Randomized Controlled Trial

History of medical research

• 562 BC - 1537: Era before James Lind (King
Nebuchadnezzar)
• 1747: James Lind and Scurvy (oranges and lemons) –
First experimental study
• 1800: Placebo introduction. First trial 1863 Austin
Flint. USA. Trial on Rheumatic fever
• 1943: First double blind RCT- Patulin for Common
Cold . UK
• 1946 First RTC- The Randomized Controlled Trial of
Streptomycin. UK
 Types of clinical studies
• Preventive studies-
• Screening studies -
• Diagnostic studies -
• Therapeutic studies -
• Quality of life studies -
• Expanded accessible programs -
 Design of clinical studies
Observational:
• Cohort studies
• Case-control studies
Interventional:
• Randomized controlled trials
 What is Randomized Controlled Trial (RCT)?

RCT - Randomized Controlled Trial is widely

acknowledged as a gold standard for assessment of
the health management measures as it allows to:
 Determine if the cause of the alternative
outcome is the treatment method rather
than any other factor.
 Definition
• RCT is a quantitative, comparative, controlled
experiment, where researcher investigates
randomly distributed two or more
interventions in individual. series
• RCT is one of the most powerful research
method (Stedman’s Medical Dictionary).
Design of Randomized Controlled Trials

 Allows matching populations to be

selected.
 Exclude individuals who: Do not
meet the requirements
Or
 Do not want to consent to
participate in randomized controlled
trials.
Development of the study protocol
 The protocol should be strict
 It should be clearly defined:
 Goals and objectives
 Questions to be answered
 Selection criteria for intervention and control
groups.
 Intervention used
 The working procedure should be
standardized
 The research schedule should be strictly
adhered to
RTC patients are randomly assigned to differe
study groups.

It is necessary to ensure
equal distribution of potential
error-producing factors (confounders) * between
groups, which should be further compared
(structural equivalence).
• These factors (confounders) are characteristics
that may affect the response to treatment:
E.g. weight, age, sex.
• Only in structurally equivalent groups is it
expected that the difference between the
outcomes will be due to the effect of the
treatment and not to any other factor.
• When confounders are known the structural
equivalence of patient groups is achieved by
stratified randomization.
 Stratified randomization

 If stratification factors - sex (male, female) and age

(<18 years, ≥18 years) are considered and 150
patients
should be randomized in a 1: 1 ratio to the active
treatment
and placebo groups (2 × 75 patients), randomization
should
be performed for each individual group (stratum).
 The two stratification factors with two corresponding
meanings define the four groups (male and <18
years, male and ≥18 years, female and <18 years,
female and ≥18 years).
Stratified randomization (example)
 In the ALIFE study patients were divided
into three treatment groups with a
randomization ratio of 1: 1: 1.
 They were randomized according to
prognostic factors: such as age (<36 or
≥ 36) and number of preterm births (2 or
≥3);
 As the research was multicenter, they
were also stratified according to the
research centers.
If patients are divided into groups intentionally
or unintentionally according to the signs associated
with the prognosis and not randomly, this will lead
to an error in comparing the treatment and distort
the results (selection bias).
The distribution in the study groups should
not be predetermined.
Determining the distribution in groups will
be avoided if the staff involved in the
study is not guaranteed to know which
treatment will be given to the next patient.
• Bias could be prevented not only through
randomization, but also through, so called,
blinding.
• The study could be double-blind, single blind,
or open.
• Double-blind

• Single-blind

• Open
Randomized Controlled Trials
Randomized controlled trials may include:

 Open, when both the patient and the

researcher know who is being treated;
 Single-blind, when either the patient or the
researcher knows who is being treated,
and
 Double-blind, when neither patients nor
researchers know who is being treated.
 There is a more complete version of the double-
blind randomized study called Cross-over
design, when study participants in an
experimental group after one type of
intervention undergo another one that was
previously performed on the control group, and
vice versa.
 E.g. When comparing A and B treatments, study
participants are divided into two groups, one
receiving first A and then B treatment; by
contrast, the other reversing first B and then A
treatment. The disadvantage of such a study is
that the effect of the first treatment can be seen
when the patient is already receiving the second
treatment.
 Randomized controlled study is one of the most
 Multicenter Clinical Trial

Multicenter clinical trial is a randomized

clinical trial conducted simultaneously
in several centers/countries with a single
protocol.
 Research ethics

Basic ethical principles:

1. Respect for the person
2. Benefit - Increased benefits and reduced losses
3. Justice - equal distribution of research
burden and benefits
 Ethics Committee

 The Ethics Committee is committed to protecting

the rights, safety and well-being of all participants
 The Ethics Committee, together with the medical
staff, includes representatives from various
spheres of society
 The ethics committee should be free from the
influence of the researcher, sponsor and others.
 Prior to the commencement of the study, the
research protocol should be submitted to the
Ethics Committee for review.
 The study can be started only after receiving the
approval of the Ethics Committee
 Informed consent
Different terms

 Patient Information Sheet (PIS)

- Provides us with information only
 Informed consent form
- Used to document consent
 Both are integrated into a single document
called
an informed consent form
Main Elements of Informed Consent

 The purpose and duration of the

study Definition
 Description of risks
 Description of benefits
 Notice of participation alternative
 Unethical studies
 Medical experiments conducted in
concentration camps by Nazi doctors
 Tuskegee syphilis experiment in USA,
etc.
 Developmental anomaly caused by
using
Thalidomide (10,000 children). Cause -

complete preclinical research has not

been
conducted
 Phases of Randomized controlled
clinical trials
• Preclinical Phase
• Phase I
• Phase II
• Phase III
• Phase IV
 Preclinical Phase

• In vitro (e.g. test tube) studies and

• In vivo (e.g. experimental animals) studies
 Phase I clinical trial

 Phase I studies are conducted on healthy

volunteers (20 - 100 people). If the drug is
highly toxic (eg chemotherapy) then the
study is performed on patients.

 Phase I studies determine:

safety, tolerability, safe dosage level,
pharmacodynamic and pharmacokinetic
parameters.
 Phase II clinical trial

 Phase II research is conducted on a relatively

large population (100-500 individuals)
 The aim of the study is to determine the
effectiveness and safety of the drug
 In phase II it is necessary to have a control group
 Phase III clinical trial
 Randomized controlled multicenter trials are held
with large populations (hundreds or thousands) to
confirm safety and efficacy.

 After the Phase III research, the company

determines the
so-called "Registration dossier " and submits it to
the
relevant authorized body for registration of the
medicinal
product
 Phase IV clinical trial

Post-registration studies Is conducted after the

registration of the drug and its aim is to further
study the safety and efficacy of the drug