11/23/2019 Database lock to Data Safety Monitoring Board meeting – More than a click of a button David Prince, PhD, Manager, Biostatistics davidp@axioresearch.com 31 July 2019

Axio Overview Experience Services Professional 11/23/2019 Axio Overview Providing Biostatistical and Clinical Trial Services for 40 Years Experience Services Professional Established in 1979 by University of Washington faculty as SERC Continuing relationship with UW: faculty as “friends” and consultants, students as employees Recently merged with Cytel DMC support Adaptive design interim analysis Randomization checks Event projection Clinical trial design Statistical analysis plans Biostatistics consulting Data Management Statistical genetics and genomics FDA Workshops CDISC Advisory Council American Statistical Association PharmaSUG Society for Clinical Trials BASS UPenn Annual Conference on Statistical Issues in Clinical Trials

Main aims from a report production perspective Having sufficient time to identify and understand or resolve all issues in the data or programming. The DMC report to accurately reflect the data at the time of the database lock.

Upcoming DMC meetings at Axio For n=34 studies with upcoming meetings (as of June 2019) Median 29 calendar days Range from 14 to 57 days

What Happens between Database Lock and the Meeting Activities before the lock Data transfer Production code re-run Validation or testing code re-run QC of the report Sponsor review Preparation of additional materials and final review DMC review and meeting

What Happens between Database Lock and the Meeting Activities before the lock Review previous meeting documents Confirmation of expected outputs (including cohorts) Timelines (Study, Contract, Charter) Changes to the protocol or data Expect specific derivations, e.g. LKDA, date imputation Data transfer Multiple sources (and portals) Raw vs. SDTM vs. analysis datasets Consistency Use of LibComp macro to identify changes

What Happens between Database Lock and the Meeting Production code re-run (and updates) Assuming Axio created Non-standard data sources checked Log search macro Validation or testing code re-run (and updates) Proc compare Confirm agreement on analysis datasets (TLFs) QC of the report Min, max, outliers (e.g. exposure) Internal consistency Early phase or trials with substudies

What Happens between Database Lock and the Meeting Sponsor review Clarity on what the sponsor can review Dummy randomization, different ratio Axio cannot change the data Preparation of additional materials and final review Use of 23-item report production checklist Formal interim Validation documentation Executive summary (include any data issues or appreciable changes) Cover page, TOC

What Happens between Database Lock and the Meeting DMC review and meeting Generally 5 business days Known issues communicated DMC understands data is imperfect Ad hoc requests common

Meeting the aims Planning Communication Review reports, review documents, review specifications…