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Treatment Once 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.
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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.
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Clinical Trials
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Experimental versus Observational Study Designs
Experimental Clinical Trials Community Trials
Observational Cohort Studies Case-Control Studies Cross-sectional Studies Ecologic Studies
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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.
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Clinical Trials: Objective
To asses the efficacy and effectiveness of a new intervention or drug
To help establish the role of the new drug or intervention in clinical practice.
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General Design of Clinical Trial
PAR S RStudy Group
Intervention
No Intervention
Outcome
NoOutcome
PAR = Population at RiskS = Sampling designR = Randomize interventionT = Elapsed time
T
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Key Principles of a Clinical Trial
Randomization Controls Blinding
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Key Elements of a Clinical Trial
Selection of subjects Allocation of exposure Blinding Data collection Statistical issues
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Clinical Trials: Selection of Subjects
Population at risk, or target population, must be defined The intervention is intended to benefit this
population Criteria must be explicitly stated that capture
the population at risk Inclusion criteria – identifies the target
population Exclusion criteria – excludes people from
target population for safety reasons
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Clinical Trials:Allocation of Treatment
Studies without controls - not a clinical trial Comparison groups
Historical controls Often advocated, but usually flawed Cannot exclude cohort effects Usually concludes that new treatment is better
than old Simultaneous non-randomized controls
Does not address bias Reduces chances of cohort effects
Randomization - true controls
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Historical Controls
Comparison of current experience with the past
Problems Data collection differences introduce potential
bias Temporal effects not related to the intervention
or therapy
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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 therapy
Problems The concurrent groups may be fundamentally
different for unrecognized reasons Systematic allocation may be abused
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Clinical Trials: Randomization
Randomization will, on average, balance the known and unknown risk factors for the outcome under study.
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Clinical Trials: Randomization
Allocation of treatment is randomized Every participant has an equal chance to
receive either the intervention or the control Stratified randomization may be used to
assign treatment within pre-defined strata Methods for randomization
Random number table Computer-generated list of assignments
Randomization often done at a coordinating center
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Clinical Trials: Data Collection
Treatment What treatment did the subject actually take?
Assigned versus received Links directly with intent-to-treat analysis
Outcome Assessment of outcome must be comparable
between groups Avoid detection bias
Prognostic Profile at Entry Groups must have similar risk for outcome at
the start of the study
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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.
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Clinical Trials: Blinding
Masking individuals participating in the trial from the treatment assignment
Levels of blinding Individual Data Collectors Investigators Analyst Data Safety Monitoring Board
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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
risk Assess risk for adverse events
Placebo arms are not ethical if there is an established intervention
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Clinical Trials: Statistical Issues
Sample Size Determine for primary study outcome Must account for multiple comparisons Often requires statistical consultation
Monitoring of events Interim analyses are performed to determine
whether to stop the study early Sample size must be adjusted for the number of
interim analyses Data Safety Monitoring Board review
Analysis
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Clinical Trials: Analysis
Fundamental measure of association Relative Risk
Efficacy
Efficacy = Incidenceplacebo
Incidencetreatment
Incidenceplacebo
-
Efficacy = 1 - Incidencetreatment
Incidenceplacebo
= 1 - Relative Risk
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Summary
Promising 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.
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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.
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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.