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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
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
Clinical Trial Objectives
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 TrialRandomized
– 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 Disadvantages
• 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
• Emotional and ethical aspects
• Rare prevalence of a disease
• Complexe, expensive and time-consuming
Non-Randomized Control Trial
Def :
Advantages Disadvantages•Easier to select patient (increased investigator and subject acceptance);
•Prefer to select the control group by means of matching key characteristics;
• Potential bias that the study groups are not strictly comparable.
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.
Historical Control Trial
Def :
Advantages Disadvantages• All new subjects can receive
the new intervention;
• Easier to select patient (increased investigator and subject acceptance);
• Ethical aspects;
• Rapid and relatively inexpensive.
• 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.
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.
Cross-Over Design
Def :
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.
Special case of a RCT; it allow each subject to serve as his own 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
Withdrawal Studies
Def :
Advantages Disadvantages• Evaluate the duration of
benefit of an intervention already known to be useful;
• Assess the efficacy of an intervention that has never conclusively been shown to be beneficial.
• 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.
Withdrawal studies have been conducted in which the subjects on a particular treatment for chronic disease are taken off or have the dosage reduced;
Factorial Design
Def :
Advantages Disadvantages• Can be very informative,
efficient and less expensive. • 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.
Factorial design attempts to evaluate two interventions compared to control in a single experiment.
Group Allocation Design
Def :
Advantages Disadvantages• May be more acceptable or
decrease the difficulty of approaching people about the idea of randomization
• 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.
In group allocation or cluster randomization design, a group of individuals, a clinic, or a community is randomized to a particular intervention or control.
Study of Equivalency
Def :
Advantages Disadvantages• Similar use of treatments with
ease to apply, less adverse effect or cost.
• 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.
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.
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 with condition
Studypopulation
Study sample
Population at large
Populationwithout
condition
Definitionof
condition
Entry
criteriaWith
conditionbut ineligible
Eligible butnot enrolled
Enrollment
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 :
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, sometimes called permuted block randomization
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 :
Advantages Disadvantages• Reduce variability
in group comparison if the stratification is used in the analysis
• Sometime the variables initially though to be most prognostic and therefore used in the stratified randomization turn out to be unimportant
• Other factors may be identified later on to be more important
For any single study, especially a small study, there is no guarantee that all baseline characteristics will be similar in the 2 groups.
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-to-treat 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
13%
(119 trials)
Inadequate reporting in specialty journals
Common
Supposed RCTs (obstetric and gyneco journals)
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
Ann Intern Med 2001; 134:666
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)
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
Preparation of the random sequence
Implementation
Enrolling participants
Assessing eligibility
Discussing the trial
Obtaining informed consent
Enrolling patient in trial
Preparation of an allocation
system (such as coded bottles or envelopes), preferably designed to be concealed from the person assigning participants to groups
Ascertaining treatment assignment (such as by opening the next envelope)
Administering intervention
Ann Intern Med 2001; 134:674
Generation and implementation of a
Random Sequence of Treatment:
Baseline characteristics
Example of reporting of Baseline Demographic and Clinical Characteristics of Trial Groups
Ann Intern Med 2001; 134:680
ResultsEnd Point Interventio
Group
(n=30)
Placebo Group
(n=30)
Difference
(95% CI)
P Value
n (%) %
Primary
Achieved psoriatic arthritis response criteria at 12 weeks
Secondary
Proportion of patients meeting ACR criteria
ACR 20
ACR50
ACR70
26 (87)
22 (73)
15 (50)
4 (13)
7(23)
4 (13)
1 (3)
0 (0)
63 (44-83)
60 (40-80)
47 (28-66)
13 ( 1-26)
<0.001
<0.001
<0.001
0.04
Ann Intern Med 2001; 134:682
Example of reporting of Summary Results for Each Study Group
… 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
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