1. 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 Statistical Design and Trial Conduct
Statistical and Practical Considerations When Terminating a Trial Early

2. 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 !

3. 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

4. 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!

5. 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.

6. 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

7. 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

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

9. 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

10. 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

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

12. 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

13. 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.

14. 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!

15. 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