Presentation on theme: "Different types of trial design"— Presentation transcript:
1 Different types of trial design and implications for reportingAlison Wearden
2 Uncontrolled trialsTest feasibility and acceptability of an intervention, and whether there are adverse effectsMay allow preliminary examination of mechanisms of changeN-of-1 designs, randomized schedule, can be used to test theory (cause and effect)
3 Methods of bias control Selection bias Randomized treatment assignment Types of BIASMethods of bias controlSelection biasRandomized treatment assignmentConcealment of assignmentBias in studymanagementStandardized operating proceduresTraining of research personnelAscertainment biasBlinding of researchers to treatment assignmentBias introduced after randomizationIntention-to-treat analysisPublication biasProspective registration of trialsPublication of negative trialsFrom D. Wang & A Bakhai (Eds) Clinical Trials. A Practical Guideto Design, Analysis and Reporting. 2006, Remedica: London, pp 57
4 The hegemony of pharmacological trials Blinded randomised controlled trials considered gold standard for testing drugsHeavily influenced guidelines for RCTsAre drug-RCT issues always appropriate for complex behavioural interventions?Can attempts to eliminate bias distort implementation and assessment of intervention?
5 Types of CONTROLLED TRIALS What factors do you need to take into account choosing a trial type and design?What is your research question?Are there ethical constraints?Where might you want to publish your trial?EfficacyExplanatoryParallel arms/factorial?EffectivenessPragmaticPatientpreferenceEquivalenceNon-inferiority
6 Explanatory vs pragmatic Efficacy vs effectiveness Explanatory, efficacyDoes this intervention work in people who receive it under carefully controlled conditions? How does it work?Pragmatic, effectivenessWhat would be the outcome if this intervention were implemented in usual clinical practice?Broad, inclusive sampleMore flexibleimplementationQualitative studies, e.g. todetermine why peopledropped outTightly defined sampleFixed protocolCompliance measuredProcess measuresSee Zwarenstein et al., 2008, BMJ, 337,
7 Intention to treat analysis Preserves the benefits of randomization, ie minimizes bias. Withdrawals may be more common in one arm of trialEcological validity (people do drop out)It gives a pragmatic estimate of the effectiveness of a treatment, rather than just a report of the efficacy of the treatmentIt requires a method for dealing with missing data
8 Equivalence trialsInstead of having a “no treatment” control, equivalence trials test whether a new intervention is as good as (or not worse than) an established treatment with proven efficacyNew intervention may have some advantage (convenience, cost) over established, but is it at least as efficacious?
9 Randomisation issues Unit of randomisation (individual, group) Simple or block design (to even up group numbers)Stratification or minimisation to achieve groups balanced on key baseline characteristicsPatient preference designsZelenWennbergRuckerComprehensive cohort
10 Preference designs Patient preference may be an issue refusal to participatereduced compliance with non-preferred armConsent may be taken AFTER randomization, e.g. Zelen design:EligiblepatientsRandomizedNovelTreatment BConsentsReceives BDeclinesReceives AStandardTreatment A(May beanalysed asrandomized)
11 Some trial designsSimple, parallel design Is A better than control? Factorial design Are effects of A and B additive or interactive? A & B each controlled Cross-over design (Unlikely – useful with small samples)AEligibleRandomised toA or controlcontrolRandomized to 1,2,3 or 4AControlfor AB1 =A+B2 =B + controlfor B3 =A + control4 =DoublecontrolEligibleRandomised toA THEN B orB THEN AABBA
12 Analysis issuesPre-specification of primary outcomes if there are multiple measuresAnalysis plan pre-specified and publishedIntention to treat vs per protocol analysisHow are missing data dealt with?
13 Where do you want to publish? Which audience do you want to reach?Does impact factor matter?Uniform requirements for “prestigious” medical journalsTrial must be registeredProtocol must be publishedCONSORT guidelines must be adhered toImportant issue of publication bias
14 Special considerations for reporting different types of trials Standard CONSORT guidance is atdesignated primary outcomessequence generationallocation concealment ….CONSORT guidelines have been elaborated for trials with complex interventions (cf. drug trials) and non-simple designs
15 Reporting of psychological trials should include Components of the intervention(s), how they were individualised (if applicable), how they were standardizedHow therapist fidelity to treatment assessedHow experimental intervention and comparator(s) were implementedDescription of therapists (specialism, experience etc) and settingBoutron et al., 2008, Ann Int Med, 148,
16 Reporting pragmatic trials Explanatory vs pragmatic “attitude”Sample description and eligibility criteria – is sample typical? Is setting typical?CONSORT diagram should explain reasons for non-participation if knownParticular attention to clinical interest of findingsDescription of key aspects of setting which affected findingsZwarenstein et al., 2008, BMJ, 337,
17 Issues with equivalence, or non-inferiority, trials People may be carrying out equivalence trials without realising it.Analysis with respect to a pre-stated margin of non-inferiority (smallest clinically interesting difference)ITT analysis may increase risk of type 1 errorChoice of outcomes importantPeople may be carrying out equivalence trials without realising it.Piaggio et al., 2006, JAMA,295,
18 Reporting equivalence trials Need to reference established efficacy of “standard” treatmentHypotheses should be framed in terms of non-inferiority“Margins of equivalence” should be reported