Session 10 - Experimental Study Design

Experimental Study Design
By Dr Supriya Phadnis
For
Term 3
Research Methodology
GIM
History of Experimental Studies
• Galen gave one of his potions to a lot of patients:
some recovered, some died. He thought that was
evidence that the potion worked.
• The problem with Galen’s line of reasoning is that no
experiment could disprove it.
All who drink of this treatment recover in short time, except those whom it did not help,
who will die ,it is obvious, therefore, that it fails only in incurable cases.
-Galen (129-C.199CE)
Unintentional Trial by Amboise Paré
• In 1537, Ambroise Paré conducted unplanned
trials in the treatment of battle wounds.
• He used digestive made of yolks of eggs, oil of
roses & turpentine due to lack of boiling oil
which was standard treatment for war
wounds during those days.
• He found that the digestive medicament
worked better.
Experimental study design
• Investigator decides who will get the exposure and who will not. So
under direct control of the investigator unlike other type prospective
study where exposure is not dictated by the investigator.
• Epidemiologist takes some action, intervention or manipulation in
contrast to descriptive studies where no action is taken but
observation is done.
More examples from history
• Planned trial on scurvy by James Lind in 1747
• James Lind, a Scottish surgeon took 12 sailors
suffering from scurvy and divided them into 6
pairs.
• He than assigned each pair to 6 different
treatments for scurvy.
• The two patients who were given lemons and
oranges recovered most quickly, suggesting a
beneficial effect of citrus.
Edward Jenner’s experiment with cowpox in
1796.
• Smallpox: deadly disease, no cure.
• Milkmaids : contracted with cowpox
• Did not get smallpox
• Deliberately infected 8 year old boy,
with cowpox, using a pus from blisters
• Then injected small pox virus
• The boy did not get the Smallpox!
Major types of experimental study design
• Non Randomized Trial
• Randomized Control Trial
Non-randomized trials
• Also known as Quasi-Experimental Designs.
• It is a type of research in which the investigator manipulates the study
factor but does not assign individual subjects randomly to the
exposed & non- exposed groups.
• These are designed as:
• It is always not possible for ethical, administrative and other reasons to resort
to a RCT.
• Some preventive measures apply only to groups or community-wide basis.
• When disease RCT require follow-up of thousands of people for a decade or
more.
As here randomization is not done. So, low comparability than RCT and chances of
spurious results are high than RCT.
Randomized control trials
• 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
Why 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
• Drawing up ‘Protocol’
• Selection of Reference and Experimental Population.
• Randomization
• Manipulation or Intervention
• Follow-up
• Assessment of outcome
The Protocol
• Should be strictly adhered to throughout the study.
• Aims at preventing bias and to reduce the source of error in study.
• What is included…
• 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.
Selection of Reference and Experimental
Population
• Reference population
• Also known as Target Population.
• May be as broad as humans or limited to specific groups.
• It is the population to which findings of the trial, if found successful, are
expected to be applicable.
• 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.
• Example
• 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
• 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.
• Randomization aims at:
• Achieving Internal Validity.
• Eliminate bias (Selection bias).
• Allowing comparability.
• Equally distributing the “other” factors which are important but not
recognized or cannot be determined, equally between the two groups.
Methods of Randomization
• Various methods are:
• Simple Random Allocation
• Randomization in groups of Two
• Systematic Allocation
• Stratified Allocation
• All methods assume that an equal number of participants is desired in
both groups.
Timing of Randomization
• Actual randomization should be delayed until just prior to initiation of
therapy after consenting.
• This prevents randomizing participants who drop out before

participating in any of the study.
• This is important because everyone who gets randomized needs to be

included in the study's analysis.
Intervention
• 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.
Events associated with the trial
• Adverse event (AE) : Undesirable health occurrence that occurs
during the trial and that may or may not have a causal relationship to
the treatment.
• Serious adverse event (SAE): Something life-threatening, requiring or
prolonging hospitalization and/or creating significant disability. E.g., A
suicide attempt - SAE in a study of any treatment.
• The SAE needs to be reported regardless of whether it bears any
relationship to the treatment or the problem being studied
• Depending on the severity and frequency of adverse events,
investigators and data safety monitors may have to decide to
terminate the trial prematurely
Loss to follow-up
• Also known as Attrition.
• Some losses to follow-up are inevitable due to factors, such as:
• Death
• Migration
• Loss of interest
• If these losses (i.e. attrition) are substantial than it may be difficult to
generalize the result for reference population
• During the trial, participants may deviate from the protocol for
various reasons including
• Developing side effects.
• Forgetting to take their medication.
• Simply withdrawing their consent after randomization.
• Avail alternative treatment on their own initiative.
• Contraindication of a therapy because of non compliance for a prolonged
period.
• Hence every effort should be made to minimize the losses to follow
up and increase the compliance of the study participants.
Assessment of outcome
• 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
• 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.
Blinding
• It prevents patients, investigators, even statisticians involved in the
study from knowing the treatment a subject is receiving.
• 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.
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.

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.
Advantages
• Random assignment and the use of a control condition ensure that
any extraneous variation not due to the intervention is either
controlled experimentally or randomized.
• That allows the study's results to be causally attributed to differences

between the intervention and control conditions.
Disadvantages
• These studies are time and energy intensive.
• An RCT is generally expensive as compared to other study designs.
• May not be feasible for all interventions or settings.
• Example: Some institutions have policies that prohibit random

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Experimental Study Design

• Eliminate bias (Selection bias).

• This prevents randomizing participants who drop out before

• This is important because everyone who gets randomized needs to be

• This constitutes the dependent variable (e.g., incidence of disease,

• Dissemination at local, national, international level.

• Publications in journals, online, conference presentations,

• Information must reach those who most need it.

• That allows the study's results to be causally attributed to differences

• An RCT is generally expensive as compared to other study designs.

• May not be feasible for all interventions or settings.

• Example: Some institutions have policies that prohibit random

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