This document provides an overview of randomized control trials (RCTs). It discusses key aspects of RCT design including types of RCTs based on interventions evaluated (explanatory vs pragmatic), participants exposed (parallel vs crossover), number of participants (from n-of-1 trials to mega-trials), blinding of investigators/participants, and accounting for participant preferences. It also covers randomization techniques and their advantages, sample size calculations, and references for further information.

1. Randomized Control Trial
Presentation By:
Bikram Adhikari
MPH-2018
1

2. Research Design

3. RCT in Hierarchy of Evidence

4. Randomized Control Trial
• It is a trial in which subjects are randomly assigned to one of two groups:
• Experimental group receiving the intervention
• Comparison group or control receiving an alternative/conventional treatment
• The two groups followed up to see any differences in outcome.
• The results and subsequent analysis of the trial:
• Used to assess the effectiveness of the intervention (treatment, procedure, or
service does patients more good than harm)
• Used to determine whether a cause-effect relation exists between the
intervention and the outcome.

5. Randomized Control Trial

6. Types of RCT
• According to the aspects of the interventions they evaluate
• Explanatory and pragmatic trials
• Efficacy and effectiveness trials
• Phase I, II, and III trials
• According to how the participants are exposed to the interventions
• Parallel trials
• Crossover trials
• Trials with factorial design

7. Types of RCT
• According to the number of participants
• From n-of-1 to mega-trials
• Fixed size
• Sequential trials
• According to whether the investigators and participants know
which intervention is being assessed
• Open trials
• Single blind trials
• Double blind trials
• Triple and quadruple-blind trials

8. • According to whether the preferences of non-randomised
individuals and participants are taken into account
• Zelen's design
• Comprehensive cohort design
• Wennberg's design

9. RCT according to the aspects of the
interventions
Explanatory trials
• Address whether or not an intervention works. If the intervention
works, then these trials attempt to establish how such intervention
works.
• It tend to use placebos as controls, fixed regimens (that is, 20 mg by
mouth every 6 hours), long washout periods (if patients have been
taking diuretics, for instance, those drugs will be stopped for a
sufficient period of time to ensure that they are ‘washed out’ of their
bodies), intention to treat analysis, and focus on ‘hard’ outcomes (that
is, blood pressure recorded at specific times after a detailed and
standardised process).

10. RCT according to the aspects of the
interventions
Pragmatic trials (aka. management trials):
• Designed not only to determine whether the intervention works, but also to
describe all the consequences of its use, good and bad, under circumstances
mimicking clinical practice.
• To achieve this, pragmatic studies tend to use more lax criteria to include
participants with heterogeneous characteristics, similar to those seen by
clinicians in their daily practice.
• In addition to the more lax inclusion criteria, pragmatic trials tend to use active
controls (that is, the new antihypertensive drug vs a b-blocker), flexible
regimens (that is, 20 mg orally every 6 hours, reducing or increasing the dose by
5 mg according to the degree of blood pressure control and adverse effects), and
analysis of the patients who received the interventions. Pragmatic trials do not
preclude the use of ‘soft’ outcome measures, such as measures of sexual
function or quality of life.

11. Explanatory Vs Pragmatic

12. RCT according to the aspects of the
interventions
Efficacy trial
• Efficacy refers to whether an intervention works in people who receive it.
• Trials designed to establish efficacy
• Tend to be explanatory trials, because they are designed to yield a ‘clean’
evaluation of the effects of the intervention.
• Investigators are not so interested in finding out how the intervention
works. Instead, their main goal is to include participants who will follow
their instructions and who will receive the intervention.

13. RCT according to the aspects of the
interventions
Effectiveness trial
• Effectiveness refers to whether an intervention works in people to whom it has
been offered.
• Tend to be pragmatic, because they try to evaluate the effects of the
intervention in circumstances similar to those found by clinicians in their daily
practice.
• The design of effectiveness trials is usually simpler than the design of efficacy
trials, because effectiveness trials tend to follow lax inclusion criteria, include
flexible regimens, and allow participants to accept or reject the interventions
offered to them.
• Typically, effectiveness trials evaluate interventions with proven efficacy
when they are offered to a heterogeneous group of people under ordinary
clinical circumstances.

14. Phases
of
Clinical
Trial

15. Phases in Trial

16. • Parallel trial:
RCT
according
to how the
participants
are exposed
to the
interventions
This design is
appropriate for chronic
conditions that are
stable over time and for
interventions that last a
short time.
A drawback of the
factorial design is the
concern over potential
drug interactions;
however, this design
also allows for the
determination of
synergies between two
This design is simple
and eliminates the
potential for drug
interaction.

17. RCT according to the number of participants
n-of-1 trials
• Aka. individual patient trials.
• Basically, they are crossover trials in which one participant receives
the experimental and the control interventions, in pairs, on multiple
occasions and in random order.
• These trials provide individual, rather than generalizable, results.
• They can be very useful when it is not clear whether a treatment will
help a particular patient.

18. Mega-trial
• Term is being used increasingly to describe RCTs with a simple design
(usually very pragmatic) which include thousands of patients and limited
data collection.
• Usually, these trials require the participation of many investigators
(sometimes hundreds of them) from multiple centers and from different
countries.
• The main purpose is to obtain ‘increased statistical power’ and to achieve
wider generalizability.
• Its main aim is to increase the chances of finding a difference between two
or more interventions, if such a difference exists.

19. • A multicenter research trial is a clinical trial conducted at more than
one medical center or clinic. Most large clinical trials, particularly
Phase III trials, are conducted at several clinical research centers.
• Benefits:
• Larger number of participants
• Different geographic locations
• Possibility of inclusion of a wider range of population groups
• Ability to compare results among centers
• All of which increase the generalizability of the study.

20. A sequential trial
• It is a study with parallel design in which the number of participants is
not specified by the investigators beforehand. Instead, the investigators
continue recruiting participants until a clear benefit of one of the
interventions is observed, or until they are convinced that there are no
important differences between the interventions.
• These trials allow a more efficient use of resources than trials with
fixed numbers of participants, but they depend on the principal
outcome being measured relatively soon after trial entry.

21. Fixed size trial
• The investigators establish deductively the number of participants that
they will include.
• This number can be decided arbitrarily or can be calculated using
statistical methods.
• The main goal of using statistical methods to calculate the sample size
is to maximize the chance of detecting a statistically and clinically
significant difference between the interventions when a difference
really exists

22. RCT according to whether the investigators and
participants know which intervention is being
assessed

23. Zelen’s Design

24. Wennberg’s Design

25. Comprehensive cohort Design

26. A) Zelen's design
B) Comprehensive cohort
design
C) Wennberg's design

27. Types of RCT
• Prophylactic Trials
• Evaluate the efficacy of intervention that is designed to prevent disease
• Example: Vaccine trials, patient education, screening, vitamin supplement
• Curative Trials
• Evaluate the efficacy of the curative drugs or intervention designed to manage
or mitigate the sign and symptoms of disease
• Example: Arthritis, Hypertension drug trials

28. RCT on the basis of Hypothesis
• Superiority studies
• It aims to show that a new drug is more effective than the comparative
treatment (placebo or current best treatment)
• Non Inferiority studies
• It is designed to prove that two drugs have the same clinical benefit.
• Equivalence studies
• It aims to show that the effect of a new treatment cannot be said to be
significantly weaker than that of the current treatment.

29. Features of a well designed RCT
• The sample to be studied will be appropriate to the hypothesis being
tested so that any results are appropriately generalizable. The study
will recruit sufficient patients to allow it to have a high probability of
detecting a clinically important difference between treatments if a
difference truly exists.
• There will be effective (concealed) randomization of the subjects to
the intervention/control groups (to eliminate selection bias and
minimize confounding variables).
• Both groups will be treated identically in all respects except for the
intervention being tested and to this end patients and investigators will
ideally be blinded to which group an individual is assigned.

30. Features of a well designed RCT
• The investigator assessing outcome will be blinded to treatment
allocation.
• Patients are analyzed within the group to which they were allocated,
irrespective of whether they experienced the intended intervention
(intention to treat analysis).
• Analysis focuses on testing the research question that initially led to
the trial (that is, according to the a priori hypothesis being tested),
rather than “trawling” to find a significant difference.

31. Randomization in RCT
Advantages
• Eliminates selection bias, balancing both known and unknown prognostic
factors, in the assignment of treatments.
• Random assignment permits the use of probability theory to express the
likelihood that any difference in outcome between intervention groups
merely reflects chance
• Random allocation, in some situations, facilitates blinding the identity of
treatments to the investigators, participants, and evaluators, possibly by use
of a placebo, which reduces bias after assignment of treatments
Confidently
attribute to cause
and effect

32. Randomization in RCT
• Randomization tends to distribute potential confounders similarly among
exposure groups, which removes this necessary precondition.

33. Randomization in RCT
Successful randomization in practice depends on three interrelated
aspects:
• Adequate generation of an unpredictable allocation sequence
• Concealment of that sequence until assignment occurs
• Implementation- Who generated random allocation sequence and
who enrolled participants

34. Randomization in RCT
• Several types of Randomization present in RCT but choice depends on
two goals:
• Balance : There should be balance of measured and unmeasured
characteristics between intervention and control group.
• Unpredictability: There should not be no predictability for enrollment
of intervention and control group.

35. Types of Randomization
• Simple Randomization
• Simple (or unrestricted) randomization is tantamount to flipping a coin.
• Every subject has an equal chance of being assigned to either group, and
all
assignments are independent of one another.
• Simple randomization thus maximizes unpredictability: the sequence
of past assignments provides no clue about the group to which the next
patient is likely to be assigned
• Possibility of chance imbalances, particularly with small sample sizes.

36. Types of Randomization
• Restricted randomization
• It refers to the use of another procedure along with random assignment
in order to promote balance in the sizes or composition of study groups.

37. Types of Randomization
• Block Randomization:
• Block randomization, the most common form of restricted
randomization, involves first grouping study subjects into sets, or blocks.
• Within each block, an equal number of subjects is then randomly
assigned to each treatment group.
• Block randomization gives priority to keeping the sizes of treatment
groups balanced. However, it does so at the expense of unpredictability.
• One way to help prevent corruption of block randomization is to use
larger block sizes.

38. Types of Randomization
Stratified Randomization
• It guarantee that a strong potential confounding factor will be
balanced between groups.
• Each level on the confounding factor becomes a stratum, and
randomization is carried out separately within each stratum.
• Block randomization (or some other form of restricted randomization)
must be used within each stratum to assure that the ratio of
experimental to control subjects is equal across strata.

39. Sample size Calculation
Dichotomous Variable

40. Sample size Calculation
Continuous Variable

41. References
• https://www.quantics.co.uk/blog/what-is-a-pp-population-or-per-protocol-population-in-
a-clinical-trial/
• https://link.springer.com/referenceworkentry/10.1007%2F978-1-4419-1005-9_1041
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359056/
• https://emj.bmj.com/content/20/2/164
• https://www1.cgmh.org.tw/intr/intr5/c6700/OBGYN/F/Randomized tial/chapter2.html
• https://i1.wp.com/basicmedicalkey.com/wp-
content/uploads/2017/09/A306168_1_En_14_Fig2_HTML.gif?w=960
• https://rwe-navigator.eu/use-real-world-evidence/generate-real-world-evidence/study-
design-pragmatic-trials/structured-summary-study-design-comprehensive-cohort-study/
• https://basicmedicalkey.com/trial-design-overview-of-study-designs-phase-i-ii-iii-iv-
factorial-design/

42. References
• https://irb.research.chop.edu/sites/default/files/documents/classificatio
nclinicalresearch_0.jpg
• https://images.slideplayer.com/32/10081697/slides/slide_6.jpg
• https://cdn.ttgtmedia.com/rms/onlineimages/healthit-clinical-trial.png
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256489/