Experimental Study

Dr. Toyosi Adekeye,

Senior Lecturer
Department of Community Medicine and Primary Healthcare
Bingham University
Randomized Control Trials
 Randomized Control Trial
( Abbreviated as RCT )

An epidemiologic experiment in which subjects in a population are randomly

allocated in to groups, usually called study and control groups to receive or not to
receive an experimental, preventive or therapeutic procedure, maneuver or
intervention.
(John M Last Dictionary of Epidemiology 2nd Edition)
 Goal of RCT
• Primary Goal
• To test whether an intervention works by comparing it to a control condition (usually
either no intervention or an alternative intervention).

• Secondary Goals
• Identify factors that influence the effects of the intervention (i.e., moderators)
• Understand the processes through which an intervention influences change (i.e.,
mediators or change mechanisms that bring about the intervention effect)
 Steps of RCT
• The basic steps include the following:

• Drawing up ‘Protocol’
• Selection of Reference and Experimental Population.
• Randomization
• Manipulation or Intervention
• Follow-up
• Assessment of outcome
 Protocol

Select suitable population

(Reference population)

Select suitable sample

(Experimental population)

Not eligible

Make necessary exclusion

Don’t consent

Randomize
Design of a Randomized Controlled Trial

Experimental group Control group

Manipulation and follow-up

Assessment
 The Protocol
• Should be strictly adhered to throughout the study.
• Aims at preventing bias and to reduce the source of error in study.
• The Protocol specifies*:
• Aims and Objectives of the study
• Questions to be answered
• Selection criteria for Study and Control group
• Sample size
• Procedures for allocation of subjects into study & control groups
• Treatment or intervention to be applied
• Standardization of working procedures and schedules
• Responsibility of parties involved in trial.
* up to the stage of evaluation of outcome of study
Selecting Reference and
Experimental Population
 Reference Population
• Also known as Target Population.

• It may be as broad as mankind or limited to specific groups.

• It is the population to which findings of the trial, if found successful, are expected to be
applicable.

• Thus, it may comprise of the population of whole city, or a population of school children,
industrial workers, obstetric population and so on according to the nature of the study.
 Experimental Population
• Also known as Study Population.
• Derived from the reference population. The actual population that participates in the study.

• Ideally, should be chosen randomly so as to have all the characteristics of the reference
population.
• If study population differs from the reference population, it may not be possible to generalize
the findings of the study to reference population

• Once defined, its members are invited to participate.

• Cooperation should be assured to avoid losses to follow up
• The participants must fulfill these three criteria:

• They must give “informed consent.”

• They should be representative of the population.
• They should be qualified or eligible for the trial. Eg:
• For testing a new drug for the treatment of anemia participants should be anemic.
• In the test of a new vaccine against whooping cough, participants already immune to the
disease in question, are not qualified.

• A participant of the study differs from those who do not participate in ways that may
affect outcome of the study.
 Exclusion and Inclusion Criteria
• Inclusion Criteria:
• To specify who will be eligible to be included in the study, based on demographic and
clinical characteristics.

• Exclusion Criteria:
• To define who will not be eligible to be included in the study.
• More the exclusion criteria:
• More precise findings, and lesser requirement of sample size.
• More difficult to find subjects and generalizability will be restricted.
 Randomization
• It is the heart of a control trial.
• Randomization entails allocating the available participants to one or another study
group.*
• One group generally receives intervention (study), other does not or receives different
intervention (control).
• It is different from Random sampling.
• Gives confidence of like being compared to like.

*Jekel’s Epidemiology, Biostatistics, Preventive Medicine, and Public Health

 Manipulation or Intervention
• Deliberate application or withdrawal or reduction of the suspected causal factor
as laid down in the protocol.

• Independent variable (e.g., drug, vaccine, a new procedure) is created by intervention

whose impact is measured in the final outcome.
• This constitutes the dependent variable (e.g., incidence of disease, survival time,
recovery period).
 Follow-up
• Examination of experimental & control group subjects,
• At defined interval of time
• In a standard manner
• With equal intensity
• Under same given circumstances
• In same time frame till final assessment of outcome.

• Duration of trial is based on expectation that a significant difference (e.g. mortality) will be
demonstrable at a given point in time after the start of trial ( i.e. the ‘natural history of
disease’).
• Thus, it may be short or long, depending upon study undertaken.
 Assessment
• The final step is assessment in terms of:
• Positive results i.e., benefits of experimental measures such as reduced incidence or
severity of disease, cost to health service etc.
• Negative results i.e., severity and frequency of side-effects and complications, if any,
including death.
• Incidence of results compared rigorously and differences are tested for significance.
• Data analysis may be done sequentially or at the end of trial (more useful).

• Errors of assessment of outcomes due to human elements may give rise to Bias.
 Bias
• Any systematic error in design, conduct or analysis of the study that results in a
mistaken estimate of an exposure’s effect on risk of disease.*
• In experimental study this may arise from three sources:
• Subject variation: Bias on part of participant, who may feel better if they knew they are
receiving a new form of treatment.
• Observer Bias: Increased positive or negative findings in interview or physical
examination if observer knows beforehand the particular procedure.
• Investigator Bias: Bias in evaluation. Investigator may subconsciously give a favorable
report.
• Randomization can’t guard against these bias, nor the size of sample.
• In order to reduce these problems, a technique known as “Blinding” is adopted.

*Epidemiology by Leon Gordis, 5th Edition

 Blinding
• Also known as “masking”.
• It prevents patients, investigators, even statisticians involved in the study from
knowing the treatment a subject is receiving.
• Can be of following types:
• Single blinding: Participant does not know about the group he belongs to.
• Double blinding : Here, neither the participant nor the investigator knows about the
group allocation and intervention done.
• Triple blinding: participant, investigator and the person analyzing the data are all blind.
• Triple blinding is considered best, while double blinding is used most.
Data Analysis and Results
 Dissemination of Results
• Research is not complete without dissemination.

• Dissemination at local, national, international level.

• Publications in journals, online, conference presentations, dissemination workshops,

website.

• Information must reach those who most need it.

 Reporting Results: CONSORT
• Consolidated Standards of Reporting Trials : Gold standard for reporting RCTs.
• Adequate reporting of randomized, controlled trials (RCTs) is necessary to allow
accurate critical appraisal of the validity and applicability of the result
• The most up-to-date revision of the CONSORT Statement is CONSORT 2010 which
is an evidence-based, minimum set of recommendations for reporting RCTs.
• The 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.
• Extensions of the CONSORT Statement have been developed for other types of
study designs, interventions and data.
 Ethical Issues
• Investigators are responsible to uphold ethical standards and guidelines.
• Declaration of Helsinki, developed by the World Medical Association, this set of
ethical principles guides medical researchers in conducting research on human
subjects.
• Some procedures for safeguarding human subjects include:
• Informed consent procedures.
• Procedures to safeguard confidentiality.
• Protocols to preserve safety and address adverse events.
• Reporting study results.
 Ethical Issues
• Three issues of utmost importance :
• A patient must never be given a treatment that is known to be inferior.
• Patients must be fully informed about all the circumstances surrounding the treatments
in the trial including possible adverse reactions and side effects they may experience.
• Patients who have entered a trial may withdraw at any time.

• In some cases, country specific information and consent forms may be required to
obtain proper consent.
 Clinical Trials
• Classical setting of an intervention (experimental) design.
• Examples include:
• Evaluation of β-Blockers in reducing cardiovascular mortality in patients surviving acute
MI.
• Trials of aspirin on cardiovascular mortality and β-carotene on cancer.
• The Unit of Study: Patients of a given disease, the therapy of which is to be studied.
• Contains four phases: Phase I to Phase IV
 Clinical Trials: Four Phases
• Phase I: Clinico-pharmacological Studies
• These refers to dose finding studies, to find out as to how large a dose can be given before
an unacceptable toxicity is experienced by patients (Maximally Tolerated Dose or MTD) as
well as looking for various toxic and pharmacological effects of the drug.
• Undertaken on small number of patients (20 to 80) or sometimes on healthy volunteers,
who are usually institutionalized, and occupy ‘Research Beds’.
• Close supervision is required along with high technology in bio-chemistry, pharmacology
and endocrinology, and varied medical expertise.
• This phase runs for a short period of time usually one or two months.
 Clinical Trials: Four Phases
• Phase II Clinical Trial
• These are clinical investigations of a larger number of patients ((100 to 200) with the
target disease, looking for pharmacokinetic and pharmaco-dynamic effects of the drug
on these patients.
• Efficacy, biological activity and relative safety of the drug also looked for.
• Rate of adverse events at that MTD also estimated.
• The purpose of Phase II is to assess the effectiveness of the drug or device, to determine the
appropriate dosage, and to investigate its safety.
• In the case of a device, its effectiveness is assessed and its configuration is tested and, if
needed, improved.
 Clinical Trials: Four Phases
• Phase III : Classical Phase
• This is the Classical Phase (the one usually referred to as a ‘clinical trial’ and reported
in health research journals).
• It is performed on patients, who should consent to being in a clinical trial.
• Strict criteria for inclusion in and exclusion from the trial are followed.
• Assessment of effectiveness, safety and dose requirement in larger and more
heterogeneous population is done.
• This phase is also known as the Randomized Controlled trial (RCT).
 Clinical Trials: Four Phases
• Phase IV : Post Marketing Surveillance
• The purpose of the Phase IV trial is to re-assess the effectiveness, safety, acceptability
and continued use of the drugs or devices under these conditions.

• Data on the effect of the drug or procedure is collected from various agencies.
• Side effects which did not appear in phase - III, are detected in this phase and the drug
may be withdrawn or its usage modified.
• Classical examples are Thalidomide, Isoprenaline containing bronchodilators, and DES.
 References
• Epidemiology by Leon Gordis, 5th Edition
• Textbook of Public Health and Community Medicine by Rajvir Bhalwar
• rd Edition
Park’s Textbook of Preventive and Social Medicine by K. Park, 23
• Jekel’s Epidemiology, Biostatistics, Preventive Medicine, and Public Health by David L Katz
et al, 4th Edition
• Health Research Methodology : A Guide for Training in Research Methods, 2nd Edition
• Basic Epidemiology by R Bonita
That’s it for my presentation.
Thank you for listening !