Randomized controlled trial (RCT)- research methodology.pptx

RANDOMIZ
ED
CONTROL
TRIAL
Dr. Afaf Mohammed Rafiq

2
Contents
Part 1
• Introduction
• Types of Epidemiological studies
• RCT
• Observational studies vs RCT
• Why RCTs?
• Aims of RCT
• History
• Types of RCT
• Things to consider when planning RCT
Part 2
• Design of RCT
o Sampling
o Randomization
o Allocation concealment
o Bias & Blinding
o Quality assessment (CONSORT)
• Ethics in Research
o RCTs & Ethics
• Advantages & Disadvantages of RCT
• RCTs in orthodontics
• Conclusion
• Bibliography

3
Introduction
EPI DEMIO LOGY
UPON PEOPLE SCIENCE
The study of the distribution and determinants of health-related
states or events in specified populations, and the application of
this study to the control of health problems.
- John M Last (1988)

4
Epidemiological
studies
Observational studies
Descriptive Study
(Describes disease by
Time, Place &
Person)
Analytical Study
Cross sectional
COHORT
Case Control
Ecological
Experimental studies
Randomized
Non Randomized
Randomized control
trials/ clinical trials
(RCT)
Unit: Patient’s
Field trial
Unit: Healthy people
Community trial
Unit: community

5
RCT
“ 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 therapeutic procedure, maneuver or
intervention”
- John M Last,2001 (prominent Canadian public health scholar,
prolific author, scientist, and teacher)
Hierarchy of scientific evidence pyramid

6
IN RCT, SUBJECTS ARE ASSIGNED TO 2
GROUPS
Study/Experimental group:
receiving the intervention that
is being tested
Control/ Comparision group:
receiving an alternative
(conventional) treatment.
Dose-comparison concurrent
control: two different doses are
administered, a different one to each
group.
No treatment concurrent control:
one group is given the treatment, the
other group is given nothing.
Active treatment concurrent
control: one group is given the
treatment, and the other group is
given an existing therapy that is
known to be effective.
Placebo concurrent control: one group
is given the treatment, the other a placebo
(“sugar pill”).

7
What is the purpose of controls in clinical trials?
• Attributes changes in outcome to the intervention. Trial participants may get well or
improve under investigation as time goes on, regardless of any therapy received. For
example, a lack of control group in an investigation of class II correction will not allow
the investigator to distinguish the degree of correction that can be attributed to the tested
appliance and that which occurs due to normal mandibular growth.
• To reduce selection bias. An investigator might select participants who are expected to
respond well to the ‘new’ class II corrector, thus overestimating the true effect of the
appliance under investigation.
• Placebo effect. Study participants may respond better to treatment just because they are
included in a study and not because they are receiving any active therapy. The addition of
a control, assures a more fair comparison since the control group may also experience the
placebo effect and therefore, the difference between the two groups would be only the
effect of the treatment.

8
The relationship between observational studies and clinical trials (both
randomized and non-randomized)
Pandis N, Cobourne M T. Clinical trial design for orthodontists. J Orthod 2013; 40:93–
103
• Clinical trials are distinct from
observational studies because
participants are followed and
assessed after the assignment of a
particular therapy, which is under
the control of the investigator.
• Observational studies lack this
control, only drawing inferences
about the possible effects of a
particular exposure, which has been
allocated outside the control of the
investigator.

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Examples:
• In a cohort design, a group of children either exposed or unexposed to facial trauma may be
followed prospectively and after a period of time, the incidence of facial asymmetry
recorded for both patient groups and an assessment made as to whether exposure to trauma
is associated with facial asymmetry.
• In a case-control design, patients with facial asymmetry (cases) and patients without facial
asymmetry (controls) would be recruited and compared in terms of their previous exposure
to trauma.
• In a situation where the investigator is assigning therapy and patients are followed
prospectively, we have a clinical trial, with this design being closest to the cohort design
from the observational group. If the investigator allocates this treatment non-randomly, this
is a non-randomized controlled clinical trial but, if the allocation of the treatment
intervention to the trial arm is random, then we have a randomized controlled trial.

10
Why RCTs? A fundamental question that any researcher may ask is, why is it that evidence based on RCTs is
considered to be of the highest quality.
• The main reason for this is that evidence-based on observational data is prone to bias.
• Bias: systematic tendency of any factors to make the estimate of the effect of a treatment or
intervention deviate from its true value.
• If two or more groups are being compared in an observational study, there are often systematic differences
between the groups, so much so that the outcome of the groups may be different because of these differences
rather than actual exposure or intervention. This is known as confounding.
• Confounding: is a distortion (inaccuracy) in the estimated measure of association that occurs when the
primary exposure of interest is mixed up with some other factor that is associated with the outcome

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• RANDOMISATION: THE CORNERSTONE OF THE RCT
• The only way to eliminate these differences is to allocate each individual to one or the
other intervention at random. Therefore, the probability of any individual receiving one
intervention or the other is decided solely by chance.
• In this scenario, if the sample size is sufficient, all the factors influential in the outcome
are likely to be distributed equally between the groups, because the allocation was at
random.
• Therefore, any difference in the observed outcome between the groups is likely to be due
to the intervention rather than any other factors.
• RCTs can sometimes be unfeasible or unethical in certain situations (for example, you
could not randomize one group of individuals to trauma and one to no trauma in order to
assess the incidence of facial asymmetry!). Thus, in some scenarios, we have to use
observational studies.

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Aims of an RCT
• To provide “scientific proof” of etiological or risk factors which may permit the
modification or control of those diseases.
• To provide a method of measuring the effectiveness and efficiency of health services for
the prevention, control and treatment of diseases and improve the health of the
community.

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History
• The ideas of intentional comparison under controlled
conditions and of elementary statistical analysis appear
in medical history within two generations of the
scientific revolution of the 1600s.
• In the 1920s, “Experimental epidemiology” – meant the
study of epidemics among colonies of experimental
animals -rats and mice.
• In modern usage, experimental epidemiology is often
equated with “Randomized Controlled Trials”.

14
A History Before and Beyond James Lind
562 BC – 1537: Pre-James Lind Era
• The world’s first clinical trial is recorded in the “Book
of Daniel” in The Bible.
• This experiment resembling a clinical trial was not
conducted by a medical, but by King Nebuchadnezzar.
• The outcome of the experiment: the vegetarians
(Legumes+ water) appeared better nourished than the
meat-eaters (meat+ wine), so the king permitted the
legume lovers to continue their diet.
• This probably was one of the first times in the evolution
of human species that an open uncontrolled human
experiment guided a decision about public health.
King Nebuchadnezzar of Babylon

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562 BC – 1537: Pre-James Lind Era
• The first clinical trial of a novel therapy was
conducted accidentally by the famous surgeon
Ambroise Parè in 1537.
• As oil was not adequate to treat all the
wounded, he had to resort to unconventional
treatment viz digestive made of yolks of eggs,
oil of roses and turpentine.
• He found those to whom he had applied the
digestive medicament were feeling but little
pain, their wounds neither swollen nor
inflamed.
In 1537, Ambroise Parè while serving with the
Mareschal de Motegni he was responsible for the
treatment of the battlefield wounded soldiers.

16
1747: James Lind and Scurvy Trial
• He was appalled by the high mortality of
scurvy amongst the sailors.
• He planned a comparative trial of the most
promising cure for scurvy.
• His vivid description of the trial covers the
essential elements of a controlled trial.
• The consequence of the trial was, that the most
sudden and visible good effects were perceived
from the use of oranges and lemons; one of
those who had taken them, being at the end of
six days were fit for duty. Dr Lind (1716-94), working as a surgeon on a ship

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1800: Arrival of Placebo
• In 1886, Flint described the study in his book
A Treatise on the Principles and Practice of
Medicine. “This (herbal extract) was given
regularly and became well known in my
wards as the ‘placeboic remedy’ for
rheumatism.
• The favourable progress of the cases was such
as to secure for the remedy generally the
entire confidence of the patients.”
United States physician Austin Flint planned
the first clinical study comparing a dummy
remedy to active treatment.

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1943: The First Double blind Controlled Trial - Patulin for Common Cold
• The UK Medical Research Council’s (MRC)
trial of patulin for common cold in 1943 was
the first double-blind controlled trial.
• MRC UK carried out a trial in 1943-4 to
investigate patulin treatment for (an extract of
Penicillium patulinum) the common cold.
• However, the outcome of the trial was
disappointing as the analysis of trial data did
not show any protective effect of patulin

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1946 First Randomized Curative Trial - The Randomized Controlled Trial of
Streptomycin
• The first randomized control trial of
streptomycin in pulmonary
tuberculosis was carried out in 1946 by
MRC of the UK.
• Over the years, as the discipline of
controlled trials grew in sophistication
and influence, the streptomycin trial
continues to be referred to as ground
breaking

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IMPORTANT HISTORICAL RANDOMIZED CONTROLLED TRIAL STUDIES IN
ORTHODONTICS ON FUNCTIONALAPPLIANCES
• In the 1990s, RCT methodology had been
used by 2 NIDCR-supported projects and
carried out at the University of North
Carolina and the University of Florida.
• Participants were randomly allotted to
control group, headgear group, and functional
appliance group.
• Results showed that early treatment with
either headgear or functional appliance
therapy reduced the severity of a Class II
skeletal pattern with 75% chance of
improvement in the jaw relationship. On
average, headgear produces greater change in
the maxilla, whereas functional appliance
therapy produces greater mandibular change.
Established in 1948, the National Institute of Dental and
Craniofacial Research (NIDCR) has helped transform dentistry into
a profession that is based firmly in prevention and technological
innovation.

21
• A 3RD
NIDCR-supported trial at the
University of Pennsylvania compared
functional appliance and headgear treatment
but did not include a control group.
• Results showed that both the headgear and
function regulators are effective in correcting
the ClassII, Division 1 malocclusion of
prepubertal children.
Established in 1948, the National Institute of Dental and
Craniofacial Research (NIDCR) has helped transform dentistry into
a profession that is based firmly in prevention and technological
innovation.

22
• An another important trial at the University of
Manchester that was supported by the Medical
Research Council of the United Kingdom.
• Class II patients were randomly allocated to twin
block group and untreated control group.
• Results showed that early treatment with twin block
‑
appliance resulted in reduction of overjet, correction
of molar relationship, and reduction in severity of
malocclusion. Most of this correction was due to
dentoalveolar change, but some were due to
favourable skeletal change.

23
Randomised Controlled Trials
BASED ON STUDY DESIGNS
Concurrent parallel study design
Cross-over type of study designs
Run-In Design

24
Types of RCT based on study design
1. Concurrent Parallel Study Designs:-
• Comparisons are made between 2 randomly
assigned groups.
• One group exposed to specific treatment, and
other group not exposed.
• Patients remain in the study group or the control
group for the duration of the investigation.

25
2) Cross-over Type Of Study Designs:-
• Each patient serves as his own control.
• Study group- treatment; control group-
alternative form of treatment or placebo.
• 2 groups observed over time.
• Patients –received the treatment under study are
changed to the control group therapy / placebo,
and vice versa. Patients – taken off their medication or placebo-
eliminated of the medication from the body and for
the possibility of any carryover effects .

Sl.
No
Parameters Parallel Crossover
1 Treatment
received
Groups assigned different
treatments
Each patient receives
both treatments
2 Duration Shorter Longer
3 Sample size Large Small
4 Carryover
effect
Not seen Is seen
5 Type of
cases
Acute cases Chronic cases, stable.
26
• Parallel vs Cross-over Study Design

27
• Advantages & Disadvantages of Cross-over Type Of Study Designs

28
• Split Person Design (similar to cross over type design)
• Occasionally, it is possible to administer the two
interventions at the same time.
• Very similar to that of the cross-over trial, except there is no
equivalent to the periods or to the wash-out although a
carry-over (now termed carry-across) effect is likely to be
present.
• Split Mouth Design: Dental arches, quadrants, sextants or
individual teeth within patients are randomized for treatment.
• Applicability: evaluate site-specific therapies.

29
• 3. RUN-IN DESIGN
• For minimizing bias associated with loss to follow-up in placebo-controlled studies.
• All participants in the cohort are placed on placebo and followed for some period of
time (usually a week or two).
• Those who remain in the study are then randomly assigned to either the treatment or
placebo arm of the study.
• A limitation of this design is that the participants in the cohort at the time of
randomization may no longer reflect the population of interest.

30
• For example, recovering heart attack patients in a selected cohort could all be placed on
a new dietary intervention, and then, after a run-in period, those who are compliant
would be randomly assigned to remain on the program or change to a standard dietary
program used for recovering heart attack patients.
• The efficacy of the new dietary intervention can be assessed, but, depending on the
extent of initial dropout, it may have limited generalization to the population of heart
attack patients as a whole.

31
• 4. Factorial Design
• If there is an interest in studying more than one
intervention at a time, a factorial design is more
efficient than a parallel design.
• Two or more series of treatments are tried in all
combinations.
• Factorial designs also offer an efficient approach
for studying combination effects of treatments on
an outcome.

33
Types of RCT based on use
1. Clinical Trials
• Concerned with evaluating therapeutic agents (drugs).
• E.g.- evaluation of β- blockers in reducing
cardiovascular mortality in patient surviving the acute
phase of MI.

34
Types:
Superiority trials:
• Compare a standard treatment or intervention with a new or alternative approach anticipated to
be more effective.
Inferiority trials:
• An alternative therapy (perhaps one that is cheaper, less toxic or easier to administer) is
suggested to replace the standard provided its efficacy is no worse than the standard one.
Equivalence:
• Test treatment is required to be neither less nor more efficacious than a standard one.

35
Stanley K. Design of Randomized Controlled Trials. Circulation 2007;115:1164-1169

2. Preventive Trials
• Prevention trials imply trials of primary preventive measures.
• Purported to prevent or eliminate disease on an experimental basis.
• Most frequently occurring type- trials of vaccines and chemoprophylactic drugs
• E.g.- A trial conducted in UK by the Medical Research Council (1946) to test the
whooping cough vaccine from 3 manufacturers in10 separate field trials.
3

37
a. Risk Factor Trials
• The investigator intervenes to interrupt the usual sequence in the development of disease
for those individuals who have risk factors for developing the disease: often this involves
risk factor modification.
• Risk factor trials can be single–factor/ multi-factor trials.
• E.g.-the WHO promoted a trial on primary prevention of coronary heart disease using
clofibrate to lower serum cholesterol- accepted as a significant risk factor for CHD.

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b. Cessation Experiment
• An attempt is made to evaluate the termination of a habit/ removal of a suspected agent
which is considered to be causally related to a disease.
• E.g.- cigarette smoking and lung cancer

39
3. Trial Of Aetiological Agents
• To confirm or refute an etiological hypothesis.
• E.g. Development of retrolental fibroplasia (RLF) in premature babies due to oxygen
therapy.

40
4. Evaluation Health Services
• To assess the effectiveness and efficiency.
• Since resources are limited and priorities must be set for the implementation of a large number of
activities.
E.g. TB regimen in India – which demonstrated that “domiciliary treatment” of pulmonary
tuberculosis was as effective as the more costlier “hospital treatment”.

41
Things to consider when planning a clinical trial
1. Research question
2. Sample size
3. Control
4. Reduce bias
5. Statistical analysis
6. Proper reporting

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Things to consider when planning a clinical trial
Research
question:
Systematic
review.
Identify
unanswered
questions.
• Sample
size: Decide-
difference to
be detected,
Calculate,
• Designs
(split mouth
or factorial if
applicable,
Feasible?,
Ethical?
Control:
Appropriate
and
concurrent
control.
Use
standard
therapy
rather than
no therapy
Reduce bias:
Randomizati
on, Blinding,
Equal
treatment,
Guard
against
losses.
Statistical
analysis:
Proper
methods,
Prespecify
subgroup
analyses,
Proper
reporting:
CONSORT
guidelines,
Report all
primary and
secondary
outcomes,
Generalizabil
ity.

CONTENTS
• Design of RCT
o Sampling
o Randomization
o Allocation concealment
o Bias & Blinding
o Quality assessment (CONSORT)
• Ethics in Research
o RCTs & Ethics
• Advantages & Disadvantages of
RCT
• RCTs in orthodontics
• Conclusion
• Bibliography
PART
2

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Drawing up a protocol
Sampling- Selecting suitable samples
Reference/ Target population &
Experimental/Study population.
Make necessary exclusions:
• Not eligible or
• Those who do not give consent
Assessment:
Positive & negative
results
Follow up
Randomize
Control/ Comparison group
Experimental/ Study group
Manipulatio
n
Bias & Blinding
Analysis:
• Intention-To-Treat
Analysis.
• Per protocol analysis.
• Early stopping
Allocation
Concealment
Quality
assessment:
CONSORT
Design of an RCT Pilot study

45
1. Drawing up a protocol
• The aims and objectives of the study.
• Questions to be answered.
• Criteria for the selection of study and
control groups.
• Size of the sample.
• The procedures for allocation of subjects
into study and control groups.
• Standardization of working procedures.
• Treatments to be applied.
• Ethics: patients consent, adverse events.

46
• Preliminary Test (Pilot Study) Runs:
• Standard scientific approach that involves a preliminary analysis - can greatly improve the
chance of funding for major studies.
• Made to find out the feasibility / operational efficiency of certain procedures/ unknown
effects/ the acceptability of certain policies.
• Useful to have a short test run of the protocol- whether it contains any flaws.

47
2. Selecting reference and experimental populations
a) Reference or Target
population:-
• Population to which the
findings of the trial, if
found successful, are
expected to be applicable.
• May be as broad as
mankind or limited to
persons of specific age,
sex, occupational or social
groups.
• Ex: Population of the
whole city, school children,
industrial workers, etc.
b) Experimental or study
population:-
• Derived from the reference
population-actual population
that participate in the study.
• Should be randomly chosen
from the reference so that it
has the same characteristics –
to generalize the findings of
the study to the reference
population.
• Its also important to choose a
stable population whose
cooperation is assured to avoid
losses to follow-up.

48
• It is important to set inclusion and exclusion criteria defining target populations that are
appropriate to the research hypothesis.
• The best design is Consecutive Sampling- a sampling technique in which every subject
meeting the criteria of inclusion is selected until the required sample size is achieved.
• The participants /volunteers must fulfill the following 3 criteria:
1. Informed consent.
2. Representative of the reference population.
3. Should be qualified /eligible for the trial.

50
• Poor sampling :
―undermine the generalizability of the study
― reduce the validity if sampling bias is introduced.

51
Outcome
Experimental Population
Reference Population
Study Population
Control Group
Study Group
Losses to follow up Losses to follow up
Extrusion Criteria
Informed Consent
Random
Allocation
Excluded,
Refused
Sampling (Population Hierarchy)

52
3. Randomization
• A statistical procedure – participants are allocated into groups usually called Study and Control groups-
to receive/ not to receive an experimental preventive/therapeutic procedure, maneuver/intervention.
• It is an attempt to eliminate bias and allow for comparability.
• Heart of a controlled trial- give the greatest confidence that the groups are comparable so that like can
be compared with the like.
• Ensures –the investigators have no control over allocation- thus eliminating selection bias.
• Every individual gets an equal chance of being allocated.
• The critical element of randomization is the unpredictability of the next assignment.

53
Why Randomization?
• To assure a balance of participant
baseline characteristics and known
and unknown outcome predictors
between treatment arms. (To balance
known and unknown confounders)
• This is more likely to guarantee that
any difference in the effect of the
intervention observed is due to the
therapy and not to some other factor
or factors.
For example, if we are assessing the effect of two functional
appliances on class II correction and if we assume that age is an
important outcome predictor, an unequal age distribution between the
two treatment arms is likely to confound the association between the
intervention and the outcome

54
Types of randomization
Simple/
Unrestricted Restricted
Permuted-
Block
Minimization
Stratified Covariate adaptive
Minimization
Sequential
designs
Rolling
designs
Cluster

55
Simple Randomization (Un-Restricted
Randomization)
Simple randomization could be generated by
• Coin-tossing, dice throwing, and shuffled
cards which represent reasonable approaches
for the generation of a simple complete
randomization sequence.
• Computer random generators or table of
random numbers may be used.

56
• Permuted-Block Randomization/ Restricted Randomization.
• It is recommended to be used in small randomized control trials
when the researchers want treatment groups of equal sizes.
• A “blocked size” or “the allocation ratio” is specified and the
subjects are allocated within each block.
AB AB
AB B A
B B AA
B AB A
B AAB

57
• Allocation prediction is usually a problem in trials where
blinding is not feasible as it is often the case in
orthodontics.
• Software is available to generate randomization list using
random permuted blocks. A user-written command for
the Stata statistical software package (StataCorp, College
Station, Texas, USA) named ‘ralloc’ (Ryan, 1998) is an
excellent tool for this purpose.
Example:
Block Size: 4
Treatment Options: 2 (Treatment A,
B)
4C2 = 6 Possibilities= AABB, ABAB,
BAAB, BBAA, BABA, ABBA.
AABB

58
• Stratified Randomization
• Specific covariates must be identified by
researcher.
• Stratified randomization achieved by generating
separate block for each combination of
covariates.
• After assignment simple randomization is
performed with in each block

60
• Covariate Adaptive Randomization
• A study design in which accumulating results are observed and
the randomization scheme is adjusted so that patients enrolled
later in the trial have a higher probability of being randomized
to the treatment arm that was more effective among earlier
patients in the trial.
• Ex: Minimization, Sequential designs, Rolling designs

61
Minimization
• The randomization list is not produced before
the trial starts but rather as the trial goes on.
• Patients are randomized to the treatment or
control in order to achieve balanced arms with
respect to the pre-selected risk/prognostic
factors.

62
Sequential Design
• Here the participants are sequentially enrolled in the study and are assigned a treatment (usually at
random).
• The efficiency, safety and efficacy of the experiment is improved by changing the rules as the
study progresses.
Rolling design
• Design that can roll on continually by introducing new treatment options from the evidence
accumulated, dropping those of either proven efficacy or if found not to be effective.

63
Cluster Randomization
• Cluster randomized trials are conducted when individual randomization is
not feasible (like water fluoridation), for the sake of convenience, or when
the risk of contamination is high.
• Contamination - occurs when participants in the trial arms share
information regarding the intervention thus affecting/contaminating the
treatment groups and thus not allowing the true effect of the intervention
to be recorded due to bias.

64
• Cluster randomized trials require more patients because, within clusters, responses tend to be more
similar thus reducing statistical efficiency.
• Ex: a family, school teachers or students, a village, or even larger geographical areas.
• In orthodontics examples of clusters would be the patient’s jaws and quadrants as they include from
several to a few teeth.
• Ex: A trial participant may be a cluster contributing 20 teeth for bonding i.e; a jaw (cluster)
contributing 10, or a quadrant (cluster) contributing 5 teeth.

65
A Decision making flow
chart

66
Nikolaos Pandis N, Polychronopoulou A, Eliades T. Randomization in clinical trials in orthodontics: its significance in
research design and methods to achieve it. European Journal of Orthodontics 2011;33:684–90

67
Allocation concealment
• Used to assure- the produced randomization lists and consequently the treatment to be
assigned to the recruited participants cannot be known or predicted by all involved parties.
• The objective – is to reduce selection bias
• An eligible patient after consenting and after the recording of his/her baseline
characteristics will be assigned to the treatment group by either calling, by himself or with
the assistance of the staff, the randomization center in order to be assigned treatment.

68
• A common and simple method is to enclose assignments into sequentially
numbered opaque envelopes which are not visible under the light.
• The patient’s baseline information and name are written outside the
envelope before opening it.
• Aluminium foil inside the envelope was used to render the envelope
impermeable to intense light.

69
Bias & Blinding
• Bias arises from errors in the assessment of the outcome
due to the human element.
• May be from 3 sources:-
i. Subject:- participants who may subjectively feel
better/report improvement if they knew they were receiving
a new form of treatment.
ii. Observer:- investigator measuring the outcome of the
therapeutic trial may be influenced if he knows beforehand
the particular procedure or therapy the patient has been
subjected to.
iii. Bias in evaluation:- the investigator subconsciously gives a
favorable report of the outcome of the trial.
People involved with the
investigation
Types Of Bias
Participant: Patient Reporting bias
Investigator: Person
delivering the
intervention.
Observer/ Interviewer bias
Assessor: Person assessing
the outcome.
Ascertainment bias
Statistician: Person
analysing the data.
Biased reporting of the
results

70
Blinding assure that the outcome is assessed objectively.
• The term “blinding” or “masking” refers to
withholding information about the assigned
interventions from people involved in the trial who
may potentially be influenced by this knowledge.
• Benjamin Franklin has been credited as being the
first to use blinding in a scientific experiment.

71
Blinding
Single blind trial:
participant- not aware
whether he belongs to the
study / control group.
Double blind trial:
neither doctor nor participant is
aware of the group allocation
and the treatment received.
Triple blind trial:
the participant, investigator
and the person analyzing the
data all are blind.

73
4. Manipulation
Intervene/manipulate the study group by the deliberate application/ withdrawal/ reduction of the
suspected causal factor as laid down in the protocol.
• Creates an Independent variable (e.g. drug, vaccine, a new procedure) whose effect is then
determined by measurement of the final outcome, which constitutes the Dependent variable
(e.g.-incidence of disease, survival time, recovery time)

74
5.Follow-up
• Examination of the study and control group subjects at defined intervals of time, in a standard
manner, with equal intensity, under the same given circumstances, in the frame till final assessment
of outcome.
• Involves visiting a clinic for medical assessment, adherence can be improved by contacting
patients by telephone or mail shortly before their appointments and providing reimbursement for
time and travel.
• Some losses to follow-up are inevitable due to factors-death, migration and loss of interest-
ATTRITION (“dropouts”).

75
Analysis of the data
Intention-To-Treat Analysis
• All participants are taken into account regardless of whether they finish the study or not
and always evaluated into groups into which they were randomized.

76
Imputation
• Data gap is taken into account in an intention to treat analysis
• Replacing missing values
1. Single imputation (missing value replaced by one plausible value)
2. Multiple imputations (missing value replaced by Several plausible values)
• Last observation carried forward
• Best observation carried forward
• Worst observation carried forward

77
Per protocol analysis: take into account only those participants who have always adhered to the
protocol, received interventions, and followed up. (excludes the participants who did not adhere to
the protocol)
1. As treated analysis: participants are evaluated as they were ultimately treated regardless of the
original group assignment.
2. A completer-only analysis includes only those who remained till the end of the study.

78
Mansournia M A. Biases in Randomized Trials. Epidemiology 2017;28: 54–59

79
Early Stopping
• RCTs can stop earlier than planned because of the result of an interim analysis showing larger than
expected benefits or harm on the experimental intervention.
• Also RCTs can stop earlier than planned when investigators find evidence of no important
difference between experimental and control interventions.
• In addition, trials may stop early because the trial becomes unviable: funding vanishes, researchers
cannot access eligible patients or study interventions, or the results of other studies make the
research question irrelevant.

80
6. ASSESSMENT
a) Positive results:
Benefits of the experimental measures such as reduced incidence or severity of the disease
cost to the health service or other appropriate outcomes in the study and control groups
b) Negative results:
Severity and frequency of side- effects and complications, if any, including death.

81
Quality Assessment
Various approaches used:
1. Checklist approach
2. Quality scoring system approach
Quality scores are complicated and tend to vary depending on the instrument used –so, not
encouraged

82
CONSORT The Consolidated Standards of Reporting Trials (CONSORT) has become the gold standard for
reporting the results of RCTs.
• CONSORT- alleviate the problems arising from inadequate reporting of randomized controlled
trials.
• CONSORT Statement- a minimum set of recommendations for reporting randomized trials.
• Standard way for authors to prepare reports of trial findings, facilitating their complete and
transparent reporting, and aiding their critical appraisal and interpretation.
• The CONSORT Statement comprises a 25-item checklist and a flow diagram.
• The checklist items focus on reporting how the trial was designed, analyzed, and interpreted; the
flow diagram displays the progress of all participants through the trial.

84
CONSORT checklist of information to include when reporting a randomized trial

86
Ethics in Research
The ethical advances in human
protection include several milestones
• Nuremberg Code 1947
Is a set of research ethical principles for
human experimentation as a result of
the Nuremberg trials at the end of
WW2.
It was the first international instrument
on ethics of medical research,
promulgated in 1947.

87
Declaration of Helsinki
• Declaration of Helsinki 1964
These recommendations guiding physicians in
biomedical research involving human subjects were
issued by the world medical association (WMA),
adopted by the 18th
world medical assembly, Helsinki,
Finland, June 1964.
• Belmont Report 1979: Ethical principals and
guidelines for the protection of human subjects of
research.

88
• ICMR 1980:
Policy statement on Ethical
considerations involved in research of
human subjects (1 year after the
release of Belmont Report)
2000, 2006 & 2017: revised ethical
guidelines
• International Conference on
Harmonization Good Clinical
Practice guidance 1996
1980 2006 2017
2000

89
RCTs & Ethics
• RCT is considered appropriate and ethical when there is “equipoise” regarding the
question of interest.
• Benjamin Freedman(1987) introduced equipoise in medicine which has been borrowed
from law to describe the necessary condition for randomization.
• Equipoise means that there is genuine uncertainty in the scientific community regarding
the effect of the intervention of interest.
• If we already know the effect of the intervention, it is considered unethical to plan a trial
for which the answer is already known since it would not be appropriate to impose a group
of patients on a potentially inferior therapy or no therapy.
• Thus, for an RCT it is unethical to initiate a clinical trial that does not include the
“standard treatment” as 1 of the therapy arms, if such a standard exists, and it is unethical
to include a therapy arm that is known to be inferior to any other treatment.

90
RCTs & Ethics
Clinical trials should follow 3 principles: (Principals of the Belmont Report)
Sl. no Principals for guiding research involving
Human participants.
Feature’s
1 Respect for person • Informed consent from participants
• Maintain confidentiality
• Avoid stigma and discrimination.
• Compensate- for time and any adverse consequences from
participation
2 Beneficence/ non-maleficence
(Action taken for the benefit of others)
• Research design and methods- scientifically sound
• Risk associated must be acceptable in relation to the
potential benefits.
3 Justice
(Moral rightness in action or attitude)
• The benefits and burdens of the research are distributed
equally.
• Equitable access to benefits of the research- ensured.
• Avoid targeting vulnerable populations who are incapable
of making informed and free choices about participation
when other populations are suitable for research.

91
Advantages of RCT
1. Comparative:
• One treatment is directly compared to
another to establish superiority.
2. Minimizes bias & confounding factors.
3. Statistical reliability
• Statistical test of significance is readily
interpretable when the study is
randomized.
• Sample size - when adequately
powered- avoids both Type 1 error
(where the null hypothesis is incorrectly
rejected) and
• Type 2 error (where the null hypothesis
is incorrectly accepted)
4. Publishable
• Considered the gold standard: more
publishable.

92
Disadvantages of RCT
1. Logistics
• Power calculation might demand vast
samples size, which requires more
resources from the investigators.
2. Applicability
• Results may not always mimic real-life
treatment situations (e.g.
inclusion/exclusion criteria; highly
controlled setting)
3. Ethical limitations
• Randomization requires clinical
equipoise: one cannot ethically
randomize patients unless both
treatments have equal support in the
clinical community.
• Informed consent is often impossible.
• Some research cannot be ethically
performed as an RCT (classically,
RCT of the effects of parachutes on
the survival of sky-divers).

93
RCTs in Orthodontics
Sl.n
o
Comparison Remarks Author
1 RCT’s in Treatment of Class II
malocclusion: Headgear vs Frankel
group
Headgear - distal effect on the maxilla and first molars;
The Frankel restrains maxillary growth, retroclination -maxillary
incisors, proclination -mandibular incisors.
The effects of both appliances on mandibular length were similar.
Ghafari et
al
2 RCT’s in distalization of molars:
Intraoral appliance vs extraoral
appliance
Intraoral appliance was more effective than the
extraoral
Bondemark
and
Karlsson
3 RCT’s in Temporary Anchorage
Devices: Anchorage capacity:
onplant, orthosystem implant,
headgear, and transpalatal bar.
Stable anchorage - Onplant and Orthosystem implant.
Stable anchorage during the leveling/ aligning phase but loss at the
end- Headgear.
Insufficient anchorage - Transpalatal bar.
Feldmann
and
Bondemark
4 RCT’s in expansion:
Quad helix and Expansion arch
Quad helix and Expansion arch were equally effective. McNally
5 RCT’s in correcting Anterior
open bite: Posterior bite blocks vs
Posterior repelling magnet splints.
Magnet treatment- Dental and skeletal vertical relation responded
quickly (4 months) but transverse problems were observed.
Posterior Bite planes- Dental and Skeletal vertical improvements
during the first months. This was followed by a ‘plateau’ period. No
transverse problems.
Kiliaridis

94
Sl.no Comparison Remarks Author
6 RCT’s in self-ligation brackets:
Efficiency, effectiveness- Self-
ligating vs Conventional pre-
adjusted edgewise.
No significant difference in alignment
self-ligating brackets are no more efficient than conventional
Scott
7 RCT’s on canine lace backs:
Active ligation, Power chain and
NiTi coil spring for space closure.
NiTi coil spring- most rapid rate of space closure.
Power chain- cheaper option as it is also effective.
Active ligatures- slowest rate of closure
Dixon
8 RCT’s on Treatment for
Obstructive sleep apnea:
Positive airway pressure vs.
mandibular advancement device.
The difference was not significant.
And mandibular advancement device was better tolerated by the
patients.
Tan
9 RCT’s on Temporomandibular
joint disorder: Review of (8 RCTs)
occlusal treatments in TMD.
Occlusal splints might be of some benefit in the treatment of TMD Forssel
10 RCT’s on Pain in Orthodontics:
Bite-wafers vs Reduced
mastication.
More pain was reported by those using bite wafers than by those who
avoided masticatory activity after placement of fixed appliances.
Otasevic
11 RCT’s in Retaining devices:
Hawley vs. vacuum formed
retainers
Vacuum-formed retainers are more effective, more cost-effective, and
more preferred.
Rowland
&
Hichens
12 RCT’s in Materials:
GIC vs composite for bonding.
GIC quadrants had a significantly reduced number of white spots. Pascotto

95
Conclusion
An RCT is considered as the most powerful research tool which provides the
highest level of evidence in the current evidence based orthodontics and,
‑
therefore, is also considered as the gold standard for evaluating the
effectiveness of interventions.
Clinical orthodontic decision making
‑ should involve the integration of skill,
clinical experience, patient preferences, and the best available evidence.

96
Bibliography
• Kaur J, Kaur H, Virdi S. An overview of evidence based dentistry and randomized controlled trials: Importance in
‑
the current orthodontic research. Int J Orthod Rehabil 2018;9:155-8
• Bhatt A. Evolution of Clinical Research: A History Before and Beyond. PICR 2010;1(1):6-10
• Pandis N. Review of randomized controlled trials: Issues to consider when designing a trial. Am J Orthod
Dentofacial Orthop 2013;143:905-7
• Stanley K. Design of Randomized Controlled Trials. Circulation 2007;115:1164-1169
• Pandis N,Cobourne M T. Clinical trial design for orthodontists. J Orthod 2013; 40:93–103
• Pandis N, Polychronopoulou A, Eliades T. Randomization in clinical trials in orthodontics: its significance in
research design and methods to achieve it. European Journal of Orthodontics 2011;33:684–90
• Muthukrishna V, Arunachalam S, Valiathan A. An overview of randomized control trials in orthodontics. JIOS.
2008;42(2):42-51
• Pandis N, Fleming P S, Hopewell S, Altman D G. The CONSORT Statement: Application within and adaptations for
orthodontic trials. Am J Orthod Dentofacial Orthop 2015;147:663-79
• Essentials of Public health dentistry (Community Dentistry). Soben Peter 5th
EDN.
• Mansournia M A. Biases in Randomized Trials. Epidemiology 2017;28: 54–59

99
Terminologies
• Equipoise means that there is genuine uncertainty in the scientific community regarding the effect of the intervention of
interest.
• Bias: Arise from errors of assessment of the outcome due to human element
• Bias is defined as the systematic tendency of any factors associated with the design, conduct, analysis, evaluation, and
interpretation of the results of a study to make the estimate of the effect of a treatment or intervention deviate from its
true value.
• Confounding: is a distortion (inaccuracy) in the estimated measure of association that occurs when the primary
exposure of interest is mixed up with some other factor that is associated with the outcome
• Systematic reviews: A systematic review answers a specific research question by collecting and evaluating all research
evidence that fits the review’s selection criteria.
It’s a review literation that’s written in a systematic manner- inclusion extrusion criteria, method of data collection, answering a specific question.
• Meta analyses: Statistical methods are applied to evaluate and synthesize quantitative results from multiple studies.
It’s an optional component of systematic review
All meta-analyses (Ph.D.) are systematic reviews first but not all systematic reviews(Masters’s degree) are meta-analysis
• Power analysis: helps the researcher to determine the smallest sample size that is suitable to detect the effect of a given
test at the desired level of significance.
• Level of significance: It defines whether the null hypothesis is assumed to be accepted or rejected.
• Null Hypothesis: it’s a hypothesis that is deemed true until proven wrong based on experimental data.

10
Terminologies
• A cohort study is a type of observational study, meaning no intervention is taken among the subjects. It
is also a type of longitudinal study in which research subjects are followed over a period of time. A cohort
study can be either prospective, which collects new data over time, or retrospective, which uses
previously acquired data or medical records. This type of study examines a group of people who share a
common trait or exposure and are assessed based on whether they develop an outcome of interest.
• Case-control study is another type of observational study. It is also a type of retrospective study, which
looks backwards in time to assess information. A case-control study compares people who have the
specified condition or outcome being studied (known as the “cases”) with people who do not have the
condition or outcome.
• Cross-sectional study examines subjects at a single point in time.
• Covariate: an independent variable that can influence the outcome of a given statistical trial, but which is
not of direct interest
• Paired T test- comparing 2 related samples(quantitative) [sample t-tests- independent samples]
• ANOVA: quantitative test to compare 3 or more independent samples [repeated ANOVA- related]
• Chi square test: test association between categorical variables (qualitative)

10
Sampling bias vs selection bias
• A distinction of sampling bias (albeit not a universally accepted one) is that it undermines the
external validity of a test (the ability of its results to be generalized to the rest of the population),
while selection bias mainly addresses internal validity for differences or similarities found in the
sample at hand.

10
Covariates vs Confounder
• Covariates are confounding variables
that may be related to a variable of
interest but are not of interest in
themselves. They can be statistically
controlled for during analysis, which
results in a more direct measurement of
the relationship between the variables of
interest.

10
Advantages Disadvantages
• All patients can be assured
that sometime during the
course of the study, will
receive the new therapy
• Economize the total number
of patients required at the
expense of the time necessary
to complete the study.
• Not suitable if the drug of
interest cures the disease,
if the drug is effective only
during a certain stage of
disease or if the disease
changes radically during
the period of time
required for the study.
Cross-over Type Of Study Designs

10
Rolling design
• Design that can roll on continually by introducing new treatment options from the evidence accumulated,
dropping those of either proven efficacy or if found not to be effective.
• Make use of intermediate endpoints (in contrast to the traditionally used endpoints that require longer patient
follow-up).

10
APPLICATIONS OF RCT
1. EVALUATION OF TREATMENT
• Chemotherapy
• Surgical procedures
2. EVALUATION OF PREVENTION
• Chemoprophylaxis
• Immuno-prophylaxis
3. EVALUATION OF Health programs, Health care services and
Patient education programs.

10
Advantages of RCT
1. Comparative:
• One treatment is directly compared to another to
establish superiority.
• This study design can make causal inferences, i.e.
it is the strongest empirical evidence of a
treatment's efficacy
2. Minimizes bias:
• Randomization minimizes allocation bias and
selection bias
• Blinding minimizes performance bias
• Double-blinding minimizes assessment bias
• Allocation concealment minimizes both
performance and assessment bias
• Prospective design minimizes recall error and
selection bias
3. Minimizes confounding factors:
• Randomization minimizes confounding due to
unequal distribution of prognostic factors
• Randomization makes groups comparable
according both known and unknown factors
• Blocked randomization makes groups comparable
within known confounding factors
4. Statistical reliability
• Statistical test of significance is readily
interpretable when the study is randomized
• Sample size - when adequately powered- avoids
both Type 1 error (where the null hypothesis is
incorrectly rejected) and Type 2 error (where
the null hypothesis is incorrectly accepted)
5. Publishable
• Considered the gold standard: more publishable

10
Disadvantages of RCT
1. Logistics:
• Power calculation might demand vast samples size,
which require more resources from the
investigators
• Validity requires multiple sites, which will be
difficult to manage
• Long trial run time may result in the loss of
relevance as practice may have moved on by the
time the trial is published
2. Statistics
• A disadvantage of block randomization is that the
allocation of participants may be predictable and
result in selection bias when the study groups are
unmasked
3. Applicability
• Trials which test for efficacy may not be widely
applicable. Trials which test for effectiveness are
larger and more expensive
• Results may not always mimic real life treatment
situation (e.g. inclusion / exclusion criteria; highly
controlled setting)
4. Ethical limitations
• Randomization requires clinical equipoise: one
cannot ethically randomize patients unless both
treatments have equal support in the clinical
community
• Informed consent is often impossible
• Some research cannot be ethically performed as
an RCT (classically, RCT of the effects of
parachutes on the survival of sky-divers)

10
Features of a well designed RCT
• The sample to be studied will be appropriate to the hypothesis being tested so that any results are
appropriately e. The study will recruit sufficient patients to allow it to have a high probability of
detecting a y important difference between treatments if a difference truly exists.
• There will be effective (concealed) n of the subjects to the intervention/ control groups (to
eliminate selection bias and e confounding variables).
• Both groups will be treated identically in all respects except for the intervention being tested and to
this end, patients and investigators will ideally be blinded to which group an individual is assigned.
• The investigator assessing the outcome will be blinded to treatment allocation.
• Patients are d within the group to which they were allocated, irrespective of whether they
experienced the intended intervention (intention to treat analysis).
• Analysis focuses on testing the research question that initially led to the trial (that is, according to
the a priori hypothesis being tested), rather than “trawling” to find a significant difference.

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