Data & Safety monitoring boards

Madhuri.M. M’pHARM: 

Madhuri.M . M’pHARM Data and Safety Monitoring Boards (DSMB)

What is a D(ata)S(afety)M(onitoring)B(oard)?: 

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, DSMC, IDMC, …

History: 

History Data and Safety Monitoring 1979 Every clinical trial should have provision for data and safety monitoring The size of the monitoring committee depends upon the nature, size, and complexity of the clinical trial The Principal Investigator was expected to perform the monitoring function but may have had others to help

PowerPoint Presentation: 

1994 It was recommended that every clinical trial, even those that pose little likelihood of harm have an external monitoring body 1998 Establishment of Data Safety Monitoring Board (DSMB) is required for multi-site clinical trials involving interventions that entail potential risk to the participants

PowerPoint Presentation: 

2006 FDA guidance : Establishment and Operation of Clinical Trial Data Monitoring Committees

Composition: 

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

PowerPoint Presentation: 

Non-Voting Study or steering committee chair Sponsor representatives Reporting statistician

Voting members: 

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 se riously

Qualifications: 

Qualifications Expertise in the field Experience in conduct of CT & statistical knowledge Independence from direct management of CT No conflict of interest

Rationale for using DSMBs in research: 

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

Trials that need a DSMB: 

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

PowerPoint Presentation: 

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

Trials that DON’T need a DSMB: 

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

Requirements for DSMB’s: 

Requirements for DSMB’s NIH Typically require DSMB Protocols that generate blinded/randomized data Multicenter protocols; > minimal risk Gene transfer protocols May require DSMB Protocols requiring special scrutiny High public interest Vulnerable populations FDA Risk to trial participants Study endpoint Large trials of long-duration Practicality Short trials Assurance of scientific validity Inclusion of new scientific knowledge without adding bias

Purpose of DSMB: 

Purpose of DSMB Identify high rates of ineligibility determined after randomization Identify protocol violations that suggest clarification of changes to protocol are needed Identify unexpectedly high drop out rates that threaten the trial’s ability to produce credible results Ensure validity of study results

Duties of DSMB: 

Duties of DSMB R eview the research protocol and plans for data and safety monitoring Evaluate the progress of the trial with periodic assessments of data quality and timeliness, participant recruitment, participant risks and benefits; Reports from related studies

PowerPoint Presentation: 

Make recommendations to the IRB and investigators concerning continuation or conclusion of the trial Review the adverse event reports.

Timing of meetings: 

Timing of meetings Meets annually Periodically when Risk to subjects is high Vulnerable subjects Large volume of data to review

Meetings: 

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

PowerPoint Presentation: 

Initially an open session is conducted members of the clinical trial may be present may focus on accrual, protocol compliance, and general toxicity issues no outcome results discussed during this session

PowerPoint Presentation: 

Followed by a closed session DSMB members only outcome results discussed statistical reports (if necessary) Finally an executive session DSMB members only discuss the general conduct of the trial all outcomes (including toxicities and AE) develop recommendations and vote if necessary

Contents and intent of report: 

Contents and intent of report Purpose –allow DSMB to make informed decisions Summary of protocol and outstanding issues Recruitment and follow-up Baseline data Check of randomization Timeliness of data & adjudication of endpoints Adverse events with study-specific coding Dosage of study medication Vital signs and laboratory parameters Outcome data

Recommendations from the DSMB: 

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?

Are There Disadvantages to Having a DSMB? : 

Are There Disadvantages to Having a DSMB? * YES! Increases complexity of trial management Increases costs If the ethical imperatives discussed earlier are not applicable, other (simpler) monitoring approaches are usually acceptable

Dechallange & Rechallange: 

Dechallange & Rechallange Dechallenge -The clinical decision to withdraw drug treatment after a possible ADR occurred Considered to be - + ve : if the reaction occurs at each dose & abates completely or partially after withdrawal of drug - ve :  if the reaction does not abate  after withdrawal of drug Not applicable where : * Drug is one dose treatment (vaccine ) * Reactions occurred after the drug was discontinued * congenital anomaly (irreversible )

PowerPoint Presentation: 

Rechallenge - Reintroduction of the same drug which had been withdrawn due to  ADR following + ve dechallenge Considered to be + ve : reoccurrance of similar signs & symptoms as that of previous - ve : failure of appearance of similar signs & symptoms as that of previous one Not applicable where * same as that of rechallenge for ethical reasons rechallenge is rarely performed but it may eb carried out when the results are in the interest of patient  suffering the reaction, particularly when there are no suitable alternative drugs

PowerPoint Presentation: 

Thank you! Merci!