Ethical Issues and Ethical Issues and Interim MonitoringInterim Monitoring in Clinical Trials in Clinical Trials

Ethical Issues and Ethical Issues and Interim MonitoringInterim Monitoring in Clinical Trials in Clinical Trials

Deborah Grady, MD, MPHProfessor of MedicineDirector, Clinical and

Translational Science Institute Training Programs

Ethical Concerns in Ethical Concerns in All ResearchAll Research

• RQ should be important, answerable RQ should be important, answerable and not already answeredand not already answered

• Benefit should outweigh riskBenefit should outweigh risk

• Participants should give consentParticipants should give consent

• Privacy should be protectedPrivacy should be protected

• Research report should be fair and Research report should be fair and honesthonest

WhatWhat’’s Special about Trials?s Special about Trials?• Randomization - Randomization - equipoiseequipoise

• Intervention - Intervention - relativelyrelatively safesafe

• Placebo – Placebo – acceptable optionacceptable option

• Roles – Roles – research vs. clinical careresearch vs. clinical care

• JusticeJustice – participation available to all – participation available to all

• Conflict of interest – Conflict of interest – interests other interests other than correct answer to the RQthan correct answer to the RQ

RandomizationRandomization

• Requires equipoiseRequires equipoise–Question important and not answeredQuestion important and not answered–Evidence of benefit, but not conclusiveEvidence of benefit, but not conclusive

• Requires willingness to be randomizedRequires willingness to be randomized–ParticipantsParticipants–CliniciansClinicians– IRB membersIRB members

InterventionIntervention

• Maximize benefitMaximize benefit–Dose high enough to be effectiveDose high enough to be effective

• Minimize harm Minimize harm –Dose low enough to be safe Dose low enough to be safe

• Qualified staff and protections for Qualified staff and protections for known potential harmsknown potential harms–Manage known adverse effectsManage known adverse effects–Pay costs of known adverse effectsPay costs of known adverse effects

Placebo ControlPlacebo Control

• Acceptable clinical optionAcceptable clinical option

• If there is a standard of care for the If there is a standard of care for the condition, may requirecondition, may require–Background treatment for allBackground treatment for all–Active control (equivalence trial)Active control (equivalence trial)

Minimize Role ConfusionMinimize Role Confusion

• Physician - InvestigatorPhysician - Investigator

• Patient - ParticipantPatient - Participant

• Treatment - ResearchTreatment - Research

JusticeJustice

• Trial risks and benefits should Trial risks and benefits should be available to all regardless ofbe available to all regardless of– EducationEducation– Race, ethnicity, genderRace, ethnicity, gender– Socioeconomic statusSocioeconomic status– AgeAge

Conflict of InterestConflict of Interest

• Professional judgment influenced by Professional judgment influenced by other interests:other interests:– Reputation or promotionReputation or promotion– Financial interestsFinancial interests• employment, stock, gifts, consulting fees, employment, stock, gifts, consulting fees,

travel and entertainment, research supporttravel and entertainment, research support

• Management of conflict of interestManagement of conflict of interest– DiscloseDisclose– ManageManage– DivestDivest

Fecal Occult Blood TestingFecal Occult Blood TestingKronborg, et al., 1996Kronborg, et al., 1996

• Randomized, controlled trialRandomized, controlled trial

• 60,000 persons in Denmark60,000 persons in Denmark– identified via central recordsidentified via central records

• FOBT biannually or usual careFOBT biannually or usual care– request for FOBT mailed by PMDrequest for FOBT mailed by PMD

• Outcome = colon cancerOutcome = colon cancer– based on national registrybased on national registry

Active Compression-Decompression for Active Compression-Decompression for CPR, Schwab et al., 1994CPR, Schwab et al., 1994

• Randomized, controlled trialRandomized, controlled trial

• 860 persons with cardiac arrest860 persons with cardiac arrest

• ACD CPR or standard CPRACD CPR or standard CPR

• Outcome = discharged aliveOutcome = discharged alive

• No informed consentNo informed consent

• Trial halted by FDATrial halted by FDA

Alternatives to Informed ConsentAlternatives to Informed Consent

• Waiver of consentWaiver of consent– life threatening situationlife threatening situation– consent not possibleconsent not possible

• Permission from parent or guardianPermission from parent or guardian

• Deferred informed consentDeferred informed consent– enter study without consententer study without consent– later consent or participation terminatedlater consent or participation terminated

• Prospective consentProspective consent

Effect of beta-blockers on mortality after MI

Cumulative Meta-analysis

Zalospirone for DepressionZalospirone for DepressionRickels, et al, 1996Rickels, et al, 1996

• Randomized trialRandomized trial

• 287 people with major depression287 people with major depression

• Placebo or 3 doses of drugPlacebo or 3 doses of drug

• Outcome - change in severity of Outcome - change in severity of depressiondepression

• High dose effective; two lower High dose effective; two lower doses notdoses not

Prevention of AIDS in Prevention of AIDS in Newborns in AfricaNewborns in Africa

• Standard care for HIV+ pregnant Standard care for HIV+ pregnant women in USwomen in US– zidovudine orally before deliveryzidovudine orally before delivery– IV during labor, then orally for newbornsIV during labor, then orally for newborns– RR .33 for infection in newbornRR .33 for infection in newborn

• Pregnant HIV+ African womenPregnant HIV+ African women– randomized to oral AZT or placeborandomized to oral AZT or placebo– funded by US agenciesfunded by US agencies

Ethics in Randomized TrialsEthics in Randomized Trials

• Informed consent isnInformed consent isn’’t enought enough

• Important ethical issues in all stages Important ethical issues in all stages of the design, conduct and of the design, conduct and presentation of findings of trialspresentation of findings of trials

• Easy to get sucked into thinking that Easy to get sucked into thinking that your research is more important your research is more important than participant safetythan participant safety

Monitoring Randomized TrialsMonitoring Randomized TrialsMonitoring Randomized TrialsMonitoring Randomized Trials

• MOST basic ethical principles:MOST basic ethical principles:– minimize risk to participantsminimize risk to participants– maximize scientific evidencemaximize scientific evidence

• Interim monitoring = looking at the Interim monitoring = looking at the data before the trial is finisheddata before the trial is finished

• Basic goals of interim monitoring:Basic goals of interim monitoring:– protect participantsprotect participants– maximize scientific evidencemaximize scientific evidence

• MOST basic ethical principles:MOST basic ethical principles:– minimize risk to participantsminimize risk to participants– maximize scientific evidencemaximize scientific evidence

• Interim monitoring = looking at the Interim monitoring = looking at the data before the trial is finisheddata before the trial is finished

• Basic goals of interim monitoring:Basic goals of interim monitoring:– protect participantsprotect participants– maximize scientific evidencemaximize scientific evidence

Monitoring Clinical TrialsMonitoring Clinical TrialsMonitoring Clinical TrialsMonitoring Clinical Trials

• Which Which trials require monitoring?trials require monitoring?

• WhyWhy alter/stop a clinical trial early? alter/stop a clinical trial early?

• WhoWho should decide? should decide?

• WhatWhat should be monitored? should be monitored?

• How oftenHow often should you monitor? should you monitor?

• What What statistical methodsstatistical methods to use? to use?

• HowHow can a trial be altered? can a trial be altered?

• Fascinating examples...Fascinating examples...

• Which Which trials require monitoring?trials require monitoring?

• WhyWhy alter/stop a clinical trial early? alter/stop a clinical trial early?

• WhoWho should decide? should decide?

• WhatWhat should be monitored? should be monitored?

• How oftenHow often should you monitor? should you monitor?

• What What statistical methodsstatistical methods to use? to use?

• HowHow can a trial be altered? can a trial be altered?

• Fascinating examples...Fascinating examples...

Which Trials to MonitorWhich Trials to MonitorWhich Trials to MonitorWhich Trials to Monitor

• Trials in which there is a possibilityTrials in which there is a possibility– of unexpected harm from the interventionof unexpected harm from the intervention– of unexpected benefit from the interventionof unexpected benefit from the intervention– that the question will not be answered…that the question will not be answered…

• Increasingly viewed by the NIH as an Increasingly viewed by the NIH as an independent advisory boardindependent advisory board

• Generally, all trials should be monitored, Generally, all trials should be monitored, but not feasible in small, short trialsbut not feasible in small, short trials

• Trials in which there is a possibilityTrials in which there is a possibility– of unexpected harm from the interventionof unexpected harm from the intervention– of unexpected benefit from the interventionof unexpected benefit from the intervention– that the question will not be answered…that the question will not be answered…

• Increasingly viewed by the NIH as an Increasingly viewed by the NIH as an independent advisory boardindependent advisory board

• Generally, all trials should be monitored, Generally, all trials should be monitored, but not feasible in small, short trialsbut not feasible in small, short trials

Why Stop a Trial Early?Why Stop a Trial Early?Why Stop a Trial Early?Why Stop a Trial Early?

• Harm clearly demonstratedHarm clearly demonstrated

• Benefit clearly demonstratedBenefit clearly demonstrated

• Not possible to demonstrate benefitNot possible to demonstrate benefit– trial design flawedtrial design flawed– low enrollment, high noncompliance, low enrollment, high noncompliance,

poor data, high drop-outpoor data, high drop-out– no difference between groupsno difference between groups

• Research question answered by Research question answered by another studyanother study

• Harm clearly demonstratedHarm clearly demonstrated

• Benefit clearly demonstratedBenefit clearly demonstrated

• Not possible to demonstrate benefitNot possible to demonstrate benefit– trial design flawedtrial design flawed– low enrollment, high noncompliance, low enrollment, high noncompliance,

poor data, high drop-outpoor data, high drop-out– no difference between groupsno difference between groups

• Research question answered by Research question answered by another studyanother study

Who Should Decide?Who Should Decide?Who Should Decide?Who Should Decide?

• SponsorSponsor

• InvestigatorsInvestigators

• IndependentIndependent monitoring board, monitoring board, without without conflict of interestconflict of interest– expertsexperts -- ? investigators? investigators– ethicistsethicists -- ? representative of ? representative of

SponsorSponsor– statisticiansstatisticians -- ? representative of NIH? representative of NIH

- ? lay persons- ? lay persons

• SponsorSponsor

• InvestigatorsInvestigators

• IndependentIndependent monitoring board, monitoring board, without without conflict of interestconflict of interest– expertsexperts -- ? investigators? investigators– ethicistsethicists -- ? representative of ? representative of

SponsorSponsor– statisticiansstatisticians -- ? representative of NIH? representative of NIH

- ? lay persons- ? lay persons

What Should You Monitor?What Should You Monitor?What Should You Monitor?What Should You Monitor?

• Issues early in the trialIssues early in the trial– trial designtrial design– recruitmentrecruitment– adherenceadherence– loss to follow-uploss to follow-up– data quality and timelinessdata quality and timeliness– information from other studiesinformation from other studies

• Issues early in the trialIssues early in the trial– trial designtrial design– recruitmentrecruitment– adherenceadherence– loss to follow-uploss to follow-up– data quality and timelinessdata quality and timeliness– information from other studiesinformation from other studies

What Should You Monitor?What Should You Monitor?What Should You Monitor?What Should You Monitor?

• Issues later in the trialIssues later in the trial– primary and secondary outcomesprimary and secondary outcomes• clear benefitclear benefit• clear harmclear harm• no conditional powerno conditional power

– adverse eventsadverse events– side effectsside effects– subgroupssubgroups

• Issues later in the trialIssues later in the trial– primary and secondary outcomesprimary and secondary outcomes• clear benefitclear benefit• clear harmclear harm• no conditional powerno conditional power

– adverse eventsadverse events– side effectsside effects– subgroupssubgroups

• Initial meeting several months before start-upInitial meeting several months before start-up– review DSM protocol, classification of outcomes review DSM protocol, classification of outcomes

and adverse events, adjudication, etcand adverse events, adjudication, etc– review and accept DSM guidelines, statistical review and accept DSM guidelines, statistical

methods, meeting schedule, data table formatsmethods, meeting schedule, data table formats

• Subsequent meetingsSubsequent meetings– often enough to achieve goalsoften enough to achieve goals– not so often that there is no new datanot so often that there is no new data– depends on the duration of the trial and perceived depends on the duration of the trial and perceived

risk of the interventionrisk of the intervention

• Initial meeting several months before start-upInitial meeting several months before start-up– review DSM protocol, classification of outcomes review DSM protocol, classification of outcomes

and adverse events, adjudication, etcand adverse events, adjudication, etc– review and accept DSM guidelines, statistical review and accept DSM guidelines, statistical

methods, meeting schedule, data table formatsmethods, meeting schedule, data table formats

• Subsequent meetingsSubsequent meetings– often enough to achieve goalsoften enough to achieve goals– not so often that there is no new datanot so often that there is no new data– depends on the duration of the trial and perceived depends on the duration of the trial and perceived

risk of the interventionrisk of the intervention

How Often to Monitor?How Often to Monitor?How Often to Monitor?How Often to Monitor?

• DSM Board usually does not share interim DSM Board usually does not share interim results with sponsors, investigators, pptsresults with sponsors, investigators, ppts

• Open sessionOpen session– DSMB, sponsor, investigators, NIH, FDADSMB, sponsor, investigators, NIH, FDA– recruitment, retention, data qualityrecruitment, retention, data quality– overall findingsoverall findings

• Closed sessionClosed session– DSMB members, DSMB members, ++ statistician statistician– between group findingsbetween group findings– discussion regarding modificationsdiscussion regarding modifications

• DSM Board usually does not share interim DSM Board usually does not share interim results with sponsors, investigators, pptsresults with sponsors, investigators, ppts

• Open sessionOpen session– DSMB, sponsor, investigators, NIH, FDADSMB, sponsor, investigators, NIH, FDA– recruitment, retention, data qualityrecruitment, retention, data quality– overall findingsoverall findings

• Closed sessionClosed session– DSMB members, DSMB members, ++ statistician statistician– between group findingsbetween group findings– discussion regarding modificationsdiscussion regarding modifications

ConfidentialityConfidentialityConfidentialityConfidentiality

Statistical Methods for Interim MonitoringStatistical Methods for Interim MonitoringStatistical Methods for Interim MonitoringStatistical Methods for Interim Monitoring

• Simple, but wrongSimple, but wrong

total teststotal tests overall alphaoverall alpha

11 .05.05

22 .08.08

55 .14.14

1010 .20.20

2020 .35.35

• Simple, but wrongSimple, but wrong

total teststotal tests overall alphaoverall alpha

11 .05.05

22 .08.08

55 .14.14

1010 .20.20

2020 .35.35

• Perform tests of significance and Perform tests of significance and

stop the trial if any p<.05stop the trial if any p<.05

• Perform tests of significance and Perform tests of significance and

stop the trial if any p<.05stop the trial if any p<.05

Interim Analyses in the Interim Analyses in the Coronary Drug ProjectCoronary Drug Project

Interim Analyses in the Interim Analyses in the Coronary Drug ProjectCoronary Drug Project

Z ValueZ ValueZ ValueZ Value

+2+2

+1+1

00

-1-1

-2-2

+2+2

+1+1

00

-1-1

-2-2

10 20 30 40 50 60 70 80 90 10010 20 30 40 50 60 70 80 90 100

Month of Follow-upMonth of Follow-up

Statistical MethodsStatistical MethodsStatistical MethodsStatistical Methods

• Perform tests of significance and Perform tests of significance and adjust the test-wise alphaadjust the test-wise alpha– BonferroniBonferroni– Classical sequential methodsClassical sequential methods– Group sequential methodsGroup sequential methods• PocockPocock• Haybittle and PetoHaybittle and Peto• OO ’’Brien and FlemmingBrien and Flemming• Lan and DeMetsLan and DeMets

• Perform tests of significance and Perform tests of significance and adjust the test-wise alphaadjust the test-wise alpha– BonferroniBonferroni– Classical sequential methodsClassical sequential methods– Group sequential methodsGroup sequential methods• PocockPocock• Haybittle and PetoHaybittle and Peto• OO ’’Brien and FlemmingBrien and Flemming• Lan and DeMetsLan and DeMets

Group Sequential MethodsGroup Sequential MethodsGroup Sequential MethodsGroup Sequential Methods

• OO ’’BrienBrien -- small small ii for early tests for early tests

FlemmingFlemming gradually increasing gradually increasing ii

N=5 interim tests; N=5 interim tests; = .05 = .05

initial initial 11=.00001; =.00001; ff=.041=.041

• Lan-Lan- spending function spending function

DeMetsDeMets defined by N previous defined by N previous ““lookslooks””

proportion of data/time proportion of data/time betweenbetween

• OO ’’BrienBrien -- small small ii for early tests for early tests

FlemmingFlemming gradually increasing gradually increasing ii

N=5 interim tests; N=5 interim tests; = .05 = .05

initial initial 11=.00001; =.00001; ff=.041=.041

• Lan-Lan- spending function spending function

DeMetsDeMets defined by N previous defined by N previous ““lookslooks””

proportion of data/time proportion of data/time betweenbetween

OO ’’Brien-Fleming Alpha Brien-Fleming Alpha Spending FunctionSpending Function

OO ’’Brien-Fleming Alpha Brien-Fleming Alpha Spending FunctionSpending Function

LookLook Z-valueZ-value P-valueP-value

11 4.564.56 .00001.00001

22 3.233.23 .0001.0001

33 2.632.63 .009.009

44 2.282.28 .023.023

55 2.042.04 .041.041

LookLook Z-valueZ-value P-valueP-value

11 4.564.56 .00001.00001

22 3.233.23 .0001.0001

33 2.632.63 .009.009

44 2.282.28 .023.023

55 2.042.04 .041.041

Symmetric Stopping BoundariesSymmetric Stopping Boundaries

4.563.23

2.632.28

2.04

-4.56-3.23

-2.63-2.28

-2.04

-6

-4

-2

0

2

4

6

1st Look 2nd Look 3rd Look 4th Look 5th Look

Stop for HarmStop for Benefit

ZZ

Conditional PowerConditional PowerConditional PowerConditional Power

Compute p(reject HCompute p(reject Hoo given data so far) given data so far)Deterministic Curtailed SamplingDeterministic Curtailed Sampling• assume all future outcomes in treatedassume all future outcomes in treated• assume all future outcomes in placeboassume all future outcomes in placebo

Stochastic Curtailed SamplingStochastic Curtailed Sampling

• assume Hassume Hoo true true

• assume Hassume Ha a truetrue

Compute p(reject HCompute p(reject Hoo given data so far) given data so far)Deterministic Curtailed SamplingDeterministic Curtailed Sampling• assume all future outcomes in treatedassume all future outcomes in treated• assume all future outcomes in placeboassume all future outcomes in placebo

Stochastic Curtailed SamplingStochastic Curtailed Sampling

• assume Hassume Hoo true true

• assume Hassume Ha a truetrue

How Can a Trial Be Altered?How Can a Trial Be Altered?How Can a Trial Be Altered?How Can a Trial Be Altered?

• Early alterationsEarly alterations– change entry criteriachange entry criteria– Increase/decrease sample sizeIncrease/decrease sample size– change outcomechange outcome– adjust doseadjust dose

• Goals of these changesGoals of these changes– make the trial successful (definitive result)make the trial successful (definitive result)– change original protocol as little as possiblechange original protocol as little as possible

• Timely, high quality data crucialTimely, high quality data crucial

• Early alterationsEarly alterations– change entry criteriachange entry criteria– Increase/decrease sample sizeIncrease/decrease sample size– change outcomechange outcome– adjust doseadjust dose

• Goals of these changesGoals of these changes– make the trial successful (definitive result)make the trial successful (definitive result)– change original protocol as little as possiblechange original protocol as little as possible

• Timely, high quality data crucialTimely, high quality data crucial

How Can a Trial Be Altered?How Can a Trial Be Altered?How Can a Trial Be Altered?How Can a Trial Be Altered?

• Later alterationsLater alterations– increase duration of the trialincrease duration of the trial– modify the trial protocolmodify the trial protocol• stop one arm of the interventionstop one arm of the intervention• terminate high risk groupsterminate high risk groups• add safety measuresadd safety measures• othersothers

– terminate the trial earlyterminate the trial early

• Later alterationsLater alterations– increase duration of the trialincrease duration of the trial– modify the trial protocolmodify the trial protocol• stop one arm of the interventionstop one arm of the intervention• terminate high risk groupsterminate high risk groups• add safety measuresadd safety measures• othersothers

– terminate the trial earlyterminate the trial early

Interim MonitoringInterim MonitoringInterim MonitoringInterim Monitoring

• NOT NOT simply a statistical issuesimply a statistical issue

• Must weigh:Must weigh:– Outcome events still in the Outcome events still in the ““pipelinepipeline””– Possible baseline differences in groupsPossible baseline differences in groups– Possible bias in assessment of outcomePossible bias in assessment of outcome– Impact of missing dataImpact of missing data– Differential co-intervention or noncomplianceDifferential co-intervention or noncompliance– Internal consistency of findingsInternal consistency of findings– Impact of early termination on medical practice Impact of early termination on medical practice

and public healthand public health

• NOT NOT simply a statistical issuesimply a statistical issue

• Must weigh:Must weigh:– Outcome events still in the Outcome events still in the ““pipelinepipeline””– Possible baseline differences in groupsPossible baseline differences in groups– Possible bias in assessment of outcomePossible bias in assessment of outcome– Impact of missing dataImpact of missing data– Differential co-intervention or noncomplianceDifferential co-intervention or noncompliance– Internal consistency of findingsInternal consistency of findings– Impact of early termination on medical practice Impact of early termination on medical practice

and public healthand public health

Data and Safety Monitoring PlanData and Safety Monitoring PlanData and Safety Monitoring PlanData and Safety Monitoring Plan

• Guidelines and examplesGuidelines and examples– FDAFDA– NIHNIH– Colleagues or mentorsColleagues or mentors– DSM Protocol LibraryDSM Protocol Library• http://ctsi.ucsf.edu/research/dsmbhttp://ctsi.ucsf.edu/research/dsmb

• Guidelines and examplesGuidelines and examples– FDAFDA– NIHNIH– Colleagues or mentorsColleagues or mentors– DSM Protocol LibraryDSM Protocol Library• http://ctsi.ucsf.edu/research/dsmbhttp://ctsi.ucsf.edu/research/dsmb

Coronary Arrhythmia Suppression Coronary Arrhythmia Suppression Trial - Stopped for HARMTrial - Stopped for HARM

Coronary Arrhythmia Suppression Coronary Arrhythmia Suppression Trial - Stopped for HARMTrial - Stopped for HARM

• 1455 of planned 4400 subjects1455 of planned 4400 subjects after MIafter MI

with ventricular ectopywith ventricular ectopy

• Flecainide or encainide vs. pboFlecainide or encainide vs. pbo

• Mean follow-up Mean follow-up 1 year of1 year of planned 5 years planned 5 years

• Outcomes - mortality from arrhythmia, Outcomes - mortality from arrhythmia,

total mortalitytotal mortality

• 1455 of planned 4400 subjects1455 of planned 4400 subjects after MIafter MI

with ventricular ectopywith ventricular ectopy

• Flecainide or encainide vs. pboFlecainide or encainide vs. pbo

• Mean follow-up Mean follow-up 1 year of1 year of planned 5 years planned 5 years

• Outcomes - mortality from arrhythmia, Outcomes - mortality from arrhythmia,

total mortalitytotal mortality

Coronary Arrhythmia Coronary Arrhythmia Suppression Trial Stopped for HarmSuppression Trial Stopped for Harm

Coronary Arrhythmia Coronary Arrhythmia Suppression Trial Stopped for HarmSuppression Trial Stopped for Harm

1 Year Outcome1 Year Outcome F/EF/E PlaceboPlacebo pp

N randomizedN randomized 730730 725725

Arrhythmic deathArrhythmic death 3333 9 9 .0006.0006

Total deathTotal death 5656 22 22 .0003.0003

1 Year Outcome1 Year Outcome F/EF/E PlaceboPlacebo pp

N randomizedN randomized 730730 725725

Arrhythmic deathArrhythmic death 3333 9 9 .0006.0006

Total deathTotal death 5656 22 22 .0003.0003

Beta-blocker Heart Attack TrialBeta-blocker Heart Attack TrialStopped for BenefitStopped for Benefit

Beta-blocker Heart Attack TrialBeta-blocker Heart Attack TrialStopped for BenefitStopped for Benefit

• Subjects - 3,837 persons 5-21 days Subjects - 3,837 persons 5-21 days after MIafter MI

• Intervention - propranolol 180-Intervention - propranolol 180-240mg/day vs placebo240mg/day vs placebo

• Follow-up - 40 of planned 48 monthsFollow-up - 40 of planned 48 months

• Outcome - mortalityOutcome - mortality

• Subjects - 3,837 persons 5-21 days Subjects - 3,837 persons 5-21 days after MIafter MI

• Intervention - propranolol 180-Intervention - propranolol 180-240mg/day vs placebo240mg/day vs placebo

• Follow-up - 40 of planned 48 monthsFollow-up - 40 of planned 48 months

• Outcome - mortalityOutcome - mortality

AnalysesAnalyses MonthMonth DeathsDeaths ZZ Critical Critical ValueValue

11 1111 5656 1.681.68 5.885.88

22 1616 7777 2.242.24 5.045.04

33 2121 126126 2.372.37 3.793.79

44 2828 177177 2.302.30 3.193.19

55 3434 247247 2.342.34 2.642.64

66 4040 318318 2.822.82 2.302.30

77 4848

AnalysesAnalyses MonthMonth DeathsDeaths ZZ Critical Critical ValueValue

11 1111 5656 1.681.68 5.885.88

22 1616 7777 2.242.24 5.045.04

33 2121 126126 2.372.37 3.793.79

44 2828 177177 2.302.30 3.193.19

55 3434 247247 2.342.34 2.642.64

66 4040 318318 2.822.82 2.302.30

77 4848

Beta-blocker Heart Attack TrialBeta-blocker Heart Attack TrialBeta-blocker Heart Attack TrialBeta-blocker Heart Attack Trial

Coronary Drug ProjectCoronary Drug ProjectCoronary Drug ProjectCoronary Drug Project

• Subjects - 8,341 men post-MISubjects - 8,341 men post-MI• Interventions -Interventions - estrogen 2.5 and 5.0 mg QDestrogen 2.5 and 5.0 mg QD

dextrothyroxine 6 mg QDdextrothyroxine 6 mg QD

clofibrate 1.8 gm QDclofibrate 1.8 gm QD

niacin 3.0 gm QDniacin 3.0 gm QD

placeboplacebo

• Follow-up - planned 5 yearsFollow-up - planned 5 years

• Outcomes - death, MIOutcomes - death, MI

• Subjects - 8,341 men post-MISubjects - 8,341 men post-MI• Interventions -Interventions - estrogen 2.5 and 5.0 mg QDestrogen 2.5 and 5.0 mg QD

dextrothyroxine 6 mg QDdextrothyroxine 6 mg QD

clofibrate 1.8 gm QDclofibrate 1.8 gm QD

niacin 3.0 gm QDniacin 3.0 gm QD

placeboplacebo

• Follow-up - planned 5 yearsFollow-up - planned 5 years

• Outcomes - death, MIOutcomes - death, MI

High-dose CEEHigh-dose CEEStopped for HARM at 1.5 YearsStopped for HARM at 1.5 Years

High-dose CEEHigh-dose CEEStopped for HARM at 1.5 YearsStopped for HARM at 1.5 Years

CEE 5 mgCEE 5 mg PlaceboPlacebo RRRR

( n=1,119)( n=1,119) (n=2,789)(n=2,789)

CHD eventCHD event 11.0%11.0% 7.5%7.5% 1.51.5

PE or DVTPE or DVT 3.5% 3.5% 1.5%1.5% 2.3*2.3*

Total mortalityTotal mortality 9.7% 9.7% 8.2%8.2% 1.21.2

JAMA, 1970JAMA, 1970

CEE 5 mgCEE 5 mg PlaceboPlacebo RRRR

( n=1,119)( n=1,119) (n=2,789)(n=2,789)

CHD eventCHD event 11.0%11.0% 7.5%7.5% 1.51.5

PE or DVTPE or DVT 3.5% 3.5% 1.5%1.5% 2.3*2.3*

Total mortalityTotal mortality 9.7% 9.7% 8.2%8.2% 1.21.2

JAMA, 1970JAMA, 1970

Coronary Drug ProjectCoronary Drug ProjectCoronary Drug ProjectCoronary Drug Project

• Low-dose CEE (2.5 mg/d) stopped Low-dose CEE (2.5 mg/d) stopped after 2.5 years for similar findingsafter 2.5 years for similar findings

• D-thyroxin found to increase death D-thyroxin found to increase death rate at 3 years in men with rate at 3 years in men with abnormal baseline EKGabnormal baseline EKG

• D-thyroxin stopped in all men with D-thyroxin stopped in all men with abnormal baseline EKGabnormal baseline EKG

• Low-dose CEE (2.5 mg/d) stopped Low-dose CEE (2.5 mg/d) stopped after 2.5 years for similar findingsafter 2.5 years for similar findings

• D-thyroxin found to increase death D-thyroxin found to increase death rate at 3 years in men with rate at 3 years in men with abnormal baseline EKGabnormal baseline EKG

• D-thyroxin stopped in all men with D-thyroxin stopped in all men with abnormal baseline EKGabnormal baseline EKG

Heart and Estrogen/progestin Heart and Estrogen/progestin Replacement Study (HERS)Replacement Study (HERS)

• 2673 postmenopausal women with CHD2673 postmenopausal women with CHD

• Randomized to estrogen plus progestin or Randomized to estrogen plus progestin or placebo, planned follow-up 4 yearsplacebo, planned follow-up 4 years

• Main outcome - CHD eventsMain outcome - CHD events

• Secondary outcomes - breast cancer, Secondary outcomes - breast cancer, fractures, venous thrombosesfractures, venous thromboses

HERS DSMB ReportHERS DSMB ReportMonitoring for Venous ThrombosisMonitoring for Venous Thrombosis

-6

-4

-2

0

2

4

6

6 mo 1.5 yr 2.5yr 3.5 yr End

Stop for HarmStop for Benefit

ZZ

.. . . . . .

..

. .

HERS DSMB ReportHERS DSMB ReportMonitoring for CHD DeathMonitoring for CHD Death

-6

-4

-2

0

2

4

6

6 mo 1.5 yr 2.5yr 3.5 yr End

Stop for HarmStop for Benefit

ZZZZ

. .. . .

. .... .

Complex TrialsComplex TrialsWomenWomen’’s Health Initiative Trialss Health Initiative Trials

HarmHarm % Change in Risk% Change in Risk

• CHDCHD ++29%29%

• StrokeStroke ++41%41%

• Breast cancer Breast cancer ++26%26%

• Pulm. embolusPulm. embolus ++2.1X2.1X

BenefitBenefit

• Hip fracture Hip fracture --34%34%

• Colorectal cancer Colorectal cancer --37%37%

Global IndexGlobal Index

Different Rules for Stopping for Different Rules for Stopping for Benefit and Harm?Benefit and Harm?

Different Rules for Stopping for Different Rules for Stopping for Benefit and Harm?Benefit and Harm?

• ““LiberalLiberal”” rules to stop for harm to protect rules to stop for harm to protect participants in the trialparticipants in the trial

• More stringent rules for benefit to answer More stringent rules for benefit to answer important questionsimportant questions– Does benefit strengthen over time?Does benefit strengthen over time?– Does treatment reduce mortality?Does treatment reduce mortality?– Were side effects underestimatedWere side effects underestimated– What is the impact on secondary outcomesWhat is the impact on secondary outcomes– What is the effect in subgroupsWhat is the effect in subgroups

• ““LiberalLiberal”” rules to stop for harm to protect rules to stop for harm to protect participants in the trialparticipants in the trial

• More stringent rules for benefit to answer More stringent rules for benefit to answer important questionsimportant questions– Does benefit strengthen over time?Does benefit strengthen over time?– Does treatment reduce mortality?Does treatment reduce mortality?– Were side effects underestimatedWere side effects underestimated– What is the impact on secondary outcomesWhat is the impact on secondary outcomes– What is the effect in subgroupsWhat is the effect in subgroups

Summary - Interim MonitoringSummary - Interim MonitoringSummary - Interim MonitoringSummary - Interim Monitoring

• Interim monitoring very importantInterim monitoring very important

• Should be planned in advanceShould be planned in advance

• Should be performed wellShould be performed well

• Any change in trial protocol should Any change in trial protocol should be carefully considered, weighing be carefully considered, weighing many issuesmany issues

• Interim monitoring very importantInterim monitoring very important

• Should be planned in advanceShould be planned in advance

• Should be performed wellShould be performed well

• Any change in trial protocol should Any change in trial protocol should be carefully considered, weighing be carefully considered, weighing many issuesmany issues