Transcript Intervention studies: experimental design

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):
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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)?
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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 antiHBP 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
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in drug abusers Lecture 16 (Oct 28, 2004)
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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