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Lecture 16: Introduction to the randomized trial

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

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Lecture 16: Introduction to the randomized trial

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  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 Lecture 16 (Oct 28, 2004)

  2. 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) Lecture 16 (Oct 28, 2004)

  3. Types of intervention • Classified by complexity (technology assessment classification): • drugs • devices • procedures • systems of care Lecture 16 (Oct 28, 2004)

  4. 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) Lecture 16 (Oct 28, 2004)

  5. 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). Lecture 16 (Oct 28, 2004)

  6. 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 Lecture 16 (Oct 28, 2004)

  7. Specification of interventions • Comparison group(s)? • no treatment • placebo • alternative treatment (e.g., standard treatment) • “usual care” • wait-list • attention Lecture 16 (Oct 28, 2004)

  8. 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 Lecture 16 (Oct 28, 2004)

  9. 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 Lecture 16 (Oct 28, 2004)

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  12. HDFP results • Groups with greatest benefit of stepped vs usual care: • mild hypertension • women • minorities Lecture 16 (Oct 28, 2004)

  13. 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 Lecture 16 (Oct 28, 2004)

  14. Ethical issues in RCTs • Clinical equipoise • Balance between potential risks and benefits of treatments • Informed consent • Interim review: • new external data • interim analyses Lecture 16 (Oct 28, 2004)

  15. 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? Lecture 16 (Oct 28, 2004)

  16. Blind (concealed) allocation • Methods: • pre-prepared pill packs (for placebo-controlled drug trials) • pre-prepared, opaque, envelopes • telephone (or e-mail) randomization centre Lecture 16 (Oct 28, 2004)

  17. Blinding (masking) • Subject: • placebo (same appearance, taste etc?) • assess effectiveness (can subjects guess?) • Observer: • methods? • Both: “double-blinding” Lecture 16 (Oct 28, 2004)

  18. 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 Lecture 16 (Oct 28, 2004)

  19. 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 Lecture 16 (Oct 28, 2004)

  20. 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 Lecture 16 (Oct 28, 2004)

  21. 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 Lecture 16 (Oct 28, 2004)

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  23. 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 Lecture 16 (Oct 28, 2004)

  24. 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 Lecture 16 (Oct 28, 2004)

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