Introduction to Clinical Trials

Afshin Ostovar

Bushehr University of Medical Sciences

Bushehr, 2011

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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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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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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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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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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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Phases of Clinical Trials

Phase I Phase II Phase III Phase IV

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Clinical trial designs

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Case series

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AfterBefor

e Intervention

Parallel Group Designs

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Randomization

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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Parallel Group Designs (Types)• Group comparison (parallel-group) design

• Two-group designFor 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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Parallel group designs (run in periods)

AdvantagesActs as a washout period to remove effects of previous

therapyCan be used to obtain baseline data and to evaluate if patient

fulfills study entry criteriaCan be used as a training period for patients and investigatorsHelps in identifying placebo respondersProvides useful information regarding patient compliance

Disadvantage: Increases the length of a study:

Extra visit and costs Decreases in enthusiasm of patients and investigators

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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Standard 2 × 2 Crossover Design

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washout

Crossover Designs

Advantages:

Allows within-patients comparisons of treatments

Removes intrapatient variabilityProvides the best unbiased estimates for

the differences between treatmentsDecreases number of patients needed

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Factorial Design

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Treatment A

+ -

+

-

Tre

atm

ent B

Factorial Design

Two applications:1. Quantifying the interaction between the two treatments

2. Opportunistic situations

Treatments groups:AO

BO

AB

OO

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Designs with ethical considerations

Adaptive Randomization Zelen design Variations of placebo-controlled trials:

Add-on designReplacement designRandomized Withdrawal design

Sequential analysis

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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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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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Purposes of Randomization

To generate comparative groups

To enable valid statistical tests

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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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Classic classification of Randomization

SimpleSystematicBalanced blockStratified

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Complete randomization(Simple randomization)

Random allocationIt 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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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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Balanced block randomization1. AABB2. ABAB3. ABBA4. BBAA5. BABA6. BAAB

1 3 2 9 1

6 4 3 8 7

3 1 2 5 8

2 4 1 7 3

4 5 3 9 6

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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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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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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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Main analysis

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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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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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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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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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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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B. Objectives

1. Primary question and response variable

2. Secondary question and response variables

3. Subgroup hypothesis

4. Adverse effects

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C. Design of the study

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Definition of Condition

Entry Criteria

EnrollmentEligible But Not

Enrolled

With Condition But Ineligible

Population Without Condition

C. Design of the study

2. Sample Size assumptions and estimates

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C. Design of the study

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C. Design of the study

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C. Design of the study

5. Follow-up visit description and schedule

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C. Design of the study

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C. Design of the study

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C. Design of the study

8. Termination policy

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D. Organization

1. Participating Investigators

a. Statistical unit or data coordinating center

b. Laboratories and other special units

c. Clinical center(s)

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D. Organization

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Appendix Definitions of eligibility criteria Definition of response variables

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Any Question?

Thank you

Any Question?