Types of rct concepts and application

RCT, Epidemiology

1. TYPES OF RCT-CONCEPTS AND APPLICATION DR.SHIBASISH BANERJEE MD(PGT) COMMUNITY MEDICINE SESSION:2014-2017 BURDWAN MEDICAL COLLEGE AND HOSPITAL MODERATOR-DR.SIMA ROY 1

2. Types of Epidemiological Study 2

3. History Ambroise pare (1510-1590) –Unintentional unplanned trial during treatment of wound with burning oil one group and digestive made of oil of rose, turpentine oil and egg yolk another group. James Lind- A planned trial of scurvy at 1747 over 12 sailors 47 year later he repeated this on entire ship and the Admiralty made lemon juice a required part of the standard diet of British seamen 3

4. The Quasi-Experimental Design Experimental design Random allocation not done due to ethical problem and practical feasibility Two types Non randomized concurrent trial Trial using historical control 4

5. Continued…. Non-Randomized Concurrent trial- The subjects keep entering the study and are divided into the two groups, not by random allocation by the investigator but by various other circumstances Example- patients of IHD may automatically get divided (depending on their clinical condition, ability to pay etc.) into a group who would continue on medical management and another who would go up for surgical treatment 5

6. Continued…. Before and After trial using Historical control : The results of a new medical procedure can be compared with the results that used to come up before the procedure was available . Example: the results of selective vagotomy may be compared with the earlier results when truncal (and not selective) vagotomy was used. 6

7. The Disadvantages of Quasi - Experimental Design Intervention and control group may not be comparable “Selection” factors may be operating; e.g. patients who are taken into surgical treatment group for IHD may be in a much better state of cardiovascular function as compared to medical treatment group. 7

8. Continued…. Improvement noticed in a ‘before and after trial’ may simply be because other patient management techniques may also have improved recently; or else because the data collected earlier was incomplete or erroneous. 8

9. So what to do? To know the efficacy of any preventive ,therapeutic or public health policy it is necessary to maintain non- predictibility in group allocation which is not possible in quasi experimental design. That is why in modern epidemiology RCT is preferred experimental design. 9

10. Definition of RCT A randomized controlled trial is an epidemiological experiment designed to study the effects of a particular intervention( therapeutic, preventive or public health policy )in which study population are randomly (i.e. by chance)allocated to intervention and control equivalent groups and the results are assessed by comparing outcomes.(Bonita 2 nd edition) 10

11. Objective of RCT To eliminate the possibility of predictability . To eliminate bias 11

12. Basic Design of RCT 12

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14. Steps of RCT Drawing a protocol Selecting Population Randomization Manipulation Follow-up Assessment of outcome Reporting 14

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16. Bias in RCT Subject Variation Observer Bias Bias in evaluation Publication bias 16

17. Blinding overcome these errors and bias Single Blind Trial Double Blind Trial- Most preferred Triple Blind Trial 17

18. Different designs of RCT Stratified RCT Cross over design Factorial design Cluster RCT Non-inferiority or Equivalence RCT Superiority RCT 18

19. Stratified Randomization In stratified randomization, we first stratify(stratum = layer) our study population by each variable that we consider important, and then randomize participants to treatment groups within each stratum. Can be done with most important prognostic indicator eg . Age,sex 19

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21. Cross over Design Planned Crossover- Each patient can serve as his or her own control, holding constant the variation between individuals in many characteristics that could potentially affect a comparison of the effectiveness of two agents in same disease Unplanned crossover-Here some study subjects of one group may be allocated to other group due to deterioration of condition or refusal of taking one group of treatment in same disease 21

22. Advantage of Planned Crossover Each subject serves as his or her own control Less sample size Improves on the ethical considerations since all subjects are exposed to both therapies, thus nobody is denied of the potential advantages of a particular therapy Efficacy of different doses of same drug can be compared 22

23. Drawback of Planned Crossover Carryover effect and wash out period order in which the therapies are given may elicit psychological responses Not possible if the new therapy is surgical or if the new therapy cures the disease. Blinding sometimes not possible e.g. one therapy oral and another parenteral 23

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25. Drawback of Unplanned crossover Pose a serious challenge in analyzing the data Current practice is to perform the primary analysis by “ intention to treat” or analyse as you randomize “ per protocol analysis” reduce the benefit of randomization Too many crossover difficult to interpret No of crossover should be kept minimum 25

26. Unplanned crossover in a study of cardiac bypass surgery and the use of intention to treat analysis. A, Original study design. B-D, Unplanned crossovers. E, Use of intention to treat analysis 26

27. Factorial Design Two testing drug of independent mechanism can be tested simultaneously Economical Time consuming Less sample size Efficacy of two drugs can be analysed separately Termination of trial can be done separately 27

28. Factorial design for studying the effects of two treatments. 28

29. Factorial design used in a study of aspirin and beta-carotene.(Physician Health Study) 29

30. Factorial design of the study of aspirin and beta-carotene in 2 × 2 table format.   30

31. Analysis of Factorial Design 31

32. Cluster RCT Cluster randomization trials are experiments in which intact social units or clusters of individuals rather than independent individuals are randomly allocated to intervention groups 32

33. Example of CRT Medical practices selected as the randomization unit Communities selected as the randomization unit Hospitals selected as the randomization unit in trials 33

34. Reasons for Adopting Cluster Randomization Intervention naturally applied at the cluster level Administrative convenience To avoid treatment group contamination To obtain cooperation of investigators To enhance subject compliance 34

35. Challenges of CRTs Unit of Randomization vs. Unit of Analysis Critical design Large no of sample and multiple cluster Analysis depends on design Blinding not possible always More chance of Post randomization recruitment bias( Zelen design) Selecting unit of inference 35

36. Name of Some CRTS Control of sexually transmitted diseases for AIDS prevention in Uganda: a randomized community trial Promotion of Breastfeeding Intervention Trial (PROBIT) A Randomized Trial in the Republic of Belarus Effect of a participatory intervention with women’s groups on birth outcomes in Nepal: cluster-randomized controlled trial 36

37. PROBIT Trial 37

38. Equivalence Study Also called non-inferiority study Efficacy of new cheaper therapies are compared with existing expensive treatment Specially HIV drug 38

39. Superiority Study Newly developed agents are evaluated whether they are more effective than existing one 39

40. Types of RCT Clinical Trial Field Trial Risk Factor Trial Health Services Evaluations Trials Cessation Experiment Trial of Etiological agent 40

41. Clinical Trial The “unit of study” in a clinical trial are “patients” suffering with a given disease, the therapy of which is to be studied. Examples are drug trials, trials of surgical procedures or other medical therapeutic procedures concerned with individual patient care. 41

42. Field Trial The unit of study are healthy individuals, usually in the community. The trial is usually undertaken in respect of a preventive procedure as a vaccine, sera, chemoprophylaxis, personal protective measures, etc. For example, the trial of injectable polio vaccine 42

43. Risk Factor Trial Same as preventive trial except intervention is a “conceptual” procedure e.g. asking a group of subjects (randomly selected, of course) to start “regular physical exercise”, Here, regular physical exercise is the “intervention” of interest which is not physically administrated (like a vaccine or drug) but is rather a “conceptual” procedure 43

44. Health Services Evaluations Trials Basically, the architecture is the same as that of community intervention trials, with an added element of health economic analysis e.g. “whether to provide 10 Doctors or 100 Multipurpose health workers within the same budget” or “whether to provide free oral rehydration salt packets or else to provide health education to mothers” etc 44

45. Cessation Experiment A harmful factor is “removed” from the intervention group contemporary of “risk factor trial” e.g. a group of smokers, free of IHD, may be randomly divided into two groups, and one group may be asked to give up smoking, while the other group continues to smoke; the two groups are then followed up for development of IHD 45

46. Trial of Etiological agent To confirm an etiological hypothesis Example-Trial for Retrolental Fibroplasia in preterm newborn 46

47. Sample Size of RCT The difference in response rates to be detected An estimate of the response rate in one of the groups Level of statistical significance (α) The value of the power desired (1 − β) Whether the test should be one-sided or two-sided 47

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50. Noncompliance Overt or Covert Dropouts Drop-ins Reduce the observed differnce between two group Can be checked by urine test of metabolites,providing detailed list of OTC drug Piloting and include compliers only?????!!!! 50

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54. Generalizability of Results Internal validity External validity (Generalizability) To generalize the results information of what extent of study population are representative of defined population is necessary Generalization can also be done to total population if sample size is large enough and trial is multicentric Characterize non-participants and identify the differences from participants 54

55. Advantages of RCT Gold standard for evaluating the efficacy of therapeutic, preventive and other measures in both clinical medicine and public health Removes biases Create two comparable groups Ensures temporal relationship between exposure and outcome Builds up “faith” in the findings of the study. 55

56. Disadvantages of RCT Study of “risk factors” or “prognostic factors”, one can not “randomly” allocate human beings into two groups Sometimes it may not be ethical to randomly divide, thus exposing the ‘exposed’ group to a potentially harmful treatment or procedure; or to deprive the ‘non exposed’ group of a potentially useful measures 56

57. Continued… Unfortunately, most randomized trials do not provide the information the physician would need to characterize an individual patient sufficiently to predict what responses his/her patient might have to the therapies available Participants in randomized trials are usually not representative of the general population every time 57

58. Continued… Publication bias i.e hiding negative trial is an issue of concern Costly Time consuming 58

59. Some Example of RCT The Hypertension Detection and Follow-up Program The Multiple Risk Factor Intervention Trial Trial of Arthroscopy to Placebo Breast cancer and tamoxifen UKPDS(United kingdom Prospective Diabetic Study 59

60. . Design of the Hypertension Detection and Follow-up Program (HDFP). DBP, diastolic blood pressure. 60

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62. CONSORT The CONSORT statement (Consolidated Standards of Reporting Trials) comprises a checklist of essential items that should be included in reports of RCTs and a diagram for documenting the flow of participants through a trial. It is aimed at primary reports of RCTs with two group, parallel designs. 62

63. Continued… The objective of CONSORT is to provide guidance to authors about how to improve the reporting of their trials. Trial reports need be clear, complete, and transparent focuses on items related to the internal and external validity of trials. 63

64. Continued… Report should include information about approval by an ethics committee, obtaining informed consent from participants, and, where relevant, existence of a data safety and monitoring committee. 64

65. Flow diagram of the progress through the phases of a parallel randomised trial of two groups (that is, enrolment, intervention allocation, follow-up, and data analysis) 65

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68. Sources Epidemiology Leon Gordis 5th Edition Jekel’s Epidemiology 4 th Edition MODERN Epidemiology Rothman 3 Rd Edition Basic Epidemiology Bonita 2 nd Edition Who Afmc Book JAMA THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION · JANUARY 2001 www.consort-statement.org . 68

69. Continued… American Journal of Public Health > March 2004 > Design and Analysis of Group-Randomized Trials Current Issues in the Design of Cluster Randomization Trials by Allan Donner, PhD, FRSC Department of Epidemiology and Biostatistics The University of Western Ontario London, Canada 69

70. Continued… Journal of Evaluation in Clinical Practice, 11 , 5, 479–483 Cluster randomized controlled trials Suezann Puffer BSc,1 David J. Torgerson PhD2 and Judith Watson PhD3 1Research Assistant, 2Director, 3Research Fellow, York Trials Unit, Department of Health Sciences, University of York, York, UK 70

71. Thank You 71