Designs of Clinical Trials Dr. Prashant Shukla Junior Resident Dept of Pharmacology
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Designs of Clinical Trials
Dr. Prashant Shukla
Junior Resident
Dept of Pharmacology
Contents
Definition
Bias- ways to reduce it.
Classification of clinical trials
Individual designs:Traditional Study designs
Study designs for small populations
Miscellaneous trials
2/18/2015 2
Clinical Trials
(As per the revised Schedule ‘Y’ of the Drugs & Cosmetic Act 2005).
122-DAA. Definition of Clinical trial
It is a systematic study of new drug(s) inhuman subjects to generate data fordiscovering and/or verifying the clinical,pharmacological, and/or adverse effectswith the objective of determining theirsafety and/or efficacy of the new drugs.
2/18/2015 3
Key elements of Clinical Trials
The acronym PICO is used by health
professionals to convey all elements of
the clinical scenario in an orderly
fashion:
P - Patient, Population of patients,
Problem
I - Intervention (a therapy, test)
C - Comparison (another therapy,
placebo)
O - Outcome (survival, response)2/18/2015 4
Bias
Bias is a systematic error contained in
the study design, conduct or
interpretation of a study. Whereas
extensive lists of particular bias forms
exist, there are two basic forms of bias:
1. Selection bias occurs if study
populations are selected in an
erroneous way that comparison
groups are not comparable.
2. Information bias occurs if
measurements are different between
comparison groups.2/18/2015 5
Techniques to avoid bias
The two most important techniques are:
1. Randomisation of subjects.
2. Blinding of subjects as well as
investigator.
3. Monitoring of clinical trial.
4. Checking original source documents.
5. Source data verification.
6. Clinical data management.
7. Quality control (QC) and Quality
assurance (QA) procedures.2/18/2015 6
Randomisation
It aims to obviate systematic differences between groups due to factors other than intervention.
It gives each patient a known (or equal) chance of being assigned to any of the groups.
The most common methods of randomisation are:
1. Simple randomization
2. Blocked randomization
3. Stratified randomization
4. Cluster randomization2/18/2015 7
Blinding
Single- blind design:
Double- blind design:
Triple- blind design:
2/18/2015 8
TYPES OF CLINICAL TRIALS
Superiority Trials: compare a std
treatment or intervention with a new or
alternative approach anticipated to be
more effective.
Inferiority Trials: An alternative therapy
(perhaps one that is cheaper, less toxic or
easier to administer) is suggested to
replace the standard provided its efficacy
is no worse than the std.
Equivalence: Test treatment is required to
be neither less nor more efficacious than
std.2/18/2015 9
Did investigator
assign exposure?
Experimental study Observational study
Analytical
study
Random allocation Comparison group?
YES
NO
Descriptiv
e study
NO
YES
RCT
Non-
rando
mize
d
YE
S
NO
Cohort
Study
Case-
control
Cross-
sectiona
l2/18/2015 10
How to categorize clinical
trials? Number of participating centers:
1. Single center vs Multicenter
2. National vs International
Control group:
1. Non comparative
2. Historical controls
3. Concurrent controls
4. “Self” controls
2/18/2015 11
How to categorize clinical
trials? Randomization:1. Non- randomized2. Simple randomized3. Balanced (stratified) randomized trials4. Cluster randomized trials
Blinding (Masking):1. Open label or non- blinded trial2. Single blinded3. Double blinded4. Triple blinded5. Double dummy
2/18/2015 12
How to categorize clinical
trials? Purpose:
1. Treatment trials
2. Prevention trials
3. Screening trials
4. Quality of life trials
5. Compassionate use trials
6. Genetics trials
2/18/2015 13
How to categorize clinical
trials? Trial format:
1. Traditional designs for clinical trialsA. Parallel group trials
B. Cross over trials
C. Factorial design
D. Add on design
E. Randomized withdrawal design
F. Early escape design
2. Special Design issues for small clinical trialsA. N- of- 1 design
B. Sequential design
C. Decision analysis- based design
D. Adaptive design
E. Risk based allocation design2/18/2015 14
How to categorize clinical
trials? Trial format (contd.):
3. Miscellaneous DesignsA. Cluster randomized design
B. Enrichment design
C. Placebo Challenging design
D. Blind Reader design
E. Trial with Zelen’s design
F. Trial with Wennberg’s design
G. Trial with Comprehensive cohort design
H. Design using historical controls
I. Rolling design
2/18/2015 15
Factors to consider in selecting a
clinical trial design
2/18/2015 16
Study population and indication
Treatment duration
Carry over effects
Cost and logistics
Patient convenience
Statistical considerations
Role of Placebo in Clinical trials No standard treatment exists.
Standard treatment is ineffective.
Standard treatment is inappropriate for
the particular clinical trials.
The placebo is reportedly effective in
treating the disease.
The disease is mild and lack of
treatment is not considered to be
medically important.2/18/2015 17
Role of Placebo in Clinical
trials... The placebo is given as an add-on
treatment to an already existing
regimen that is not sufficient to treat
patients.
The disease process is characterized
by frequent spontaneous
exacerbations and remission(e.g.,
peptic ulcer).
“Escape clauses” or points are
designed into the protocol.2/18/2015 18
Run in periodBefore randomization of patients a run-in (or lead-in)
period of placebo, no active treatment, dietary control, or active maintenance therapy is usually employed.
Advantages:
1. It acts as a washout period to remove effects of previous therapy.
2. It can be used to obtain baseline data and to evaluate if patient fulfills study entry criteria.
3. It can be used as a training period for patients, investigators, and their staff.
4. It helps in identifying placebo responders.
5. It provides useful information regarding patient compliance.
6. It can be used to estimate and compare the magnitude of possible placebo effects between groups. 2/18/2015 19
2/18/2015 20
Traditional
Study designs
Parallel Group Design
• It is of two types:
1. Group comparison parallel design: In this
method, efficacy of treatment is using
two groups (Treatment vs Control group).
2. Matched pair parallel design: In this
method, pairs of subjects are formed
possessing the same characteristics and
who might be expected to respond
similarly to the treatments.
2/18/2015 21
Group comparison Parallel
DesignTreatment Group/ Arm Control Group/ Arm
• Most common clinical design.
• Complete randomized design in which each
patient receives one and only one treatment in
a randomized fashion.
2/18/2015 22
Exp.
Drug
Group comparison Parallel
DesignAdvantages:
a) It’s simple and easy to implement.
b) It is universally acceptable.
c) It is applicable to acute conditions.
d) Analysis is less complicated and
interpretation is straight forward.
Disadvantages:
a) It does not into account the inter-
individual variability.2/18/2015 23
Matched Pair Parallel DesignPair A Pair B Pair C Pair D
• In this method, pairs of subjects are formed
possessing the same characteristics and who
might be expected to respond similarly to the
treatments.
• Matching of patients is done before
randomization. 2/18/2015 24
Matched Pair Parallel Design...
Advantages:
a) Requires small study population.
b) Can reduce variability from treatment comparison (compared with parallel froupdesigns).
Disadvantages:
a) The prognostic characteristics are not easily defined.
b) Patient recruitment is slow.
c) When the number of co-variates is large, this design is difficult to implement.
2/18/2015 25
Cross over design
A crossover design is a modified
randomized block design in which each
block receives >1 treatment at different
dosing periods.
A block can be a patient or a group of
patients. Patients in each block receive
different sequences of treatments.
A crossover design is called a complete
crossover design if each sequence
contains all treatments under 2/18/2015 26
Cross over design...
Group A Group B
WASH OUT PERIOD WASH OUT PERIOD
2/18/2015 27
Drug A
Drug B
Drug B
Drug A
RANDOMIZATION
Cross over design...
Crossover designs may be used in clinical trials in the following situations where
1. Objective measures and interpretable data for both efficacy and safety are obtained.
2. Chronic (relatively stable) disease are under study.
3. Prophylactic drugs with relatively short half-life are being investigated.
4. Relatively short treatment periods are considered.
5. Baseline and washout periods are feasible.
2/18/2015 28
Cross over design...
Advantages:
1. It allows a within-patient comparison between treatments, since each patient serves as his or her own control.
2. It removes the interpatient variability from the comparison between treatments.
3. With a proper randomization of patients to the treatment sequences, it provides the best unbiased estimates for the differences between treatments.
2/18/2015 29
Cross over design...
Disadvantages:
1. Carry- over effects: The residual
influence of treatments on subsequent
treatment periods. Avoided by wash out
period.
2. Order effects: Order in which the tt are
administered affects the outcome.
3. Period effects: The diff. between the
study periods.
4. Drop-outs can be higher.2/18/2015 30
Concept of Wash-out effects
AKA carry over / residual effects.
It is the rest period between 2 treatment
periods.
It permits the effect of previous treatment
to wane off.
It should be long enough for the treatment
effect to wear off so that there is no
carryover effect of previous treatment to
next.
It depends upon the nature of the drug.
2/18/2015 31
Williams design
When there are more than two treatments
to be compared, a complete crossover
design is called William’s design.
I. William’s design with three treatments
ACB BAC CBA
BCA CAB ABC
II. William’s design with four treatments
ADBC BACD CBDA DCAB2/18/2015 32
Split person design
2/18/2015 33
• Occasionally, it is possible to administer the
two interventions at the same time.
•Very similar to that of the cross-over trial,
except there is no equivalent to the periods or
to the wash-out although a carry-over (now
termed carry-across) effect is likely to be
present.
Drug A Drug B
Split Mouth Design
Split person design...
2/18/2015 34
Drug A Drug B
Psoriasis patient
• Occasionally, it is possible to administer the
two interventions at the same time.
•Very similar to that of the cross-over trial,
except there is no equivalent to the periods or
to the wash-out although a carry-over (now
termed carry-across) effect is likely to be
present.
Split person design...
• Occasionally, it is possible to administer the
two interventions at the same time.
•Very similar to that of the cross-over trial,
except there is no equivalent to the periods or
to the wash-out although a carry-over (now
termed carry-across) effect is likely to be
present. 2/18/2015 35
Drug A Drug B
Paired Organs
2/18/2015 36
Factorial designs
2× 2 Factorial design
•Used when it is desired to study the influence
of a number of factors on the treatments
compared as well as their interaction with
different treatments.
+Drug A Drug B Drug
A+BNeither Drug
Factorial designs...
Uses:
1. Make efficient use of clinical trial
subjects by evaluating two treatments
with same no. of individuals.
2. Influence of a number of factors can be
studied together which might require
many trials if done individually.
3. Establish dose-response
characteristics of the combination of A
and B when efficacy of each has been
previously established.2/18/2015 37
Factorial designs...
Advantages:
1. A greater precision can be obtained in estimating the overall main factor effects.
2. Interaction between different factors can be explored.
3. Additional factors can help to extend validity of conclusions derived.
Disadvantages:
1. Difficult to analyse.
2. Large designs require large no of subjects.
3. Between subjects design lacks statistical power.
2/18/2015 38
Add- on DesignGroup A Group B
• A placebo-controlled trial of an experimental
intervention is tested with people already receiving an
established, effective treatment.
2/18/2015 39
+ +Std. treatment Std. treatment
Exp.
Intervention
Add- on Design...
Uses:
1. Add on design is especially useful for
testing of an experimental interventions
that have mechanism of action different
from that of established effective
treatment.
2. It can be used for long term studies of
treatments of conditions like heart
failure since established treatment is
life saving and is not being denied.
2/18/2015 40
Randomized Withdrawal
Design
• Here, individuals who respond (+)ly to an experimental
intervention are randomized to continue receiving that
intervention or to receive a placebo.
• Return of symptoms in placebo group causes
withdrawal of subject from that group.2/18/2015 41
WITHDRAWN
FROM STUDY
Exp.
Intervention
Randomized Withdrawal
Design... Advantage: This trial design minimizes
the amount of time that individuals
receive a placebo.
Disadvantages:
1. Carry over effects.
2. Difficulties in assessing whether the
underlying disease process is still
active.
3. Long lag times to adverse events if
the disease is in remission.2/18/2015 42
Early escape designIntervention Arm Placebo Arm
• Participants are removed from the study if
symptoms reached a defined level or they fail to
respond to a defined extent.
• The patient could then be switched over to
another
therapy, including the test treatment if
appropriate.2/18/2015 43
Exp.
Intervention
Predefined negative
efficacy criterion
Early escape design...
Advantages:
1. It minimizes an individual’s duration of
exposure to a placebo.
2. Ethically justifiable.
Disadvantages:
1. Complex statistical analysis.
2. Difficulties in assessing whether
underlying disease is active or not (like
Randomised withdrawal design).2/18/2015 44
2/18/2015 45
Study designs for
Small Populations
Study designs for small
populations Defined as <50 possible patients recruited
in 5years with multicentre∕ multinational recruitment.
1. Rare diseases2. Unique study populations (e.g. Astronauts)3. Individually tailored therapies4. Environments that are isolated5. Emergency situations6. Public health urgency7. Restricted resources coupled with an
important need
2/18/2015 46
N- of- 1 Design
They are cross over trials in which one
participant receives the experimental
and the control interventions.
Typically the number of pair of
interventions varies from two to seven.
The number of interventions is not pre
specified so that the clinician and the
patient can decide to stop at will. 2/18/2015 47
N- of- 1 Design...
Indications:
1. If an RCT has shown that some
patients are unresponsive to treatment.
2. If there is doubt about whether a
treatment is really providing benefit to
the patient.
2/18/2015 48
Decision Analysis based
DesignOutcome Intervention A Intervention B
Beneficial
outcome
1. Utility (0-1)
2. Probability
1. Utility (0-1)
2. Probability
Adverse
Outcome
1. Utility (0-1)
2. Probability
1. Utility (0-1)
2. Probability
•Utility are numeric values assigned to each outcome
which reflects the “desirability of the event”.
• Probability are the “chances of event to occur”.
•Decision analysis combines the probability with utility to
calculate an “expected utility”.
2/18/2015 49
Decision Analysis based
Design... Thus decision analysis is used during the
planning phase to structure the question.
One obtains best estimates of for each
probability and utility.
Sensitivity analysis is done where
potential important values (utility and
probability) are changed over a likely
range to create a model structure.
This design is dependent upon on the
assumptions made about parameter
values and model structure.2/18/2015 50
Adaptive design
2/18/2015 51
These designs are used when an RCT
clearly begin to favour one intervention
over another.
Advantage: Over time more patients will
be assigned to the more successful
treatment.
Disadvantages:
1. In most trials, patients are
heterogeneous with respect to
important prognostic factors.
Adaptive design
2. It does not protect against bias
introduced by changes in the types of
patients entering into trial overtime.
Adaptive designs can be of two types:
1. Sequential designs
2. Rolling designs
2/18/2015 52
Sequential Design
Here the participants are sequentially
enrolled in the study and are assigned a
treatment (usually at random).
The efficiency, safety and efficacy of the
experiment is improved by changing the
rules as the study progresses.
Various for sequential designs are:1. Up & down methods (Most Common)
2. Stochastic approximation methods
3. Maximum likelihood methods
4. Bayesian methods2/18/2015 53
Sequential Design...
2/18/2015 54
Abandon the
Study
If low dose is ineffective
and
High dose is effective
If low dose is effective
and
High dose has ADRs
If both low dose and
High dose are ineffective
Low
dose
High
dose
Up & down method
Sequential Design...
Problems with sequential designs:
1) Uncertainty of sample size.
2) Duration of trial cannot be stipulated in
advance.
3) Resources (funding).
2/18/2015 55
Rolling design
• Design that can roll on continually by
introducing new treatment options
from the evidence accumulated, dropping
those of either proven efficacy or if found
not to be effective.
• Make use of intermediate endpoints (in
contrast to the traditionally used
endpoints that require longer patient
follow-up).
2/18/2015 56
Intervention A Intervention B Control Group
2/18/2015 57
Discontinue
Intervention B
Subsequent
recruitment favours
beneficial profiles
Randomized
recruitment to
control arm
continues
Drug A Drug B Std.
drug
Risk based Allocation Design
• This design allows individuals at higher risk or
with greater disease severity to benefit from a
potentially superior experimental treatment.
•Advantages: Ethically more justifiable.
•Disadvantage: It is a non-randomized design.
2/18/2015 58
Individuals with higher
risk or greater disease
severity
Individuals with lesser
risk or lesser disease
severity
Potentially superior
Experimental treatment
Relatively inferior
Experimental treatment
2/18/2015 59
Miscellaneou
s Study
designs
Cluster Randomized DesignCluster/ Group A Cluster/ Group B Cluster/ Group C
• For assessment of non-therapeutic
interventions such as lifestyle intervention or
new educational programs for smoking
cessation.
• Randomization can be performed on intact
social units- family, school, worksites, athletic
teams, etc.
•Randomization is done at cluster level rather
than individual level.
2/18/2015 60
Intervention A Intervention B Intervention C
Cluster Randomized Design...
Although the trials adopt a cluster
randomization, the analysis of data
completely ignores this fact and uses
subject as the unit of analysis.
Thus, the unit of analysis may not be
necessarily the same as the unit of
randomization.
2/18/2015 61
Enrichment Design
Enrichment
phase
Randomizatio
n phase
• Phase of manipulation of dose levels of a
therapeutic agent for identification of patients
with drug efficacy is Enrichment phase.
• The patients with drug efficacy identified at
enrichment phase are randomized to receive
either efficacious dose of drug or matching
placebo. 2/18/2015 62
Placebo Challenging design
For treatment of erection dysfunction, a
design that consists of a :-
1. “Titration phase” for achieving optimal
dose and
2. “Crossover active treatment phase”
with two placebo challenges (i.e., pre-
and post-treatment) is often
considered.
Design of this kind is a placebo-
challenging design.2/18/2015 63
Placebo Challenging design..
1. In-clinic
evaluation
(double-blind
placebo-
challenging)
2. Three-month
home treatment
3. In-clinic
evaluation (double-
blind
placebo-
challenging)
2/18/2015 64
Titration phase
Active drug
Active drug
Placebo
Placebo Active drug
Active drug
Blinded reader designs
A clinical trial for evaluation of medical imaging products with blinded imaging evaluation is said to have a blinded reader design.
It is not feasible to blind the investigators who administer the investigational medical imaging agents.
So effectiveness of medical imaging drug products should be evaluated based on the images by readers (usually trained radiologists) obtained with the investigational agents or controls under different conditions.
2/18/2015 65
Trial with Zelen’s design
Here, the patients are randomised beforethey give consent to participate in the trial.
Those who are allocated to standardtreatment group are not told that they arepart of the trial.
Those who are allocated to the experimentalintervention group are told that they are partof the trial. If they refuse to participate in thetrial, they are given the standard treatmentbut analysed as if they had received theexperimental intervention.2/18/2015 66
Trial with Zelen’s design...
Advantages:
1. Almost all eligible individuals are included in the trial.
2. Allows the evaluation of true effect of experimental intervention in patients.
Disadvantages:
1. Open trials.
2. The statistical power of the study gets compromised if large no of patients choose the standard treatment.
2/18/2015 67
Trial with Zelen’s design...
2/18/2015 68
Trial with Zelen’s design...
There is ethical concerns of not telling
patients that they have been randomised
to receive the standard treatment.
So, the original Zelen’s design can be
modified by informing participants of the
group to which they have been allocated
and by offering them opportunity to switch
the group.
Disadvantages:
1. Lack of blinding
2. Potential loss of statistical power2/18/2015 69
Trial with Zelen’s design...
2/18/2015 70
Trial with Wennberg’s design
In this design, eligible individuals are
randomised to:
1. “Preference group” where patients can
choose between exp. or std. treatment at
will.
2. “RCT group” where patients are
randomised between both arms.
Rarely used.
They are likely to be more frequently used
as consumer participation in healthcare
decisions and research is increasing.2/18/2015 71
Trial with Wennberg’s design...
2/18/2015 72
Preference Group RCT Group
ELIGIBLE INDIVIDUALS
Std.
drug
Exp.
drug
Std.
drug
Exp.
drug
2/18/2015 73
Trial with comprehensive cohort
design
• A comprehensive cohort trial is a study in
which all participants are followed up,
regardless of their randomisation status.
1. If a person agrees for RCT, he is
randomised to one of the study
interventions.
2. If a person does not agree for RCT, he is
given his intervention of choice and
followed up as if he were a part of a cohort
study.
•At the end, the outcomes of RCT and cohort
study are compared to assess their similarities
and differences.
Trial with comprehensive cohort
design
2/18/2015 74
Outcomes of Cohort studies and RCT group are then
compared
Cohort Group RCT Group
ELIGIBLE INDIVIDUALS
Std.
drug
Exp.
drug
Std.
drug
Exp.
drug
Designs using historical
controls Very rarely, a new treatment is given to all
patients and result are compared with the past (historical controls).
It is almost always unacceptable even for disease like leukaemia because:
1. Standards of diagnosis and treatment change with time
2. Severity of some diseases fluctuates
An exception to this rule is the case-control study
2/18/2015 75
Factors in choosing clinical trials
designs1. Chronology of events: Chronological
effects may be very important in any trial
design, but particularly in cross over
design.
2. Subject convenience: Lengthy trials
requiring multiple visits and involving
washout periods may compromise patient
compliance.
3. Trial cost: Very lengthy trials may not be
routinely feasible due to prohibitive costs
involved.
2/18/2015 76
Trial designs phase wise
Phase I CT: All patients receive the drug, thus an unblinded, open label trial is suitable.
Phase II through III CT: Parallel designs, Cross over, Factorial designs are most commonly used.
Phase IV CT: Non experimental (observational) designs- These include epidemiologic designs such as case control or cohort studies.2/18/2015 77
2/18/2015 78
Knowledge is the root and practice is the
bough and there is no bough without a
root behind it, although roots may be
found which can as yet boast no
boughs.
Moses
Maimonides
Thank you for your patience!!
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