Transcript No Slide Title

Clinical Trials
Jean Bourbeau, MD
Respiratory Epidemiology and Clinical Research Unit
McGill University
Clinical Epidemiology (679)
June 17, 2005
Clinical Trial Objectives
a) Define an experimental study and distinguish the major
types
b) Define and distinguish the population involved in planning
and conducting experimental studies, and the impact that
it might have on generalization and recruitment
c) Discuss the role of randomization in experimental studies,
and distinguish individual vs group randomization
d) Define unblinded and blinded studies, distinguish the
types of blinded studies, their advantages and
disadvantages
Clinical Trial Objectives
e) Define and discuss the consequence of withdrawal
f) Discuss various issues in data analysis
g) Discuss ethical considerations
h) Define and distinguish : efficacy and effectiveness
i) Describe the factors that might influence the response
to a treatment or an intervention
Reading
Fletcher, Chapter 7
Study Design
Fundamental point
• Sound scientific clinical investigation almost
always demands that a control group be used
against which the new intervention can be
compared. Randomization is the preferred way
of assigning participants to control and
intervention groups
Experimental/Clinical trial
Definition:
Prospective study comparing the effect and
value of intervention technique(s) against a
control in human subjects
Experimental/Clinical trial
•Employ one or more intervention techniques
(prophylactic, diagnostic or therapeutic agents,
devices, regimens, procedures, etc.);
•Contain a control group against which the
intervention group is compared.
Randomized clinical trial
RCT remains the research methodology
of choice whenever randomization is
feasible, but a study’s use of this
methodology does not necessarily confer
certainty on its conclusion
Randomized clinical trial
RCT have become the sine qua non for
the proof of efficacy the Food and Drug
Administration requires for marketing
new drugs
Clinical trial phases (drugs)
Phase I Studies: Pharmaco/Toxicity
–Participants have already tried and failed to
improve on the existing standard intervention.
–Maximally tolerated dose (MTD).
Phase II Studies: Treatment effect
–Once the MTD is established, the next goal is to
evaluate whether the drug has any biologic
activity or effect and to estimate the rate of
adverse events.
Clinical trial phases (drugs)
Phase III/IV Studies: Full-scale
evaluation/Postmarketing surveillance
–Clinical trial (Phase III): generally designed to
assess the effectiveness of the new intervention,
and thereby, its role in clinical practice.
–Long term studies, which do not involve control
groups, are referred to as Phase IV Studies
Types of Clinical Trial
Randomized
– Control
Non randomized
– Concurrent control
– Historical
Others
– Cross-over
– Withdrawal
– Factorial
–Group allocation design
–Studies of equivalency
Randomized Control Trial
Def : Comparative study with an intervention and a
control groups; the assignment of the subject to a group is
determined by formal procedure of randomization.
Advantages
• Removes the potential of bias
in the allocation of subjects to
the study groups
• Tends to balance study groups
in covariates
• Guarantees the validity of
statistical tests of significance
Disadvantages
• Emotional and ethical aspects
• Rare prevalence of a disease
• Complexe, expensive and
time-consuming
Non-Randomized Control Trial
Def :
Comparative study with an intervention and a control
group where subjects of either groups are treated at
approximately the same time; the assignment is
not done by a random process.
Advantages
Disadvantages
•Easier to select patient (increased • Potential bias that the study
investigator and subject
groups are not strictly
acceptance);
comparable.
•Prefer to select the control group
by means of matching key
characteristics;
Historical Control Trial
Def :
Comparative study with an intervention and a control
group where a new intervention is used in a series of
subjects and the results are compared to the outcome
in a previous series of comparable subjects; this type
of study is non-randomized and non-concurrent.
Advantages
• All new subjects can receive
the new intervention;
• Easier to select patient
(increased investigator and
subject acceptance);
• Ethical aspects;
• Rapid and relatively
inexpensive.
Disadvantages
• Potential bias introduced by
time changes in the nature of
the patient population, in
exposure to pathological
agents, or in supportive care
and diagnostic criteria;
• Missing data.
Cross-Over Design
case of a RCT; it allow each subject to serve as his own
Def : Special
control. In the two period cross-over design, each subject will
receive either intervention or control in the 1st period and the
alternative in the succeeding period; the order in which the
intervention and the control treatments are given is randomized
Advantages
Disadvantages
• Reduction in variability
enables to use smaller
sample size to detect a
specific difference in
treatment response.
• A fairly strict assumption must be made,
that the effect of the intervention during
the first period must not carry over into the
second period;
• Both subjects and disease state change
over time; it cannot apply to treatment
administered immediately after an acute
disease.
Withdrawal Studies
Def :
Withdrawal studies have been conducted in which the
subjects on a particular treatment for chronic disease
are taken off or have the dosage reduced;
Advantages
Disadvantages
• Evaluate the duration of
benefit of an intervention
already known to be useful;
• Highly selected sample is evaluated,
e.g. only those subjects who
physicians thought were benefiting
from the intervention were to have
been on it and anyone who had a
major side effect would have been
taken off. Thus it can overestimate
benefit and underestimate toxicity.
• Assess the efficacy of an
intervention that has never
conclusively been shown to
be beneficial.
Factorial Design
Def :
Factorial design attempts to evaluate two
interventions compared to control in a single
experiment.
Advantages
• Can be very informative,
efficient and less expensive.
Disadvantages
• Possibility of the existence of
interaction and its impact on
the sample size;
• Added complexity, impact on
compliance or recruitment and
potential adverse effects of
polypharmacy.
Group Allocation Design
Def :
In group allocation or cluster randomization
design, a group of individuals, a clinic, or a
community is randomized to a particular
intervention or control.
Advantages
• May be more acceptable or
decrease the difficulty of
approaching people about the
idea of randomization
Disadvantages
• May not be as efficient as the
traditional one (sampling units
and the units of analysis are
groups)
• If the response rate vary
across clinics or groups,
efficiency is further decreased.
Study of Equivalency
Def :
In study of equivalency or trial with positive
control, the objective is to test whether a new
intervention is as good as an established one;
the investigator must specify what is meant by
equivalence.
Advantages
• Similar use of treatments with
ease to apply, less adverse
effect or cost.
Disadvantages
• It cannot be statistically shown
that two therapies are
identical, as an infinite sample
size would be required
• Control or standard treatment
have been shown to be
effective; that is, truly better
than placebo.
Study population
Fundamental point
• The study population should be defined in
advance, stating unambiguous inclusion
(eligibility) criteria. The impact that these criteria
will have on study design, ability to generalize,
and participant recruitment must be considered.
Study population
Defining the study population is an
integral part of posing the primary
question
–It is not enough to claim that a treatment is or
not effective
–The description requires specifications of
criteria for subject eligibility
Study population
Population
at large
Population
without
condition
With
condition
but ineligible
Eligible but
not enrolled
Population
with condition
Definition
of
condition
Entry
criteria
Study
population
Enrollment
Study sample
Eligibility criteria
In general, eligibility criteria relate to
participant safety and anticipated effect of
the intervention.
Eligibility criteria
These criteria will have an impact on:
• Study design
• Ability to generalize
• Participant recruitment
Generalization
Generalize to a broader population:
• Study subjects are usually non randomly
chosen from the study population, which in
turn is defined by eligibility criteria.
• Selective participation in a trial entails the
risk that the findings may not be
generalizable.
Generalization
It is often forgotten that participants
must agree to enrol in a study:
What sort of person volunteers for a study ?
Why do some agree to participate while
others do not ?
Randomization in
Experimental Studies
Fundamental point
Randomization tends to :
• produce study groups comparable with
respect to known/unknown risk factors
• remove investigator bias in the allocation of
subject
• guarantee that statistical tests will have valid
significance levels
Experimental bias
Two forms:
• Selection bias, occurs if the allocation
process is predictable
• Accidental bias, can arise if the
randomization procedure does not achieve
balance on risk factors or prognostic
covariates
Types of randomization
Individual randomization
• Simple
• Blocked
• Stratified
Group randomization
Simple randomization
The most elementary form of
randomization:
 toss an unbiased coin each time a subject
is eligible;
 use a random number producing algorithm
(a more convenient method for large
studies).
Blocked randomization
Def : Blocked randomization, sometimes
called permuted block randomization
Advantages
Disadvantages
• Avoid imbalance in the
number of subjects
assigned to each group;
this is true particularly if
the sample size is small
• If the study is not blinded,
the study staff know the
assignment for the last
person before
randomization of that
person
Blocked randomization
For example, in the case of blocksize 4,
there are 6 possible combinations of group
assignments :
AABB, ABAB, BAAB, BABA, BBAA, and ABBA.
Blocked randomization
For example, another method :
Assignment
Random number
Rank
A
0.069
1
A
0.734
3
B
0.867
4
B
0.312
2
Stratified randomization
Def : For any single study, especially a small study,
there is no guarantee that all baseline
characteristics will be similar in the 2 groups.
Advantages
Disadvantages
• Reduce variability • Sometime the variables initially
in group
though to be most prognostic
comparison if the
and therefore used in the
stratification is
stratified randomization turn out
used in the
to be unimportant
analysis
• Other factors may be identified
later on to be more important
Stratified randomization
Age
Sex
Smoking Hx
1.
40-49 yr
1. Male
1. Current sm.
2.
50-59 yr
2. Female
2. Ex-sm.
3.
60-69 yr
In this example, there will be 18 strata…
Stratified randomization with
block size of four
Group randomization
• For some interventions (psychosocial, education, etc)
random assignment by individuals can be detrimental,
because of the potential risk of interaction among
subjects.
• Group of individuals, a clinic or a community are
randomized to a particular intervention or control; in this
design, the basic sampling units are groups, not
subjects.
• Because the basic sampling units are groups, the
design is not as efficient as the traditional one
Blindness
Fundamental point
• A clinical trial should, ideally, have a double-blind
design to avoid potential problems of bias during
data collection and assessment. In a study where
such design is not possible, a single-blinded
approach and other measures to reduce potential
bias are favored
Unblinded and Blinded Studies
Definition
• Bias can occur at a number of places in a clinical
study, and it can be caused by conscious factors,
subconscious factors, or both
• The general solution to the problem of bias is to
keep the subject and the investigator blinded, or
masked, to the identity of the assigned
intervention
Types of Blinded Studies
Single Blind
• Only the investigator is aware of which intervention each
subject is receiving.
Double Blind
• Neither the subjects nor the investigators responsible for
following the subjects know the identity of the
intervention assignment.
Triple-Blind
• An extension of the double-blind design; the committee
monitoring response variables is not told the identity of
the groups.
Importance of Blindness
in a study
Example :
Benefits of the ascorbic acid (vit C) in the common cold
Lewis et al. Ann NY Acad Sci 1975; 258 : 505-12
Participants: medical staff, discovered whether
they were on Vit C or placebo
Evaluation: severity and duration self-reported by
the participants
Importance of Blindness
in a study
Results:
• Participants who claimed not to know
the identity of the Rx Vit C not better than placebo
• Participants who claimed to know
the identity of the Rx Vit C better than placebo
Sample size
Fundamental point
• Clinical trials should have sufficient statistical power to
detect differences between groups considered to be of
clinical interest. Therefore, calculation of sample size with
provision for adequate levels of significance and power is an
essential part of planning a trial.
Baseline assessment
Fundamental point
• Relevant baseline data should be measured in all study
participants before the start of the intervention
Baseline assessment
Use of baseline data:
• analysis of baseline comparability
• stratification and subgrouping
• evaluation of change
• natural history analysis
Data collection and
quality control
Major types of problems:
• missing data (one indicator of the quality of the trial)
• erroneous data (error will not necessarily be
recognized)
• variability in the observed characteristics (reduce
the opportunity to detect the real changes): random,
systematic or combination of both
Adverse Effects in RCT
Difficulties in using clinical trials:
•Most clinical trials are
•Too small
•Too short duration
to detect uncommon adverse effects
•Patients are very selected
(those more likely to develop AE are excluded)
Issues in Data analysis
Fundamental point
• Excluding randomized participants or observed outcomes
from analysis on the basis of outcome or response variables
can lead to biased results of unknown magnitude or
direction
Issues in Data analysis
Exclusion are peoples who are screened as potential
participants but who do not meet all of the entry criteria; this
will not impact on the internal validity of the study but on the
external validity (capacity to generalize)
Withdrawals are participants who have been randomized
but are deliberately not included in the analysis; this can
bias the results of the study (consequently, the participants
remaining may not be comparable)
Reasons for withdrawing
• Ineligibility
• Nonadherence or non-compliance
• Poor quality or missing data
Ineligible patients
• Any trial requires a precise definition of which patients
are eligible for inclusion
• If the proportion of ineligible patients becomes unduly
large (these patients have to be detected and
reported),
• this may reflect a generally poor standard of study
organization;
• It could also indicate that the study’s eligibility criteria were too
restrictive.
• Another issue is whether ineligible patients should be
included in the analysis of study results : Intention-totreat vs Per protocol analysis
Non-compliance
Definition:
Behaviours that are not consistent with health
care recommendations
Compliance
Factors that minimize compliance problems :
• Study design; the shorter the study, the more likely
subjects are to comply with the intervention;
• Simplicity of the intervention; for example, single dose
drug regimens are preferable to multiple dose regimens;
• Subject selection; people likely to follow the study
protocol (run-in period can be used);
• A truly informed subject is likely to be better complier
(provider-patient interactions are the most consistent
determinants).
Compliance
The ultimate in non-compliance is for
patients to withdraw totally from the
study. Withdrawal from treatment,
whatever the reason, should not
preclude a patient from subsequent
evaluation.
Compliance
One need to draw a distinction between
• non-compliance attributed to lack of patient
cooperation or misunderstanding,
• as opposed to cessation or modification of
therapy because of adverse reactions or
disease progression.
Poor quality or missing data
Participants may be withdrawn from trial
because their data are found to be of poor
quality, the extreme being missing data.
Comparison of multiple
variables
If many significance tests are done, some of
them may be significant by chance alone:
• Repeat look at the same response variable
• Comparison of multiple variables
Comparison of multiple
variables
For example:
If an investigator has 100 independent
comparisons, 5 of them, on the average, will
be significantly different by chance alone ( if
the 0.05 level of significance is used)
K comparisons, each comparison should be
made at the significance level of α/k
Comparison of multiple
variables
Therefore it is more reasonable to calculate
sample size based on one primary response
variable comparison and be cautious in
claiming significanct results for other
comparisons.
Efficacy and Effectiveness
Efficacy :
The extent to which a specific intervention,
procedure, regimen, or service produce a
beneficial result under ideal conditions;
ideally, the determination of efficacy is
based on the results of a randomized
control study .
Efficacy and Effectiveness
Effectiveness
In the usage made standard among epidemiologists
by A. L. Cochrane (1909-88), effectiveness is a
measure of the extent to which a specific
intervention, procedure, regimen, or service, when
deployed in the field in routine circumstances, does
what it is intended to do for a specified population
(Cochrane AL. Effectiveness and efficiency;
Random reflections on health service. London :
nuffield Provincial Hospitals Trust, 1972).
Efficacy and Effectiveness
Intention-to-treat
A procedure in the conduct and analysis of
randomized controlled trial. All patients allocated
too each arm of the treatment regimen are
analysed together as representing that treatment
arm, whether or not they received or completed
the prescribed regimen. Failure to follow this step
defeats the main purpose of random allocation
and can invalidate the results (Newell DJ.
Editorial, Int J Epidemiol 1992; 21 : 837-41).
Ethical Considerations
The most serious objections to randomized
control studies are ethical issues.
A randomized control study can usually be undertaken
when :
• There is uncertainty about the value of a new therapy
or dispute about the relative merits of existing therapies.
Although studies might not actually prove the superiority
of a new treatment, it can show that either new or
existing treatment is valueless or even hazardous.
These facts are also important to discover.
Real Treatment effect?
Factors that might influence the
response to a treatment or an
intervention
• Natural history of the disease
• Placebo effect
• Effect of participation : Hawthorne
effect
• Real treatment or intervention effect
Assessing quality of RCT
• Overwhelming evidence indicates that the
quality of reporting RCT is less than
optimal
• Bias results from poorly designed and
reported trials; mislead medical decision
• Reporting often incomplete,
compounding problems arising from poor
methodology
Altman et al. Ann Intern Med 2001
Deficiencies in reports RCT
Blind assessment of
outcome (1979-80)
30% (67 trials)
Primary endpoint
defined (1985)
27% (45 trials)
Sample size
calculation
43% (37 trials)
Report method of
allocation
Most
Reporting inaccurate
Intention-to-treat but did
not analyse all patients
Inadequate reporting in
specialty journals
Supposed RCTs
(obstetric and gyneco journals)
13%
(119 trials)
Common
5%
(206 trials)
Improving reporting RCTs
The CONSORT statement
(consolidated standards or reporting trials)
•The CONSORT statement - JAMA 1996
•The Revised CONSORT Statement.
Ann Intern Med 2001
Trial profile
Revised template of the CONSORT (Consolidated Standards
of Reporting Trials) diagram showing the flow of participants
through each stage of a randomized trial (56-58)
Ann Intern Med 2001; 134:666
Trial profile
Trial profile based on completion of telephone interviews for evaluation
of acute exacerbation's and other health problems and related health
service utilization
Randomization process
Generation and implementation of a
Random Sequence of Treatment:
Generation
Implementation
Preparation of the random
sequence
Enrolling participants
Assessing eligibility
Discussing the trial
Obtaining informed consent
Enrolling patient in trial
Preparation of an allocation
Ascertaining treatment assignment
(such as by opening the next
envelope)
system (such as coded bottles
or envelopes), preferably
designed to be concealed from Administering intervention
the person assigning
participants to groups
Ann Intern Med 2001; 134:674
Baseline characteristics
Example of reporting of Baseline Demographic and Clinical
Characteristics of Trial Groups
Ann Intern Med 2001; 134:680
Results
End Point
Interventio
Group
Placebo
Group
(n=30)
(n=30)
n (%)
Primary
Difference
(95% CI)
P
Value
%
26 (87)
7(23)
63 (44-83)
<0.001
ACR 20
22 (73)
4 (13)
60 (40-80)
<0.001
ACR50
15 (50)
1 (3)
47 (28-66)
<0.001
ACR70
4 (13)
0 (0)
13 ( 1-26)
0.04
Achieved psoriatic arthritis response criteria at 12
weeks
Secondary
Proportion of patients meeting ACR criteria
Example of reporting of Summary Results for Each Study Group
Ann Intern Med 2001; 134:682
… Discussion
• Brief
synopsis
•Consideration of possible explanation
•Comparison with relevant findings from
other published studies
•Limitations of the study (method used to
minimize or compensate)
•Summary of clinical and research
implications