Randomized controlled trials. Aboubakr Elnashar

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Randomized Controlled Trials Prof. Aboubakr Elnashar Benha university Hospital, Egypt [email protected] ABOUBAKR ELNASHAR

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  1. 1. Randomized Controlled Trials Prof. Aboubakr Elnashar Benha university Hospital, Egypt [email protected] ABOUBAKR ELNASHAR
  5. 5. 1. DEFINITION 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) ABOUBAKR ELNASHAR
  6. 6. Randomized Controlled Trial (RCT) ABOUBAKR ELNASHAR
  7. 7. Patients are followed over time (prospective) RCT: evaluate effectiveness of drugs, exercise, diet, counseling, . determine cause and effect. ABOUBAKR ELNASHAR
  8. 8. 2. Advantages and Disadvantages ABOUBAKR ELNASHAR
  9. 9. RCT may not be possible or practical 1. Not ethical/possible to assign intervention Cigarette smoking and lung cancer H. pylori infection and ulcers 2. Impractically large sample size Very low-incidence outcome e.g., rare side effect of medication 3. Impractically long duration Outcome requires many years to develop e.g., development of cancer ABOUBAKR ELNASHAR
  12. 12. 3. STEPS IN CONDUCT OF RCT 1. The protocol 2. Selecting reference and experimental populations 3. Randomization 4. Intervention 5. Follow up 6. Assessment of outcome ABOUBAKR ELNASHAR
  13. 13. 1. The Protocol 1. Rationale 2. Aims & objectives, Questions to be answered 3. Design of the study: 1. Criteria of selection: Study & control groups 2. Intervention to be applied 3. Standardization of working procedures 4. Ethics: patient consent, adverse events 5. Documentation ABOUBAKR ELNASHAR
  14. 14. 2. Selecting Reference and Experimental Populations a. Reference or target population Population to which the findings of the trial are expected to be applicable (eg. drugs, vaccines, etc.) b. Experimental or study population It is derived from the reference population. Ideally should be randomly chosen from the reference population. Sample size should be deermined: sufficient statistical power to detect differences between groups ABOUBAKR ELNASHAR
  15. 15. 3. Randomization Procedure: Done only after the participant has entered the study Participants are allocated into study and control groups every individual gets an equal chance of being allocated into either group. ABOUBAKR ELNASHAR
  16. 16. Goals of randomization 1. Equal Group Sizes for Adequate Statistical Power (Especially Subgroup Analyses) 2. Low selection bias (investigator cannot predict the next subject's group assignment by examining which group has been assigned the fewest subjects up to that point) 3. Low probability of confounding (i.e., a low probability of "accidental bias"), (i.e. a balance in covariates across groups). ABOUBAKR ELNASHAR
  17. 17. Methods 1. Random assignment 2. Table of random numbers 3. Computer generated list ABOUBAKR ELNASHAR
  19. 19. Types of randomization 1. Random (simple) assignment: Flip a coin oHeadstx A oTailstx B Roll a six-sided dice oEven numbertx A oOdd numbertx B ABOUBAKR ELNASHAR
  20. 20. Alphabetical Tx A = patients with last name AM Tx B = patients with last name NZ Telephone number/social security number Tx A = last digit odd Tx B = last digit even Sequential Tx A = morning patients Tx B = afternoon patients Bed number Tx A = odd bed number Tx B = even bed number ABOUBAKR ELNASHAR
  21. 21. Simple randomisation ABOUBAKR ELNASHAR
  22. 22. 2. Block randomization: Subjects are divided into blocks and randomization is carried out in each blocks. Ex: for two treatments and a block size of four, two of every four consecutive patients would receive the experimental therapy and the other two would receive control therapy. EECC,ECEC, ECCE, CCEE, CECE,.. ABOUBAKR ELNASHAR
  23. 23. 3. Stratified randomization: Ensure that the treatment and control groups are balanced on important prognostic factors that can influence the study outcome (e.g., gender, ethnicity, age, socioeconomic status). ABOUBAKR ELNASHAR
  24. 24. Stratified randomization Stratify, then do block randomization Male; 25-44 yrs ABBA BBAA BABA ABAB BAAB Female; 45-60 yrs AABB ABBA BBAA BABA ABAB ABOUBAKR ELNASHAR
  25. 25. Stratified randomisation ABOUBAKR ELNASHAR
  26. 26. 4. Manipulation/Intervention Manipulation creates an independent variable: drug, vaccine, new procedure, dietary component, habit whose effect is then determined by the measurement of the final outcome, which constitutes the dependant variable incidence of disease, survival time, recovery period. ABOUBAKR ELNASHAR
  27. 27. 5. Follow Up Examination of the experimental and control group subjects at defined intervals of time There may be loss of subjects from either group due to a number of reasons. This is called as attrition. Death Migration Loss of interest ABOUBAKR ELNASHAR
  28. 28. 6. Assessment Positive results Negative results Errors in assessment can lead to Bias. Bias can arise from three sources: 1. Subject variation 2. Observer bias 3. Evaluation Bias Randomization cannot guard against these sort of bias. To avoid the above situations, Blinding is done. ABOUBAKR ELNASHAR
  29. 29. Blinding can be done in three ways 1. Single blind trial: Participant is not aware whether he belongs to the study group or control group 2. Double blind trial: Neither the doctor nor the participant is aware of the group allocation and the treatment received 3. Triple blind trial: The participant, the investigator and the person analyzing the data are all "blind". Ideally, of course, triple blinding should be used; but double blinding is the most frequently used method when a blind trial is conducted. ABOUBAKR ELNASHAR
  31. 31. Design of RCT Reference population Experimental population Exclusion criteria Informed consent Excluded Refused Study population Intervention group Control group Outcome Losses to follow-up Losses to follow-up Random allocation ABOUBAKR ELNASHAR
  32. 32. Flowchart of 4 phases (enrollment, intervention allocation, follow-up, and data analysis) of a parallel randomized trial of two groups, modified from the CONSORT (Consolidated Standards of Reporting Trials) 2010 Statement[1] ABOUBAKR ELNASHAR
  33. 33. Trial registration In 2004, the International Committee of Medical Journal Editors (ICMJE) announced that all trials starting enrolment after July 1, 2005 must be registered prior to consideration for publication in one of the 12 member journals of the committee. ABOUBAKR ELNASHAR
  34. 34. Avoidance of bias 1. Use of a control group Placebo Most widely accepted treatment Most accepted prevention intervention Usual care Accepted means of detection 2. Blindness 3. Allocation concealment 4. Randomization ABOUBAKR ELNASHAR
  35. 35. 4. TYPES OF RANDOMIZED CONTROLLED TRIALS I. Based on randomization: 1. Randomized controlled trials: where randomization is used for allocation of products and / or subjects. 2. Non-randomized or non-experiment or quasi-experiment: those departing from strict randomization for practical purposes in such a manner that non-randomization does not seriously affect the theoretical basis of conclusions e.g. natural experiments, water fluoridation studies ABOUBAKR ELNASHAR
  36. 36. II. Based on study designs: 1. Parallel study design: Comparisons are made between two randomly assigned groups, one group exposed to specific treatment, and the other group not exposed. Patients remain in the study group or the control group for the duration of the investigation. ABOUBAKR ELNASHAR
  37. 37. 2. Factorial Design: more efficient than a parallel design if there is an interest in studying more than one intervention at a time. Each participant is randomly assigned to a group that receives a particular combination of interventions or non-interventions e.g: group 1 receives vitamin X and vitamin Y group 2 receives vitamin X and placebo Y, group 3 receives placebo X and vitamin Y group 4 receives placebo X and placebo Y. ABOUBAKR ELNASHAR
  38. 38. 3. Cross-over study designs: Each patient serves as his own control. Patients are randomly assigned to a study group and control group. The study group receives the treatment under consideration. The control group receives some alternate form of active treatment or placebo. Two treatments, two period cross-overs Must eliminate carryover effects Need sufficient washout period ABOUBAKR ELNASHAR
  39. 39. Cross over ABOUBAKR ELNASHAR
  41. 41. An analysis of the 616 RCTs indexed in PubMed during December 2006 found that 78% were parallel-group trials, 16% were crossover, 2% were split-body, 2% were cluster, and 2% were factorial.[32] ABOUBAKR ELNASHAR
  42. 42. II. Based on hypothesis which differ in methodology and reporting 1. Superiority Most RCTs are superiority trials, in which one intervention is hypothesized to be superior to another in a statistically significant way 2. Noninferiority To determine whether a new treatment is no worse than a reference treatment. 3. Equivalence the hypothesis is that two interventions are indistinguishable from each other. ABOUBAKR ELNASHAR
  43. 43. 1. superiority trials" (most) statistically significant 2. noninferiority trials new treatment no worse than existing Rx 3. equivalence trials" - x2 Rx indistiguishable ABOUBAKR ELNASHAR
  44. 44. III. Based on uses: 1. Clinical trials 2. Preventive trials 3. Risk factor trials 4. Cessation experiment 5. Trial of etiological agents 6. Evaluation of health services 7. Community intervention trials ABOUBAKR ELNASHAR
  45. 45. 5. ETHICAL ISSUES IN CLINICAL TRIALS Clinical trials should follow 3 principles: 1. Beneficence: which require that good should result, harm should be avoided, or that benefits should justify the expected risk or harm 2. Respect for rights: including the free choice of the subject and protection for those diminished autonomy 3. Justice: which require an equal distribution of burden and benefits ABOUBAKR ELNASHAR
  46. 46. How: 1. Proper information to all the study subjects 2. Informed consent 3. The trial is conducted ethically 4. Avoid bias in results 5. Sample size is adequate to give the results ABOUBAKR ELNASHAR
  47. 47. Informed consent: of all study participants The nature of informed consent may differ in different countries and cultures, but the concept of individual choice to join or not join a trial must be universal (Nuremberg Code 1949; World Medical Association 2000). ABOUBAKR ELNASHAR
  48. 48. Ethical clearance 1. Institutional review boards 2. Ethical committees 3. Indian Counsel Medical Research (ICMR) guidelines 4. Federal/state guidelines ABOUBAKR ELNASHAR
  49. 49. Institutional review board/independent ethics committee Safeguards the rights, safety, and well-being of all trial subjects. Should include: at least 5 members at least one member whose primary area of interest is in non-scientific area at least one member who is independent of the institution/trial site ABOUBAKR ELNASHAR
  50. 50. Documents which should be submitted 1. Trial protocol with amendments 2. Written informed consent form 3. Subject recruitment procedure 4. Written information provided to the subjects 5. Investigators brochure 6. Available safety information 7. Information about payments and compensation ABOUBAKR ELNASHAR
  52. 52. 6. QUALITY ASSESSMENT OF RCT I. Checklist approach II. Quality scoring system approach Complicated vary depending on the instrument used not encouraged ABOUBAKR ELNASHAR
  53. 53. I. Checklist approach 1. ABOUBAKR ELNASHAR
  54. 54. 2. Consolidated Standards of Reporting Trials (CONSORT) gold standard for reporting the results of RCTs. alleviate the problems arising from inadequate reporting of RCT. standard way for authors to prepare reports of trial findings facilitating their complete and transparent reporting aiding their critical appraisal and interpretation. ABOUBAKR ELNASHAR
  55. 55. Comprises 1. Checklist 25 items focus on reporting how the trial was designed, analyzed, and interpreted 2. Flow diagram displays the progress of all participants through the trial. ABOUBAKR ELNASHAR
  56. 56. CONSORT: checklist and flow diagram ABOUBAKR ELNASHAR
  58. 58. Flow diagram of the progress through the phases of a randomized trial ABOUBAKR ELNASHAR
  59. 59. Flow diagram of the progress through the phases of a randomized trial ABOUBAKR ELNASHAR
  60. 60. Ii. Quality score approach Jadad AR, et al. Assessing the quality of reports on randomized clinical trials: Is blinding necessary? Controlled Clin Trials1996;17:1-12. URL: http://www.bmjpg.com/rct/chapter4.html 59 ABOUBAKR ELNASHAR
  61. 61. CONCLUSIONS Gold standard of research designs Individual patients are randomly allocated to receive the experimental treatment (intervention group) or the standard treatment (control group) Maximizes the potential for attribution Good internal validity May lack generalisability due to highly selected participants Can be costly to set up and conduct, ethical issues. ABOUBAKR ELNASHAR
  62. 62. ABOUBAKR ELNASHAR You can get this lecture from: 1.My scientific page on Face book: Aboubakr Elnashar Lectures. https://www.facebook.com/groups/2277 44884091351/ 2.Slide share web site [email protected] 4.My clinic: Elthwara St. Mansura