2. Definition
clinical trial is research in humans expected to reveal or
confirm the clinical, pharmacological, and/or other
pharmacodynamic effects of a research product(s), and/or to
determine any adverse reactions to a research product(s),
and/or to study absorption, distribution, metabolism, and
excretion of a research product(s) with the aim to discover
its safety and/or efficacy
3. Randomized controlled trials
RCT provide the highest
level of evidence
Meta-analyses
& systematic
reviews
RCT
Cohort studies
Case-control studies
Cross-sectional studies
Animal trials & in vitro studies
Case reports, opinion papers and lettersHierarchy of scientific evidence
4. Path of the RCT
formulate a specific research question to be answered
decision on the method of selecting the subjects
ensure the maximum possible number of the subjects
during the study period
5. Path of the RCT
after sampling, randomization is required in order to divide
the subjects into at least two investigated group (exposed
and unexposed or control group)
unexposed group will receive either a placebo if it is a
healthy subject, or a gold standard, if it is a subject with
illness
6. Randomization
process that allows unpredictability of the distribution of
subjects in the exposed group and the group of unexposed
ones
allows us to eliminate the effect of confounding factors
achieve comparability of a group of subjects with respect to
certain significant characteristics of the subjects (we achieve
an equal distribution of all characteristics)
7. Randomization
can be accomplished in many ways: using random number
tables, using sealed envelopes, drawing red or green balls,
and today it is easiest to do it with the computer, using
statistical programs
stratified randomization approach ensures complete
comparability of subjects in groups according to very
important confounding factors, such as age and sex
8. Monitoring and data collection
data collection must follow a predefined protocol and must
be performed equally well in both groups of subjects in order
to avoid the occurrence of a discontinuation of the
diagnostic procedure
ensured by using blinding, masking, which can be single,
double or triple
9. Monitoring and data collection
single blinding - only the subjects do not know in which
group they had been signed into
double-blinding - neither the subjects nor the researchers
who collect the data during the follow-up period of the
subjects do not know who from the subjects is in which
group
10. Monitoring and data collection
triple-blinding - neither the subjects, neither the
researchers nor the person analyzing the data do not know
who from the subjects is in which group
the blinding can only be done if placebo, or gold standard
drug, are of the same appearance (color and shape), weight,
taste and odor as the drug being investigated
11. Monitoring and data collection
it is possible to have a placebo effect when the ineffective
substance also improves health status as well as the
appearance of Hawthorne's effect, which is marked by the
"positive" reaction of subjects because researchers care
about them
12. Measurement of health outcomes
depends on the research question and the disease we are
investigating
the outcomes are divided into primary and secondary
the primary health outcome in research is usually one and that
is the answer to the most important part of the research
question
the secondary outcome may be drug side effects, but also a
recurrence of the disease, functional impairment, disability, etc.
13. Types of RCT design
besides most commonly used design where subjects are
randomized to one of two or more arms and where each arm
allocated different treatment – so called parallel design
other possible approaches in research in experimental
epidemiology is the use of so-called cross-over design or the
use of factorial design
15. Types of RCT design
the basic principle of cross-over type of design is to put the
subjects in the groups by randomization, application of the
investigated drug in the exposed group and placebo / gold
standard drug in the unexposed group, and follow-up of the
health outcomes over time
what is specific to this approach is the change in exposure in
the investigated groups and the exposed group in the second
part of the research becomes unexposed and vice versa
16. Types of RCT design
this change in the exposure and non-exposure status of each
subject can be accomplished after a certain amount of time has
passed required for the previously applied substance to be
completely excreted from the body
in this design every subject is control to itself
17. Types of RCT design
problem: the permanent effect of the initial exposure (or non-
exposure) that is misleadingly interpreted by the effect of non-
exposure (or exposure)
problem: order of exposure and unexposure because the
placebo effect is more pronounced at the beginning of the
study, as well as the fact that this approach can not always be
applied
18. Types of RCT design
by using factorial design, we simultaneously investigate the
effect of multiple drugs
these drugs must inevitably have different pharmacokinetics
and their activity must be completely independent
advantage: the use of one sample of subjects to investigate the
effect of multiple drugs, which can save considerable amount of
money and other resources
19. Types of RCT design
advantage: during the monitoring of the subjects we can stop
the exposure for one drug, if there is a need for that, and that
the second part of the research continue without interruption
problem: complexity of trial design and statistical analysis
20. Presentation of results
we can calculate the relative risk for health outcomes using the
incidence in the exposed and non-exposed group of subjects
we can show survival of the subjects in the groups, for which
we can use Kaplan-Meier survival curve, which shows the
proportion of survivors during the follow-up time
21. Presentation of results
for the analysis of survival, we can use the multivariate analysis
of survival - Cox regression model (proportional-hazards model),
and as a result, we get the hazard ratio
unlike Kaplan-Meier's method, Cox's regression takes into
account the effect of the confounding factors
22. Presentation of results
finally we can calculate efficacy
the exposed group is the group that received the investigated
drug, while the unexposed group is the one who received a
placebo or a gold standard drug
𝐸𝑓𝑓𝑖𝑐𝑎𝑐𝑦 =
𝑖𝑛𝑐𝑖𝑑𝑒𝑛𝑐𝑒 𝑖𝑛 𝑢𝑛𝑒𝑥𝑝𝑜𝑠𝑒𝑑 𝑔𝑟𝑜𝑢𝑝 − 𝑖𝑛𝑐𝑖𝑑𝑒𝑛𝑐𝑒 𝑖𝑛 𝑒𝑥𝑝𝑜𝑠𝑒𝑑 𝑔𝑟𝑜𝑢𝑝
𝑖𝑛𝑐𝑖𝑑𝑒𝑛𝑐𝑒 𝑖𝑛 𝑢𝑛𝑒𝑥𝑝𝑜𝑠𝑒𝑑 𝑔𝑟𝑜𝑢𝑝
× 100
23. Presentation of results
we can calculate the number of people you need to treat in a
certain way in order to prevent one undesirable outcome
(number needed to treat - NNT)
𝑁𝑁𝑇 =
1
𝑖𝑛𝑐𝑖𝑑𝑒𝑛𝑐𝑒 𝑖𝑛 𝑢𝑛𝑒𝑥𝑝𝑜𝑠𝑒𝑑 𝑔𝑟𝑜𝑢𝑝 − 𝑖𝑛𝑐𝑖𝑑𝑒𝑛𝑐𝑒 𝑖𝑛 𝑒𝑥𝑝𝑜𝑠𝑒𝑑 𝑔𝑟𝑜𝑢𝑝
24. Conclusions
as the results of a randomized controlled clinical trial can have
a significant impact on human health and on the way that
health care is provided, it is very important to understand the
overall course of each individual research
CONSORT (Consolidated Standards of Reporting Trials) - which
consist of a list of the constituent parts of the research that
must be described in the scientific article and the diagram of
the course of the survey
25. Types of RCT design? (mark the correct answer)
cross-sectional, case-control, cohort
WRONG
parallel, cross-over, factorial
CORRECT
26. Randomization? (mark the correct answer)
allows us to eliminate the effect of confounding factors
CORRECT
simple is better than stratified
WRONG
27. Hierarchy of scientific evidence? (mark the correct answer)
cohort studies provide highest level of evidence
WRONG
RCT provides highest level of evidence
CORRECT
