Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.
-
Upload
olivia-chavez -
Category
Documents
-
view
219 -
download
0
Transcript of Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.
![Page 1: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/1.jpg)
Randomized controlled trials
Hilde Kløvstad
Tallin, 6 September 2005
![Page 2: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/2.jpg)
Contents
• Why randomized controlled trials?
• Design and conduct– Selection of study population– Allocation of study regimes– Follow-up of participants– Analysis and interpretation– Publication
![Page 3: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/3.jpg)
Question design
• We need different studies to answer different study questions
• The study question decides what design
![Page 4: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/4.jpg)
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)
![Page 5: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/5.jpg)
Different study designs
Epidemiological studies
Analytical studies Descriptive studies
Observational studies
Experimental studies
Ex. Case –controlCohort
Ex. RCT
![Page 6: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/6.jpg)
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
![Page 7: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/7.jpg)
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
![Page 8: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/8.jpg)
Why RCT?
• ”Gold standard” in epidemiological research
• Makes study groups comparable– Controls for confounding (known and
unknown)
– Prevents selection bias
![Page 9: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/9.jpg)
Intervention studies
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
![Page 10: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/10.jpg)
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
![Page 11: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/11.jpg)
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
![Page 12: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/12.jpg)
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
![Page 13: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/13.jpg)
Population hierarchy for intervention study
Reference population
Experimental populationExclusion criteriaInformed consent
ExcludedRefused
Study population
Intervention group Control group
Outcome
Losses to follow-up Losses to follow-up
Random allocation
![Page 14: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/14.jpg)
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 participateStudy results generizable beyond trial group
![Page 15: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/15.jpg)
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
![Page 16: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/16.jpg)
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
![Page 17: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/17.jpg)
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– ………..
![Page 18: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/18.jpg)
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
![Page 19: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/19.jpg)
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
![Page 20: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/20.jpg)
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
![Page 21: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/21.jpg)
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
![Page 22: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/22.jpg)
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
![Page 23: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/23.jpg)
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
![Page 24: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/24.jpg)
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
![Page 25: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/25.jpg)
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
![Page 26: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/26.jpg)
Population hierarchy for intervention study
Reference population
Experimental populationExclusion criteriaInformed consent
ExcludedRefused
Study population
Intervention group Control group
Outcome
Losses to follow-up Losses to follow-up
Random allocation
![Page 27: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/27.jpg)
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
![Page 28: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/28.jpg)
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
![Page 29: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/29.jpg)
![Page 30: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/30.jpg)
![Page 31: Randomized controlled trials Hilde Kløvstad Tallin, 6 September 2005.](https://reader034.fdocuments.in/reader034/viewer/2022052315/5514ad5f550346b2598b60ea/html5/thumbnails/31.jpg)
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