TICR Professional Conduct TICR Professional Conduct Statement Statement Clarifications for this class Clarifications for this class • I will maintain the highest standards of I will maintain the highest standards of academic honesty academic honesty • I will neither give nor receive aid in I will neither give nor receive aid in examinations or assignments examinations or assignments unless such unless such cooperation is expressly permitted by the cooperation is expressly permitted by the instructor instructor • I will conduct research in an unbiased manner, I will conduct research in an unbiased manner, reports results truthfully, and credit ideas reports results truthfully, and credit ideas developed and work done by others developed and work done by others • I will not use answer keys from prior years I will not use answer keys from prior years • I will write answers in my own words, and, I will write answers in my own words, and, when collaboration is permitted, when collaboration is permitted, acknowledge acknowledge collaborators when answers are jointly collaborators when answers are jointly formulated formulated
Transcript
TICR Professional Conduct StatementTICR Professional Conduct StatementClarifications for this classClarifications for this class
• I will maintain the highest standards of academic honestyI will maintain the highest standards of academic honesty
• I will neither give nor receive aid in examinations or I will neither give nor receive aid in examinations or assignments assignments unless such cooperation is expressly unless such cooperation is expressly permitted by the instructorpermitted by the instructor
• I will conduct research in an unbiased manner, reports I will conduct research in an unbiased manner, reports results truthfully, and credit ideas developed and work results truthfully, and credit ideas developed and work done by othersdone by others
• I will not use answer keys from prior yearsI will not use answer keys from prior years
• I will write answers in my own words, and, when I will write answers in my own words, and, when collaboration is permitted, collaboration is permitted, acknowledge collaborators acknowledge collaborators when answers are jointly formulatedwhen answers are jointly formulated
Randomized Trials: Design, Randomized Trials: Design, Subjects, and RandomizationSubjects, and Randomization
Clay Johnston, MD, PhDClay Johnston, MD, PhD
Neurology and EpidemiologyNeurology and Epidemiology
Randomized Trials: the Randomized Trials: the EvidenceEvidence in in “Evidence-Based”“Evidence-Based”
An experiment in which subjects are randomly An experiment in which subjects are randomly allocated into groups, usually called allocated into groups, usually called studystudy and and controlcontrol groups, to receive or not to receive an groups, to receive or not to receive an experimental preventive or therapeutic procedure, experimental preventive or therapeutic procedure, maneuver, or intervention. maneuver, or intervention. The results are assessed by The results are assessed by rigorousrigorous comparison comparison of rates of disease, death, recovery, or other of rates of disease, death, recovery, or other appropriate outcome in the study and control appropriate outcome in the study and control groups, respectively.groups, respectively.
Number of randomized trials published*Number of randomized trials published*
* Based on Medline search restricted to “Randomized clinical trials”* Based on Medline search restricted to “Randomized clinical trials”
Disadvantages of RCTsDisadvantages of RCTs
• Expensive: typically in $ millionsExpensive: typically in $ millions
• Time Consuming: typically yearsTime Consuming: typically years
• Can only answer a single questionCan only answer a single question
• May not apply to most patients in practiceMay not apply to most patients in practice
• May not be practicalMay not be practical
• Generally very difficult to get fundedGenerally very difficult to get funded
• Time consuming, organizationally complexTime consuming, organizationally complex
Class dismissed.Class dismissed.
Alternatives to RCTsAlternatives to RCTs
• Observational studiesObservational studies
–Case-control studiesCase-control studies
–Cross-sectional studiesCross-sectional studies
–Cohort studies Cohort studies
Reasons for doing RCTsReasons for doing RCTs
• Only study design that can prove causationOnly study design that can prove causation
• Required by FDA (and others) for Required by FDA (and others) for new drugsnew drugs and and some devicessome devices
• Most influential to clinical practiceMost influential to clinical practice
Examples: When Have Trials Trumped Examples: When Have Trials Trumped Observational StudiesObservational Studies
• HRT and heart diseaseHRT and heart disease
• Vitamin E and heart diseaseVitamin E and heart disease
• Vitamin C and heart diseaseVitamin C and heart disease
• Beta carotene and heart diseaseBeta carotene and heart disease
• Oats and colon cancerOats and colon cancer
• ““Epidemiology—Is It Time to Call It a Day?”Epidemiology—Is It Time to Call It a Day?”
– Editors of The International Journal of EpiEditors of The International Journal of Epi
Beta carotene and CV mortality
“Epidemiology—Is It Time to Call It a Day? --Editors of The International Journal of Epi
Major Observational Study LimitationMajor Observational Study Limitation
• CHARMCHARM
– Candesartan in Heart failure: Candesartan in Heart failure: Assessment of Reduction in Mortality Assessment of Reduction in Mortality and morbidity and morbidity
– Compared those taking vs. not taking Compared those taking vs. not taking either drug or placeboeither drug or placebo
– 35% RRR in all-cause mortality35% RRR in all-cause mortality
• For drug and placebo.
• Take homeTake home
– Confounders are impossible to fully Confounders are impossible to fully identifyidentify
Lancet 2005, 366:2005Lancet 2005, 366:2005
CLINICAL TRIALS IN THE NEWS:CLINICAL TRIALS IN THE NEWS:
• Lots of trials of things other than drugsLots of trials of things other than drugs
• Surgical techniquesSurgical techniques
• Weight lossWeight loss
Clinical Trials in the News:Clinical Trials in the News:JAMA 1/5/05JAMA 1/5/05
Vs.Vs.Vs.Vs. VsVs..
RCT of 4 Popular Weight Loss ProgramsRCT of 4 Popular Weight Loss Programs
Extracranial/Intracranial Arterial Anastomosis Study
66 NA 67 $ (325,476,690) $ 296,277,864
Total 462,522 $ 3,251,892,981 $ 15,202,872,245
*Negative numbers are in parentheses and represent soci etal cost savings. NA = not available. Net value includes cost of trial, treatment costs, and quality-adjusted life years valued at 2004 per capita gross domestic product ($40,310). Costs were inflated to 2004 dollars with the medical care portion of the Consumer Price Index.
– Blocks within strata of prognostic variableBlocks within strata of prognostic variable
– e.g., Stroke prevention after TIA. Time from event e.g., Stroke prevention after TIA. Time from event a key predictora key predictor
– StratumStratum
<12 hour: aabb baba …<12 hour: aabb baba …
>=12 hour: baab abab ….>=12 hour: baab abab ….
– Limited number of risk factors Limited number of risk factors
– Very commonly used in multicenter studies to Very commonly used in multicenter studies to balance within clinical centerbalance within clinical center
• Fancier techniques for assuring balanceFancier techniques for assuring balance
– Adaptive randomizationAdaptive randomization
Adaptive RandomizationAdaptive Randomization
• Various designs that reduce the total number of subjects Various designs that reduce the total number of subjects necessary when comparing multiple groupsnecessary when comparing multiple groups
– Determine assignment on the fly based on prior dataDetermine assignment on the fly based on prior data
– Often used for dose findingOften used for dose finding
• Simple designs based on a priori decision rulesSimple designs based on a priori decision rules
– Eg, go to next highest dose if no side effects in first 4 Eg, go to next highest dose if no side effects in first 4 treatedtreated
• Complex designs based on recalculation of oddsComplex designs based on recalculation of odds
– ASTIN trial of 15 doses of neutrophil inhibitory factor ASTIN trial of 15 doses of neutrophil inhibitory factor (Stroke, 2003)(Stroke, 2003)
Implementation of randomizationImplementation of randomization
• Less challenging for blinded studiesLess challenging for blinded studies
– Sealed envelopes in fixed order at clinical sitesSealed envelopes in fixed order at clinical sites
– List of drug numbersList of drug numbers
• a b a b b b a a• 1 2 3 4 5 6 7 8• Clinic receives bottles labeled only by numbers--
assign in order
– IVRS: Interactive Voice Response SystemIVRS: Interactive Voice Response System
• Unblinded studies: important to keep next Unblinded studies: important to keep next assignment secret assignment secret
– Problem with blocks within strataProblem with blocks within strata
Randomization: SummaryRandomization: Summary
• Key element of clinical trialsKey element of clinical trials
• Not really very complicated (usually)Not really very complicated (usually)
Who to Study: Who to Study: Principles for Inclusion/exclusionPrinciples for Inclusion/exclusion
• Widest possible generalizabilityWidest possible generalizability
• Sufficiently high event rate (for power to Sufficiently high event rate (for power to be adequate)be adequate)
• Population in whom intervention likely to Population in whom intervention likely to be effective and safebe effective and safe
• Ease of recruitmentEase of recruitment
• Likelihood of compliance with treatment Likelihood of compliance with treatment and F/Uand F/U
Who to Study: Who to Study: Principles for Inclusion/exclusionPrinciples for Inclusion/exclusion
Explicit criteria for inclusion in a trialExplicit criteria for inclusion in a trial
• Typically written as “inclusion/exclusion” criteria in Typically written as “inclusion/exclusion” criteria in protocolprotocol
• Generally, the more explicit the betterGenerally, the more explicit the better
– Want centers or investigators to be consistentWant centers or investigators to be consistent
• Examples of exclusion criteria decisionsExamples of exclusion criteria decisions
1. Women with headache vs. Women with 1. Women with headache vs. Women with debilitating headache (with explicit criteria) debilitating headache (with explicit criteria) occurring >1/week. occurring >1/week.
2. Smokers vs Smokers of >=0.5 pack of cigarettes 2. Smokers vs Smokers of >=0.5 pack of cigarettes per day on average over the last 3 months. per day on average over the last 3 months.
Valid reasons to exclude participantsValid reasons to exclude participants
• Treatment would be unsafeTreatment would be unsafe
– Adverse experience from active treatmentAdverse experience from active treatment
– ““Risk” of placeboRisk” of placebo
• Active treatment cannot/unlikely to be effectiveActive treatment cannot/unlikely to be effective
– No risk of outcomeNo risk of outcome
– Disease type unlikely to respondDisease type unlikely to respond
Legend: Average recruitment per site per month as a function of the maximum time from stroke to enrollment. ESPS-2CAPRIE
order based on the total number of subjects enrolled. Note: The x-axis is log scale. IST CAST
Named studies are ones that enrolled more than 2000 subjects. Other studies are numbered in ascending
Ave
rag
e S
ub
ject
s P
er
Site
Pe
r M
on
th
Days
.125 1 2 90 1800
0
1
2
3
4
12
3
4
5
6
7
8
9
10 11
1213
14
1516
17
18
192021
22
23
24
25
26
2728 WARS
VISP
PROGRESS
ESPS-2
CAPRIE
IST
CAST
Example of Inclusions/Exclusions in Example of Inclusions/Exclusions in ProtocolProtocol
• Inclusion CriteriaInclusion Criteria
– Male or female Male or female >> 40 years 40 years
– TIA (TIA (>> 10 minutes) or minor acute ischemic stroke (NIHSS 10 minutes) or minor acute ischemic stroke (NIHSS << 2 at time of randomization) occurring less than 24 2 at time of randomization) occurring less than 24 hours before randomizationhours before randomization
– Informed consent signedInformed consent signed
– Able to have MRI scan within 24 hours of symptoms onsetAble to have MRI scan within 24 hours of symptoms onset
• Exclusion CriteriaExclusion Criteria
– Related to absolute contraindications to the use of clopidogrel and/or ASA:Related to absolute contraindications to the use of clopidogrel and/or ASA:
• History of drug allergy to thienopyridine derivatives or ASA• Severe uncontrolled hypertension (SBP > 160 mm Hg or DBP > 110 mm Hg on two or more measures over the last 6
months)• History of clinically significant or persistent thrompocytopenia• History of clinically significant or persistent neutropenia• Women of child-bearing potential who are not following an effective method of contraception• Women who are breast-feeding
Example of Inclusions/Exclusions in Example of Inclusions/Exclusions in ProtocolProtocol
• Inclusion CriteriaInclusion Criteria
– Male or female Male or female >> 40 years 40 years
– TIA (TIA (>> 10 minutes) or minor acute ischemic stroke (NIHSS 10 minutes) or minor acute ischemic stroke (NIHSS << 2 at time of randomization) 2 at time of randomization) occurring less than 24 hours before randomizationoccurring less than 24 hours before randomization
– Informed consent signedInformed consent signed
– Able to have MRI scan within 24 hours of symptoms onsetAble to have MRI scan within 24 hours of symptoms onset
• Exclusion CriteriaExclusion Criteria
– Related to absolute contraindications to the use of clopidogrel and/or ASA:Related to absolute contraindications to the use of clopidogrel and/or ASA:
– Related to concomitant or planned medication(s) / treatment(s):Related to concomitant or planned medication(s) / treatment(s):
– Related to TIA/Stroke characteristics:Related to TIA/Stroke characteristics:
– Related to the presence of other medical problems that would either interfere with Related to the presence of other medical problems that would either interfere with participation in the trial or lead to inability to complete the trial:participation in the trial or lead to inability to complete the trial:
Aspirin vs. Aspirin vs. no aspirin no aspirin (MI)(MI)
Aspirin vs. Aspirin vs. no aspirin no aspirin (MI)(MI)
Beta carotene Beta carotene vs. no beta vs. no beta carotene carotene (cancer)(cancer)
Beta carotene Beta carotene vs. no beta vs. no beta carotene carotene (cancer)(cancer)
Music, imagery, touch, and prayer as adjuncts to Music, imagery, touch, and prayer as adjuncts to interventional cardiac care: the Monitoring and Actualisation interventional cardiac care: the Monitoring and Actualisation
of Noetic Trainings (MANTRA) II randomised study of Noetic Trainings (MANTRA) II randomised study
A Factorial Trial of Six Interventions for the A Factorial Trial of Six Interventions for the Prevention of Postoperative Nausea and VomitingPrevention of Postoperative Nausea and Vomiting
• One third of patients have post-op N/VOne third of patients have post-op N/V
• 5200 patients randomized to test 6 5200 patients randomized to test 6 individual medicationsindividual medications
– 2^6 = 64 combinations2^6 = 64 combinations
• Ondansetron
• Dexamethosone
• Droperidol
• Propofol vs. other
• Nitrogen vs. nitrous oxide
• Remifentanil vs. fentanyl
Apfel, C. C. et al. N Engl J Med 2004;350:2441-2451
Factorial design issuesFactorial design issues
• Do treatments interact?Do treatments interact?
– Effect of chlorthalidone likely greater with Effect of chlorthalidone likely greater with potassium citrate on boardpotassium citrate on board
• Must test for interaction of treatments Must test for interaction of treatments
– If present, power is lower: large sample If present, power is lower: large sample requiredrequired
– May require more complicated stopping rulesMay require more complicated stopping rules
– May require more complicated analysis plan May require more complicated analysis plan (eg, logistic regression)(eg, logistic regression)
• Factorial designs are seductive but Factorial designs are seductive but complicated complicated – Some attraction in combining a low-risk Some attraction in combining a low-risk
hypothesis with a high-risk hypothesishypothesis with a high-risk hypothesis
• Must weigh benefits in efficiency against Must weigh benefits in efficiency against compounded uncertainty and complexitycompounded uncertainty and complexity
Cross-over designsCross-over designs
• Both active treatment and control are Both active treatment and control are administered sequentially to all subjectsadministered sequentially to all subjects
• Subject serves as own control, random Subject serves as own control, random orderorder
• Compare treatment period vs. control Compare treatment period vs. control periodperiod
– Increases power by reducing person-to-Increases power by reducing person-to-person variabilityperson variability
Cross-over designsCross-over designs
• Diuretic vs. beta blocker for blood pressureDiuretic vs. beta blocker for blood pressure
– 1/2 get diuretic followed by beta blocker1/2 get diuretic followed by beta blocker
– 1/2 get beta blocker followed by diuretic1/2 get beta blocker followed by diuretic
• Migraine prophylaxisMigraine prophylaxis
– Treatment x 3 months followed by placeboTreatment x 3 months followed by placebo
– Placebo x 3 months followed by treatmentPlacebo x 3 months followed by treatment
• Atrial Overdrive Pacing in sleep apneaAtrial Overdrive Pacing in sleep apnea
– AOP x 1 month followed by controlAOP x 1 month followed by control
– Control x 1 month followed by AOPControl x 1 month followed by AOP
• Example: two eyes within an individual (one Example: two eyes within an individual (one to each treatment)to each treatment)–Diabetic Retinopathy studyDiabetic Retinopathy study
• Example: Filter for carotid arteries in Example: Filter for carotid arteries in patients with atrial fibrillationpatients with atrial fibrillation–Random side of interventionRandom side of intervention
• Example: Quality Improvement in Stroke Example: Quality Improvement in Stroke Prevention (QUISP) trialPrevention (QUISP) trial–Randomize paired Kaiser facilitiesRandomize paired Kaiser facilities
• Not necessary when sample size makes Not necessary when sample size makes balanced randomization likelybalanced randomization likely
–Loss in efficiencyLoss in efficiency
• May not be feasible: must be able to identify May not be feasible: must be able to identify the pair before randomizationthe pair before randomization
• Arguments about how to analyze the dataArguments about how to analyze the data
–Maintaining the match vs. breaking itMaintaining the match vs. breaking it
Cluster or grouped randomizationCluster or grouped randomization
• Randomize groups to treatmentsRandomize groups to treatments
• Often useful especially for public health-Often useful especially for public health-type interventionstype interventions
• May be only way to study a questionMay be only way to study a question
– Intervention is at the group levelIntervention is at the group level
–Cross-contamination between individualsCross-contamination between individuals
Cluster or grouped randomizationCluster or grouped randomization
• ExamplesExamples
–Quality Improvement in Stroke Prevention Quality Improvement in Stroke Prevention (QUISP) trial(QUISP) trial
–DTC Advertising TrialDTC Advertising Trial
• Randomize matched cities
–Cities to public health risk factor reduction Cities to public health risk factor reduction (5 Cities Project)(5 Cities Project)
Cluster or grouped randomizationCluster or grouped randomization
• Sample size complex: true n is between n Sample size complex: true n is between n clusters and n individuals (closer to clusters)clusters and n individuals (closer to clusters)
–Tendency to underestimate necessary Tendency to underestimate necessary sample sizesample size
• Analysis complexAnalysis complex
–Must account for clusteringMust account for clustering
–Mixed models bestMixed models best
Randomized Trials: the Randomized Trials: the EvidenceEvidence in in “Evidence-Based”“Evidence-Based”
