Presentation on theme: "Clinical Trials Hanyan Yang"— Presentation transcript:
1 Clinical Trials Hanyan Yang email@example.com 2008.12
2 TreatmentOnce the nature of a patient’s illness has been established and its expected, the next question is: what can be done about it? Is there a treatment that improves the outcome of disease?This chapter describes ways of deciding whether a well-intentioned treatment dose in fact do more good than harms.
3 Studies of treatment effects ideas about what might be useful treatment arise from virtually any activity within medicine.Usually, the effects of treatments are considerably less dramatic. It is then nece- ssary to put ideas about treatment to a formal test, because a variety of conditions----coin- cidence, faulty comparisons, spontaneous changes in the course of disease, wishful thinking, etc----can obscure the true relation- ship between treatment and effect.
5 Experimental versus Observational Study Designs Clinical TrialsCommunity TrialsObservationalCohort StudiesCase-Control StudiesCross-sectional StudiesEcologic Studies
6 Clinical Trial: Definition A clinical trial is a prospective study comparing the effect and value of intervention(s) against a control in human beings.A special kind of cohort study in which the conditions of study ---selection of treatment groups, nature of intervention, management during follow-up,etc.---are specified by the investigator for the purpose of making unbiased comparison.
7 Clinical Trials: Objective To asses the efficacy and effectiveness of a new intervention or drugTo help establish the role of the new drug or intervention in clinical practice.
8 General Design of Clinical Trial InterventionOutcomeNoStudyGroupPARTSRNoInterventionPAR = Population at RiskS = Sampling designR = Randomize interventionT = Elapsed time
9 Key Principles of a Clinical Trial RandomizationControlsBlinding
10 Key Elements of a Clinical Trial Selection of subjectsAllocation of exposureBlindingData collectionStatistical issues
11 Clinical Trials: Selection of Subjects Population at risk, or target population, must be definedThe intervention is intended to benefit this populationCriteria must be explicitly stated that capture the population at riskInclusion criteria – identifies the target populationExclusion criteria – excludes people from target population for safety reasons
12 Clinical Trials: Allocation of Treatment Studies without controls - not a clinical trialComparison groupsHistorical controlsOften advocated, but usually flawedCannot exclude cohort effectsUsually concludes that new treatment is better than oldSimultaneous non-randomized controlsDoes not address biasReduces chances of cohort effectsRandomization - true controls
13 Historical Controls Comparison of current experience with the past ProblemsData collection differences introduce potential biasTemporal effects not related to the intervention or therapy
14 Clinical Trials: Simultaneous Non-Randomized Controls A concurrent group of subjects is selected to act as a comparison group but are not offered the intervention or therapyProblemsThe concurrent groups may be fundamentally different for unrecognized reasonsSystematic allocation may be abused
15 Clinical Trials: Randomization Randomization will, on average, balance the known and unknown risk factors for the outcome under study.
16 Clinical Trials: Randomization Allocation of treatment is randomizedEvery participant has an equal chance to receive either the intervention or the controlStratified randomization may be used to assign treatment within pre-defined strataMethods for randomizationRandom number tableComputer-generated list of assignmentsRandomization often done at a coordinating center
17 Clinical Trials: Data Collection TreatmentWhat treatment did the subject actually take?Assigned versus receivedLinks directly with intent-to-treat analysisOutcomeAssessment of outcome must be comparable between groupsAvoid detection biasPrognostic Profile at EntryGroups must have similar risk for outcome at the start of the study
18 Clinical Trials: Blinding Blinding refers to any attempt to make the various participants in a study unware of which treatment patients have been offered, so that the knowledge cannot cause them to act differently and thereby damage the internal validity of the study.
19 Clinical Trials: Blinding Masking individuals participating in the trial from the treatment assignmentLevels of blindingIndividualData CollectorsInvestigatorsAnalystData Safety Monitoring Board
20 Clinical Trials: Placebo Placebo is an inert compound randomly allocated to subjects in a clinical trial.Placebo arm is a true control for an intervention.Assess relative effect of intervention - relative riskAssess risk for adverse eventsPlacebo arms are not ethical if there is an established intervention
21 Clinical Trials: Statistical Issues Sample SizeDetermine for primary study outcomeMust account for multiple comparisonsOften requires statistical consultationMonitoring of eventsInterim analyses are performed to determine whether to stop the study earlySample size must be adjusted for the number of interim analysesData Safety Monitoring Board reviewAnalysis
22 Clinical Trials: Analysis Fundamental measure of associationRelative RiskEfficacyEfficacy =IncidenceplaceboIncidencetreatment-Efficacy = 1 -= 1 - Relative Risk
23 SummaryPromising ideas about what might be good treatment should be put to a rigorous test before being accepted.The best test is a randomized controlled trial, a special case of a cohort study in which the intervention is allocated without bias.
24 Patients in clinical trials are usually highly selected, reducing generalizability. They are randomly allocated to receive either an experimental intervention or some comparison management: usual treatment, a placebo, or simple observation.
25 On the average, the compared groups have a similar prognosis just after randomization (and before the interventions), but differences not attributable to treatment can arise later, including dropouts and crossovers, co-interventions, and non-compliance.Blinding all participants in the trial can help to minimize bias.