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Randomized Controlled Trial
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Randomised controlled trials

  1. 1. Randomized controlled trials The Basics
  2. 2. Definition <ul><li>RCT is a study in which a group of investigators studies two interventions in a series of individuals who receive them in a random order. </li></ul><ul><li>Intervention to be tested is called the experimental group </li></ul>
  3. 3. <ul><li>The other intervention is regarded as a standard of comparison or control, and the group of participants who receive it is called the control group. </li></ul><ul><li>The control can be conventional practice, a placebo, or no intervention at all </li></ul>
  4. 4. Schema of a simple trial Eligible patients Rx group 1 Rx group 2 Randomize
  5. 5. Why Randomize? <ul><li>Compare groups at the end of the trial </li></ul><ul><li>Difference is because of the Rx </li></ul><ul><li>For this you need comparable groups </li></ul><ul><li>Purpose of randomization is to make the treatment groups comparable </li></ul><ul><li>Ensures that only difference in groups is due to trial treatments </li></ul>
  6. 6. RCT <ul><li>‘ the most powerful tool in modern clinical research “ </li></ul><ul><li>Prospective </li></ul><ul><li>Controlled </li></ul><ul><li>unbiased </li></ul>
  7. 7. What is wrong with non-randomized studies? <ul><li>Two main types of study, those with and those without concurrent control groups </li></ul>
  8. 8. Non-randomized studies II <ul><li>Without concurrent controls </li></ul><ul><ul><li>Uncontrolled </li></ul></ul><ul><ul><ul><li>cannot really make much of such studies if there is any variation in outcomes. </li></ul></ul></ul><ul><ul><li>Historical controls </li></ul></ul><ul><ul><ul><li>type of patient may change, due to eligibility criteria </li></ul></ul></ul><ul><ul><ul><li>environment changes, due to trial </li></ul></ul></ul><ul><ul><ul><li>data quality often quite different between groups </li></ul></ul></ul>
  9. 9. Non-randomized studies III <ul><li>Non-randomized concurrent controls </li></ul><ul><ul><li>Alternation </li></ul></ul><ul><ul><li>Odd/Even hospital no. or date of birth </li></ul></ul><ul><ul><li>First letter of surname </li></ul></ul><ul><li>Difficult to argue that one group is different from another but allocation is predictable, so bias can arise from selection of patients </li></ul><ul><ul><li>so randomization must be unpredictabl e </li></ul></ul>
  10. 10. Random allocation <ul><li>all participants have the same chance of being assigned to each of the study groups </li></ul><ul><li>the purpose is to keep both groups as similar to each as possible at the start of the trial. </li></ul>
  11. 11. Is coin tossing OK? <ul><li>OK for big trials </li></ul><ul><li>For small trials, such ‘simple randomization’ can lead to imbalance in group sizes </li></ul>
  12. 12. Example: trial with 30 patients <ul><li>If 30 patients are in a trial randomized using coin tossing there is a 14% chance of 15:15 split </li></ul><ul><li>For 16:14 chance is 27% </li></ul><ul><li>‘ Worse’ than 20:10 is 10% </li></ul><ul><li>Why ‘worse’? </li></ul><ul><li>Because imbalance leads to loss of power </li></ul>
  13. 13. But we need randomization <ul><li>to be done properly </li></ul><ul><li>to ensure similar numbers in groups </li></ul><ul><li>To combine with stratification - in large trials- to ensure comparability for prognostic factors </li></ul>
  14. 14. Pseudo-randomisation <ul><li>Alternating record number </li></ul><ul><li>Date of birth </li></ul><ul><li>Geographical distribution </li></ul><ul><li>Open list </li></ul>
  15. 15. True randomization <ul><li>Need to separate the person who generates allocation from those who assess eligibility </li></ul><ul><li>Third party schemes </li></ul><ul><ul><ul><li>Telephone randomization service </li></ul></ul></ul><ul><ul><ul><li>Pharmacy randomization </li></ul></ul></ul><ul><ul><ul><li>Web-based service? </li></ul></ul></ul><ul><li>Envelopes </li></ul><ul><ul><ul><li>Sealed envelopes (preferably opaque) </li></ul></ul></ul>
  16. 16. Value of randomization <ul><li>it reduces the risk of serious imbalance in unknown but important factors that could influence the clinical course of the participants. </li></ul>
  17. 17. Types of RCTs <ul><li>RCTs according to whether the investigators and participants know which intervention is being assessed </li></ul><ul><li>Open trials </li></ul><ul><li>Single blind trials </li></ul><ul><li>Double blind trials </li></ul><ul><li>Triple blind trials </li></ul>
  18. 18. <ul><li>RCTs according to how the participants are exposed to the interventions </li></ul><ul><li>Parallel trials </li></ul><ul><li>Crossover trials </li></ul><ul><li>Trials with factorial design </li></ul>
  19. 19. Blinding <ul><li>The best way to protect a trial against is by keeping the people involved in the trial unaware of the identity of the interventions for as long as possible </li></ul>
  20. 20. Blinding <ul><li>Could be single </li></ul><ul><li>Could be double </li></ul><ul><li>Could be triple </li></ul>
  21. 21. Blinding is difficult <ul><li>Having placebo in the same shape , formula and taste is very costly, and time consuming. </li></ul><ul><li>The drug side effects e.g. local reaction at the site of injection would partially unblind . </li></ul><ul><li>Impossible if surgical and medical treatments are compared. </li></ul><ul><li>The need for urgent unblinding code in case of serious side effects </li></ul>
  22. 22. Follow up <ul><li>Adherence to the study protocol </li></ul><ul><li>Patients compliance with treatment and follow up </li></ul><ul><li>sufficiently long and complete </li></ul>
  23. 23. Analysis of clinical trials Analysis of clinical trials Intension to treat analysis Per protocol analysis Sub group analysis
  24. 24. Disadvantages of RCTs <ul><li>expensive: time and money; </li></ul><ul><li>volunteer bias; </li></ul><ul><li>ethically problematic at times. </li></ul>
  25. 25. Interim Analysis <ul><li>Done in large multicenter RCTs </li></ul><ul><li>To explore the results after recruiting of half of the participants </li></ul><ul><li>If marked difference is recognized , then trial should be stopped </li></ul><ul><li>Examples: WHI trial </li></ul><ul><li> Breech Trial </li></ul><ul><li> AIDS trial </li></ul>
  26. 26. RCTs <ul><li>The gold standard for therapeutic research </li></ul><ul><li>Basis for Meta-analysis </li></ul><ul><li>Search for it first </li></ul>
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