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Randomised Controlled TrialsRandomised Controlled Trials
Prof. Craig Jackson Head of Psychology Division
School of Social SciencesBCU
health.bcu.ac.uk/craigjackson#WPwork
@Workplace_Prof@bcu_psychology
[email protected]@bcu.ac.uk
ObjectivesObjectives
Experimental studiesExperimental studieswithin-subjects studieswithin-subjects studiesbetween-subjects studiesbetween-subjects studies
Observational studiesObservational studiescase-controlscase-controlscohortscohortsRCTsRCTs
BiasBias
PlaceboPlacebo
Control GroupsControl Groups!!
IntroductionIntroduction
Types of researchTypes of research Experimental vs. ObservationalExperimental vs. Observational
Longitudinal vs. Cross-sectionalLongitudinal vs. Cross-sectional
Prospective vs. RetrospectiveProspective vs. Retrospective
LongitudinalLongitudinal
ProspectiveProspective
ExperimentalExperimental
Randomised Controlled TrialRandomised Controlled Trial
Qualititative VS Quantitative ResearchQualititative VS Quantitative Research
False oppositionFalse opposition
Observational methods equally validObservational methods equally valid
Complementary rolesComplementary roles
Qualitative equally as hard to doQualitative equally as hard to do
Quantitative
Qualitative
Experimental StudiesExperimental Studies
Investigator makes interventionInvestigator makes intervention
A “manipulation”A “manipulation”
Then studies the effects of that intervention Then studies the effects of that intervention
Features:Features:
Comparison e.g. before vs. afterComparison e.g. before vs. after control vs. treatmentcontrol vs. treatment
Always longitudinal Always longitudinal
Always prospective Always prospective
Experimental Experimental
Clinical Clinical
TrialsTrials
RCTsRCTs
Rationale of Experimental StudiesRationale of Experimental Studies
Evaluate effectiveness of intervention / therapyEvaluate effectiveness of intervention / therapy
Use similar samples – comparable groupsUse similar samples – comparable groups
Samples reflect populationSamples reflect population
Differences in outcomes due to interventions (not differences Differences in outcomes due to interventions (not differences between groups)between groups)
Independent Variable (IV) alters Dependent Variable (DV)Independent Variable (IV) alters Dependent Variable (DV)
Best evidence of cause and effectBest evidence of cause and effect
Sometimes inconclusiveSometimes inconclusive
Types of Experimental StudiesTypes of Experimental Studies
Between Subjects StudiesBetween Subjects Studies
Each group receives different treatmentEach group receives different treatment
Groups comparedGroups compared
Within Subjects StudiesWithin Subjects Studies
Each individual is measured before & after interventionEach individual is measured before & after intervention
Advantage that each participant is own controlAdvantage that each participant is own control Between subject variability removedBetween subject variability removed
Within Subjects StudiesWithin Subjects Studies
Cross-over-studies Cross-over-studies Each patient receives treatment in sequenceEach patient receives treatment in sequence““Washout” period between treatmentsWashout” period between treatmentsOrder of treatments randomisedOrder of treatments randomised
Matched-pairs studyMatched-pairs studyParallel studyParallel studyPatient in arm 1 matched with patient in arm 2Patient in arm 1 matched with patient in arm 2Matched based on prognostic factorsMatched based on prognostic factorsData is linkedData is linkedPaired individualsPaired individuals
Treatment Treatment 11Treatment 2Treatment 2
Gp AGp A
Gp BGp B
Treatment 2Treatment 2
Treatment Treatment 11
Avoiding BiasAvoiding Bias
Validity of study depends on Validity of study depends on avoiding biasavoiding bias
Bias = “Systematic distortion of results due to unforeseen factors”Bias = “Systematic distortion of results due to unforeseen factors”
e.g.e.g.gp1 = pillgp1 = pill gp2 = no pillgp2 = no pill
How will the “no pill”group progress?How will the “no pill”group progress?Any effects of them knowing they have no treatment?Any effects of them knowing they have no treatment?
Handling differences may influence + complicate trial resultsHandling differences may influence + complicate trial results
Known as Known as confounding factorsconfounding factors
To minimize bias… To minimize bias… control groupcontrol group randomisationrandomisation blindingblinding
Placebo effect – it really does work!Placebo effect – it really does work!
Most effectiveMost effective medication known medication known
In approx. 30% of pop.In approx. 30% of pop.
Subjected to more clinical trialsSubjected to more clinical trials than any other medicament than any other medicament
Nearly always does better thanNearly always does better than anticipatedanticipated
The range of susceptible conditions seems limitlessThe range of susceptible conditions seems limitless
Does not always occurDoes not always occur
Present in subjective and objective outcomesPresent in subjective and objective outcomes
Negative outcomes can occur (Nocebo effect)Negative outcomes can occur (Nocebo effect)
PlaceboPlacebo•Big pills better than smaller pillsBig pills better than smaller pills•Red pills better than blueRed pills better than blue•4 pills better than 24 pills better than 2•30% of pop.30% of pop. Patient’s “knowledge” of their treatment causes bias
Patient’s “knowledge” of their treatment causes bias
e.g. Benedetti & the Turin study
e.g. Benedetti & the Turin study
Control GroupsControl Groups
Allow comparison in Between Group studies Allow comparison in Between Group studies
Evaluations without comparison?Evaluations without comparison?
Patient knowledge of their treatment causes biasPatient knowledge of their treatment causes bias
e.g. Benedetti & the Turin studye.g. Benedetti & the Turin study
Types of Control GroupsTypes of Control Groups
•““no treatment” group no treatment” group likely to be confounded by conditionlikely to be confounded by condition
•““placebo” groupplacebo” group ethically dodgy? ethically dodgy?
•““low dose” grouplow dose” group avoids ethical issuesavoids ethical issues
•““standard treatment” groupstandard treatment” group avoids ethical issues avoids ethical issues
•““gold standard” group gold standard” group avoids ethical issuesavoids ethical issues
•““historical controls”historical controls” too many confounderstoo many confounders
Drug XDrug X
53 yrs53 yrs
80% male80% male20% fem20% fem
Gp AGp A(500)(500)
Gp BGp B(500)(500)
Drug YDrug Y
27 years27 years
50% male50% male50% fem50% fem
PopulationPopulation(60 million)(60 million)
SampleSample(1000)(1000)
Control Groups: Random Control Groups: Random AllocationAllocation
Doesn’t guarantee groups will be Doesn’t guarantee groups will be homogonoushomogonous
Ensures allocation independent of patient Ensures allocation independent of patient featuresfeatures
Avoids (sub)conscious allocation biasAvoids (sub)conscious allocation biase.g. severely sick into treatment groupse.g. severely sick into treatment groups
Guarantees Guarantees allocationallocation to be bias-freeto be bias-free
Non-homogenous groups may still occur Non-homogenous groups may still occur due to chance – random errorsdue to chance – random errors
Comparison Groups: Random SamplingComparison Groups: Random Sampling
Ensures generalizability of findings to larger pop.Ensures generalizability of findings to larger pop.e.g. in-custody sample limitationse.g. in-custody sample limitations
Treatment effects best detected if little between-group variabilityTreatment effects best detected if little between-group variability
Exclusion Criteria & Inclusion Criteria keep groups comparableExclusion Criteria & Inclusion Criteria keep groups comparable
Paradox:Paradox:greater uniformity of sample = less generalizable to gen. popgreater uniformity of sample = less generalizable to gen. pop
Blinding: Importance of doing itBlinding: Importance of doing it
Investigator or Subject know treatment = BiasInvestigator or Subject know treatment = Bias
Observations and Judgements become less reliableObservations and Judgements become less reliable
Patient responses change:Patient responses change:Positive outcomes in active armPositive outcomes in active armNegative outcomes in passive armNegative outcomes in passive arme.g. known cancer diagnoses and deterioratione.g. known cancer diagnoses and deterioration
Use max. degree of blindness possibleUse max. degree of blindness possiblee.g. make subject and investigator both blind if possiblee.g. make subject and investigator both blind if possiblee.g. A.A.Mason & Congenital Ichthyosis and Hypnosis 1951e.g. A.A.Mason & Congenital Ichthyosis and Hypnosis 1951
Blinding: MethodsBlinding: Methods
Double-blindDouble-blind patient & investigator blindpatient & investigator blind
Single-blindSingle-blind patient blindpatient blind
Triple-blindTriple-blind patient & investigator & data monitor blindpatient & investigator & data monitor blind
Double-dummyDouble-dummy 2 treatments2 treatments patients get 2 pills (1 active, 1 dummy)patients get 2 pills (1 active, 1 dummy)
Open trialsOpen trials patient & investigator aware of treatmentpatient & investigator aware of treatment
Randomisation in a double-blind trialRandomisation in a double-blind trialEnvelope technique commonEnvelope technique common
Un-blinding – ethical necessityUn-blinding – ethical necessity
Subject Variables that confound researchSubject Variables that confound researchSTABLE FACTORSSTABLE FACTORS SITUATIONAL FACTORSSITUATIONAL FACTORS
AgeAge Alcohol (recent useAlcohol (recent useEducationEducation Caffeine (recent use)Caffeine (recent use)SexSex Nicotine (recent use)Nicotine (recent use)SocioeconomicsSocioeconomics Medication (recent use)Medication (recent use)LanguageLanguage Paints, glues, pesticides Paints, glues, pesticides HandednessHandedness Time of day Time of dayPhysical activity Time of yearPhysical activity Time of yearNear visual acuityNear visual acuity Screen luminanceScreen luminanceComputer experienceComputer experience Restricted movement (injury)Restricted movement (injury)Caffeine (habitual use)Caffeine (habitual use) Cold / fluCold / fluAlcohol (habitual use)Alcohol (habitual use) StressStressNicotine (habitual use)Nicotine (habitual use) Arousal / FatigueArousal / FatigueMedication (habitual use)Medication (habitual use) SleepSleepPaints, glues, pesticides Paints, glues, pesticides DiabetesDiabetesEpilepsyEpilepsyOther CNS / PNS diseaseOther CNS / PNS diseaseHead injury (out >1 hr)Head injury (out >1 hr)Alcohol / drug addictionAlcohol / drug addiction
Randomized Controlled Trials in PracticeRandomized Controlled Trials in Practice
90% consultations take place in GP surgery90% consultations take place in GP surgery
RCT is really 50 years oldRCT is really 50 years old
Potential problemsPotential problems
2 Key areas:2 Key areas: Recruitment BiasRecruitment Bias
Randomisation BiasRandomisation Bias
Over-focus on failings of RCTsOver-focus on failings of RCTs
RCTs in PracticeRCTs in Practice
RCTs justified inRCTs justified in situations of genuine clinical uncertaintysituations of genuine clinical uncertainty
Samples large enough to establish any worthwhile benefit Samples large enough to establish any worthwhile benefit
(effectiveness or cost, or both) (effectiveness or cost, or both)
Need for larger numbers of participants Need for larger numbers of participants
More than are availableMore than are available to single practicesto single practices
Requires “club together” approachRequires “club together” approach
Practitioners: no contractual obligationPractitioners: no contractual obligation
(i)(i) unwilling to take part if no immediate benefit for clientsunwilling to take part if no immediate benefit for clients
(ii)(ii) while possibly disruptingwhile possibly disrupting the delivery of service/carethe delivery of service/care
RCTs in PracticeRCTs in Practice
Conflict of interest between:Conflict of interest between:Role and Wish to benefit patientsRole and Wish to benefit patientsAcademic meritAcademic merit
Long term nature of practitionerLong term nature of practitioner and client relationship and client relationship may engender loyaltiesmay engender loyaltiesunfairly coerce clientsunfairly coerce clients to give consentto give consent
Patients' fearsPatients' fears about:about:confidentialityconfidentialityrisks of the interventionrisks of the interventionapparent disadvantage of being allocated to a control groupapparent disadvantage of being allocated to a control group
may further inhibit recruitmentmay further inhibit recruitmentFail to recruit consecutiveFail to recruit consecutive clients may introduce selection biasclients may introduce selection bias
RCTs in PracticeRCTs in Practice
Provides rigorous,Provides rigorous, sound basis for evaluating treatmentssound basis for evaluating treatments
May disrupt care May disrupt care Too much disruption = no reflection of real practiceToo much disruption = no reflection of real practice
MethodologicalMethodological problems reduce reliability of the results problems reduce reliability of the results (Recruitment & Randomisation) (Recruitment & Randomisation)
Practice not a laboratoryPractice not a laboratoryPeoplePeople are not experimental animalsare not experimental animals
Case-control studies, retrospectiveCase-control studies, retrospective, , prospective cohort prospective cohort studies,observation and descriptive studies arestudies,observation and descriptive studies are all acceptable all acceptable
methods. methods.
Accept alternative methodsAccept alternative methods when RCT difficult or flawedwhen RCT difficult or flawed
RCT DeficienciesRCT Deficiencies
Trials too smallTrials too small
Trials too shortTrials too short
Poor qualityPoor quality
Poorly presentedPoorly presented
Address wrong questionAddress wrong question
Methodological inadequaciesMethodological inadequacies
Inadequate measures of quality of life (changing)Inadequate measures of quality of life (changing)
Cost-data poorly presentedCost-data poorly presented
Ethical neglectEthical neglect
Participants given limited understandingParticipants given limited understanding
Poor trial managementPoor trial management
PoliticsPolitics
MarketeeringMarketeering
Why still the dominant model?Why still the dominant model?
Observational StudiesObservational Studies
Investigator observes existing situationInvestigator observes existing situation
DescribesDescribes
Analyses Analyses
Interprets Interprets
No influence on events No influence on events
Longitudinal observation studiesLongitudinal observation studies
case-control studies: retrospectivecase-control studies: retrospective
cohort-studies: prospective cohort-studies: prospective
Cross-sectional observation studiesCross-sectional observation studies
surveys examining subjects at one point in timesurveys examining subjects at one point in time
based on random sample of interest populationbased on random sample of interest population
Observational Studies:Observational Studies:
Look for associationsLook for associations• Cause --> EffectCause --> Effect• Exposure --> IllnessExposure --> Illness• EpidemiologicalEpidemiological• IncidenceIncidence• CauseCause• PreventionPrevention
No controlNo controlCannot use classical experimentationCannot use classical experimentationNo randomisationNo randomisationBiasBias
Case-Control StudyCase-Control Study
Identify group with condition / offence (cases)Identify group with condition / offence (cases)
Identify group without condition / offence (controls)Identify group without condition / offence (controls)
Both groups compared for exposure to (hypothesized) risk factorsBoth groups compared for exposure to (hypothesized) risk factors
Greater exposure to risk factor in cases = “causal relation”Greater exposure to risk factor in cases = “causal relation”
BiasesBiases
Lead time biasLead time bias
Recruitment of cases at similar points in timeRecruitment of cases at similar points in time
Newly labelled casesNewly labelled cases
Selection of ControlsSelection of Controls
Cases have lung cancerCases have lung cancer
Controls could be other patients or “normals”Controls could be other patients or “normals”
Matched Cases & Controls for age & genderMatched Cases & Controls for age & gender
Option of 2 Controls per CaseOption of 2 Controls per Case
Smoking years of cases and controls Smoking years of cases and controls (matched for age and sex)(matched for age and sex)
CasesCases ControlsControls
n=456n=456 n=456n=456
FF PPSmoking yrsSmoking yrs 13.7513.75 6.126.12 7.57.5 0.040.04
(± 1.5)(± 1.5) (± 2.1)(± 2.1)
Case-Control Study: Other BiasesCase-Control Study: Other Biases
Recall BiasRecall BiasCases > associations with exposures / risk factorsCases > associations with exposures / risk factors
Unreliable MemoriesUnreliable MemoriesRetrospective natureRetrospective natureOver-reliance on recallOver-reliance on recall
Unreliable RecordsUnreliable RecordsPoor hospital recordsPoor hospital recordsRepetitive, incomplete, inaccurate, irretrievable, interpretationRepetitive, incomplete, inaccurate, irretrievable, interpretation
Interview BiasInterview BiasDifferent interviewersDifferent interviewers
Cohort StudyCohort Study
ID and examination of a group (cohort)ID and examination of a group (cohort)
Followed over time (20 years common!)Followed over time (20 years common!)
Looking for condition development / other end-pointLooking for condition development / other end-point
Aetiology of condition (based on data collected)Aetiology of condition (based on data collected)Data more reliable than case-control studiesData more reliable than case-control studies
• Requires large NRequires large N• Requires long follow upRequires long follow up• InefficientInefficient• Expensive (espec. rare outcomes)Expensive (espec. rare outcomes)
Cohort Study: MethodsCohort Study: Methods
Volunteers in 2 groups e.g. exposed vs non-exposedVolunteers in 2 groups e.g. exposed vs non-exposed
All complete attitude survey every 12 monthsAll complete attitude survey every 12 months
End point at 5 years: groups compared for Health StatusEnd point at 5 years: groups compared for Health Status
Comparison of general health between users and non-users Comparison of general health between users and non-users of mobile phonesof mobile phones
illill healthyhealthy
mobile phone usermobile phone user 292292 108108 400400
non-phone usernon-phone user 8989 313313 402402
381381 421421 802802
Cohort Study: Other BiasesCohort Study: Other Biases
Lost to follow upLost to follow upBias if reason related to exposureBias if reason related to exposureValidity affectedValidity affected
Group sizes changeGroup sizes changeMembership changes e.g ex-smokersMembership changes e.g ex-smokersDifferential mortalityDifferential mortality
Change in circumstanceChange in circumstancee.g. job changee.g. job changeExposures need calculation or re-calculationExposures need calculation or re-calculation
Surveillance biasSurveillance biasInvestigator aware of group membershipInvestigator aware of group membershipInvestigating exposed members moreInvestigating exposed members more
Cross Sectional StudyCross Sectional Study
Subjects contacted & surveyed just onceSubjects contacted & surveyed just once
Questionnaire (post, email, phone)Questionnaire (post, email, phone)
Random sample of defined pop.Random sample of defined pop.
Limited causalityLimited causalityNot temporal relationshipsNot temporal relationshipsLittle insight into aetiologyLittle insight into aetiologySource of descriptive dataSource of descriptive dataPrevalence ratesPrevalence ratesVolunteer biasVolunteer biasNon responsesNon responsesSelf-selectionSelf-selectionUnrepresentative sampleUnrepresentative sample
Further ReadingFurther Reading
Altman, D.G. “Designing Research”. In: Altman, D.G., (ed.) Altman, D.G. “Designing Research”. In: Altman, D.G., (ed.) Practical Practical Statistics For Medical ResearchStatistics For Medical Research. London, Chapman and Hall, 1991; . London, Chapman and Hall, 1991; 74-106.74-106.
Bland, M. “The design of experiments”. In: Bland, M., (ed.) Bland, M. “The design of experiments”. In: Bland, M., (ed.) An An introduction to medical statisticsintroduction to medical statistics. Oxford, Oxford Medical . Oxford, Oxford Medical Publications, 1995; 5-25.Publications, 1995; 5-25.
Daly, L.E., Bourke, G.J. “Epidemiological and clinical research Daly, L.E., Bourke, G.J. “Epidemiological and clinical research methods”. In: Daly L.E., Bourke, G.J., (eds.) methods”. In: Daly L.E., Bourke, G.J., (eds.) Interpretation and uses Interpretation and uses of medical statistics.of medical statistics. Oxford, Blackwell Science Ltd, 2000; 143-201. Oxford, Blackwell Science Ltd, 2000; 143-201.
Jackson, C.A. “Study Design” & “Sample Size and Power”. In: Gao Jackson, C.A. “Study Design” & “Sample Size and Power”. In: Gao Smith, F. and Smith, J. (eds.)Smith, F. and Smith, J. (eds.) Key Topics in Clinical Research Key Topics in Clinical Research. . Oxford, BIOS scientific Publications,Oxford, BIOS scientific Publications, 2002 2002. .
Further ReadingFurther Reading
Jackson, C.A. “Planning Health & Safety Research Projects in the Jackson, C.A. “Planning Health & Safety Research Projects in the Workplace”. Workplace”. Croner Health and Safety at Work Special ReportCroner Health and Safety at Work Special Report 2002; 2002; 62: 1-16. 62: 1-16.
Kumar, R. Kumar, R. Research Methodology: a step by step guide for Research Methodology: a step by step guide for beginnersbeginners. Sage, London 1999.. Sage, London 1999.
Abbott, P. and Sapsford. Abbott, P. and Sapsford. Research methods for nurses and the Research methods for nurses and the caring professions.caring professions. Open University Press, Buckingham 1988. Open University Press, Buckingham 1988.
Bowling, A. Measuring Health. Open University Press, Milton Keynes Bowling, A. Measuring Health. Open University Press, Milton Keynes 19941994
Polit, D. & Hungler, B. Nursing research: Principles and methods (7th Polit, D. & Hungler, B. Nursing research: Principles and methods (7th ed.). Philadelphia: Lippincott, Williams & Wilkins 2003.ed.). Philadelphia: Lippincott, Williams & Wilkins 2003.