DATA MONITORINGCOMMITTEES: COMMENTSON PRESENTATIONS
Susan S. Ellenberg, Ph.D.
Department of Biostatistics andEpidemiology
University of Pennsylvania School ofMedicine
FDA/Industry Workshop
Washington, DC
September 28, 2006
CHANGING ROLE OF DMC
•Increasing structure
–Policies of funders (NIH, industry) andregulatory agencies
•More transparency of process
–Study protocol
–Statistical analysis plan
–DMC Charter
–Publications describing standard and/orrecommended practices
3 CATEGORIES OF DMCACTIVITIES AND PROCESSES
•Governed by well-established and widelyaccepted principles
–Maintaining confidentiality of interim data
–Minimizing conflicts of interest
•Subject to controversy regarding optimalapproaches
–Review of coded vs unblinded interim data
–Presentations by “independent statistician”
•Not yet discussed to any great extent—anything goes (?)
RALPH D’AGOSTINO: ISSUESFACED BY DMCs
•Recommending or approving changes inendpoints
•Mortality as a safety or efficacyendpoint
•Timing of reporting unexpected results
•Balancing safety and efficacy
•DMC authorship on study paper
RALPH D’AGOSTINO ISSUESFACED BY DMCs
•Recommending or approving changes inendpoints (2)
•Mortality as a safety or efficacyendpoint (1)
•Timing of reporting unexpected results(3)
•Balancing safety and efficacy (3)
•DMC authorship on study paper (3)
CHANGING ROLE OFSTATISTICIANS ON DMCs?
•Maybe no longer the only DMC memberwith prior DMC experience
•Involvement of “independentstatisticians” may put increasedpressure on experienced DMCstatistician
•Increased use of DMCs may make DMCdecisions of more variable quality, asthose who serve may be lessexperienced
BRAM ZUCKERMAN: DMCs FORDEVICE TRIALS
•Traditional mantra of device industry:DEVICES ARE NOT DRUGS!
•Still, generally recognized that trials ofdevices intended to save lives or impacton health in a major way require thesame type of interim monitoring as drugtrials
•FDA guidance on DMCs developed withfull input and support of CDRH
WHAT DEVICES REQUIRESTUDY IN TRIAL WITH DMC?
•Novel use requiring invasive procedures
–Implantable devices
–Stents
•Use has implications for diagnosis ortreatment of serious disease andrequires evaluation in controlled trial
–Assays
–Imaging
SPECIFIC ISSUES
•DMC involved in modifying sample size
–Inadvisable if DMC has already seen unblindedinterim comparison
–Could affect trial conduct, interpretation of finalcomparisons
•DMC viewing unblinded data in closed session
–Should be routine, rather than “not uncommon”
•Disputes between DMC and FDA
–If happening commonly, might be helpful toconvene a workshop specifically on data monitoringin device trials
PAUL GALLO: ADAPTIVEDESIGNS AND DMCs
•Much has been written about thestatistical properties of adaptivedesigns involving sample size re-estimation
•Little has been written about how thesedesigns would actually be implemented
–Prespecified plans, with automatic samplesize changes effected if boundaries arecrossed?
–Up to judgment of DMC or statisticiandoing interim analysis for DMC?
IMPLICATIONS FORCONFIDENTIALITY
•Clinical trial initiated
•Protocol known to sponsors, investigators,FDA, others
•Interim data known only by DMC andstatistician analyzing interim data
•Partway through the trial, sample size isincreased
•What information does this provide toinvestigators, sponsors, external sources(eg, Wall Street)?
UNBLINDING
•Sample size increases will have to bemade known to sponsor, others involvedin trial
•If procedures are pre-specified, samplesize increases can be used to back-calculate interim estimate of treatmenteffect
•If procedures are not pre-specified,sponsor is essentially committing toopen sequential design; seemsimpractical
IS THIS REALLY A PROBLEM?
•Seattle Times, August 2005
–Investment firms interviewing physiciansinvolved in clinical trials as investigatorsor DMC members
–Firms have been able to glean sufficientknowledge to make highly accurateguesses about trial outcomes
–Major effects on stock prices
–All without this extra information
PROBLEM RECOGNIZED
•Schäfer and Müller: “[A]… problem is thatknowledgeable observers can draw conclusionsabout the current observed treatmentdifferences from the action determined.”
•Chen, DeMets, Lan: “Further research is stillneeded to investigate the impact…on theconduct of the trial and to find ways toprotect the integrity of the study.”
HOW MUCH INFORMATIONEMERGES FROM OTHERDESIGNS?
•Group sequential design
–If DMC stops study, full information but study isover; doesn’t matter
–If DMC continues study, know results are betweenstopping bounds—pretty minimal information
–If futility analyses also done, narrower bound onpossible outcome as study approaches planned size
•Triangular design may provide moreinformation
•Depends on frequency of interim looks
SEAMLESS DESIGNS
•Designs permitting “seamless” transition fromphase 2 to phase 3 have potentially greatefficiency
–Avoids stopping and restarting enrollment
–Avoids one IRB approval process
•Major issue is whether one can anticipate to asufficient extent everything that mighthappen in phase 2 that could affect approachto phase 3
–Sponsor will not have opportunity to review dataand incorporate new information in design of nextphase
–May place unreasonably heavy reliance on DMCjudgment
WHAT IS THE DIFFERENCE
•…between a study designed for 500subjects that could get bumped up to1000, and a study designed for 1000subjects that could stop at 500?
WHAT IS THE DIFFERENCE
•…between a study designed for 500subjects that could get bumped up to1000, and a study designed for 1000subjects that could stop at 500?
–Big difference
–Enlarging the sample size gives outinformation that could affect the furtherconduct and interpretation of the study
–Stopping early gives out information, butstudy is over