1. Introduction to Clinical Trials
Afshin Ostovar
Bushehr University of Medical Sciences
Bushehr, 2011
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2. Research Design Epidemiology
Descriptive Studies
Case Reports
Case Series
Cross Sectional Survey
Analytic Studies
Observational Studies
Case-Control or Case-Comparison
Cohort Studies
Intervention Studies
Clinical Trials
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3. Definition
A clinical trial is defined as a prospective study comparing the effect and value of intervention(s) against a control in human beings.
They need not all be followed from an identical calendar date. In fact, this will occur only rarely. Each participant, however, must be followed from a well-defined point, which becomes time zero or baseline for the study.
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4. Definition “cont’d”
A clinical trial must employ one or more intervention techniques. These may be "prophylactic, diagnostic or therapeutic agents, devices, regimens, procedures, etc.“
Intervention techniques should be applied to participants in a standard fashion in an effort to change some aspect of the participants.
Follow-up of people over time without active intervention may measure the natural history of a disease process, but it does not constitute a clinical trial. Without active intervention the study is observational because no experiment is being performed.
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5. Definition “cont’d”
A clinical trial must contain a control group against which the intervention group is compared.
At baseline, the control group must be sufficiently similar in relevant respects to the intervention group so that differences in outcome may reasonably be attributed to the action of the intervention.
Most often a new intervention is compared with best current standard therapy. If no such standard exists, the people in the intervention group may be compared with people who are on no active intervention. "No active intervention" means that the participant may receive either a placebo or no intervention at all.
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6. Counterfactual concept
The effect of any treatment for a given patient is the difference between what happened to the patient as a result of giving the treatment and what would have happened had treatment been denied. (counterfactual view)
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7. Phases of Clinical Trials
Phase I
Phase II
Phase III
Phase IV
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8. Clinical trial designs
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9. Case series
Before
After
Intervention
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10. Parallel Group Designs
Defined Population
New Treatment
Improved
Not Improved
Current Treatment
Randomization
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11. Parallel Group Designs (Adventages)
Simple and easy to implement
Universally accepted
Applicable to acute conditions
Analysis is less complicated and interpretation of the results is straightforward
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12. Parallel Group Designs (Types)
Group comparison (parallel-group) design
Two-group design
For ethical consideration with control (placebo), we can allocate patients unequally to treatment groups (at random) to allow more patients to receive the treatment.
Three-group design
Matched pairs parallel designs
Power increased
Two drawbacks:
The prognostic characteristics are not easily defined
Patient recruitment is usually slow
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13. Parallel group designs (run in periods)
Advantages
Acts as a washout period to remove effects of previous therapy
Can be used to obtain baseline data and to evaluate if patient fulfills study entry criteria
Can be used as a training period for patients and investigators
Helps in identifying placebo responders
Provides useful information regarding patient compliance
Disadvantage:
Increases the length of a study:
Extra visit and costs
Decreases in enthusiasm of patients and investigators

14. Crossover Designs
A crossover design is a modified randomized block design in which each block receives more than one treatment at different periods.
A p × q crossover design: there are p sequences of treatments administered at q different periods
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15. Standard 2 × 2 Crossover Design
Randomization
Drug
Placebo
Period 1
Period 2
washout
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16. Crossover Designs Allows within-patients comparisons of treatments
Advantages:
Allows within-patients comparisons of treatments
Removes intrapatient variability
Provides the best unbiased estimates for the differences between treatments
Decreases number of patients needed
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17. Factorial Design A &B B A NONE Treatment A Treatment B + - + -
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18. Factorial Design Two applications: Treatments groups: AO BO AB OO
Quantifying the interaction between the two treatments
Opportunistic situations
Treatments groups: AO BO AB OO
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19. Designs with ethical considerations
Adaptive Randomization
Zelen design
Variations of placebo-controlled trials:
Add-on design
Replacement design
Randomized Withdrawal design
Sequential analysis
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20. Multicenter trials
The limitations of patient population in a single center and/or sources and capacity in a single center make a multicenter trial justified.
A multicenter study is a single study involving several study centers. The data collected from these centers are intended to be analyzed as a whole.
At each center an identical study protocol is used. A center or site is considered a natural blocking or stratified variable.
A rule of thumb is that the number of patients in each center should not be less than the number of centers
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21. The Randomization Process
The randomized clinical trial is the standard by which all trials are judged
In the simplest case, randomization is a process by which each participant has the same chance of being assigned to either intervention or control
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22. Purposes of Randomization
To generate comparative groups
To enable valid statistical tests
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23. Blindness Open label (unblinding) Single blinding (patients only)
Double blinding (patients and investigators)
Triple blinding (patients and investigators and Monitoring investigators)
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24. Classic classification of Randomization
Simple
Systematic
Balanced block
Stratified
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25. Complete randomization (Simple randomization)
Random allocation
It is a form of restricted randomization
It randomly selects the N/2 out of a total of N patients without replacement and assigns these N/2 patients to receive the test drug and the other half to receive the placebo.
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26. Permuted block randomization (Balanced block randomization)
One of the major disadvantages of simple randomization is that treatment imbalance can occur periodically
If the demographic factors or baseline characteristics change over time, it is quite possible to have a serious covariate imbalance between treatment groups.
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27. Balanced block randomization
AABB
ABAB
ABBA
BBAA
BABA
BAAB 1 3 2 9 6 4 8 7 5
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28. Treatment adaptive randomization
The Treatment adaptive randomization adjusts for the assigning probability of the current patient with respect to the number of patients who have been randomized to each treatment group.
Methods:
biased coin randomization
A constant assigning probability is used during the entire course of the study
Urn randomization
The probability of the assignment of the current patient is a function of the current treatment imbalance
It requires a much more complicated analysis
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29. Steps in Analysis Baseline data analysis Main analysis
Protocol deviation
Intention to treat and per protocol approaches
Covariates analysis
Multiple outcomes analysis
Subgroup analysis
Multiplicity in analysis of clinical trials
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30. Baseline Data Analysis
To:
Check generalizability
Check comparability of treatment groups
The variables should be considered:
The characteristics of the disease (type, severity, duration, …)
Prognostic variables
Other coincidence diseases
Previous treatments
Use of statistical tests!
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31. Main analysis Three approaches: Outcome analysis Change score analysis
Analysis of Covariance (ANCOVA)
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32. Covariates analysis Covariate = prognostic factor = confounder
In the case where covariates are not balanced between the treatment groups, to obtain a valid inference of treatment effect, it is necessary to adjust for covariates
An adjustment of covariates not only provides unbiased statistical inference but also increases precision of the statistical inference
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33. Study Protocol
The study protocol can be viewed as a written agreement between the investigator, the participants, and the scientific community.
The contents provide the background, specify the objectives and describe the design and organization of the trial.
Every detail explaining how the trial is carried out does not need to be included, provided that the comprehensive manual of procedures contains such information.
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34. Study Protocol
The protocol serves as a document to assist communication among those working in the trial.
It should be also be made available to others on request.
The protocol should be developed before the beginning of participant enrollment and should remain essentially unchanged except perhaps for minor updates.
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35. Study Protocol
Careful thought and justification should go into any changes.
Major revisions that alter the direction of the trial should be rare.
If they occur, the rational behind such changes need to be clearly descried.
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36. A. Background of the study
1. Reviewing the related articles. 2. Why is the results of this trial needed? 3. How does the study provide evidence for decision making?
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37. B. Objectives Primary question and response variable
Secondary question and response variables
Subgroup hypothesis
Adverse effects
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38. C. Design of the study Study population Inclusion criteria
Exclusion Criteria
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39. Population At Large Population Without Condition
With Condition
Population
Study Population
Study Sample
Population Without Condition
Definition of Condition
With Condition But Ineligible
Entry Criteria
Eligible But Not Enrolled
Enrollment
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40. C. Design of the study 2. Sample Size assumptions and estimates
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41. 3. Enrollment of participants
C. Design of the study
3. Enrollment of participants
Informed consent
Assessment of eligibility
Baseline examination
Intervention allocation (e.g., Randomization method)
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42. C. Design of the study 4. Intervention Description and schedule
Measures of compliance
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43. C. Design of the study 5. Follow-up visit description and schedule
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44. 6. Ascertainment of response variables
C. Design of the study
6. Ascertainment of response variables
Training
Data collection
Quality control
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45. C. Design of the study 7. Data analysis Interim monitoring
Final analysis
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46. C. Design of the study
8. Termination policy
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47. 1. Participating Investigators
D. Organization
1. Participating Investigators
Statistical unit or data coordinating center
Laboratories and other special units
Clinical center(s)
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48. D. Organization 2. Study administration
Steering committees and subcommittees
Data monitoring committee
Funding organization
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49. Appendix Definitions of eligibility criteria
Definition of response variables
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50. Any Question?
Any Question?
Thank you
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