GOODMORNING

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 RANDOMIZED

CONTROLLED TRIAL

Presented by,
Dr. Nitha Willy
First year PG
Department Of Oral Medicine And Radiology 2
Contents

i. History

ii. Introduction

iii. Goal of RCT

iv. Applications of RCT

v. Design of RCT

vi. Types of controls

vii. Classification of RCT

viii. Summary
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 HISTORY

»The first instance of random allocation of

patients to experimental and control

conditions is attributed to James Lind, a naval

surgeon, in 1747.

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»Lind randomly assigned 12 sailors to 6 different treatments for scurvy. The

two patients who were given lemons and oranges recovered most quickly,

suggesting a beneficial effect of citrus.

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»The first RCT in medicine is credited to Sir A. Bradford

Hill, an epidemiologist for England's Medical Research

Council.

»The trial, published in the British Medical Journal in

1948, tested whether streptomycin is effective in treating

tuberculosis.
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INTRODUCTION

Randomized controlled trial is an epidemiological experiment to evaluate new

preventive or therapeutic regimens. Subjects are randomly allocated to treatment and

control groups.

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Gold standard among epidemiological studies in terms of validity.

Allow the investigators high degree of control over the study subjects and conditions

Randomized controlled trial with double blinding is of very high validity.

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 GOAL OF RCT

Primary Goal Secondary Goal

• To test whether an intervention works • Identify factors that influence the

by comparing it to a control condition effects of the intervention

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 APPLICATIONS OF RCT

Evaluation of Evaluation of
prevention Evaluation of
treatment

• Chemotherapy • Chemo- prophylaxis • Health programs

• Surgical procedures • Immuno- prophylaxis • Healthcare services
• Any other treatment • Patient education
process programs
• Administrative
strategies

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 DESIGN OF RANDOMIZED CONTROLLED TRIALS

1. Drawing up a protocol

2. Selecting reference and experimental

populations

3. Randomization

4. Manipulation or intervention

5. Follow –up

6. Assessment of outcome
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Drawing Up Protocol

 It is conducted under a strict protocol.

Prevents bias and reduces source of errors in the study.

Preliminary or pilot test runs of protocol can be held so to see whether it contains any flaw.

Final version of protocol should be agreed upon by all concerned before the trial begins.

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The protocol specifies

the aims and objectives of the study

Criteria for the selection of study and control groups

Size of sample

The procedures for allocation of subjects into the study and control groups

Treatments to be applied

Standardization of working procedures and schedules

Up to the stage of evaluation of outcome of the study

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Selecting Reference And Study Population

I. Reference /Target Population:

 It is the population to which findings of the trial ,if found successful , are

applicable.

 e.g. whole population, population of school children, population of a city, industrial

workers or social groups

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II. Experimental /Study Population:

 Derived from reference population.

 Ideally, it should be chosen randomly from reference population so that it is

representation of reference population.

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Selection of study subjects

 Inclusion & exclusion criteria : for determining who will or will not be included

in the study must be spelled out with great precision, and in writing.

To ensure the replicability by others.

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Randomization

a statistical procedure by which the participants are allocated to “Study” and “Control”

groups.

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RANDOMIZED, DOUBLE-BLIND, CONTROLLED TRIAL is considered as

research design par excellence and “GOLD STANDARD” amongst research designs

with which results of other studies are often compared.

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Theory of Randomization

Randomization ensures each participant a known chance of being assigned to any of

the groups.

Why randomization…?

• The intervention exhibits a real effect.

• Generally minimizes the selection bias.

• More or less confounders get equally distributed between the groups.

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Manipulation:

To manipulate the study group by withdrawal or reduction of the suspected

causal factor (e.g. This may be a drug, vaccine etc.) As laid down in the protocol

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Masking the intervention:

Experimental and control interventions are made to look alike

The taste, texture, color, flavor of the drug should be similar.

In surgical trials that’s why sham surgery is performed in the control group

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Follow up

Examination of the experimental and control group subjects at defined intervals

of time.

Thus the follow up may be short or may require many years depending upon the

study undertaken.

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Assessment

The final step is outcome of trials in terms of rates of outcome of interest in the

intervention group, is compared with that of the control group.

beneficial effects and adverse effects have to be compared.

The comparison can be in terms of differences in mean, differences in

proportions, relative risk, absolute risk reduction, number needed to treat,

percentage change, median ratio or hazard ratio (HR).

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Even if some participants have crossed over from intervention group to control

group or from control group to intervention group, analysis should be done as

randomized. This is known as intention to treat analysis.

Appropriate statistical test of significance should be done to find out if the point

estimate has occurred by chance or no.

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Absolute Risk Reduction (ARR)

ARR = incidence rate of (bad) event or outcome in control group –

incidence rate of the same event or outcome in the intervention

group.

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Number Needed to Treat (NNT)

It indicates the number of patients who are to be treated in order to prevent one bad

event or outcome.

It is the inverse of Absolute Risk Reduction (ARR).

NNT =1/ARR

The NNT is an important measure in clinical economics. If a clinical endpoint is

devastating enough, drugs with a high NNT may still be indicated in particular

situations. 26
Median Ratio

Clinical trials commonly record the length of time from study entry to a disease

endpoint for the intervention group and the control group.

These data are commonly depicted with a Kaplan – Meier curve (survival analysis)

from which the median time (time at which 50% of cases are resolved) and the mean

time (average resolution time) can be derived.

The groups are compared by time to event analysis.

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Median ratio is calculated by dividing control group median time by intervention

group median time.

The mean time (the average resolution time) between the two groups can be

compared based on the area under the Kaplan – Meier curve.

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Hazard ratio (HR)

Hazard ratio is a type of relative risk.

The Cox proportional hazard model (by Sir David Cox) estimates the hazard ratio

and its confidence interval.

The hazard ratio is an estimation of the ratio of the hazard rate in the intervention

versus the control group.

The hazard ratio is equivalent to the odds that an individual in the group with the

higher hazard reaches the end point first.

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Controls are comparison groups.

They are needed to defend the results of a trial(to counter balance).

Is essential for evaluation of benefits of a particular agent or product.

The choice of controls depends on many aspects.

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BENCH MARK CONTROL:

A control which is commercially available product which has set a benchmark

of its own.

Find out whether the tested product is superior than a set benchmark

Ex: Listerine mouth wash

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POSITIVE CONTROL:

It is an agent considered to be best and available agent

NEGATIVE CONTROL:

The type of control commonly employed to determine whether an agent provides

activity over and above its vehicle.

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PLACEBO CONTROL:

Placebo control consists of a placebo(inert substance)

Very similar to the test drug

Counteract the placebo effect.

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TYPES OF RANDOMIZED CONTROLLED TRIALS

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TRIALS 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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Superiority Design:

Show that new treatment is better than the control or standard (maybe a placebo)

Non-inferiority:

Show that the new treatment

a) Is not worse that the standard by more than some margin

b) Would have beaten placebo if a placebo arm had been included (regulatory)

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Equivalent design

Trial with active (positive) controls

The question is whether new (easier or cheaper) treatment is as good as the current

treatment

Must specify margin of “equivalence” or non- inferiority

Can't statistically prove equivalency -- only show that difference is less than

something with specified probability

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BASED ON BLINDING

Open trials

Blinded trial

Blinding
. is the concealment of group assignment to either the treatment or control
Hiding the knowledge of particular treatment

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WHY DO WE DO BLINDING ?

To reduce the following biases

i. Information bias

ii. Investigator/Assessor bias

iii. Patient bias

iv. Statistician bias

v. Interpretation bias
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Tests for blinding:

Asking participants to which group they belong

If they do not know, they are asked to make a

guess.

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Types of RCT

Clinical trials

Preventive trials

Risk factor trials

Cessation experiments

Trial of etiological agents

Evaluation of health services

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Preventive Trials:

These trials are purported to prevent or eliminate disease on an experimental basis.

The most frequently occurring type of preventive trials is vaccines and chemo-

prophylactic drugs.

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Risk factor trials:

In this the investigator intervenes to interrupt the usual sequence in the

development of disease for those individuals who have "risk factor" for developing

the disease.

Ex: Risk factors of coronary heart disease are elevated blood cholesterol, smoking,

hypertension.

Risk factor trials can be "Single factor" or "Multi factor" trials. 46

Cessation experiments:

In this study, an attempt is made to evaluate the termination of a habit (or removal

of suspected agent) which is considered to be casually related to a disease.

If such action is followed by a significant reduction in the disease, the hypothesis of

cause is greatly strengthened.

Ex: cigarette smoking and lung cancer.

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Trial of etiological agents :

One of the aims of experimental epidemiology is to confirm or refute an

etiological hypothesis.

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Evaluation Of 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.

Eg: TB regimen in India – which demonstrated that “domiciliary treatment” of

pulmonary tuberculosis was as effective as the more costlier “hospital treatment”.

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COMMUNITY INTERVENTION TRIALS(CITs)

CITs are usually carried out in hospitals or clinics, and are usually directed at

a patient group with specific health conditions.

In these types of studies, the major difference from the RCT is that the

randomization is done on communities rather than individuals.

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Typical examples of such trials include:

I. Evaluating the need for a service, i.e. Community diagnosis

II. Evaluating the design of a health service

III. Evaluating the performance or efficiency of the process of delivery of the

services

IV. Evaluating the effectiveness and impact of the programme or procedure

V. Relating the outcome to the input and constraints of the programme including

cost-benefit analysis.
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OTHER TRIAL DESIGNS:

Efficacy and Effectiveness trials:

An efficacy trial answers the question: "Does this intervention work under optimal

conditions?"

An effectiveness trial answers the question: "Does this intervention work under

usual conditions?”

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Explanatory trials:

Efficacy trials are sometimes called explanatory trials

Main purpose is to provide biological information ( about the way the drug acts and the

way body reacts to them)

Pragmatic trials:

Effectiveness trials are also known as pragmatic trials.

Which aims to test procedures under the condition in which they would be applied in

practice. 53
Equivalence trial:

A randomized clinical trial in which two distinct agents are compared head-to-head

against each other, and sometimes, but not always, against an inert agent (a

placebo) as well.

Non – inferiority trial:

A clinical trial that shows that a new treatment is as good as the standard treatment

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QUALITY ASSESSMENT OF RCT

Various approaches used:

Checklist approach

Quality scoring system approach

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SUMMARY

• “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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“BETTER H E A LT H

OUTCOMES FOR

ALL WHEN

PAT I E N T S

PA RT N E R WITH

RESEARCHERS”

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 CLINICAL TRIALS

Presented by,
Dr. Nitha Willy
First year PG
60
Department Of Oral Medicine And Radiology
CONTENTS

I. Introduction

II. Types of clinical trials

III. Phases of clinical trials

IV. Importance of clinical trials

V. Types of randomized clinical trial designs

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 Clinical Trials

Clinical trials are scientific investigations that examine and evaluate

safety and efficacy of different therapies in human subjects.

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The World Health Organization (WHO) definition for a clinical trial

is:

“ any research study that prospectively assigns human participants or

groups of humans to one or more health related interventions to

evaluate the effects on health outcome.”

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 Usually medical or Human subjects
clinical studies volunteer to participate

Constitute the last Last for about 5-7

step of the research
years
process

Investigations are
carefully conducted Approval of relevant
following a pre- governing and ethical
determined research committees is essential
protocol
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Types Of Clinical Trials

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Prophylactic Trials/Prevention Trials : look for

better ways to prevent disease in people who have

never had the disease or to prevent a disease from

returning e.g immunization

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Therapeutic/ Treatment Trials : test new treatment, new combinations of

drugs or new approaches to surgery or radiation therapy

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Risk factor trials: eg. proving the etiology of a

disease by inducing it with the agent in animals or

withdrawing the agent(e.g.smoking) through

cessation.

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Diagnostic trials are conducted to find

better tests or procedures for diagnosing a

particular disease or condition.

Diagnostic trials usually include people

who gave signs or symptoms of the

disease or condition being studied.

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Screening (Early Detection) Trials: test the

best way to detect certain disease or health

conditions.

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Quality of Life Trials( or

Supportive Care Trials)

explore ways to improve

comfort and the quality of

life for individuals with a

chronic illness
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Clinical trials help to find out if:

 treatments are safe

treatments have any side effects

new treatments are better than the standard available treatments

Clinical trials show us what works (and what doesn’t) in medicine and

health care.

They are the best way to learn what works best in treating diseases like

cancer. 72
Clinical trials are designed to answer 2 important questions:

Does the new treatment work in humans?

Is the new treatment safe?

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PHASES OF CLINICAL TRIALS

Clinical trials used in drug development are sometimes described by phase.

These phases are defined by the Food and Drug Administration (FDA).

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Clinical trials involving new drugs are commonly classified into four

phases(I,II,III,IV).

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PHASE 0:

Officially named as an exploratory

investigational new drug study and

also known as a “microdosing” study.

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Phase 0 studies do not re- place formal Phase I drug

safety testing and do not offer any possibility of patient

benefit.

Intended to speed drug development as part of the FDA

Critical Path Initiative by quickly weeding out ineffective

drugs early in the development process. (No therapeutic or

diagnostic intent.) 77
PHASE I:

Initial studies

to determine the metabolism and pharmacologic actions of the agent in

humans

the side effects associated with increasing doses

 to gain early evidence of effectiveness

test a new drug or treatment in a small group of healthy people ( 20 -50)

20 -50
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PHASE I/II (Device – Pilot):

Some trials combine Phase I and Phase II, and test

both efficacy and toxicity (safety, dosage levels,

and response to new treatment).

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PHASE II:

Controlled clinical studies

to evaluate the effectiveness of the agent for a particular indication or

indications in patients with the disease or condition under study

to determine the common short- term side effects and risks.

The study drug or treatment is given to A selected group of patients

(100 – 300).

100 – 300 80
PHASE II/III:

Some trials combine Phase II and Phase III, and test for both efficacy and

overall benefit-risk relationship.

The new treatment is compared to a standard treatment regimen.

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PHASE III (DEVICE – PIVOTAL)

to evaluate the overall benefit-risk relationship and provide an adequate

basis for physician labeling.

 Compares new agent/test article against commonly used agents/test

articles.

The study drug or treatment is given to a large group of patients (1000

– 3000)

1000 – 3000 82
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PHASE IV:

Post-marketing studies

designed to monitor the effectiveness of the approved intervention in the

general population

 to collect information about any adverse effects associated with widespread

use.

1000+
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IMPORTANCE OF CLINICAL TRIALS

Doctors and other healthcare professionals and patients need evidence

from clinical trials to know which treatments work best.

Without this evidence, there's a risk that people could be given

treatments that have no advantage, waste resources, and might even be

harmful.
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Ethical issues in Clinical trials

Ethical considerations are very important in the design of clinical

trials.

No patient should be denied appropriate treatment as a result of

participation in an experiment.

The intervention being tested must be acceptable in the light of

current knowledge.

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Types Of Randomized Clinical Trial Designs

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Concurrent Parallel Study Design

Classical clinical trial approach

Two study groups

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Cross-over Type of Study Design

 Will patient do better on drug A or drug B?

 Removes “patient effect” reducing

variability and increasing precision of

estimation

 Needs to determine appropriate length of

washout period.

 “Period” effects : Progression of disease,

Dropout
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Run in design

 Assign all eligible patients a placebo to be taken for a “brief” period of time.

Patients who are “judged” compliant are enrolled into the study. This is often referred to

as the “Placebo Run-In” period.

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Factorial Design

 Evaluates multiple factors simultaneously

 Major concern: interaction of interventions

 Patients must be willing and able to take any of

the treatment combinations may be hard to

determine

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Cluster Design

 Groups or clusters randomly assigned,

not individuals. E.g. : villages,

classrooms , platoons Examples:

Community trials on fluoridation of

water

Smoking cessation intervention trial

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Sequential Design:

A large statistical literature for classical sequential designs

Developed for industrial setting

Modified for clinical trials

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SUMMARY

Trials are the primary way that researchers determine if a new form of

treatment or prevention, such as a new drug, diet, or medical device, is

safe and effective in people.

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 NON- RANDOMIZED CONTROLLED TRIAL

Presented by,
Dr. Nitha Willy
First year PG
99
Department Of Oral Medicine And Radiology
Contents

i. Definition

ii. Goal

iii. Source of bias

iv. When is it appropriate to use a non- randomized trial design?

v. Reasons for the use of nonrandomized studies

vi. Disadvantages of the nonrandomized clinical trial

vii. Summary
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Definition

A study where participants have been assigned to the treatment,

procedure, or intervention alternatives by a method that is not random.

The investigator defines and manages the alternatives.

Participants may choose which group they want to be in, or they may

be assigned to the groups by researchers.

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The ultimate goal of the evaluation of healthcare interventions is to produce

a valid estimate of effectiveness, in terms of both internal and external

validity.

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Internal validity - the extent to which the results of a study can be

reliably attributed to the intervention under evaluation

External validity - the extent to which a study’s results can be

generalized beyond the given study context.

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SOURCES OF BIAS IN NRCT

Selection Bias: will be introduced when participants chosen for one

intervention have different characteristics from those allocated to the

alternative intervention (or not treated).

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Systematic Bias : When faced with a patient who may be eligible to

receive a given intervention, the decision to treat will be influenced

by some factor that in turn is related to the treatment outcome.

This introduces systematic bias leading to either over- or

underestimates of treatment effects, depending on the treatment

decision mechanism.

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Attrition bias : will occur if there are dropouts

Detection bias : if the assessment of outcomes is not standardized and

blinded

Performance bias: if there are errors and inconsistencies in the

allocation, application and recording of interventions.

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When is it appropriate to use a non- randomized trial design?

The first is when an RCT would be ideal but practical considerations

make a high-quality RCT infeasible.

When the act of random allocation may reduce the effectiveness of the

intervention

When there are legal or political obstacles to random allocation

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REASONS FOR THE USE OF NONRANDOMIZED STUDIES

The only ethical way to conduct an investigation.

The only ones possible in certain investigations that require the

implementation of treatments that may affect people's lives.

Usually less expensive.

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reduce the threats to external validity that limit the value of RCTs

results.

Does not require the extensive planning and control

often involve more providers and settings, making the results more

generalisable

the lack of randomization often facilitates recruitment of a larger

proportion of eligible patients

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DISADVANTAGES OF THE NONRANDOMIZED CLINICAL TRIAL

The potential for bias from confounding.

The direction of this bias is unpredictable from study to study.

The results of these trials must be evaluated in a larger context, and internal

and external validity may be best assessed through the replication of results in

a variety of clinical settings

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SUMMARY

Uses natural groups or assigns participants to groups using a non-random

procedure.

While nonrandomized studies are cheaper, more easily carried out, and can

be done retrospectively, inferences from them are generally more suspect

than are those from randomized studies.

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