Randomised Controlled Trial, RCT, Experimental study

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 intervention .

1. RANDOMISED CONTROLLED
TRIAL (RCT)
Dr Lipilekha Patnaik
Professor, Community Medicine
Institute of Medical Sciences & SUM Hospital
Siksha‘O’ A nusandhandeemed to be University
Bhubaneswar, ODISHA, INDIA
E mail–[email protected]
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2. Presentation outline
uWhy do Randomized Controlled Trials?
uRandomization why and how it is done
uRCT classification
uStudy design & Steps of RCT
uMinimizing bias in intervention studies
uAllocation concealment and blinding
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3. Human experiments –Can you identify?
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4. uIn1947Lindtestedtheeffectoflimejuiceon
theoccurrenceofscurvyonRoyalNavyships
-amajorhealthproblemonlongvoyages.
uCruciallyLindrandomisedwhichofhis
patientsreceivedthetreatment(limejuice
plusseveralotherliquidtested).
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5. 1948:
Sir Austin Bradford Hill –streptomycin for TB
uThe first published RCT in medicine appeared in the
1948 paper entitled "Streptomycintreatment of
pulmonary tuberculosis", which described a Medical
Research Councilinvestigation.
uOne of the authors of that paper was Austin
Bradford Hill, who is credited as having conceived
the modern RCT.
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6. Definition of RCT
An epidemiological experiment in which subjects in a
population are randomly allocated into groups, usually
called studyand control groups to receive and not receive an
experimental preventive or therapetuic procedure, maneuver,
or intervention
John M.Last, 2001
RCTcanbeusedto:
§Evaluatethesafetyofanewdruginhealthyhumanvolunteers
§Assesstreatmentbenefitsinpatientswithaspecificdisease
§Compareanewdrugagainstexistingdrugsoragainstdummy
medications(placebo).
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7. Randomized Controlled Trial (RCT)
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8. Randomized
–Eliminate bias in selection / allocation
–Balances all confounders: known or unknown
Controlled
–Intervention compared to a control
–Control: active or placebo
–Both groups identical except for intervention / exposure
–Investigator has control over the process
Trial
–Experimental intervention
–Effects unknown to investigator
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9. Ethics in RCT
uAlthough the principle of clinical equipoise("genuine uncertainty within the expert
medical community... about the preferred treatment") common to clinical trials
has been applied to RCTs, the ethicsof RCTs have special considerations.
ualmost always provide informed consentfor their participation in an RCT.
Trial registration
uIn 2004, the International Committee of Medical Journal Editors(ICMJE)
announced that all trials starting enrolment after July 1, 2005 must be registered.
uClinical trial registry of India -(CTRI), hosted at the ICMR's National Institute of
Medical Statistics (http://nims-icmr.nic.in), is a free and online public record
system for registration of clinical trials being conducted in India that was launched
on 20
th
July 2007 (www.ctri.nic.in). in the CTRI has been made mandatory by the
Drugs Controller General (India) (DCGI)
uClinicaltrials.gov-by U.S. National Institutes of Health
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10. Randomization
uProcess by which, allocation of subjects to treatment groups
is left to chance (or randomness)
The major purpose of random assignment
a)Ensure that the study groups are comparable on baseline
characteristics. It tends to balance prognostic factors
(Balance in prognosis)
b)Reduce selection bias in allocation to groups
c)Facilitate double blinding
d)Facilitate measurements of outcome variables
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11. Randomization is a key feature
And heart of RCT
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12. How randomization is done
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13. Simple Randomization
uThis method is equivalent to tossing a coin for each
subject that enters a trial, such as
Heads = Active, Tails = Placebo.
uHowever, imbalanced randomization can happen in
smaller trials, reducing statistical power.
uE.g. In trial of 10 participants, instead of 5-5 split 7-3
or 8-2 split can occur.
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14. Block Randomization
uBlock randomization is balanced within each block
uThe basic idea of block randomization
udivide potential patients into m blocks of size 2n
urandomize each block such that n patients are allocated to A
and n to B
uthen choose the blocks randomly
uExample: Two treatments of A, B and Block size of
2 x 2= 4
uPossible treatment allocations within each block are (1) AABB, (2)
BBAA, (3) ABAB, (4) BABA, (5) ABBA, (6) BAAB
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15. Stratified Randomization
uAn RCT may not be considered valid if it is not well balanced
across prognostic factors
uE.g., Age Group: < 40, 41-60, >60; Sex: M, F; Total number
of strata = 3 x 2 = 6
uStratification can balance subjects on baseline covariates, tend
to produce comparable groups with regard to certain
characteristics (e.g., gender, age, race, disease severity)thus
produces valid statistical tests
uThe block size should be relative small to maintain balance in
small strata.
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16. 1000 PATIENTS
600 MALES 400 FEMALES
360 Young 240 Old
300 Young 100 Old
180+120+150+50=500
NEW TREATMENT
180+120+150+50=500
CURRENT TREATMENT
Stratify by sex
Stratify by Age
Randomize
each age
group
STRATIFIED RANDOMIZATI
ON
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17. 1. On the basis of study design
(This classification is more descriptive in terms of how patients
are randomized to treatment)
2. On the basis of hypothesis
3. On the basis of outcome of interest
4. Purpose of study
5. Phases of study
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CLASSIFICATION OF RCTs

18. On the basis of study design
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•Parallel-group–
•each participant is randomly assigned to a group, and all the
participants in the group receive (or do not receive) an intervention.
•Crossover–over time, each participant receives (or does not receive)
an intervention in a random sequence.
•Cluster–pre-existing groups of participants (e.g., villages, schools)
are randomly selected to receive (or not receive) an intervention.
•Factorial–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,
and group 4 receives placebo X and placebo Y)

19. CONCURRENT PARALLEL STUDY DESIGN
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20. DEFINED POPULATION
RANDOMIZED
NEW
TREATMENT
CURRENT
TREATNENT
IMPROVED NOT IMPROVED IMPROVED NOT IMPROVED
DESIGN OF A RANDOMISED TRIALPARALLEL STUDY DESIGN
Patients are randomized into two groups: the new treatment or to the standard treatment
and followed-up, to determine the effect of each treatment in parallel groups
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21. CROSS OVER STUDY DESIGN
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22. RANDOMIZED
GROUP 1
GROUP 1
GROUP 2
GROUP 2
GROUP 2
GROUP 2
GROUP 1
GROUP 1
OBSERVED
OBSERVED
THERAPY A THERAPY B
CROSSOVER STUDY DESIGN
randomize patients to different sequences of
treatments, but all patients eventually get all
treatments in varying order. The patient act as,
his/her own control
Time for elimination / carry over effect
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23. Advantages & disadvantages of crossover type of
RCT study design:
Advantage:
uInfluence of confounding factors is reduced because each crossover
patient serves as his or her own control
uPatients assured that some time during the course of investigation, they
will receive the new therapy
Disadvantage:
uNot suitable if the drug cures the disease, effective in certain stage of
the disease or rapidly changing conditions
uthe issue of "order" effects: It is possible that the order in which
treatments are administered may affect the outcome.
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24. FACTORIAL STUDY DESIGN
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25. uFactorialtrialsassignpatientstomorethanonetreatment-
comparisongroup.
uThesearerandomizedinonetrialatthesametime,ie,while
drugAisbeingtestedagainstplacebo,patientsarere-
randomizedtodrugBorplacebo,makingfourpossible
treatmentcombinationsintotal.
uEg.StudytheeffectofaBPloweringmedication(ACEI)on
MACE&effectofvitaminEincancerpreventioninolder
patientsaged>60years-HopeStudy)
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26. SUBJECTS RANDOMIZED
RAMIPRIL PLACEBO
VITAMIN E PLACEBO VITAMIN E PLACEBO
FACTORIAL DESIGN USED IN STUDY OF RAMIPRIL & VITAMIN E
The HOPE Study: Ramipril vs Placebo; Vitamin E vs Placebo
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27. Both Ramipril &
Vitamin E (a)
Vitamin E Only (b)
Ramipril only
(c)
Neither Ramipril
Nor Vitamin E (d)
Ramipril
+ -
RAMIPRIL
+ -
VITAMIN E
|
+
VITAMIN
E
-
+
Both Ramipril &
Vitamin E (a)
Vitamin E Only (b)
Ramipril only
(c)
Neither Ramipril
Nor Vitamin E (d)
Both Ramipril &
Vitamin E (a)
Vitamin E
Only (b)
Ramipril only
(c)
Neither Ramipril
Nor Vitamin E (d)
RAMIPRIL
+ -
Factorial design of the
study of Ramipril &
Vitamin E in 2x2 table
Factorial design studying
the effects of Ramipril
(pink cells) vs No Ramipril
(ac vs bd)*
Factorial design studying the
effects of Vitamin E versus
No Vitamin E (ab vs cd)*
VITAMIN E
* No treatment interaction
-
+
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28. Advantages:
–Two trials for (almost) the price of one
–Design is best if: two intervention have different mechanisms
of actions or different outcomes
Disadvantages:
–Need to test for possibility of interaction (e.g. A differs based
on the presence or absence of B)
–Need to consider gain in cost vs. increased complexity,
recruitment and adherence issues
–potential for adverse events
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29. Clusterrandomizedtrials
uPerformedwhenlargergroups(e.g.patientsofasinglepractitioner
orhospital)arerandomizedinsteadofindividualpatients.
uInaruralareawithanendemicdisease,wemightrandomizewhole
villagestohavetheinterventionornot,ratherthanindividual
people.
uTo evaluate health systems interventions
Eg; educational intervention in schools for prevention of CV risk
factors
uTo avoid treatment group contamination
uAdministrative convenience
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30. RCTcanalsobedescribedonthebasisofhypothesis:
uSuperioritystudies
uEquivalencestudies
uNoninferioritystudies
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31. uAsuperioritystudyaimstoshowthatanewdrugismore
effectivethanthecomparativetreatment(placeboorcurrentbest
treatment)
uAnequivalencestudyisdesignedtoprovethattwodrugshavethe
sameclinicalbenefit.
uAnoninferioritystudyaimstoshowthattheeffectofanew
treatmentcannotbesaidtobesignificantlyweakerthanthatofthe
currenttreatment.
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32. By outcome of interest (efficacy vs.
effectiveness)
uExplanatory RCTs: test efficacyin a research setting
with highly selected participants and under highly
controlled conditions.
uPragmatic RCTs: test effectivenessin everyday
practice with relatively unselected participants and
under flexible conditions; in this way, pragmatic RCTs
can "inform decisions about practice."
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33. Types of Randomized Controlled Trials
1.Clinical Trials
2.Preventive Trial
3.Risk Factor Trials
4.Cessation Experiment
5.Trial of etiological agents
6.Evaluation of health services
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34. Types of Randomized Controlled Trials:
1. Clinical Trial
-Concerned with evaluating therapeutic agent, mainly drugs
eg. Evaluation of beta-blockers in reducing cardiovascular
mortality
2. Preventive Trials:
-Trial of primary preventive measures eg. Vaccines
-Analysis of preventive trials must result in clear statement
about benefits to community, risk involved and cost to health
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35. 3. Risk Factor Trials:
-Investigator intervenes to interrupt the usual sequence in the
development of disease for those individuals who have risk factor
for developing the disease
-Primary prevention of CHD using clofibrate to lower serum
cholesterol
4. Cessation Experiment:
-An attempt is made to evaluate the termination of a habit which is
considered to be causally related to disease
-Cigarette smoking and lung cancer
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36. 5. Trials of Etiological Agents:
-To confirm or refute an etiological hypothesis
6. Evaluation of Health Services:
-Domiciliary treatment of PTB was as effective as
more costlier hospital or sanatorium treatment
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37. Phases of clinical trials
Phase –I Trial done on group of healthy individuals to know safety,
efficacy and the side effects
Phase –II carried in diseased group to know safety and efficacy done in
multiple centers.
Phase –III carried in thousands of people to study safety, efficacy and
whether fit for manufacturing. Determine the effectiveness (overall
benefit/risk-cost assessment) of new therapies relative to standard
therapy
Phase –IV Post-marketingstudy as the drug has already been granted
regulatory approval/license.
ucontinuous on going process to know the long term effects,
additional safety information, rare side effects. Often non
randomized
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38. Steps of conducting a RCT
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1.Drawing up a protocol
2.Selecting reference & experimental population
3.Randomization
4.Manipulation or intervention
5.Follow up
6.Assessment of outcome

39. DESIGN OF A RANDOMISED CONTROL TRIAL
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SELECT SUITABLE POPULATION
(Reference or Target Population)
SELECT SUITABLE SAMPLE
(Experimental or Study Population
RANDOMISE
EXPERIMENTAL GROUP CONTROL GROUP
MANIPULATION AND FOLLOW -UP
ASSESMENT

40. 1. THE PROTOCOL
-Rationale
-Aims and objectives
-Research questions
-Design of the study: selection of study and control groups
-Size of the sample & allocation of subjects in both groups
-Treatment to be applied –when, where, how
-Standard of Operations (SOP)
-Ethics: patient consent, confidentiality, adverse events
-Documentation
-Procedure
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41. 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 (eg. drugs,
vaccines, etc.)
B.Experimental or study population –
uActual population that participates in the experimental study
uDerived from the reference population
uHas same characteristics as the reference population
uMust give informed consent
uShould be qualified or eligible for the trial
uEffectiveness of drug in treating anemia –subjects should be anemic
uEffectiveness of a vaccine against a disease –subjects should not be
already immune
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42. 3.RANDOMIZATION
-Heart of the control trial
-Procedure: Participants are allocated into study
and control groups
-Eliminates bias and allows comparability
-Both groups should be alike with regards to
certain variables that might affect the outcome of
the experiment
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43. 4. MANIPULATION / INTERVENTION
-Deliberateapplicationorwithdrawalorreductionof
asuspectedcausalfactor
-Itcreatesanindependentvariable(drugs,vaccine,
newprocedure)whoseeffectismeasuredinfinal
outcomeconstitutingthedependentvariable
(incidenceofdisease,survivaltime,controlofevents
etc)
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44. 5. FOLLOW UP
-Implies examination of the experimental and control
group subjects
-at defined intervals of time,
-in a standard manner
-with equal intensity
-under the same given circumstances
-Attrition: Inevitable losses to follow up (death,
migration, loss of interest)
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45. 6. ASSESSMENT
-Positive results:
-Reduced incidence or severity of disease
-Reduced cost to health service
-Appropriate outcome in the study
-Negative results:
-Increased severity or frequency of side effects
-Complications
-Deaths
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46. Approach to analysis
• Intention to treat (ITT)
–All patient analyzedin the group allocated to
Even -did not take the treatment / follow protocol
–Randomization maintained, statistical assumptions
valid
• Per Protocol
–Only those who followed the protocol
–State in advance
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47. Missing data in ITT analysis
1. Last Value Carried Forward (LCVF)
–last observation for missing observations
–assumes this is an unbiased estimate
–variability and time-trends NOT considered
2. Maximum Likelihood Estimation (MLE)……(Shib1987)
–mixed-model approach
–predictor used to reflect a true relationship with the missing
value
• When data are largely missing at random –MLE is
statistically valid (Hogan 1996)
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48. Advantages & disadvantages of RCT
uRandomization tends to balance prognostic factors
across study groups.
uDetailed information can be collected on baseline and
subsequent characteristics of participants.
uDose levels can be predetermined by the investigator.
uBlinding of participants can reduce distortion in
assessment of outcomes.
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Advantages:

49. Disadvantages:
uSubject exclusions may limit ability to generalize
findings to other participants.
uA long period of time is often required to reach a
conclusion.
uA large number of participants usually required.
uFinancial costs are typically high.
uEthical concerns may arise.
uCompliance.
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50. Bias in intervention evaluation
1.Selection Bias –bias in patient selection
2.Confounding/ Imbalance in baseline prognostic factors/
allocation bias
3.Hawthorne effect -improved performance in intervention
subjects due to psychological benefit that he/she is receiving
some new treatment
4.Observer bias
–bias in outcome assessment (may affect patient care (dose
modification or closer observation)
–may report favourable outcome for new treatment
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51. Allocation concealment
Refers to the stringent precautions taken to ensure that the group
assignment of patients are not revealed prior to definitively
allocating them to their respective groups.
uprevent selection bias by concealing the allocation sequence .
uSome standard methods of ensuring allocation concealment
include sequentially numbered, opaque, sealed envelopes
(SNOSE)
uNon-random "systematic" methods of group assignment, such
as alternating subjects between one group and the other, can
cause can cause a breach of allocation concealment.
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52. Blinding/masking
Single
The participants are unaware to which group they belong. (study/
control)
Double
The investigator or the participant do not know the group
allocation.
Triple
None of the patients, investigators or trial administratorknow
Quadruple
Patient, investigator, trial administrator and data analyser blinded
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53. Purpose of blinding
uTo remove subjective / judgmental bias in
–Reporting
–Evaluation
–Management
–Analysis of data
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54. End Points (Outcome Measures)
uClinical outcome (e.g, death, stroke, BP )
uSymptom/ sign
uLab abnormality
2 types, depending on nature :
uHard end points
uSurrogate end points
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55. Hard End Points Surrogate End Points
A biomarker
intended to substitute
for a clinical end
point
uHbA1c
uSerum cholesterol
levels
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•Generally clinical end-points
•Death due to any cause
•Death due to cardiovascular /
diabetic causes
•Non-fatal myocardial
infarction/ strokes
•End stage renal disease
•Time to clinical event

56. Measures of effect
To compare frequency of outcome between two groups.
Magnitude of relationship generally expressed as:
uRelative measures of effect
–Relative risks
–Odds ratios
uAbsolute measure of effect
–Risk difference
–Number needed to treat (NNT)
» calculated using risk difference
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57. Experimental & Control Event Rates
uEvent rates –to compute measures of risk
–Experimental event rate (EER)
• The proportion of people with intervention with
the outcome or A/(A + B).
–Control event rate (CER)
• The proportion of people without the intervention
who develop the outcome, or C/(C + D).
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58. The Relative Risk (RR)`
uThe ratio of incidence of outcome in those
exposed to those not exposed
• RR = EER / CER
• RR: applies to cohort study or clinical trial
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59. Relative Risk Reduction (RRR)
uAmount of risk reduction relative to
baseline risk
OR
• The reduction in risk with a new therapy
relative to the risk without the new therapy
• RRR = (EER –CER) / CER
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60. SUMMARY
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61. Reporting of results Trial
(Consolidated Standards of Reporting trials)
uThe CONSORT 2010 Statementis "an evidence-based,
minimum set of recommendations for reporting RCTs."
uThe CONSORT 2010 checklist contains 25 items (many with
sub-items) focusing on "individually randomised, two group,
parallel trials" which are the most common type of RCT.
uFor other RCT study designs, "CONSORT extensions" have
been published, some examples are:
•Consort 2010 Statement: Extension to Cluster Randomised
Trials
•Consort 2010 Statement: Non-Pharmacologic Treatment
Interventions
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62. THANK YOU
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