This document discusses randomized controlled trials (RCTs). It defines RCTs as epidemiological experiments that randomly allocate subjects to study and control groups to receive or not receive an experimental procedure or intervention. The document outlines the advantages of RCTs in evaluating treatments and determining causality. It describes the typical steps in conducting an RCT, including developing a protocol, randomizing subjects, administering interventions, following up, and assessing outcomes. It also discusses types of RCTs, ethical considerations, and ways to assess RCT quality.

1. Randomized Controlled Trials
Prof. Aboubakr Elnashar
Benha university Hospital, Egypt
elnashar53@hotmail.com
ABOUBAKR ELNASHAR

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4. CONTENTS
1.DEFINITION
2.ADVANTAGES AND DISADVANTAGES
3.STEPS IN CONDUCT OF RCT
4.TYPES OF RANDOMIZED CONTROLLED TRIALS
5.ETHICAL ISSUES IN CLINICAL TRIALS
6.QUALITY ASSESSMENT OF RCT
CONCLUSIONS
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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)
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6. Randomized Controlled Trial (RCT)
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7.  Patients are followed over time (prospective)
 RCT:
 evaluate effectiveness of drugs, exercise, diet,
counseling, …………….
 determine cause and effect.
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8. 2. Advantages and Disadvantages
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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
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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
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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
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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
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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.
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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).
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17.  Methods
1. Random assignment
2. Table of random numbers
3. Computer generated list
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19.  Types of randomization
1. Random (simple) assignment:
 Flip a coin
o“Heads”—tx A
o“Tails”—tx B
 Roll a six-sided dice
oEven number—tx A
oOdd number—tx B
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20.  Alphabetical
 Tx A = patients with last name A–M
 Tx B = patients with last name N–Z
 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
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21. Simple randomisation
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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,……..
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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).
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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
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25. Stratified randomisation
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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.
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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
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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.
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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.
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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
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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]
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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.
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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
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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
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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.
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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.
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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
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39. Cross over
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40. INTERVENTION
SUBJECTS
CONTROL
RANDOM
ALLOCATION
PERIOD 2
CROSS OVER DESIGN
PERIOD 1
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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]
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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.
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43. 1. superiority trials" (most)
– statistically significant
2. noninferiority trials”
– new treatment no worse than existing Rx
3. equivalence trials"
- x2 Rx indistiguishable
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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
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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
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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
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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).
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48. Ethical clearance
1. Institutional review boards
2. Ethical committees
3. Indian Counsel Medical Research (ICMR)
guidelines
4. Federal/state guidelines
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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
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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. Investigator’s brochure
6. Available safety information
7. Information about payments and compensation
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52. 6. QUALITY ASSESSMENT OF RCT
I. Checklist approach
II. Quality scoring system approach
 Complicated
 vary depending on the instrument used
 not encouraged
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53. I. Checklist approach
1.
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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.
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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.
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56. CONSORT: checklist and flow diagram
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58. Flow diagram of the progress through the phases of a randomized trial
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59. Flow diagram of the progress through the phases of a randomized trial
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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
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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.
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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
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2.Slide share web site
3.elnashar53@hotmail.com
4.My clinic: Elthwara St. Mansura