1. 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

2. 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)

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

4. 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)

5. 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).

6. 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

7. 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

8. 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

9. 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

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

13. 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

14. 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

15. 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?

16. 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

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

18. 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

19. 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

20. 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

21. 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

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23. Lecture 16 (Oct 28, 2004)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

24. 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

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