1. Data Safety Monitoring BoardsData Safety Monitoring Boards
and Safety in High Riskand Safety in High Risk
Therapeutic Trials in YouthsTherapeutic Trials in Youths
Carlo Carandang, MD, ABPN (Dip.)Carlo Carandang, MD, ABPN (Dip.)
Division of Child & Adolescent PsychiatryDivision of Child & Adolescent Psychiatry
Department of PsychiatryDepartment of Psychiatry
Dalhousie UniversityDalhousie University
IWK Mental Health and Addictions ProgramIWK Mental Health and Addictions Program

2. DisclosureDisclosure
 Pharmaceutical Industry Conflicts: none over pastPharmaceutical Industry Conflicts: none over past
12 months12 months
 Member, Dalhousie University Health SciencesMember, Dalhousie University Health Sciences
Research Ethics BoardResearch Ethics Board
 Member, 2006 NIMH Antidepressants andMember, 2006 NIMH Antidepressants and
Suicidality Review CommitteeSuicidality Review Committee
 Ad Hoc Reviewer, Pediatric PsychopharmacologicAd Hoc Reviewer, Pediatric Psychopharmacologic
Trials, JAACAPTrials, JAACAP
 PI, lamotrigine study (2003-2005) with DSMBPI, lamotrigine study (2003-2005) with DSMB
oversightoversight

3. ObjectivesObjectives
 Safety in high risk randomized controlled trialsSafety in high risk randomized controlled trials
(RCTs) in young persons(RCTs) in young persons
 Data Safety Monitoring Boards (DSMBs)Data Safety Monitoring Boards (DSMBs)
 Defining the concept of “high risk”Defining the concept of “high risk”
 Capturing Adverse EventsCapturing Adverse Events
 Recommendations for improvement of safety inRecommendations for improvement of safety in
pediatric psychiatry trialspediatric psychiatry trials
 Case Study: Evaluating safety in a clinical trialCase Study: Evaluating safety in a clinical trial

4. Safety in High Risk RCTs: Suicidality inSafety in High Risk RCTs: Suicidality in
Pediatric Antidepressant TrialsPediatric Antidepressant Trials
 Increase risk of suicidality onIncrease risk of suicidality on
antidepressant vs. placebo group (4% vsantidepressant vs. placebo group (4% vs
2%)2%)
– FDA metanalysis (Hammad et al., 2006)FDA metanalysis (Hammad et al., 2006)
 Investigators of Pediatric SSRI trials:Investigators of Pediatric SSRI trials:
– ““The trials were not designed to assessThe trials were not designed to assess
suicidality.”suicidality.”
 What they really meant:What they really meant:
– ““The trials were not designed to assess safetyThe trials were not designed to assess safety
and adverse events.”and adverse events.”

5. Safety in High Risk RCTs: Suicidality inSafety in High Risk RCTs: Suicidality in
Pediatric Antidepressant TrialsPediatric Antidepressant Trials
 Controversy of antidepressant treatment-Controversy of antidepressant treatment-
emergent suicidality has raised criticalemergent suicidality has raised critical
issues with regards to safety of youngissues with regards to safety of young
persons in high risk RCTspersons in high risk RCTs
 Also uncovered serious issues with regardsAlso uncovered serious issues with regards
to how adverse events are captured andto how adverse events are captured and
addressed in RCTsaddressed in RCTs

6. Safety in High Risk RCTs: Suicidality inSafety in High Risk RCTs: Suicidality in
Pediatric Antidepressant TrialsPediatric Antidepressant Trials
 Retrospective analysis and armchairRetrospective analysis and armchair
criticisms have inherent flaws, but the PIscriticisms have inherent flaws, but the PIs
and sponsors should have anticipatedand sponsors should have anticipated
suicidality in light of:suicidality in light of:
– Increased impulsivity of adolescentsIncreased impulsivity of adolescents
– Depression as a risk factor for suicidalityDepression as a risk factor for suicidality
– Available RCTs did not reveal robust effect,Available RCTs did not reveal robust effect,
and therefore should have erred on the side ofand therefore should have erred on the side of
expecting no therapeutic effectexpecting no therapeutic effect

7. Safety Concerns: Emslie 2007Safety Concerns: Emslie 2007
Venlafaxine ER trial in Pediatric MDDVenlafaxine ER trial in Pediatric MDD
 When reviewing the Emslie manuscript forWhen reviewing the Emslie manuscript for
publication, serious concerns arose overpublication, serious concerns arose over
safety of trial subjects in this studysafety of trial subjects in this study
– (Emslie et al., 2007)(Emslie et al., 2007)
 Commentary on this concern:Commentary on this concern:
– Formation of a Data and Safety MonitoringFormation of a Data and Safety Monitoring
Board may have addressed safety concerns in aBoard may have addressed safety concerns in a
methodical, prospective fashionmethodical, prospective fashion
» (Carandang et al., 2007)(Carandang et al., 2007)

8. Safety Concerns: Emslie 2007 VenlafaxineSafety Concerns: Emslie 2007 Venlafaxine
ER trial in Pediatric DepressionER trial in Pediatric Depression
 Clear signal of risk, and no efficacy advantage ofClear signal of risk, and no efficacy advantage of
venlafaxine over placebovenlafaxine over placebo
 No third party oversight of adverse events in realNo third party oversight of adverse events in real
timetime
– REB only has oversight at study inception and onceREB only has oversight at study inception and once
yearly basisyearly basis
 Spontaneous reporting by subjects of adverseSpontaneous reporting by subjects of adverse
eventsevents
 No interim safety analysis to determine if risk ofNo interim safety analysis to determine if risk of
harm greater on drug vs. placeboharm greater on drug vs. placebo

9. Data and Safety MonitoringData and Safety Monitoring
BoardsBoards
 The use of DSMBs is one method to assureThe use of DSMBs is one method to assure
subject safety in “high risk” therapeutic trialssubject safety in “high risk” therapeutic trials
 A DSMB is an autonomous structure, independentA DSMB is an autonomous structure, independent
of study sponsors and investigatorsof study sponsors and investigators
 Composed of a multidisciplinary group ofComposed of a multidisciplinary group of
individuals who have expertise in the study areaindividuals who have expertise in the study area
and clinical trial methodologyand clinical trial methodology
 Also known as Data Monitoring CommitteeAlso known as Data Monitoring Committee
(DMC)(DMC)

10. DSMBDSMB
 Commonly composed of biostatisticians,Commonly composed of biostatisticians,
scientists, bioethicists, and clinicians who arescientists, bioethicists, and clinicians who are
knowledgeable about the question being studiedknowledgeable about the question being studied
 Principal role: ensure safety of study patients byPrincipal role: ensure safety of study patients by
analyzing adverse events and performing interimanalyzing adverse events and performing interim
analyses of the outcome dataanalyses of the outcome data
 Authority to terminate a trial based on evidence ofAuthority to terminate a trial based on evidence of
harm or on evidence of efficacy; “stopping rules”harm or on evidence of efficacy; “stopping rules”

11. DSMBs and Youth AntidepressantDSMBs and Youth Antidepressant
TrialsTrials
 Of the 14 published SSRI controlled trials:Of the 14 published SSRI controlled trials:
– Only 1 study reported the use of a DSMB andOnly 1 study reported the use of a DSMB and
an interim safety analysisan interim safety analysis
» TADS study (March et al. 2004)TADS study (March et al. 2004)
– Only 3 reported the prospective use of anOnly 3 reported the prospective use of an
Adverse Event ChecklistAdverse Event Checklist
– Most trials relied on spontaneous reporting ofMost trials relied on spontaneous reporting of
adverse eventsadverse events

12. Published Youth SSRI TrialsPublished Youth SSRI Trials
 StudyStudy DrugDrug DSMBDSMB Interim AnalysisInterim Analysis Adverse EventsAdverse Events
 Emslie 2007Emslie 2007 VenlafaxineVenlafaxine NoNo NoNo SpontaneousSpontaneous
 Emslie 2006Emslie 2006 ParoxetineParoxetine NoNo NoNo SpontaneousSpontaneous
 Von Knorring 2006Von Knorring 2006 CitalopramCitalopram NoNo NoNo SpontaneousSpontaneous
 Wagner 2006Wagner 2006 EscitalopramEscitalopram NoNo NoNo SpontaneousSpontaneous
 Emslie 2004Emslie 2004 FluoxetineFluoxetine NoNo NoNo AE ChecklistAE Checklist
 March 2004March 2004 FluoxetineFluoxetine YesYes YesYes AE ChecklistAE Checklist
 Wagner 2004Wagner 2004 CitalopramCitalopram NoNo NoNo SpontaneousSpontaneous
 Wagner 2003Wagner 2003 SertralineSertraline NoNo NoNo SpontaneousSpontaneous
 Braconnier 2003Braconnier 2003 ParoxetineParoxetine NoNo NoNo SpontaneousSpontaneous
 Emslie 2002Emslie 2002 FluoxetineFluoxetine NoNo NoNo AE ChecklistAE Checklist
 Keller 2001Keller 2001 ParoxetineParoxetine NoNo NoNo SpontaneousSpontaneous
 Emslie 1997Emslie 1997 FluoxetineFluoxetine NoNo NoNo SpontaneousSpontaneous
 Mandoki 1997Mandoki 1997 VenlafaxineVenlafaxine NoNo NoNo SpontaneousSpontaneous
 Simeon 1990Simeon 1990 FluoxetineFluoxetine NoNo NoNo SpontaneousSpontaneous

13. DSMBs and RandomizedDSMBs and Randomized
Controlled Trials (RCTs)Controlled Trials (RCTs)
 Most RCTs (psychiatric and non-Most RCTs (psychiatric and non-
psychiatric) to date have not utilizedpsychiatric) to date have not utilized
DSMBs to monitor safetyDSMBs to monitor safety
– About a quarter of RCTs utilized DSMBsAbout a quarter of RCTs utilized DSMBs
(Sydes et al. 2004)(Sydes et al. 2004)
 DSMBs are currently being recommendedDSMBs are currently being recommended
as standards in National Institutes of Healthas standards in National Institutes of Health
(USA) and Medical Research Council (UK)(USA) and Medical Research Council (UK)
sponsored trialssponsored trials

14. Defining “High Risk” in TherapeuticDefining “High Risk” in Therapeutic
Trials as proposed by Dr. KutcherTrials as proposed by Dr. Kutcher
 Features of the illness (SI)Features of the illness (SI)
 Features of the intervention (activation)Features of the intervention (activation)
 Features of the research environmentFeatures of the research environment
(nonacademic study sites with(nonacademic study sites with
inexperienced investigators)inexperienced investigators)
 Novel cohorts (youth)Novel cohorts (youth)
 Novel interventions (no data for particularNovel interventions (no data for particular
condition in particular population)condition in particular population)

15. Study Risk Assessment: University of IllinoisStudy Risk Assessment: University of Illinois
at Chicago General Clinical Research Centerat Chicago General Clinical Research Center
 I. Experimental TreatmentI. Experimental Treatment
– Low Risk:Low Risk:
» No experimental treatment (1 point)No experimental treatment (1 point)
– Mod Risk:Mod Risk:
» Treatment effects documented from studies withTreatment effects documented from studies with
similar and/or different populations and/or settings.similar and/or different populations and/or settings.
No serious adverse events expected. Specific plansNo serious adverse events expected. Specific plans
to monitor AE’s detailed in DSMP (2 points)to monitor AE’s detailed in DSMP (2 points)
– High Risk:High Risk:
» Experimental treatment regulated by FDA (4 points)Experimental treatment regulated by FDA (4 points)

16. Study Risk Assessment: University of IllinoisStudy Risk Assessment: University of Illinois
at Chicago General Clinical Research Centerat Chicago General Clinical Research Center
 II. Procedures, Measurements, and DataII. Procedures, Measurements, and Data
Collection MethodsCollection Methods
– Low Risk:Low Risk:
» Minimally invasive with low degree of emotional and/orMinimally invasive with low degree of emotional and/or
physical discomfort. Probability of adverse events is low.physical discomfort. Probability of adverse events is low.
Severity (magnitude) of adverse events is low (1 point)Severity (magnitude) of adverse events is low (1 point)
– Moderate Risk:Moderate Risk:
» Moderate degree of emotional and/or physicalModerate degree of emotional and/or physical
discomfort. Probability of adverse events is low.discomfort. Probability of adverse events is low.
Severity of adverse events is moderate to high (2 points)Severity of adverse events is moderate to high (2 points)
– High Risk:High Risk:
» Moderate to high degree of emotional and/or physicalModerate to high degree of emotional and/or physical
discomfort. Probability of adverse events is moderate todiscomfort. Probability of adverse events is moderate to
high. Severity of adverse events is high (4 points)high. Severity of adverse events is high (4 points)

17. Study Risk Assessment: University of IllinoisStudy Risk Assessment: University of Illinois
at Chicago General Clinical Research Centerat Chicago General Clinical Research Center
 III. Decision-making CapabilityIII. Decision-making Capability
– Non-vulnerable:Non-vulnerable:
» Adult who 1) demonstrates decision-makingAdult who 1) demonstrates decision-making
capacitycapacity andand 2) demonstrates no perception of2) demonstrates no perception of
undue influence or coercion to participate (1undue influence or coercion to participate (1
point)point)
– Vulnerable:Vulnerable:
» Any minor. Adult who 1) demonstratesAny minor. Adult who 1) demonstrates
limitations in decision-making capacitylimitations in decision-making capacity and/orand/or
2) is prone to perception of undue influence or2) is prone to perception of undue influence or
coercion to participatecoercion to participate (2 points)(2 points)

18. Study Risk Assessment: University of IllinoisStudy Risk Assessment: University of Illinois
at Chicago General Clinical Research Centerat Chicago General Clinical Research Center
 Overall Risk: tally pointsOverall Risk: tally points
– Low risk: 3 or 4 pointsLow risk: 3 or 4 points
– Moderate risk: 5 pointsModerate risk: 5 points
– Severe risk: 6 to 10 pointsSevere risk: 6 to 10 points
 The monitor for low and moderate risk studiesThe monitor for low and moderate risk studies
may be the PImay be the PI
 High (6 points) risk studies require a quarterlyHigh (6 points) risk studies require a quarterly
review of accumulated safety data and the monitorreview of accumulated safety data and the monitor
may be the PImay be the PI
 High (7-10 points) risk, single site (UIC) studiesHigh (7-10 points) risk, single site (UIC) studies
must have an independent monitor (i.e. DSMB)must have an independent monitor (i.e. DSMB)

19. Measurement of Treatment-Measurement of Treatment-
Emergent Adverse EventsEmergent Adverse Events
 Spontaneous ReportsSpontaneous Reports
 General InquiryGeneral Inquiry
 Specific InquirySpecific Inquiry
 Specific following General InquirySpecific following General Inquiry

20. Tools to Capture Treatment-EmergentTools to Capture Treatment-Emergent
Adverse Events in Youth RCTsAdverse Events in Youth RCTs
 No validated gold standard in youthNo validated gold standard in youth
psychopharmacologic trialspsychopharmacologic trials
 Emslie: Side Effects Checklist, 30-itemEmslie: Side Effects Checklist, 30-item
– Based on the Subjective Treatment EmergentBased on the Subjective Treatment Emergent
Symptoms Scale from NIMHSymptoms Scale from NIMH
– Needs to include questions specific to psychiatry and toNeeds to include questions specific to psychiatry and to
youth population (suicidality, activation, catarsis, EPS,youth population (suicidality, activation, catarsis, EPS,
etc.)etc.)
 March: ASAP, Emergency/Adjunct Services andMarch: ASAP, Emergency/Adjunct Services and
Attrition Prevention for Randomized ClinicalAttrition Prevention for Randomized Clinical
Trials in ChildrenTrials in Children
– Manual-based…too intensiveManual-based…too intensive

21. Recommendations for Improvement ofRecommendations for Improvement of
Safety in High Risk Clinical TrialsSafety in High Risk Clinical Trials
 Establishment of Data and SafetyEstablishment of Data and Safety
Monitoring Plan (DSMP) for all trialsMonitoring Plan (DSMP) for all trials
 A DSMP is a prospective strategy to assessA DSMP is a prospective strategy to assess
the progress of a research study on athe progress of a research study on a
periodic basis to ensure the safety ofperiodic basis to ensure the safety of
participants and the validity and integrity ofparticipants and the validity and integrity of
the datathe data
 A DSMP for a high risk trial should almostA DSMP for a high risk trial should almost
always include a DSMBalways include a DSMB

22. Recommendations for Improvement ofRecommendations for Improvement of
Safety in High Risk Clinical TrialsSafety in High Risk Clinical Trials
 DSMP and DSMB especially important forDSMP and DSMB especially important for
investigator-initiated, single-site trialsinvestigator-initiated, single-site trials
 Multi-site trials usually have a DSMP, andMulti-site trials usually have a DSMP, and
usually have oversight from a DSMB, asusually have oversight from a DSMB, as
required by the sponsorrequired by the sponsor
– However, not all sponsors require a DSMBHowever, not all sponsors require a DSMB
(venlafaxine multi-site trial in pediatric(venlafaxine multi-site trial in pediatric
depression)depression)

23. Recommendations for Improvement ofRecommendations for Improvement of
Safety in High Risk Clinical TrialsSafety in High Risk Clinical Trials
 In Summary, all human subjects research shouldIn Summary, all human subjects research should
have a Data and Safety Monitoring Plan (DSMP)have a Data and Safety Monitoring Plan (DSMP)
– Especially for investigator-initiated, single-site trialsEspecially for investigator-initiated, single-site trials
 More risk entailing more oversight and increasingMore risk entailing more oversight and increasing
independence from study investigators, sponsorsindependence from study investigators, sponsors
– PI and REB monitoring for low risk trialsPI and REB monitoring for low risk trials
– DSMB monitoring for high risk trialsDSMB monitoring for high risk trials
– Interim analysis of data by those delegated by REB forInterim analysis of data by those delegated by REB for
moderate risk trials; may not need independent DSMBmoderate risk trials; may not need independent DSMB
 All high risk youth trials should have a DSMBAll high risk youth trials should have a DSMB

24. Why a DSMB? Isn’t REB oversightWhy a DSMB? Isn’t REB oversight
enough?enough?
 Unpractical for REB to analyze all dataUnpractical for REB to analyze all data
from all trials in a rigorous fashionfrom all trials in a rigorous fashion
– Manpower issuesManpower issues
– Not able to provide real-time oversightNot able to provide real-time oversight
 REBs at most institutions are not reallyREBs at most institutions are not really
independent…answer to VP Researchindependent…answer to VP Research
 REBs may not have the specific expertise toREBs may not have the specific expertise to
critically analyze safety issues involved in acritically analyze safety issues involved in a
given trialgiven trial

25. Advantage of DSMB rather than justAdvantage of DSMB rather than just
REB oversightREB oversight
 DSMBs are independent of investigators,DSMBs are independent of investigators,
sponsors, and institutionssponsors, and institutions
– No conflicts of interest to make difficult decisions, suchNo conflicts of interest to make difficult decisions, such
as terminating a trialas terminating a trial
 DSMBs provide oversight of trial in real timeDSMBs provide oversight of trial in real time
– DSMB chair convenes immediate meeting whenDSMB chair convenes immediate meeting when
serious adverse events occurserious adverse events occur
 DSMB members are appointed by the REB and PIDSMB members are appointed by the REB and PI
according to specific expertise in the particularaccording to specific expertise in the particular
trialtrial

26. Disadvantages of DSMBsDisadvantages of DSMBs
 Who pays the DSMB members’ time andWho pays the DSMB members’ time and
infrastructure support?infrastructure support?
– Unfair to expect investigators to pay all these costs, asUnfair to expect investigators to pay all these costs, as
it can be a substantial portion a grantit can be a substantial portion a grant
 DSMB decisions can be contentiousDSMB decisions can be contentious
– Stopping a trial early due to safety concerns risksStopping a trial early due to safety concerns risks
losing valuable information that can potentially benefitlosing valuable information that can potentially benefit
othersothers
– Presupposes an optimal method to collect AE dataPresupposes an optimal method to collect AE data
– What are the thresholds for ending a study if validWhat are the thresholds for ending a study if valid
indicators are not present?indicators are not present?

27. Disadvantages of DSMBs: InterimDisadvantages of DSMBs: Interim
Analysis and Type I ErrorsAnalysis and Type I Errors
 If the null hypothesis, HIf the null hypothesis, H00, of no difference between, of no difference between
groups is in fact true, and repeated tests of thatgroups is in fact true, and repeated tests of that
hypothesis are made at the same level ofhypothesis are made at the same level of
significance using accumulating data, at some timesignificance using accumulating data, at some time
the repeated test will be significant by chancethe repeated test will be significant by chance
alone and be larger than the significance selectedalone and be larger than the significance selected
(commonly P<0.05)(commonly P<0.05)
 If repeated testing occurs indefinitely, the nullIf repeated testing occurs indefinitely, the null
hypothesis will eventually be rejected (incorrectly)hypothesis will eventually be rejected (incorrectly)
 Type I error, rejecting the null hypothesisType I error, rejecting the null hypothesis
incorrectly, may result from multiple testingincorrectly, may result from multiple testing

28. Disadvantages of DSMBs: InterimDisadvantages of DSMBs: Interim
Analysis and Type I ErrorsAnalysis and Type I Errors
 Solution to multiple testing problem:Solution to multiple testing problem:
– Limit the number of interim testingLimit the number of interim testing
– Stop trials only when there is overwhelmingStop trials only when there is overwhelming
evidence that one intervention is more effectiveevidence that one intervention is more effective
(or more harmful) than the other(or more harmful) than the other
» Set P<0.001 instead of P<0.05Set P<0.001 instead of P<0.05
– Stopping rules can be less stringent with respectStopping rules can be less stringent with respect
to evidence of harm than with respect toto evidence of harm than with respect to
evidence of efficacyevidence of efficacy

29. Case Study: Evaluating Safety inCase Study: Evaluating Safety in
a Clinical Triala Clinical Trial
 Lamotrigine crossover trial, randomized,Lamotrigine crossover trial, randomized,
double-blinded, placebo controldouble-blinded, placebo control
 Investigator-initiated, single-site trial,Investigator-initiated, single-site trial,
funded by GlaxoSmithKlinefunded by GlaxoSmithKline
 Inclusion criteria: ages 13-18, has moderateInclusion criteria: ages 13-18, has moderate
to severe MDD (via KSADS)to severe MDD (via KSADS)
 Power analysis: N=30Power analysis: N=30
– 81% power and 0.05 significance level81% power and 0.05 significance level

30. Group CBT/IPT with fluoxetine
8 weeks (Stage 1)
No Response: Augment fluoxetine with
either lamotrigine or placebo (Stage 2)
Fluoxetine with
lamotrigine: 8 weeks
Fluoxetine with placebo:
8 weeks
Response: continue fluoxetine and
psychotherapy
Taper lamotrigine, then
discontinue: 3 weeks
Taper placebo, then
discontinue: 3 weeks
Fluoxetine with placebo:
8 weeks
Fluoxetine with
lamotrigine: 8 weeks
No response: consider
alternative treatment
Response: continue
treatment for 6 months
(Stage 3)
Response: continue
treatment for 6 months
(Stage 3)
No response: consider
alternative treatment
Flowchart: LTG Study

31. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
 Deemed moderate to high risk trial due to:Deemed moderate to high risk trial due to:
– Vulnerable population: adolescentsVulnerable population: adolescents
– Risk of serious rash with lamotrigineRisk of serious rash with lamotrigine
– Risk of suicide in youth with severe,Risk of suicide in youth with severe,
treatment-refractory depressiontreatment-refractory depression
 The IRB mandated the formation of anThe IRB mandated the formation of an
independent DSMB, given the above risksindependent DSMB, given the above risks
factorsfactors

32. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
 Adverse Event Grading SystemAdverse Event Grading System::
 The following adverse event grading system will be used:The following adverse event grading system will be used:
 MildMild: Experience of sign, symptom, or event, but easily: Experience of sign, symptom, or event, but easily
tolerated. The experience does not require treatment, andtolerated. The experience does not require treatment, and
does not interfere with daily activities.does not interfere with daily activities.
 ModerateModerate: Discomfort enough to cause interference with: Discomfort enough to cause interference with
usual activity and may require treatment.usual activity and may require treatment.
 SevereSevere: Incapacitating with inability to do usual activities: Incapacitating with inability to do usual activities
or significantly affects clinical status, and requiresor significantly affects clinical status, and requires
treatment. If hospitalization is required, it becomes atreatment. If hospitalization is required, it becomes a
serious adverse event.serious adverse event.
 Life-threateningLife-threatening: Immediate risk of death.: Immediate risk of death.

33. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
 Serious Adverse Events (SAE’s)Serious Adverse Events (SAE’s)::
 All serious adverse events, whether or not deemedAll serious adverse events, whether or not deemed
procedure-related or expected, must be reported by theprocedure-related or expected, must be reported by the
investigator to the IRB and DSMB within 24 hours (oneinvestigator to the IRB and DSMB within 24 hours (one
working day) by telephone.working day) by telephone.
 A serious adverse event is any event that:A serious adverse event is any event that:
– Is fatal or life threateningIs fatal or life threatening
– Is significantly or permanently disablingIs significantly or permanently disabling
– Requires hospitalization, or prolongs hospitalizationRequires hospitalization, or prolongs hospitalization
– Is a congenital anomaly or birth defectIs a congenital anomaly or birth defect
 In this trial, SAE may be Stevens Johnson Syndrome orIn this trial, SAE may be Stevens Johnson Syndrome or
suicidalitysuicidality

34. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
 Interim Efficacy AnalysisInterim Efficacy Analysis::
 An interim analysis for efficacy will be conducted after 15An interim analysis for efficacy will be conducted after 15
study subjects have completed the protocol (half of thestudy subjects have completed the protocol (half of the
projected sample size, n=30). At the time of interimprojected sample size, n=30). At the time of interim
efficacy analysis, a comprehensive statistical report will beefficacy analysis, a comprehensive statistical report will be
generated for all members of the DSMB to review. Agenerated for all members of the DSMB to review. A
compilation of the outcome data will be prepared by thecompilation of the outcome data will be prepared by the
study methodologist/CI, William Cook Ph.D. The DSMBstudy methodologist/CI, William Cook Ph.D. The DSMB
will analyze the data unblinded, and will compare efficacywill analyze the data unblinded, and will compare efficacy
of lamotrigine versus placebo. The purpose of this reviewof lamotrigine versus placebo. The purpose of this review
is to determine whether or not the study should beis to determine whether or not the study should be
terminated for reasons of efficacyterminated for reasons of efficacy

35. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
 Stopping Rules Based on EfficacyStopping Rules Based on Efficacy::
 The DSMB may recommend termination of theThe DSMB may recommend termination of the
study if there is a sufficiently robust effectstudy if there is a sufficiently robust effect
favoring lamotrigine over placebo, such thatfavoring lamotrigine over placebo, such that
subsequent subjects will experience thesubsequent subjects will experience the
categorical risk of being denied optimal andcategorical risk of being denied optimal and
efficacious (as demonstrated in the DSMBefficacious (as demonstrated in the DSMB
analysis) treatment. A significant effect at n of 15analysis) treatment. A significant effect at n of 15
would indicate an effect size so large that it wouldwould indicate an effect size so large that it would
subject the placebo group to excess risk.subject the placebo group to excess risk.

36. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
 Interim Safety AnalysisInterim Safety Analysis::
 Interim safety analysis will be conducted on a quarterlyInterim safety analysis will be conducted on a quarterly
basis. At the time of interim analysis, a comprehensivebasis. At the time of interim analysis, a comprehensive
safety report will be generated for all members of thesafety report will be generated for all members of the
DSMB to review. The safety report will be prepared byDSMB to review. The safety report will be prepared by
the study methodologist/CI, William Cook Ph.D., and willthe study methodologist/CI, William Cook Ph.D., and will
include a blinded summary of adverse event rates. Theinclude a blinded summary of adverse event rates. The
DSMB will have the option to assess safety data unblindedDSMB will have the option to assess safety data unblinded
to compare treatment group and placebo group. Theto compare treatment group and placebo group. The
purpose of this review is to determine whether or not thepurpose of this review is to determine whether or not the
study should be terminated for reasons of subject safety.study should be terminated for reasons of subject safety.
The quarterly interim analysis will only address safetyThe quarterly interim analysis will only address safety
concerns and not efficacy.concerns and not efficacy.

37. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
 Stopping Rules Based on SafetyStopping Rules Based on Safety::
 The DSMB may recommend early termination ofThe DSMB may recommend early termination of
the study for reasons of patient safety based on thethe study for reasons of patient safety based on the
interim review of this data.interim review of this data.
 As an example of a stopping rule based on safety,As an example of a stopping rule based on safety,
a pattern of suicide attempts while on lamotriginea pattern of suicide attempts while on lamotrigine
or a pattern of serious rash occurrence withor a pattern of serious rash occurrence with
lamotrigine compared to placebo may prompt thelamotrigine compared to placebo may prompt the
DSMB to terminate the study.DSMB to terminate the study.
 DSMB recommendations for early terminationDSMB recommendations for early termination
will be communicated directly to the PI, Carlowill be communicated directly to the PI, Carlo
Carandang M.D.Carandang M.D.

38. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
 When considering termination, the DSMB shouldWhen considering termination, the DSMB should
consider the following selected reasons to proceed withconsider the following selected reasons to proceed with
this clinical trialthis clinical trial::
 A different conclusion might result.A different conclusion might result.
 Greater acceptance of the data will occur.Greater acceptance of the data will occur.
 This clinical trial is unique and complex, and it may neverThis clinical trial is unique and complex, and it may never
be possible to repeat it.be possible to repeat it.
 Almost no data exists for treatment-refractory depressionAlmost no data exists for treatment-refractory depression
in youth.in youth.
 Effective treatments for depression in youth areEffective treatments for depression in youth are
desperately needed, as a common outcome for youth withdesperately needed, as a common outcome for youth with
untreated depression is suicide.untreated depression is suicide.

39. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
 DSMB Communication with the PIDSMB Communication with the PI::
 The DSMB will communicate with the PI andThe DSMB will communicate with the PI and
report the following:report the following:
– The nature of the review (including pertinent safetyThe nature of the review (including pertinent safety
data).data).
– A brief description of any serious adverse events orA brief description of any serious adverse events or
concerns regarding systematic adverse events.concerns regarding systematic adverse events.
– Decisions of the DSMB regarding the study.Decisions of the DSMB regarding the study.
 The PI will forward the DSMB communications toThe PI will forward the DSMB communications to
the IRB.the IRB.

40. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
 DSMB MembersDSMB Members::
 Chair: Francis L. Lucas, Ph.D.,Chair: Francis L. Lucas, Ph.D.,
biostatisticianbiostatistician
 Members :Members :
– Paul Dyment, M.D., pediatricianPaul Dyment, M.D., pediatrician
– Jessica Oesterheld, M.D., child psychiatristJessica Oesterheld, M.D., child psychiatrist
– Alyce Schultz, Ph.D., research nurseAlyce Schultz, Ph.D., research nurse

41. Further Needs: Safety of Youths inFurther Needs: Safety of Youths in
High Risk Therapeutic TrialsHigh Risk Therapeutic Trials
 Need standard guidelines to delineate riskNeed standard guidelines to delineate risk
levels in pediatric trialslevels in pediatric trials
 Need optimal and validated method ofNeed optimal and validated method of
collecting adverse event data in childcollecting adverse event data in child
psychiatry trialspsychiatry trials
 Standardizing (or at least requiring) DataStandardizing (or at least requiring) Data
and Safety Monitoring Plans acrossand Safety Monitoring Plans across
institutions, with special monitoring of childinstitutions, with special monitoring of child
and adolescent populations in research trialsand adolescent populations in research trials

42. Safety and Research Ethics inSafety and Research Ethics in
YouthsYouths
 Research Ethics based on 3 principles asResearch Ethics based on 3 principles as
articulated in the Belmont Report (1978)articulated in the Belmont Report (1978)
– Respect for PersonsRespect for Persons
– BeneficienceBeneficience
– JusticeJustice

43. Safety and Research Ethics inSafety and Research Ethics in
Youths: Respect for PersonsYouths: Respect for Persons
 Respect for PersonsRespect for Persons. Researchers have an. Researchers have an
obligation to treat individuals asobligation to treat individuals as
autonomous beings and to provide specialautonomous beings and to provide special
protection to those persons with diminishedprotection to those persons with diminished
autonomy.autonomy.
– Enrolling vulnerable children in high riskEnrolling vulnerable children in high risk
research studies without rigorous safetyresearch studies without rigorous safety
oversight is not in line with this principle.oversight is not in line with this principle.

44. Safety and Research Ethics inSafety and Research Ethics in
Youths: BeneficenceYouths: Beneficence
 Beneficence.Beneficence. Researchers have a responsibility toResearchers have a responsibility to
maximize the benefits and minimize the potentialmaximize the benefits and minimize the potential
for harm or risk that the research poses to subjects.for harm or risk that the research poses to subjects.
– Allowing subjects to continue in a trial whereAllowing subjects to continue in a trial where
suicidality is twice that on drug versus placebo is not insuicidality is twice that on drug versus placebo is not in
line with this principle.line with this principle.
– Use of placebo in vulnerable youths where a standardUse of placebo in vulnerable youths where a standard
treatment exists is not in line with this principletreatment exists is not in line with this principle..
» Clinical EquipoiseClinical Equipoise

45. Safety and Research Ethics inSafety and Research Ethics in
Youths: JusticeYouths: Justice
 Justice.Justice. This principle relates primarily to howThis principle relates primarily to how
subjects are selected for research, and to thesubjects are selected for research, and to the
responsibility of researchers to spread both theresponsibility of researchers to spread both the
benefits and burdens of the research equitably.benefits and burdens of the research equitably.
– Not performing research studies in youths due toNot performing research studies in youths due to
paternalistic concerns that children need protection ispaternalistic concerns that children need protection is
not in line with this principle, as the benefits ofnot in line with this principle, as the benefits of
research should not be reserved for adults only.research should not be reserved for adults only.
Adult data does not generalize to youths.Adult data does not generalize to youths.

46. Safety and Research Ethics inSafety and Research Ethics in
YouthsYouths
 Take home point: Unethical to avoidTake home point: Unethical to avoid
research in youths due to paternalisticresearch in youths due to paternalistic
concerns to protect children, but alsoconcerns to protect children, but also
unethical to avoid rigorous safety oversightunethical to avoid rigorous safety oversight
in youths who enroll in high risk trialsin youths who enroll in high risk trials
 Win-win: PI, sponsor, and REB can rely onWin-win: PI, sponsor, and REB can rely on
the DSMB to rigorously assess safety, andthe DSMB to rigorously assess safety, and
research subjects will feel saferresearch subjects will feel safer

47. Suggested ReadingSuggested Reading
 Friedman L, Furberg C, DeMets D (1998),Friedman L, Furberg C, DeMets D (1998),
Fundamentals of Clinical Trials.Fundamentals of Clinical Trials. New York:New York:
Springer, Chapter 15 (Monitoring ResponseSpringer, Chapter 15 (Monitoring Response
Variables)Variables)
 Slutsky A, Lavery J (2004), Data safety andSlutsky A, Lavery J (2004), Data safety and
monitoring boards.monitoring boards. NEJMNEJM 350:1143-1146.350:1143-1146.
 Ellenberg SS, Fleming TR, DeMets DL(2002),Ellenberg SS, Fleming TR, DeMets DL(2002),
Data monitoring committees in clinical trials: aData monitoring committees in clinical trials: a
practical perspectivepractical perspective. Chichester, UK: Wiley. Chichester, UK: Wiley..

48. AcknowledgementsAcknowledgements
 Darcy Santor PhD, University of OttawaDarcy Santor PhD, University of Ottawa
 David Gardner PharmD, DalDavid Gardner PharmD, Dal
 Normand Carrey MD, DalNormand Carrey MD, Dal
 Stan Kutcher MD, DalStan Kutcher MD, Dal
 Mina Dulcan MD, Past Editor JAACAPMina Dulcan MD, Past Editor JAACAP