Lecture 16 (Oct 28, 2004) 1

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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