Lecture 16: Introduction to the randomized trial
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Transcript of Lecture 16: Introduction to the randomized trial
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Lecture 16: Introduction to the randomized trial
• Introduction to intervention studies• The research question:
• Efficacy vs effectiveness
• The comparison groups (treatments) • Intervention
• Control
• Allocation to treatment group• Methods of randomization
• Allocation concealement
• Prevention of bias• Information bias: Blinding
• Selection bias
• Ethical issues
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Types of intervention
• Classified by purpose:
– preventive (prophylactic)
– treatment
• Levels of prevention
– primary prevention (prevention of onset of disease)
– secondary prevention (screening, early detection, and prompt treatment)
– tertiary prevention (of chronic conditions, to decrease disability and increase quality of life)
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Types of intervention
• Classified by complexity (technology assessment classification):– drugs– devices– procedures– systems of care
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Intervention study or study of an intervention?
• Intervention study (referring to a study design): An investigation involving intentional change in some aspect of the status of the subjects, e.g., introduction of a preventive or therapeutic regimen, or designed to test a hypothesized relationship; usually an experiment such as a randomized controlled trial (Definitions from Last’s Dictionary of Epidemiology)
• Study of an intervention (referring to the study purpose): study of a health care intervention; may be experimental or non-experimental (observational)
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Efficacy vs effectiveness(Definitions from Last’s Dictionary of Epidemiology)
• Efficacy (Can it work?) The extent to which a specific intervention procedure, regimen or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized controlled trial.
• Effectiveness (Does it work?): The extent to which a specific intervention procedure regimen or service when deployed in the field does what it is intended to do for a defined population. (The main distinction between effectiveness and efficacy is that effectiveness refers to average rather than ideal conditions of use).
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Specification of interventions
• Intervention: Fixed or flexible?
• Example:– fixed vs varied dose of drugs– geriatric assessment and management:
individually-tailored
• In either case, need measures of adherence
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Specification of interventions
• Comparison group(s)?– no treatment – placebo– alternative treatment (e.g., standard treatment) – “usual care” – wait-list– attention
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Usual care control group
• Can vary by population and over time
• Intervention will show greatest benefit when usual care is poor
• Example: community-based treatment of hypertension (HDFP)
• Followed placebo-controlled RCTs of anti-HBP medications
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Hypertension trials (1970s)
• VA study:• placebo controls
• moderate-severe hypertension
• men only
• HDFP study• intervention: stepped care program with interventions to
improve adherence
• usual care controls
• included mild hypertension
• included women and minorities
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HDFP results
• Groups with greatest benefit of stepped vs usual care:– mild hypertension– women– minorities
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Controls in counseling, education, and support
interventions • No placebo possible
• Need to control for non-specific effects of intervention (e.g., extra attention)
• Solutions:– control for time and attention (“attention”
controls)– example: general health education as control for
disease-specific intervention
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Ethical issues in RCTs
• Clinical equipoise– Balance between potential risks and benefits of
treatments
• Informed consent
• Interim review:– new external data– interim analyses
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Methods of allocation• Pseudo-randomization
– Systematic (e.g., alternate days) – Random units of time (e.g. days
• True Randomization– simple randomization– stratified randomization
• 2 or more strata (e.g., sex)
– blocked randomization• randomization in blocks (groups)
– fixed or variable size?
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Blind (concealed) allocation
• Methods:– pre-prepared pill packs (for placebo-controlled
drug trials)– pre-prepared, opaque, envelopes– telephone (or e-mail) randomization centre
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Blinding (masking)
• Subject:– placebo (same appearance, taste etc?)– assess effectiveness (can subjects guess?)
• Observer:– methods?
• Both: “double-blinding”
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Bias in RCTs
• Selection bias– Are the study groups comparable?
• Information bias– Measurement of outcomes
• Many other issues:– Confounding variables, contamination effects,
Hawthorne effects, etc
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Selection bias
• What is selection bias in an RCT?– Are 2 study groups comparable?– Distinguish from sample selection bias?
• Can occur at 3 times:– Selection of study groups (allocation method) – Differential attrition– Analysis (missing data)
• Example: attrition in AIDS prevention trials in drug abusers
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Bias in RCTs: Selection bias• at enrollment
– method of allocation/randomization– blinding (concealement) of allocation
• during follow-up– reasons for attrition– differential attrition
• at time of analysis – exclusion of subjects with missing data
– exclusion of subjects who did not adhere to allocated treatment
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Attrition in RCTs
• Compare study groups for:– Attrition rates– Reasons for attrition
• Example:– RCT of St John’s Wort vs SSRI for treatment
of mild depression in adults in primary care
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Another example of attrition: time to first drug use
• RCTs of residential drug abuse treatment programs of different planned duration:
– traditional therapeutic community (TC)
• abstinence-oriented
• 6 vs 12 months
– modified TC incorporating relapse prevention and health education
• 3 vs 6 months
• PRIMARY OUTCOME: time to first drug use
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Methodological Questions• Time zero:
• date of admission vs date of exit from treatment?
• primary analyses using admission, secondary analyses using exit
• Censoring:• how to treat loss to follow-up: outcome or censored data?
– primary analyses: censoring of loss to follow-up
– secondary analyses: loss to follow-up considered to have used drugs on day after exit from program
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