This document outlines the key elements of clinical trials and experimental studies. It discusses the objectives and advantages of randomized clinical trials, including their ability to control for confounding factors and minimize biases. The document describes different types of clinical trial designs, such as parallel, crossover, and factorial designs. It also covers limitations of clinical trials, variables in study design, phases of clinical trials, and methods for analyzing trial results.

1. Research Methodology and
Evidence Based Healthcare (EBHC481)
Experimental studies
Dr. Samer Rastam MD, PhD
1
Lecture 6
Level 8
Year 4

2. Research Methodology and
Evidence Based Healthcare (EBHC481)
Objectives
• Understand the advantages and disadvantages of randomize
clinical trials
• Understand the concepts of clinical trials.
• Understand the different designs for clinical trails.
• Understand the elements of the study design.
2

3. Research Methodology and
Evidence Based Healthcare (EBHC481)
Clinical Trials
• Definition: The evaluation of intervention (treatment) on disease in a
controlled setting in human participants.
• Ideally: Two identical groups. The intervention will be applied to one group
(intervention group) and results will be compared with the control group (no
intervention), so all differences are due to the intervention
• Like a cohort study, participants are selected based on their exposure status.
• A clinical trial is usually a prospective study where an intervention is allocated
to different groups of subjects and are followed-up over time to identify those
who develop the outcome under consideration.
• Clinical trials are used to assess whether the new intervention is safe,
efficacious and effective.
3

4. Research Methodology and
Evidence Based Healthcare (EBHC481)
Clinical Trials
No retinopathy
Retinopathy
Eligible
subjects
(DM)
Intensive
insulin
therapy
Standard
insulin
therapy
Randomize
Time
Onset of study
No retinopathy
Retinopathy

5. Research Methodology and
Evidence Based Healthcare (EBHC481)
Advantages of RCTs
• Ability to control confounding (Randomization)
• Randomization: Minimize selection bias.
• Controlled setting: Minimize information bias.
• The ability to ensure temporality.
• The ability to replicate findings.

6. Research Methodology and
Evidence Based Healthcare (EBHC481)
The limitations of RCTs
• Lack of reality
• Ethical problems
• Can’t be used to detect the effects of risk factors
• Even in treatment studies, it must be used with cautions
• Expensive and take long periods of time.
• Major problems:
1. Non-representativeness of samples: volunteers (healthy or patients)
2. Compliance, as some patients might not comply properly to the
intervention under study.
3. Loss to follow-up, especially when the duration of follow-up is very
long, which might introduce selection bias.
4. Generalizability of the study results might be limited, especially when
researchers use restrictive inclusion/exclusion criteria

7. Research Methodology and
Evidence Based Healthcare (EBHC481)

8. Research Methodology and
Evidence Based Healthcare (EBHC481)
• The reference population (also known as the target population) is
the population to which generalizations of the results of the
experiment apply.
• Sampling:
• The best choice for this study population would be to obtain a
simple random sample, so that there will be no bias in the
selection of study subjects. This is usually difficult, or sometimes
impossible.
• Usually the study is often restricted to a few sites and patients
reporting to these sites, either voluntarily or through some
referral system.
• The success of the experiment, and whether the results of the
experiment can be generalized to the target population, will
depend on how representative this sample is.
• Selection bias is often a very serious issue.

9. Research Methodology and
Evidence Based Healthcare (EBHC481)
• Applying Inclusion/exclusion criteria
• The inclusion criteria identify the target group in a consistent
and reliable manner. The definitions should be precise and reproducible.
• The exclusion criteria list characteristics of the study subjects that would
make them ineligible to enter the study:
• To minimize potential dangers (pregnant women, kids, …)
• To select relatively homogeneous subjects to reduce the required
sample size.
• Getting ‘informed consent’ from the participants before they are subjected
to experiments.
• The subjects left after the preceding exclusions form the study
participants
• The subjects in this group will then be randomly allocated to the various
intervention factors and the control group.
• The usual design is the randomized, controlled, double-blind clinical trial

10. Research Methodology and
Evidence Based Healthcare (EBHC481)
• Preclinical (drug discovery): experimentation before a drug is given to human subjects
• lab testing for biologic activity (in vitro)
• testing on animals (in vivo)
• Phase I:
• To explore possible toxic effects of drugs and determine a tolerated dose for
further experimentation.
• Phase II:
• Screening and feasibility by initial assessment for therapeutic effects; dose finding
and further assessment of toxicities (safety and tolerability)
• Phase III:
• Comparison of new intervention (drug or therapy) to the current standard of
treatment; both with respect to efficacy and toxicity.
• Phase IV: (post marketing)
• Observational study of morbidity/ad adverse effects.

11. Research Methodology and
Evidence Based Healthcare (EBHC481)
Study Variables
• The independent variable is the specific study “intervention” or
prediction variable (treatments or diagnostic techniques).
• The dependent variable is the main study “outcome” that
is being measured. In general, the dependent variable is believed to be
affected by the independent variable
• Extraneous variables (other, potentially confounding factors): might
have an important impact on the results.
• If the study involves treatment of asthma, then smoking history
might be an important potential confounder variable.
• Predicting all of confounding variables in advance is impossible.
11

12. Research Methodology and
Evidence Based Healthcare (EBHC481)
Study Design Elements (major)
1. Manipulation: the ability to influence or direct the independent
variable.
2. Control: the ability to direct or influence important confounding
variables and study measurements.
• In a study of high dose versus standard dose albuterol for
severe asthmatics, is the administration of O2, steroids,
antibiotics, and so forth, also standardized by the protocol?
3. Randomization: The unbiased (random) subject assignment to
each group.
12

13. Research Methodology and
Evidence Based Healthcare (EBHC481)
• Additional element is Blinding
• Hiding the identity of the treatment from the participant
(single-blinded), and the investigator who evaluates the
outcome (double-blinded), and sometimes from the person
who enters and analyses the data (triple-blinding)
• To ensure the blinding we can use placebo in control group.
• In some cases, blinding may not be feasible. For example, in
most surgical trials. This trials is called open-label trial.
13

14. Research Methodology and
Evidence Based Healthcare (EBHC481)
Classification of Research Designs by Degree of Scientific Rigor
• True experimental
• Have all three design elements.
• Are always prospective.
• Have high scientific validity.
14

15. Research Methodology and
Evidence Based Healthcare (EBHC481)
• Quasi-experimental:
• Only have one or two design elements
• Have manipulation or control
• Generally lack randomization
• Are generally prospective in nature
• Are moderate in scientific validity
• Non-experimental
• Have one or none of the core design elements
• Lack manipulation and randomization
• May also lack control
• Are generally retrospective
• Have the lowest scientific validity
15

16. Research Methodology and
Evidence Based Healthcare (EBHC481)
Quasi-experimental design
• Usually non-randomize.
• Examples:
• Uncontrolled before-and-after study: baseline measurements
are The intervention is then applied. At some point following
the intervention, the outcome and other measurements are
repeated.
• Controlled before-and-after-study: A similar design to the
uncontrolled before-and-after study, but with the addition of
one or more control groups, for which baseline and follow-up
measurements are made, but no intervention is applied.
16

17. Research Methodology and
Evidence Based Healthcare (EBHC481)
Designs of RCT
• Parallel (two-arm design, three-arm design): The design compares the new therapy
with a placebo or other control and examines the outcome of patients
randomized to the two groups
• Follow-up: a special case of parallel design, when outcome is measured many
times.
• Crossover: patients receive each intervention in a random order. Each subject
becomes their own control (self-control) , thereby directly controlling for most
confounding variables. The disadvantage is that it requires a lengthy period of
study (“wash-out” period) and therefore is generally not appropriate for the acute
care setting.
• Factorial: looks at the effect of multiple interventions, both individually and in
various combinations.

18. Research Methodology and
Evidence Based Healthcare (EBHC481)
Parallel
No retinopathy
Retinopathy
Eligible
subjects
(DM)
Intensive
insulin therapy
Standard
insulin therapy
Randomize
Time
Onset of study
No retinopathy
Retinopathy

19. Research Methodology and
Evidence Based Healthcare (EBHC481)
Crossover RCT
Randomization
Treatment A
Treatment A
Treatment B
Treatment B
Time
Group 1Group 2

20. Research Methodology and
Evidence Based Healthcare (EBHC481)
Factorial
Weight loss
• Active A: Diet
• Active B: Physical activity
• Placebo
Placebo AActive A
Active B
Placebo A
Active A
and B
Active B
Placebo A and BActive A
Placebo B
Placebo B

21. Research Methodology and
Evidence Based Healthcare (EBHC481)
Units of observation in RCT
• Randomized clinical trial (RCT): Individuals.
• Community intervention trial (CIT)
• In the community (testing a vaccine , introduction of iron-
fortified salt, … )
• Usually to test health care programs.
• The randomization is done on communities rather than
individuals

22. Research Methodology and
Evidence Based Healthcare (EBHC481)
Main purpose of the RCT
• Prophylactic trials, e.g. immunization, …
• Therapeutic trials, e.g. drug treatment, surgical procedure, …
• Safety trials, e.g. side-effects of oral contraceptives.
• Risk-factor trials

23. Research Methodology and
Evidence Based Healthcare (EBHC481)
RCT according to sample size
• RCT (Classical): fixed pre-determined sample size.
• Sequential clinical trial: where the results are analyzed frequently,
and the trial stopped as soon as statistically significant differences
are observed.

24. Research Methodology and
Evidence Based Healthcare (EBHC481)
Analysis of clinical trial
• There are different types of clinical trials based on the main objective
of the study:
• Superiority trial: It is the most frequently used type of clinical trials,
where the objective is to show that a new therapeutic agent is superior
to the conventional one.
• Equivalence trial: It is a type of clinical trial which is used to show
bioequivalence, thus, to show that the new therapeutic agent is
equivalent to the conventional one.
• Non-inferiority trial: It is a type of clinical trial which is used to show
that the new therapeutic agent is not worse than the conventional
one.
24

25. Research Methodology and
Evidence Based Healthcare (EBHC481)
Effectiveness vs. Efficacy analyses
• Effectiveness analyses are carried out to assess the effect of treatment
on the outcome in the “real world”, which include poor compliers and
those who switch to other medications. It includes all patients as
originally allocated after randomization. This type of analyses is called
“intention to treat” analyses. This is the recommended method in
superiority trials to avoid any bias
• Efficacy analyses: are carried out to assess the efficacy of treatment on
the outcome among those who actually took the medication. It
includes only those patients who completed the treatment originally
allocated This type is called per-protocol analysis. This analysis leads to
bias. Sometimes it is used in noninferiority trials
25

26. Research Methodology and
Evidence Based Healthcare (EBHC481)
References
1. Health Research Methodology- A Guide for Training in Research
Methods, 2nd Ed WHO, 2001
2. Introduction to Clinical Research for Residents, Saudi
Commission for Health Specialties, 2014
3. Oxford Handbook of Clinical and Healthcare Research,
Sumantra Ray, Oxford, 2016
4. Principles and Practice of Clinical Research, John I. Gallin, 2002
26