NHLBI Perspective Yves Rosenberg, M.D, M.P.H. Statistical and Practical Considerations When Terminating a Trial Early: Contrasting early stopping due to harm (ACCORD) versus for benefit (SPRINT) NHLBI Perspective Yves Rosenberg, M.D, M.P.H. Chief, Atherothrombosis and Coronary Artery Disease Branch Division of Cardiovascular Sciences National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, MD Liverpool, UK, May 8th, 2017 Invited Session 2.1 - Statistical Design and Trial Conduct Statistical and Practical Considerations When Terminating a Trial Early

ACCORD Deputy Project Officer My personal view ! Contrasting early stopping due to harm (ACCORD) versus for benefit (SPRINT): NHLBI Perspective Disclosures ACCORD Deputy Project Officer My personal view !

Contrasting early stopping due to harm versus for benefit Early Close-out Objectives For Any Study Patient safety first! Inform participants prior to any public announcement An orderly close-out: Plans the organization structure, timeline, and tasks ahead of a close-out decision; Who will lead the effort initially and draft possible timelines; Who needs to be notified when, how, what is their role, task, and responsibility, for all internal and external parties; How roles, tasks, and responsibility may change as the close-out progresses. Has a clear message Provides clearly written documents & procedures to stakeholders in a timely way

Contrasting early “stopping” due to harm (ACCORD) versus for benefit (SPRINT) Some Key Differences Based on safety findings, the ACCORD DSMB recommended stopping the glycemia intervention arm of the trial because the risk of harm outweighed the potential benefit The DSMB did not make any specific recommendation regarding the blood pressure and the lipid trials. The SPRINT DSMB recommended unmasking trial investigators and notifying participants of the lower rate of cardiovascular outcomes and total mortality in the intensive arm They also recommended developing a transition plan for collecting additional outcome data and for managing study participants’ blood pressure. Stopping in parenthesis: intervention/trials continue! BUT: Trials are not stopped! The intervention is!

Oversight Role of NHLBI Contrasting early stopping due to harm (ACCORD) versus for benefit (SPRINT) Oversight Role of NHLBI NHLBI is responsible for the oversight of data and safety monitoring to ensure: that an appropriate monitoring system is in place for all NHLBI-supported studies and that the Institute is kept informed of recommendations emanating from these monitoring activities. NHLBI’s role is not to usurp IRBs or other regulatory and monitoring bodies, but rather, to oversee monitoring, make sure it is commensurate with the risk level of the study and to ensure that appropriate approvals have been obtained.

Oversight Role of NHLBI Contrasting early stopping due to harm (ACCORD) versus for benefit (SPRINT) Oversight Role of NHLBI The DSMB is an independent group providing recommendations to the Office of the Director, NHLBI, and is required to provide recommendations about starting, continuing, and stopping the study If the DSMB does identify concerns, the NHLBI staff will distribute, as soon as feasible, preferably within 7 calendar days of the DSMB meeting, the Summary Report outlining the concerns and the basis for any recommendations that the DSMB has made in response to the concerns https://www.nhlbi.nih.gov/research/funding/human-subjects/data-safety-monitoring-policy

Intervention stopped for safety Intervention stopped for efficacy Contrasting early stopping” due to harm (ACCORD) versus for benefit (SPRINT) Role of NHLBI NHLBI unmasked NHLBI masked Intervention stopped for safety D+ 14 Intervention stopped for efficacy D+22

Contrasting early stopping due to harm versus for benefit NHLBI Flow Chart of Early Study Closure

Contrasting early stopping in ACCORD and SPRINT NHLBI Initial Actions Actions ACCORD Timing SPRINT Timing DSMB recommendation to NHLBI Director -13d -16d NHLBI Director accepts DSMB recommendation 0d NHLBI Project Office unmasked NA Study Leadership notified of decision +1d +3d Coordinating Center IRB notified +2d Investigators notified +11d +19d Clinical Site IRBs notified

Contrasting early stopping in ACCORD and SPRINT Communication to Stakeholders Actions ACCORD Timing SPRINT Timing Study staff notified +12d +20 to 22d Contact FDA +2d NA Pharmaceutical Sponsor and/or other Federal or non- Federal Sponsors contacted +2-3d +21d Trial participants contacted +16d Media contacted +15d Physician groups and professional societies contacted +13d Public Announcement and Press Release +17d +22d

Contrasting early stopping due to harm versus for benefit ACCORD Gantt Chart Red line: NHLBI accepts recommendation Some event occurs in succession, others simultaneously!

Documents to Prepare and Other Actions ACCORD Close-out Planning Communication Responsible Party First Draft Memo to clinic investigators and staff describing impending action, timeline and instructions Contingency Planning Task Force NHLBI PO Talking points for staff to use with participants, Q&A NHLBI PO and CC IRB letters CC Letter for participants Letter for referring/PCP Press materials, including “talking points” press releases, Q&A NHLBI CO   Consent Form Change Follow-up Forms Primary Outcome Manuscript SC

Documents to Prepare and Other Actions NHLBI ACCORD “Message Box” Structured communication centered around key message. Clockwise: Summary of results. Message for participants. Further actions. Details of results.

Role of NHLBI: Lessons Learned Contrasting early stopping due to harm (ACCORD) versus for benefit (SPRINT) Role of NHLBI: Lessons Learned Establish clear guidelines for early stopping - DSMB Charter Coordinate/facilitate close-out teams What needs to be prepared - checklists Who will be unmasked when – Timelines Assignments – before and after unmasking Unmask key study staff (coordinators) early NHLBI unmasked close out team: Involve key study staff ASAP Parallel vs. sequential events? Keep it small and organized – clear leadership!

Role of NHLBI: Lessons Learned Contrasting early stopping due to harm (ACCORD) versus for benefit (SPRINT) Role of NHLBI: Lessons Learned Keep patients first! Participants notification : speed vs. effectiveness? Stay on message – “message box” Stay on schedule Always be prepared Prepare for the unexpected