2. 1 Setting up a Data Safety Monitoring Board ASENT Meeting March 6, 2008 Jennifer Schumi, PhD Statistics Collaborative, Inc. jennifer@statcollab.com

3. 2 Five steps to setting up a DSMB 1.Decide why you need one 2.Choose the Board and its chairman 3.Choose the reporting statistician 4.Define how the Board operates 5.Write its charter

4. 3 What is a D(ata)S(afety)M(onitoring)B(oard)? A committee charged with monitoring safety efficacy progress of a clinical trial Aka DMC, IDMC, …

5. Rationale for using DSMBs in research Ethical compact protecting trial participants Sponsor: regulatory responsibilities for reporting financial incentive to end trial early May also advise about changes in protocol, procedures NIH often uses DSMB in an advisory capacity – different from industry-sponsored trials

6. 5 1. Define why you need an external DSMB Scope of advice and decisions  Broad: Safety and efficacy and data quality  More limited: safety only Who makes final decisions for each area

7. 6 Standards for clinical trials NIH Clinical Trial Committee Guide, 1979 “every clinical trial should have provision for data and safety monitoring… should be commensurate with risks” During the 1980’s Many models developed; vary across U.S. & Europe 1994 NIH Committee on Clinical Trial Monitoring: “all trials, even those that pose little likelihood of harm, should consider an external monitoring body.”

8. 7 Standards for clinical trials, continued 2006 FDA guidance document: Establishment and Operation of Clinical Trial Data Monitoring Committees “Full employment act” for statisticians Describes in detail… need for independence of DMC possible models for reporting statistician role of study team, interaction with sponsor

9. 8 Trials that need a DSMB Double-blind Large (hundreds, thousands of subjects) Multi-center/multi-national Long duration Endpoint: death or stroke or …

10. 9 Trials that need a DSMB, cont’d Participants have high intrinsic mortality risk  HIV infection, cancer  Sepsis, pulmonary disease, cardiac failure Trial studying a new chemical entity Recommended (strongly) by regulatory agency

11. 10 Trials that DON’T need a DSMB  Phase I studies, pilot studies (some)  Studies of symptom relief  Studies with other very close safety monitoring  Timeline so short the DSMB can’t operate

12. 11 NIH-type trial

13. 12 Industry trial

14. 13 Monitoring safety data Serious adverse events (in cancer, Grades 3 and 4) Adverse events (severity, related to drug) Laboratory data liver function tests, hematology, changes over time Disease/treatment specific scales Discontinuation rates

15. 14 Who watches safety? And how? Investigators – individual patients Pharmacovigilance – SAEs, case by case, across study IRBs – SAEs at individual study sites Study team (sponsor) – SAEs, other data, individual cases pooled across all treatment groups DSMB – SAEs, other data, aggregated by treatment group

16. Problems with knowing unblinded interim results New science, finances may cause want to change:  primary endpoint  entry criteria, evaluable population  concomitant medications  size of the trial Not appropriate if proposer of change knows interim results

17. 16 Roles of DSMB – safety and efficacy Establish statistical boundaries for efficacy and futility Statistical issues for efficacy settled Statistical issues for futility in flux but reasonably settled Type I error not the most important thing to protect

18. 17 Roles of DSMB-expanded Safety Efficacy Study and scientific integrity Review protocol, CRFs Review procedures that would affect data quality Review quality & integrity of study data Monitor accrual & drop out, compliance

19. 18 2. Members and chairman Voting Physician(s) in specialty area (disease, side effects) Epidemiologist/trial methodologist Statistician Clinical pharmacologist/safety specialist? Ethicist, patient representative, lawyer? Need effective chairman

20. 19 2. Members and chairman Non-Voting Study or steering committee chair Sponsor representatives Reporting statistician

21. 20 Voting members 3-10 experts in disease, study drug, clinical trials Multidisciplinary, independent Disinterested – no conflict of interest Experience on other DSMBs  Chair & statistician  Some inexperienced to train them Must take responsibilities seriously

22. 21 3. Choose the reporter NIH – someone from the coordinating center Industry –  In-house statistician  Contract research organization  Independent statistical group  Statistician on the DSMB Independence  ignorance

23. 22 4. Define the operations Data  “Cleanliness is next to godliness” Not for DSMB!!!  Timeliness more important than cleanliness  Report must aim for clarity and focus Structure of meetings

24. 23 Meetings (Brief executive session) Open session Closed session Executive session Disseminate recommendations Open session Directly to sponsor representative

25. Purpose of open session Update on progress of the trial  Report from the sponsor, Steering Committee  Relevant information from related trials Open and honest discussions Sponsor, investigators, and DSMB can share concerns

26. Participants in closed session The DSMB only? + the statistician(s) preparing the report? +the Chair of the Steering Committee? +the sponsor? Executive session – DSMB only

27. 26 Contents and intent of report Purpose –allow DSMB to make informed decisions 1.Summary of protocol and outstanding issues 2.Recruitment and follow-up 3.Baseline data 4.Check of randomization 5.Timeliness of data & adjudication of endpoints 6.Adverse events with study-specific coding 7.Dosage of study medication 8.Vital signs and laboratory parameters 9.Outcome data

28. 27 Reports to the DSMB: comments Should not just be a subset of final tables Purpose of interim monitoring  purpose of final analysis Changing the study during the trial  what does the study show Don’t be locked into rigid rules! Data should NOT be blind (not everyone agrees)

29. 28 Recommendations from the DSMB Shared with Sponsor, Steering Committee, IRBs Must prevent unblinding of study team Be careful with communications! During the trial, everyone reads tea leaves DSMB must keep impeccable records  What did they know and when did they know it?  Did they change their behavior and rules in response to data?

30. 29 Monitoring for safety Searching for the unknown Rare and often unexpected events Extreme problem of multiplicity “I make no mockery of honest ad hockery”- I. J. Good

31. 30 What type of safety bounds? None – just rely on the judgment of the DSMB Futility bounds for efficacy Symmetric – as hard to call unsafe as to call efficacy Asymmetric – less stringent than for efficacy we do not want to prove harm Careful balance of risks and benefits

32. 31 Taxonomy of adverse events Expected events – balance risk to benefits Unexpected, but not serious Unexpected, serious Unexpected, very serious Not credible, but scary if true

33. 32 Enhancing safety data Spontaneous reports notoriously ambiguous Formal data collection  Diaries  Endpoint committees  Ongoing reporting of prognostic factors  Special data collection forms

34. 33 Reporting safety data Don’t rely on coding systems Classify and reclassify Look at relevant lab data  Means (remember the CLT!)  High percentiles (but not min and max)  Outliers for very rare events

35. 34 5. Write the Charter  Mission and goals  Responsibilities (confidentiality, lack of conflict)  Communications by DSMB  Governance: chair, minutes, quorum, tie votes  Frequency of meetings  Requirement for decision rules, statistical guidelines  Obtaining data for review

36. 35 Issues to hammer out Blind, unblind, or partially blind Sharing data with other DSMBs Participating on related committees

37. Stopping a trial Early stopping is a major decision  Can hurt patients/product if stopping delayed  Can doom product if stopping premature DSMB must aim for defensible decisions Once recommended – very hard to change

38. After the door is open Full and honest disclosure of what happened

39. Recommendations to sponsor Sponsor and DSMB must trust each other Must choose DSMB on basis of expertise  Membership is not a “reward” for good recruitment in other trials  Structure of the meeting should not impede the ability of the DSMB to do its work  Always have face-to-face meetings when the DSMB is thinking about stopping

40. 39 Recommendations to investigators Need careful safety monitoring plan Investigators in a multi-center trial should look at the monitoring plan

41. 40 Suggestions from other DSMBs Should be multidisciplinary Should be committed to the trial Meet in person when possible Reporting group must understand trial and data DSMB must have the right  to ask for additional presentations without telling sponsor  to hold executive sessions  to request/recommend additional expertise

42. 41 Questions?

43. 42 Informed consent Agreement describing risks and benefits People don’t enter trials to prove intervention is harmful