This document discusses randomized controlled trials (RCTs) and non-randomized trials. It defines non-randomized trials as studies where participants are assigned to treatment groups by a non-random method controlled by the investigator. The document outlines sources of bias in non-randomized studies, statistical adjustment methods, and appropriate uses of non-randomized designs. It compares RCTs and non-randomized trials, noting similarities in measuring outcomes but differences in potential for bias, validity, and cost-effectiveness.

1. PRESENTED BY :-
HIMIKA RATHI
MPHARM-DEPARTMENT OF
PHARMACOLOGY
L.M COLLEGE OF PHARMACY

2. CONTENT
Taxonomy of study designs to assess the effectiveness of an intervention
Definition of a Non-Randomized Trial
Introduction
Sources of bias in nonrandomised studies
Commonly used methods of statistical adjustment
When is it appropriate to use a non-randomized trial design?
Disadvantages of the Nonrandomized Clinical Trial
Similarities between RCT and NON RCT
Differences between RCT and NON RCT
Summary

3. • Experimental designs
• A study in which the investigator has control over
at least some study conditions, particularly
decisions concerning the allocation of participants
to different intervention groups.
• 1. Randomised controlled trial
• Participants are randomly allocated to
intervention or control groups and followed up
over time to assess any differences in outcome
rates. Randomisation with allocation concealment
ensures that on average known and unknown
determinants of outcome are evenly distributed
between groups.

4. • 2. Quasi-randomised trial
• Participants are ,
but the method of allocation falls short of genuine randomisation and allocation
concealment (e.g.
• 3.Non-randomised trial/quasi-experimental study
• The investigator has control over the allocation of participants to groups, but
Differs
from a ‘cohort study’ in that the intention is experimental rather than
observational.

5. • Observational designs:-
• A study in which natural variation in interventions (or exposure) among study
participants is investigated
• 4. Controlled before-and-after study
of participants who have received an intervention and those who have
not,
It can also be considered an experimental design if the investigator has control over, or
can deliberately manipulate, the introduction of the intervention.

6. Observational designs
• 5. Concurrent cohort study
• A follow-up study that compares outcomes between participants who have
received an intervention and those who have not
• 6. Historical cohort study
• A variation on the traditional cohort study where the
, i.e.
participants are not studied concurrently.

7. • 7. Case–control study
• Participants with and without a given outcome are identified (cases and controls
respectively) and exposure to a given intervention(s) between the two groups
compared.
• 8. Before-and-after study
• Comparison of outcomes from study participants before and after an intervention
is introduced. The before and after measurements may be made in the same
participants, or in different samples. It can also be considered an experimental
design if the investigator has control over, or can deliberately manipulate, the
introduction of the intervention

8. • 9. Cross-sectional study
• Examination of the
• 10. Case series
• Description of a number of cases of an intervention and outcome (no comparison
with a control group).

10. Definition of a
Non-
Randomized
Trial
A study where participants have been
assigned to the treatment, procedure, or
intervention alternatives by a method that
is not random. The investigator defines and
manages the alternatives.
A clinical trial in which the participants are
not assigned by chance to different
treatment groups. Participants may choose
which group they want to be in, or they may
be assigned to the groups by researchers.

11. INTRODUCTION
The ultimate goal of the evaluation of healthcare
interventions is to produce a valid estimate of
effectiveness, in terms of both internal and external
validity.
Internal validity concerns the extent to which the
results of a study can be reliably attributed to the
intervention under evaluation, whereas external
validity concerns the extent to which a study’s results
can be generalised beyond the given study context.
The randomised controlled trial (RCT) is widely
regarded as the design of choice for the assessment
of the effectiveness of healthcare interventions.

12. The main benefit of the RCT is the use of a randomisation procedure that, when
properly implemented, ensures that the allocation of any participant to one
treatment or another cannot be predicted.
RCTs are also more likely to employ specific measures to reduce or remove bias,
such as blinded outcome assessment.
several scenarios remain under which an RCT may be unnecessary, inappropriate,
impossible or inadequate. Examples include the assessment of rare side-effects of
treatments, some preventive interventions and policy changes

13. Sources of bias in
nonrandomised
studies
In non-randomised studies, selection bias will be introduced when
participants chosen for one intervention have different
characteristics from those allocated to the alternative intervention
(or not treated).
The choice of an intervention under these circumstances will be
influenced not only by a clinician’s own personal preference for
one intervention over another but also by patient preference,
patient characteristics and clinical history.
when faced with a patient who may be eligible to receive a given
intervention, the decision to treat will be influenced by some
factor that in turn is related to the treatment outcome. This
introduces systematic bias leading to either over- or
underestimates of treatment effects, depending on the treatment
decision mechanism.

14. Non-randomised studies are also susceptible to attrition, detection and
performance bias. For example, attrition bias will occur if there are dropouts,
detection bias if the assessment of outcomes is not standardised and blinded,
and performance bias if there are errors and inconsistencies in the allocation,
application and recording of interventions.
The traditional solution to removing selection bias in non-randomised studies has
been to attempt to control for known prognostic factors, either by design and/or
by analysis. Alternative statistical techniques for removing bias in non-
randomised studies are also present.

15. Commonly used methods of statistical
adjustment
Standardisation:- Participants are analysed in groups (strata) which have similar
characteristics, the overall effect being estimated by averaging the effects seen in each of
the groups.
Propensity scores :- Propensity probabilities are calculated for each participant from
the data set, estimating their chance of receiving treatment according to their
characteristics. Treatment effects are estimated either by comparing groups that have
similar propensity scores (using matching or stratification methods), or by calculating a
regression adjustment based on the difference in average propensity score between the
groups.

16. When is it
appropriate
to use a non-
randomized
trial design?
The first is when an
RCT would be ideal but
practical considerations
(e.g., costs,
unacceptability to
patients or providers)
make a high-quality
RCT infeasible.
When the act of
random allocation may
reduce the
effectiveness of the
intervention
–Occurs when the
effectiveness of the
intervention depends
on the participant’s
active participation
which is influenced by
their beliefs and
preferences)
When there are legal
or political obstacles to
random allocation

17. Define Inclusion/Exclusion Criteria
Specific inclusion and exclusion criteria need to be established for the study
population. Inclusion criteria must be identical for both the intervention
and comparison groups.
There is an inherent tension between using criteria that are broad enough
to ensure that recruitment of an adequate sample and generalizability, but
not so broad that meaningful comparison is not possible.
Exclusion criteria have two main purposes:
(1) to exclude study subjects who present substantial risk to the scientific
quality of the study (e.g., inability to follow up, plan to move out of state)

18. • (2) to assure safe and ethical conduct of the study (e.g., inability to tolerate
general anaesthesia , contraindications to the one or both of the treatment
arms, unable to give informed consent)
Both clinical characteristics of potential study subjects and social/cognitive
criteria should be considered when identifying exclusion criteria.

19. Allocate Subjects Between Groups
The selection of study sites and the allocation of subjects to treatment
groups are among the most challenging issues in nonrandomly assigned
control group studies.
For example, the investigator may choose to randomly select one of two
comparable private hospitals as the intervention site and the other as the
comparison site. Whether to randomize by hospital, ward or clinic, or
physician will depend on feasibility, risk of contamination, and the nature of
the intervention.
The use of patient or physician preference to allocate patients to
treatments can be used

20. Collect Baseline Data
In the nonrandomized controlled trial, it is crucial to collect a
comprehensive dataset including all variables that can reasonably be
expected to influence the outcome of the procedure.
Baseline and follow-up (i.e., pre/post) measures should be collected at both
the intervention site and the control sites. This data will allow the
investigator to judge the comparability of the two groups and can also be
used to statistically adjust for measured differences between the groups.

21. Measure the Outcome
The outcome of interest should be
established before initiating the study
and measured as accurately and reliably
as possible. Because neither the patient
nor the investigator is blinded to the
nature of the procedure, the use of
physician- and patient-reported
outcomes can be quite problematic.
The use of independent, blinded
evaluators, imaging studies, or
physiologic measurements (e.g., blood
flow rate, degree, residual stenosis) may
be less prone to bias than patient-
reported outcomes.

22. REASONS FOR THE
USE OF
NONRANDOMIZED
STUDIES
1. Nonrandomized studies are sometimes the only
ethical way to conduct an investigation. If the
treatment is potentially harmful, it is generally
unethical for an investigator to assign people to this
treatment.
An example of this is a study of the effects of
malnutrition, where we simply cannot assign subjects
to intolerable diets. Thus we compare malnourished
populations with those on adequate diets.
2. Nonrandomized studies are sometimes the only
ones possible. Certain investigations require the
implementation of treatments that may affect
people's lives.

23. REASONS
FOR THE USE
OF NON
RANDOMIZE
D STUDIES
3. Nonrandomized studies are usually less expensive. An
advantage of nonrandomized studies is that they usually cost less
per subject and may not require the extensive planning and
control that are needed for randomized studies. This makes
nonrandomized studies particularly attractive in the early stages
of any research effort
4.The use of a nonrandomized control group may also reduce the
threats to external validity that limit the value of RCTs results.
First, RCTs tend to be done at a few, highly selected sites, and are
rarely done in community settings. Quasi-experimental designs
can often involve more providers and settings, making the results
more generalizable.Second, the lack of randomization often
facilitates recruitment of a larger proportion of eligible patients,
thus further increasing generalizability.

24. Disadvantages of the Nonrandomized Clinical
Trial
The principal disadvantage of this design is the potential for bias from
confounding. The direction of this bias is unpredictable from study to study.
For example, clinicians may differentially include the sicker patients in the
intervention trial to provide the “best chance” for the patient, thus biasing
the trial against the intervention.
Alternatively, the healthiest patients may be included to ensure that the
intervention has the optimal opportunity to work. Therefore, the
investigator should try to pre-empt “hand-picking” study subjects who
receive the intervention.

25. Disadvantages of the Nonrandomized Clinical
Trial
Even when optimally conducted, this design can never ensure that
unmeasured or imprecisely measured social, economic, cultural, or
clinical variables do not account for the apparent treatment effect.
Thus the results of these trials must be evaluated in a larger context, and
internal and external validity may be best assessed through the replication
of results in a variety of clinical settings.

26. Similarities between RCT and NON RCT
These are both experimental
study designs.
Study participants in both
studies are subjected to some
type of treatment/ intervention
and control group.
Some outcome of interest is
measured.
The researchers test whether
differences in this outcome are
related to the treatment/
intervention or not.

28. Differences between RCT and NON RCT
RANDOMIZED CONTROLLED TRIAL
1. RCT is an experimental study
design where the subjects in a
population are randomly
allocated to different groups.
2. Also known as randomized study.
3. Study population are selected
randomly.
4. Randomization is the main
ingredient of RCT.
NON RANDOMIZED CONTROLLED
TRIAL
1. NON RCT is an experimental study
design where the subjects in a
population are non randomly
allocated to different groups.
2. Also known as Quasi experimental
design.
3. Study population are chosen
4. Randomization is not the main
ingredient of NON RCT

29. RANDOMIZED CONTROLLED TRIAL
5. Have high scientific validity.
6. It provides the best scientific
evidence to any study.
7. It is considered as an ideal design
for evaluating both the
effectiveness and side effects of
interventions.
8. RCT can be used up to a point
unless there is any real world
constraint for random assignment.
NON RANDOMIZED CONTROLLED
TRIAL
5. It has moderate scientific validity.
6. Evidences generated from this
design are relatively of low
significance while compared to
RCT.
7. It is not considered as an ideal
design for evaluating both the
effectiveness and side effects of
interventions.
8. NON RCT is used real world
constraints like ethical, political or
logistical constraints do not allow
for randomization

30. RANDOMIZED CONTROLLED TRIAL
9. It has less potential for bias, or
confounding and study validity is
not compromised.
10. RCTs cannot be conducted and are
not realistic at all times due to
some practical or ethical reasons.
Example:- while conducting
studies related to exposure of
harmful chemicals, we cannot
randomized people to receive the
harmful chemicals.
11. These are generally quite
expensive.
NON RANDOMIZED CONTROLLED
TRIAL
9. It has relatively increased
potential for bias, or confounding
and study validity is compromised.
10. It can be conducted without
violating ethical considerations.
11. These are generally less expensive.

31. SUMMARY
• Uses natural groups or assigns participants to groups using a non-random
procedure.
• While nonrandomized studies are cheaper, more easily carried out, and
can be done retrospectively, inferences from them are generally more
suspect than are those from randomized studies.
• But even when optimally conducted, this design can never ensure that
unmeasured or imprecisely measured social, economic, cultural, or clinical
variables do not account for the apparent treatment effect.

33. REFERENCES
• http://archpedi.ama-assn.org/cgi/content/full/161/5/495
• Nonrandomized Interventional Study Designs (Quasi-Experimental
Designs) David A. Axelrod, MD, MBA and Rodney Hayward, MD
• Evaluating non-randomised intervention studies BY JJ Deeks and
J Dinnes
• https://doi.org/10.1136/bmj.g4115