RANDOMIZED CLINICAL TRIALS

Jonathan Lambo, MD (Vienna) DTM&H (RCPLond.)

Professor of Epidemiology and Public Health

EPIDEMIOLOGY & PREVENTIVE MEDICINE MD 1 SEPTEMBER 2020

 Schedule for November 12/13 (Week 11)

 Intended Learning
Outcomes
 Lecture 13: Randomized
Clinical Trials
 Lecture 14:The Dynamics
of Disease Transmission
and Disease Surveillance
Structure of Session

 Development of criticality in students

 Engaging students in Research Informed Teaching
 Lecture 13: Randomized Clinical Trials (RCT)
 Key RCT Concepts
 Active Learning Exercises
Outline
 Learning Outcomes
 Control of confounding
 Key Concepts

 Placebo and Placebo Effect  Selection of subjects

 What is a randomized clinical  Allocation of subjects to

trial study? treatment groups

 Design of an RCT?
 Data collection on subjects

 Why randomization?
 Questions
Intended Learning Outcomes
 By the end of this lecture, students should be able to:
 Define a randomized controlled trial.

 Define and apply key concepts related to randomized controlled trial

 Explain the basic design of RCT and discuss the rationale for randomization

 Explain how study populations are selected for randomized controlled trials

 Explain how subjects are allocated to treatment groups

 Describe the methods for controlling for confounding in epidemiological studies

 Discuss when a randomized controlled design is warranted

 Discuss the advantages and disadvantages of randomized controlled trials

 What is RCT?

 An epidemiological experiment or intervention designed to

study the effects of a particular intervention, usually a
treatment for a specific disease (clinical trial)

 Randomized trial design has applicability outside the clinical

setting, such as field trials and community-based trials

 The effects of an intervention are measured by comparing the

outcome in the experimental group with that in a control
group

 RCT follows a strict study protocol and ethical considerations,

informed consent from study participants, and confidentiality
are of paramount importance
 Key Concepts
 Efficacy versus Effectiveness-How efficacious is (are) …. compared
with… in the treatment of…
 Efficacy: Does the intervention “work” under ideal, “laboratory” or “field”
conditions? Efficacy is a measure in a situation in which all conditions are
controlled to maximize the effect of the agent.
 Effectiveness: If we administer the agent in a “real-life” situation, does it
work?
 Efficiency: If an agent is shown to be effective, what is the cost-benefit
ratio? Is it possible to achieve our goals in a cheaper and better way. Cost
includes not only money, but also discomfort, pain, absenteeism, disability
and social stigma.
 Randomization or random allocation is the allocation of individuals to
groups, such as experimental and control regimens, by chance.
Randomization means, in effect, tossing a coin to decide the assignment of
a patient to a study group. The critical element of randomization is the
unpredictability of the next assignment.
 Key Concepts

 Assessment of Methodological Quality of Trials

Question: How can selection bias arise in intervention studies?
 1.The generation of allocation sequence: ensuring that the

allocation sequences were unpredictable (e.g. computer-

generated random numbers, table of random numbers)

 2.Allocation concealment: procedure ensuring that participants

and the investigators who recruited them could not anticipate
the assignment (e.g. by using central randomization;
sequentially-numbered, opaque, sealed envelopes)
 Key Concepts

 3. Blinding: Subjects/observers/therapists/investigators/provider/outcome
assessors are kept in ignorance of the group to which the patients have
been assigned,i.e.they do not know who receives the intervention or who
receives the placebo or comparison drug avoid
Subjects/observers/therapists/investigators/provider/outcome assessors
bias.
 4. Intention to treat analysis: analysis including the persons as randomized
whether or not they actually received the intended “treatment.”
 Other Key Concepts

Number needed to treat (NNT) =1/Risk Difference

 NNT is defined as the number of patients who need to be treated to achieve
1 additional good outcome or to prevent 1 adverse outcome such as one
death.
Number needed to harm (NNH)
 NNH is defined as the number of patients who need to be treated to cause 1
additional person to be harmed. It is used to look at the risk of side effects.
 Placebo and Placebo Effect

 Placebo: a biologically inert intervention, which is used to

induce any non-specific psychological effects of the test
intervention. It is indistinguishable in appearance from the
active therapy. ‘I shall please.’

 Placebo effect: any effect attributable to a pill, potion or

procedure, but not to its pharmacological or specific
properties.

 True effect of drug = effect seen with drug – effect seen with
placebo.
 Assessing the Efficacy of Preventive and
Therapeutic Measures

 Randomized trials (RTs) are ideal for evaluating

effectiveness and side effects of new forms of
intervention

 RTs can be used for many purposes:

 For evaluating new drugs and other treatments, including

tests of new health and medical technology

 For assessing new programs for screening and early

detection, or new ways of organizing and delivering health
services
 Basic Design of a Randomized Trial

Study population: defined population

↓ ↓
Randomly Assigned
↓ ↓
Current Treatment New Treatment
↓ ↓ ↓ ↓
Improve Do not Improve Improve Do not
Improve
 Why Randomization?

 Benefits in terms of
 Not allowing clinicians to manipulate assignment

 Unpredictability of the next assignment: ‘To eliminate the possibility that the
investigator will know what the assignment of the next patient will be, because such
knowledge introduces the possibility of selection bias’ (Gordis)

 Comparability: To ensure that the groups will be comparable in regard to such

characteristics as sex, age, race, and severity of disease that may affect prognosis

 The main benefit of randomization is the control of confounding

 Randomization is not a guarantee of comparability , because chance may play a

role in the process , but over the long term, the groups will tend to be similar
 Control of Confounding

 5 methods

 In the design of an epidemiological study,

confounding are commonly controlled by:
 Randomization
 Restriction
 Matching

 At the analysis stage, confounding can be

controlled by:
 Stratification
 Statistical Modelling
 Selection of Subjects
 Study protocol should clearly and precisely specify:

 Eligibility criteria including Inclusion and exclusion

criteria (with reason (s) for exclusion)

 There should be no subjective decision-making on

the part of the investigator in deciding who is
included or not included in the study

 In principle, any study must be replicable by others

 Allocation of Subjects to Treatment
Groups-1
 Alternatives to randomization that could be used:

1. Studies without comparison

 In case study or case series, no comparison is made with an untreated
group or with a group that is receiving some other treatment. The issue of
comparison is important because we want to be able to derive a causal
inference regarding the relationship of a treatment and subsequent outcome

2. Studies with comparison

Possible designs
 Historical controls: A comparison group from the past. For
comparison, we go back to the records of patients with the same disease
who were treated before the new therapy became available.
 Allocation of Subjects to Treatment
Groups-2
 Advantages: Seems inherently simple and attractive

 Problems:
(1) historical data would not be as detailed, as they were not collected for
research purposes; and if at the end we find a difference between treated
group and control, we would not know whether the outcome is due to
treatment or just the difference in the quality of data collection
(2) if we do observe difference, many things other than therapy changed over
time (living conditions, nutrition, lifestyles, etc.)

3. Simultaneous nonrandomized controls use of simultaneous controls that

are not selected in a randomized manner e.g. assigning patients by the day of
the month on which the patient was admitted to hospital

 Problem: assignments of subjects is predictable; investigator will know

which group subject is assigned to.
Allocation of Subjects to Treatment Groups-3

 Randomization: The best approach in the design of

a trial

 By randomizing we achieve:

 non-predictability of the next assignment;

 no subjective biases of investigators, either overt or

covert that may be introduced into the process of
selecting patients for one treatment group or the
other;
Allocation of Subjects to Treatment Groups-4

 Stratified Randomization
 We first stratify our study population by each
variable that we consider important (e.g. sex and age)
and then

 Randomize participants to treatment groups within

each stratum

 By doing this, we increase the likelihood that the two

groups (treatment vs no treatment) are comparable in
the important variables (age, sex).
 Data Collection on Subjects
 Variables:

 Treatment (Assigned and Received) we must know to which treatment group

patient was assigned to and whether or not they complied and received the
treatment

 Outcome both improvement and side effects must be measured carefully in the
study groups

 Prognostic profile at entry randomization must make risk factors to bad outcome
comparable between the two groups (i.e. if age is a risk factor, it should be
comparable in the two groups)

 Masking (Blinding) subjects should not know which group they are assigned to,
often done using placebo. This is very important when the outcome is a subjective
measure (back pain, headaches). Placebo is also important for studying side effects
and reactions. Placebo plays a major role in identifying both the real benefits of an
agent and its side effects. Observers may be masked/blinded to which group patient
is in (double blinding).
 References

 Gordis L. (2014). Epidemiology: fifth edition.

Saunders Elsevier: Philadelphia, PA
 Last JM(2001). A Dictionary of Epidemiology (4th
ed.). Oxford University Press: New York, NY
 MRC Vitamin Study Research Group Prevention of
neural tube defects: results of the Medical Research
Council Vitamin Study. Lancet 1991; 338 (8760) :
131-137
 Bonita. R., Beaglehole, R., Kjellstrom, T. (2006).
Basic Epidemiology: 2nd edition. World Health
Organization (WHO) Press: Geneva, Switzerland.
Available online at
http://whqlibdoc.who.int/publications/2006/92415470
73_eng.pdf
 Active Learning Exercises

1. In a randomized controlled clinical trial, the

purpose of randomization is to

A. keep the study subjects “blind” to treatment

received
B. keep the observers “blind” to treatment received
C. get a random sample of the population for
treatment
D. minimize the bias between the two groups
E. minimize the error in analysis
 Active Learning Exercises

2. A “double blind” study of a vaccine is one in which

 A. The study group receives the vaccine and the control
group receives a placebo
B. Neither observer nor subjects know the nature of the
placebo
C. Neither observer nor subjects know which subjects
receives the vaccine and which receives the placebo
D. Neither the study group nor the control group knows
the identity of the observers
E. The control group does not know the identity of the
study group
 Active Learning Exercises

3. The purpose of a double blind or double masked

study is to

A. Achieve comparability of treated and untreated

subjects
B. Reduce the effects of sampling variation
C. Avoid observer bias and sampling variation
D. Avoid observer and subject bias
E. Avoid subject bias and sampling variation
 Active Learning Exercises

 Questions 4-10. In the Randomized Control Trial (a

randomized double-blind placebo-controlled trial) comparing
antibiotic treatment with placebo for conjunctivitis in
children, the main result of the study is the proportion of
children clinically cured, i.e. symptom free, at 7 days, as
assessed by the parents’ diaries is shown in the table below.
Outcome/ Clinica Not Total Proportio Percentage
Assignment l cure cured randomized n cured cured

Chloramphenicol 140 23 163    

Placebo 128 35 163    

Total 268 58 326    
 Active Learning Exercises

 4. Calculate an estimate for the proportion cured for

treatment group and for the placebo group
 Risk Calculations: Calculate the relative risk (risk
ratio),odds ratio, risk difference, & the number needed to
treat (NNT)
 5. Risk ratio =
 6. Odds ratio =
 7. Risk difference=
 8. Number needed to treat=
 9. How do you interpret your estimate for the NNT?
 Active Learning Exercises
10. If the 95% confidence interval for the risk difference (risk
difference estimate for the intention-to-treat comparison is 7.4%)
is -0.9% to 15.6%. What conclusion would you draw from this
study?
A. The result is compatible with increased risk i.e. statistically
significant
B. The result is compatible with no difference in risk i.e. not
statistically significant
C. The result is compatible with decreased risk i.e. statistically
significant
D. The number of children studied was not sufficient to achieve a
conclusive result
E. No conclusion can be drawn from the information given
 Schedule for Class November 19

 Lecture 15:Outbreak
Management and Global
Health
Any Questions?