Data and Safety Monitoring Boards

Transcription

1 Data and Safety Monitoring Boards Purposes, Roles and Challenges IACCT2017 Nov 29, 2017, Tel Aviv, Israel Arthur Weinstein, MD, FACP, FRCP, MACR Attending Rheumatologist Emeritus, MedStar Washington Hospital Center Clinical Professor Emeritus of Medicine, Georgetown University Chief Medical Officer, Exagen Diagnostics, Inc

2 DSMBs/DMCs guided by Declaration of Helsinki Ethical Principles (1964) protection of research subjects, ethical considerations; and the Belmont Report (1979) respect for persons, beneficence, justice FDA Guidance Document on the Establishment and Operations of Clinical Trial Data Monitoring Committees 2006 an external [from the sponsor], independent [and unbiased in decision making] body of experts [relevant to the study at hand] to perform interim monitoring of accumulating data to determine risk versus benefit in randomized controlled clinical trials

3 DSMBs Overview When to establish Other oversight committees Composition Organization and Responsibilities Issues and Challenges

4 ?Establish a DSMB Not mandated but highly recommended for large multi-centered controlled clinical trials A priori reasons for safety concerns, such as prior information suggesting the possibility of serious toxicity, eg MACE events, liver toxicity Selected fragile population under study pregnant women, children, elderly, terminally ill May expect highly favorable or unfavorable results leading to the possibility of early termination Long duration studies where protocol modifications may be needed, eg trial end points, inclusion/exclusion criteria - done by a group (eg steering committee) blinded to trial data (advantage to having a separate unblinded DSMB)

5 DSMBs are not alone Steering Committees sponsor/cro Adjudication Committees selected SAE s, end point assessments usually blinded DSMB-recommended expert review (eg, unexpected SAE) IRBs Site monitoring sponsor/cro FDA

6 DSMB Composition I Expertise in clinical trials Knowledge of area under study clinicians, clinical investigators Expertise in expected SAE s of concern infections, CV AEs, liver toxicity Epidemiological/biostatistical expertise clinical trials, prior DSMB experience +/- medical ethicist Chair prior DSMB experience

7 DSMB Composition II Representative of countries involved especially for unique responses/ SE s eg Japan Experts in special groups being studied pediatrics, geriatrics Unblinded liaison - often statistician - independent group/cro No conflicts of interest financial, intellectual 3+ members

8 DSMB Organization Insulation of DSMB from Sponsor Information Flow Investigators Sponsor Coordination Group* DSMB *Coordination Group [eg, CRO] paper flow, DSMB meetings, logistics, maintain blinding, provide unblinded statistician

9 Face to face/web q 3-6 months DSMB Meetings Charter Open Session - provided by sponsor - aggregate data recruitment, dropouts, demographic data Closed Session -unblinded data provided by coordination group/statistician -focus on SAEs, unexpected, frequent AEs, adjudicated end points -+/- unblinded efficacy data Executive Session as needed without coordination group Letter of recommendation to sponsor DSMB is ADVISORY

10 DSMB Responsibilities RESPONSIBILITY EXTENT Review of Protocol ++ Approval of Protocol +/- Review of Investigator Brochure ++ Assessment of recruitment progress +++ Assessment of data quality (drop rates, withdrawals, demographics, etc) +++ Assessment of safety +++ Assessment of efficacy (risk/benefit analysis) ++ Recommendation regarding trial continuation/early termination +++ Review of presentations/manuscripts +/- Approval of presentations/manuscripts +/- Modified from: Demets DL, Ellenberg SS. NEJM 2016;375:

11 DSMB ISSUES Should there be an unblinded Sponsor participant, other than statistical group eg, single sponsor point of contact? In general, no Firewall documentation Should the DSMB receive unblinded efficacy data? In general, yes but Should there be sharing of data across separate trials using the same therapeutic for different indications? In general, no

12 DSMB Challenges Liability for actions or lack of them all members must agree to monitoring plan Early Study Termination? Large early benefit - mortality (beta blocker heart attack trial) - JAMA 1982 No benefit - futility analysis Higher mortality - SAE with treatment antiarrhythmics after MI- NEJM 1989 Sharing of data across separate trials Occasionally of value- eg, significant or unexpected AE in one trial (cancer) - did it occur in another trial that is farther along?

13 DSMB Challenges Personal Examples neurological SAEs early in study in one group - watchful waiting vs termination higher mortality in one treatment arm evaluation by sponsor statistician - statistical plan for termination frequent monitoring q 3months heads up to FDA (blinded to SAE) frequent high CPK s -? reason ask sponsor for outside expert to evaluate written report hyperlipidemia consequences shared data from a recently completed study in another condition

14 DSMBs Summary independent, unbiased assessment of risk versus benefit in controlled clinical trials clinical and statistical expertise composition and organization defined by charter advisory to sponsor prepared to meet responsibilities and challenges

15 Selected References 1. Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees. U.S. Department of Health and Human Services. Food and Drug Administration, 2006: Fleming TR, DeMets DL: Monitoring of Clinical Trials: Issues and Recommendations. Controlled Clin Trials 1993; 14: Drazen JM, Wood AJJ: Don t Mess with the DSMB. New Engl J Med 2010; 365: Swedberg K, Borer JS, Pitt B, Pocock S, Rouleau J. Challenges to Data Monitoring Committees when regulatory authorities intervene. New Engl J Med 2016; 374: DeMets DL, Ellenberg SS. Data Monitoring Committees Expect the Unexpected. New Engl J Med 2016; 375: