Randomized controlled trials (RCTs) are considered the gold standard for evaluating the efficacy of therapeutic, preventive, and other measures. There are different types of RCT designs, including stratified, crossover, factorial, and cluster RCTs. Key steps in conducting an RCT include developing a protocol, selecting and randomizing a study population, implementing the intervention, following up participants, and assessing outcomes. RCTs aim to reduce biases by creating comparable intervention and control groups through randomization. While powerful, RCTs also have limitations such as cost, time requirements, and lack of applicability to entire populations. Reporting guidelines like CONSORT provide guidance on transparently reporting RCT methods and results.

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
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2. Types of Epidemiological Study
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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.
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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.
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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.
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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 2nd
edition)
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11. Objective of RCT
• To eliminate the possibility of predictability .
• To eliminate bias
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12. Basic Design of RCT
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13. Continued…
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14. Steps of RCT
• Drawing a protocol
• Selecting Population
• Randomization
• Manipulation
• Follow-up
• Assessment of outcome
• Reporting
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15. 15

16. Bias in RCT
• Subject Variation
• Observer Bias
• Bias in evaluation
• Publication bias
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17. Blinding
• overcome these errors and bias
• Single Blind Trial
• Double Blind Trial- Most preferred
• Triple Blind Trial
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18. Different designs of RCT
• Stratified RCT
• Cross over design
• Factorial design
• Cluster RCT
• Non-inferiority or Equivalence RCT
• Superiority RCT
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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
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20. 20

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
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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
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24. 24

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
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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
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37. PROBIT Trial
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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

48. Continued…
48

49. Continued…
49

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

51. Continued…
51

52. Continued…
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53. Continued…
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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.
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61. 61

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)
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66. 66

67. 67

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