Randomized controlled trials

1. Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005

2. Contents • Why randomized controlled trials? • Design and conduct • Selection of study population • Allocation of study regimes • Follow-up of participants • Analysis and interpretation • Publication

3. Question design • We need different studies to answer different study questions • The study question decides what design

4. Key questions • How many are (becoming) ill? (occurence) • Why do some people become ill why others stay healthy? (etiology/causiality) • How can we determine if somebody has a spesific health condition? (diagnostics) • What can we do to improve the health condition of individuals/populations? (effect of measures) • What will happen to those who are ill? (prognosis) • What is it like to use the health service? (experience)

5. Different study designs

6. Intervention study –important characteristic • Case – control study • Participants enrolled on basis of disease status • Cohort study • Participants enrolled on basis of exposure status • RCT • Investigator allocates the exposure

7. Randomized controlled trials (RCT) ”An epidemiological experiment in which subjects in a population are randomly allocated into groups, usually called study and control groups to receive and not receive an experimental preventive or therapetuic procedure, maneuver, or interventition” John M.Last, 2001

8. Why RCT? • ”Gold standard” in epidemiological research • Makes study groups comparable • Controls for confounding (known and unknown) • Prevents selection bias

9. Therapeutic Study population Patients with disease Objectives Cure patients Diminish symptoms Prevent recurrence of disease/risk of death Preventive Study Population Population at risk Objectives Reduce the risk of developing disease Intervention studies

10. Design - conduct Different phases • Enrollment (selection of study population) • Allocation of study regimes • Follow-up • Maintainence and assessment of adherence • High and uniform rates of ascertainment • Analysis and interpretation

11. Selection of study population 1 • Reference (source) population • The population to whom the results of the trial is applicable • Generalizability • Experimental population • The actual group in which the trial is conducted • Sample size • Sufficient number of outcome (endpoints) • Possibility for accurate follow up of information during the trial

12. Selection of study population 2 • Participants must be fully informed • Risks • Benefits • Blinding/placebo • Willing to participate • Informed consent • Screened for eligibility • Inclusion criteria • Exclusion criteria

13. Population hierarchy for intervention study Reference population Experimental population Exclusion criteria Informed consent Excluded Refused Study population Random allocation Intervention group Control group Losses to follow-up Losses to follow-up Outcome

14. Selection of study population 3 • The actual study population = selected subgroup of the experimental population • Generalizability • Volunteerism • Obtain baseline data and/or ascertain outcome for subjects eligible, but unwilling to participate • Study results generizable beyond trial group

15. Allocation of study regimes 1 • After eligible and willing • Different comparisons: • Another dosage of same drug • Another therapy or program • Continuation of standard medical practise • Placebo • Nohting ……. • Allocation by randomization

16. Allocation of study regimes 2-randomization • Random = governed by chance • Randomization = allocation of individuals to groups by chance • Each sampling unit has the same chance of selection • Makes intervention and control group comparable at the start of the investigation • Favourable effect on those reading the published result

17. Allocation of study regimes 3-randomization • Simple randomization • First option • Stratified randomization • Classified into subgroups before randomization • Randomize within subgroups • (if sample size is limited) • blocking • Methods: • Table of random numbers • Computer generated randomization-list • Sealed envelopes • Telephone lists • ………..

18. Allocation of study regimes 4-potential bias • Knowledge on study regimes might influence the evaluation of the outcome • Blinding • Hiding information about the allocated study regimes from key participants in a trial • Depending on outcome of interest • Ethics, feasibility, compromise

19. Allocation of study regimes 5- potential bias • Placebo • Inert medication or prosedure, i.e • No effect • Intended to give the patient the perception they are receiving treatment • Single – blind • Observer or subject are kept ignorant about allocated study regime • Double blind • Both observer and the subject are kept ignorant about allocated study regime

20. Follow-up of participants 1- adherence • Adherence = Health related behaviour that abides by the recommendations from the investigator • Possible reasons for non-adherence • Developing side effects • Forgetting to take medication • Withdrawing consent • Decide alternative treatment • Health issues: treatment contraindicated • Extent of non-adherence is related to length of study time

21. Follow-up of participants 2-adherence • Non-adherence will decrease the statistical power to detect the true effect of the study intervention • Strategies to enhance adherence • Selection of interested/reliable study population (generelizability) • Frequent contact with participants • Monitoring adherence (difficult to measure) • Self report • Pill counts • Biochemical parameters

22. Follow-up of participants 3ascertainment of outcome of interest • Uniform ascertainment – all study groups • Complete follow-up of all study participants • Keep number of individuals lost to follow-up an aboslute minimun

23. Factorial design • Advantage • Answer two or more questions in a single trial for only a marginal increase in cost • Should not • Complicate trial operation • Affect eligibility reqirements • Cause side effects – poor adherence • Interaction between study regimes

24. Early termination of a trial- stopping rules • Possible reasons for early termination/modifcation • Data indicates clear benefit from intervention • Intervention is harmful • Develop guidelines before trial begins • Statistical tests • Interim data • Interim results to be modified by independent body

25. Analysis and interpretation • Compare baseline characteristics in study groups to assess balance • If imbalance, control for known confounding factors • Inclusion or exclusion of non-adherent participants in analysis? • Randomization is done on the basis of OFFERING intervention • analysis on the same basis • Non-adherence may be related to factors that also affect the risk of outcome under study • Failure to include all subjects allocated to one study regime will lead to biased results • Intention to treat analysis • All subjects allocated to one study regime are analyzed together

26. Population hierarchy for intervention study Reference population Experimental population Exclusion criteria Informed consent Excluded Refused Study population Random allocation Intervention group Control group Losses to follow-up Losses to follow-up Outcome

27. Unique problemes of intervetion studies • Ethics • Sufficients doubts to withold from half the population • Sufficient believes to expose half the population • Requires high scientific standards • Feasibility • Widespread adaption of measures by community • Problems of finding sufficiently large eligeble sample size • Costs • Expensive

28. Publication • Ensure a comprehensive, publically available database on RCTs • International Committée of Medical Journals Editors (ICMJE) • Registration of all clinical trials (1July, 2005) • Registration before enrollment of participants • Only registered trials will be published • Consort statement • Checklist • Flow chart

31. Summary • Gold standard in epidemiological research • Makes study groups comparable • Random allocation • Sufficient sample size • Unique problems of ethics, feasibility and costs • Ensure transparancy of all trials