Randomized controlled trials (RCTs) provide the highest level of evidence in clinical research. RCTs involve randomly assigning subjects to experimental and control groups to test clinical interventions. Key aspects of RCTs include formulating a research question, randomization to eliminate confounding factors, blinding of subjects and researchers, monitoring outcomes in both groups, and presenting results including relative risk, efficacy and number needed to treat. Common RCT designs are parallel, cross-over and factorial designs. RCTs aim to discover safety and efficacy of clinical interventions.

1. Randomized controlled trials
Professor Maja Miskulin, MD, PhD

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

14. Types of RCT 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

28. Thank You for Your kind attention!