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. Intervention studies Therapeutic Study population Objectives
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

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 3 ascertainment 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 Should not
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