Multi-Disciplinary Collaboration 6. Site PI partnership VERSION 2.0, MAY 18, 2016 4 5.0 Ancillary Study Committee Review and Procedures for EC Approval (See attached flow chart) 6.0 Initial Evaluations of Concept Proposals The ASC will evaluate the importance, scientific merit and the proposed approach for each concept. In addition, it will determine feasibility of the study and assure that it will not have an adverse effect on: 1) the conduct of the primary study, including unintentional unblinding, and issues of patient safety and comfort; 2) patient enrollment and retention; and 3) the human and financial resources required to conduct the primary study. The ASC will review whether any additional blood is needed to conduct the ancillary study, how this will be obtained, shipped and stored and whether this will affect the blood drawing and storage limits of the main REPRIEVE study. For proposals that come from investigators outside the ACTG, the ASC will also review the proposal with the ACTG leadership to insure that the proposal is consistent with the goals of the ACTG, and can be accomplished as a REPRIEVE substudy using the existing ACTG infrastructure and trial structure. The ASC will make recommendations about each proposed ancillary study to the Executive Committee which will then vote on the proposed ancillary study. In addition, concept proposals approved by the EC will be briefly reviewed by the DSMB Chair at this initial stage, before a decision is communicated to the proposing investigative team, to insure the concept proposal is consistent with the goals of REPRIEVE. It is possible that a concept proposal will be returned for revision before a final decision is made. 7.0 Development and Peer Review of Approved Concept Proposals Proposals approved by the REPRIEVE EC and DSMB at the concept stage, will be sent back to the proposing investigative team for further development. During the period of detailed protocol development, the investigative team of an approved concept proposal will be required to consult with the REPRIEVE ASC and will be assigned a designated protocol committee liaison to maximize the opportunity of obtaining important information without posing risks to the conduct of the trial and to insure adequate funding is requested to cover the costs of the trial. The ASC will review the fully developed protocol prior to submission for external peer review, to insure that the proposed application and fully developed protocol, remains of high scientific merit and is consistent with the goals of REPRIEVE and continues to satisfy criteria outlined above, in terms of feasibility/ impact, detailed budget, collaborative nature of proposal. This review will include a formal statistical review to ensure studies are adequately powered and do not compromise blinding in any way. Fully developed ancillary study protocols that are approved VERSION 2.0, MAY 18, 2016 5 by the REPRIEVE ASC and EC, will be submitted to external peer review for funding consideration by the ancillary study proposal team. Protocols approved for submission for external peer review by REPRIEVE will receive a Letter of Support from REPRIEVE to attach to the peer review application. For protocols developed within the ACTG, the ACTG Protocol review process will constitute peer review if external funds are not needed and the ACTG can cover the cost of the proposed ancillary study. If external funds beyond ACTG resources are needed, external peer review to obtain these funds, will be also necessary. 8.0 Final Approval of Ancillary Study Upon approval of funding by the relevant peer review organization, fully developed protocols and peer review comments will be submitted back to the REPRIEVE ASC and EC for a final determination of impact and merit and detailed protocol review, including a review by the DSMB to insure that implementation of the fully funded, detailed peer reviewed protocol remains consistent with the goals of REPRIEVE. In all cases the EC will have final authority to request further development or final changes to an ancillary study. All ancillary studies must address any final protocol design issues prior to final REPRIEVE EC approval and implementation. Based on initial acceptance of the protocol by REPRIEVE, it is not anticipated that final approval will be withheld, but a detailed protocol incorporating peer review comments must be approved by REPRIEVE before implementation. An ancillary study that is approved will be developed as a co-enrolled study managed and overseen through the ACTG/DAIDS trial network in parallel with REPRIEVE, unless the ancillary study is proposing to request use of existing samples from REPRIEVE, in this case the ancillary study would not require a separate enrollment process. Proposals that are submitted for peer review but are not funded can be resubmitted for peer review. In such cases, the Investigative team will review the peer review comments with the ASC and again the ASC will review a detailed protocol before it is resubmitted for peer review. 9.0 Ancillary Databank Studies Proposing the Use of Already Collected Specimens Ancillary studies that propose only to analyze stored specimens or images may also be put forth. Such proposals will be solicited toward the end of REPRIEVE (A5332). As above the ASC and REPRIEVE team will review concept sheets for approval. Consideration of merit, funding, peer review, and feasibility will be considered, as will impact on availability of stored blood. Approved concept proposals will be sent back to the proposing investigative teams for further development. As outlined above, final approval will be determined by the REPRIEVE team, after review of final protocol, analysis plan, funding sources, peer review, feasibility, etc. It VERSION 2.0, MAY 18, 2016 6 is anticipated there will be a high demand for valuable and limited blood, serum and plasma resources generated from REPRIEVE, and thus the ASC and EC will have to prioritize such proposals before approving them. Input from the Biomarker Committee will be solicited in this process. For studies which propose to use existing collected samples, the EC will take into consideration the scientific priority of the proposed ancillary study and the amount of extra blood available in REPRIEVE (A5332) before committing any blood for an ancillary study. In general, the REPRIEVE leadership will need to verify that required samples will be available, that the protocol is statistically sound, and that financial and data analysis issues are adequately addressed. 10. Data Analysis Collection and analyses of the data will be carried out by or under the direct supervision of the Data Coordinating Center (DCC) and adequate funds should be requested for this purpose. The data base will not be released to an investigator outside the DCC framework, unless mandated by NHLBI policy with respect to Data Sharing agreements in place pertaining to complete and analyzed data after the study is finished. Unless an exception is approved in advance, ancillary study data will become part of the REPRIEVE TRIAL database. In no case will study data for an ancillary study be unblinded prior to unblinding for REPRIEVE (A5332). 11.0 Oversight of Approved Ancillary studies Proposals that have received final scientific review and approval by REPRIEVE will be placed on the REPRIEVE restricted website. The ASC and DSMB will review approved ancillary studies for progress annually. Ancillary studies are subject to the review, approval and ongoing oversight of the REPRIEVE DSMB. The ancillary study Principal Investigator must submit annual summaries of study progress to the REPRIEVE ASC. Annual summaries will be required prior to February 1 of each year so they can be included in annual progress reports to NHLBI and should include the number of samples/patients analyzed, preliminary results, any problems encountered, published abstracts and manuscripts, etc. At the annual review, the DSMB will recommend continued approval, termination, or request modifications/clarifications to the ancillary study to the Executive Committee. Ancillary studies will not be approved for continuation that compromise the progress of REPRIEVE (A5332) or the Mechanistic Substudy of REPRIEVE (A5333s), eg by impacting recruitment, blinding, and accomplishment of the primary goals of the study. Recruitment and existence of ongoing ancillary funding will be taken into consideration during annual review of ongoing ancillary studies. VERSION 2.0, MAY 18, 2016 7 12.0 Publication of Ancillary Studies Proposals for abstracts and manuscripts from the ancillary studies must be sent to the REPRIEVE Publications Committee for review and approval in a manner similar to other REPRIEVE publications and presentations. VERSION 2.0, MAY 18, 2016 8 APPENDIX I. Call for Applications: REPRIEVE Ancillary Studies I. Jurisdiction The Executive Committee (EC) will appoint the members and chair of the Ancillary Studies Committee (ASC). The ASC will perform initial evaluation of all ancillary studies proposals and forward meritorious proposals for final approval by the EC. II. Definition of Appropriate Ancillary Studies Ancillary studies are investigations that are not part of the REPRIEVE main trial but that propose questions and test hypotheses that are relevant to the goals and purposes of the REPRIEVE trial. Studies are of three types: 1) Studies which require recording of additional data elements and/or generation of additional data, i.e. imaging, biomarkers, genetic and outcome data, and physiologic measurements. 2) Studies that do not require generation of additional data but rather propose novel and incremental analyses not planned by REPRIEVE within or across studies using data collected in the course of the studies. 3) Studies using stored blood or images for analyses not envisioned or funded in the initial grant III. Funding The ancillary studies investigators are responsible for obtaining funding for their proposals and must outline a reasonable plan to obtain funding in the concept proposal and document adequate external funding or resources before final approval by REPRIEVE. This funding should include adequate funding to compensate the ACTG/DAIDS trial network for costs associated with implementation and monitoring of the trial as well as the CCC and DCC for costs associated with managing the substudy and storing and analyzing the ancillary study data. Studies proposing additional data collection (extra questionnaires, imaging, additional visits, blood tests, etc) as well as those merely needing additional statistical analyses will require adequate resources to perform the proposed tests and analyses. The Institutes of the NIH have programs designed to fund ancillary studies in clinical trials and exploratory/development research. These programs may or may not be a feasible avenue for those studies proposing to collect more data depending on timing of proposal, funding availability, and ongoing REPRIEVE recruitment. Investigators are encouraged to consider the timing of funding, as well other sources of funds. Funding may also be provided by ACTG itself, industry or by an investigator’s institution. Studies which propose only analysis of existing data within or across trials will also need additional funding to support analysis by the DCC. The extent of the funding required by VERSION 2.0, MAY 18, 2016 9