CLINICAL TRIAL DESIGN

Dr Urmila M. AswarDepartment of Pharmacology, SIOP, Narhe

Classification of CT study

oProof of concept/Feasibility: < 5 subjects or patients; one site, safety and some effectiveness, usually investigator-sponsored study

oPilot study: 20-30 subjects; initial effectiveness and safety; two sites, usually investigator-sponsored study

oPivotal study: 50 - 500 subjects; multiple sites; main supporting study for claims

Observational Studies

Cohort (Incidence, Longitudinal)Case-Control Cross-Sectional (Prevalence)Case SeriesCase Report

Clinical Trial Design:Experimental

Experimental trials

Uncontrolled Controlled

Non randomized Randomized Cross-over Factorial Latin square

• In such a design a single test group is selected and the dependent variable is measured before the introduction of the treatment. The treatment is then introduced and the dependent variable is measured again after the treatment has been introduced. The design can be represented thus:

1. Before-and-after without Control Design

Before-and-after without Control Design

• Test area:• Level of phenomenon Treatment introduced Level of phenomenon

before treatment (X) after treatment(Y)

• Treatment Effect = (Y)-(X)

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Non-randomized Trials

• Early studies of new and untried therapies

• Uncontrolled early phase studies where the standard is relatively ineffective

• Investigations which cannot be done within the current climate of controversy

WITH CONTROL NON RANDOMISED STUDIES

1. After-only with Control Design

• In this design two groups are selected and the treatment is introduced into the test group only. The dependent variable is then measured in both the areas at the same time. This can be exhibited in the following form:

After-only with Control Design

Test group Treatment introduced Level of phenomenon after Control group treatment (Y)

Level of phenomenon Without treatment (Z) Treatment Effect = (Y) – (Z)

2. Before-and-After with Control Design

• In this design two groups are selected and the dependent variable is measured in both the group for an identical time-period before the treatment. The treatment is then introduced into the test area only, and the dependent variable is measured in both for an identical time-period after the introduction of the treatment.

This design can be shown in this way:

Time Period I Time Period II

Treatment

Test group: Level of phenomenon Level of phenomenon after

before Treatment (X) introduced Treatment (Y)

Control group: Level of phenomenon Level of phenomenon without

without Treatment (A) Treatment (Z)

Treatment Effect = (Y – X) – (Z – A)

Before-and-After with Control Design

RANDOMIZED CONTROLLED TRIALS

Randomized Controlled trials• 1948 paper entitled "Streptomycin treatment of

pulmonary tuberculosis“• Randomized control:• Well-designed RCTs are considered the gold standard

for measuring an intervention’s impact across many diverse fields of human inquiry, such as education, welfare and employment, medicine, and psychology

• Large patient study

• Allocation of patient before intervention• To study efficacy and adverse effects• Patients are followed at one time

(except procedures, tests, outpatient visits, and follow-up calls)

• Advantage of proper randomization is that it minimizes allocation bias, balancing both known and unknown prognostic factors, in the assignment of treatments.

• Outcomes between the two groups can confidently be attributed to the intervention and not to other factors.

RCT• Content a control group Positive control group• It eliminates bias in treatment assignment,"

specifically selection bias.• It facilitates blinding (masking) of the identity of

treatments from investigators, participants, and assessors.

• It permits the use of probability theory to express the likelihood that any difference in outcome between treatment groups merely indicates chance.

Advantages

• Maximize statistical power, especially in subgroup analyses.

• Minimize selection bias• Minimize allocation bias

Disadvantages

1. Recruitment– Hard

2. Acceptability of Randomization Process– Some physicians will refuse– Some participants will refuse3. Administrative Complexity

4.Generalizable Results?– Participants studied may not represent general study

population.

Types

1. Parallel-group trial

Each participant is randomly assigned to a group, and all the participants in the group receive (or do not receive) an intervention.

2. Crossover

Over the time, each participant receives (or does not receive) an intervention in a random sequence.

3. Cluster

Pre-existing groups of participants (e.g., villages, schools) are randomly selected to receive (or not receive) an intervention.

4. Factorial Design

Each participant is randomly assigned to a group that receives a particular combination of interventions or non-interventions.

Testing the treatment effects independently or When the treatments are thought to be complementary and a

specific aim is to investigate the treatment interactions. In the simplest case, a 2×2 design is a study when two treatment factors are involved each with two levels.

(e.g., group 1 receives vitamin X and vitamin Y, group 2 receives vitamin X and placebo Y, group 3 receives placebo X and vitamin Y, and group 4 receives placebo X and placebo Y).

5. Latin Square Design

Summary

• Zelen’s design: randomizes the patient before they give consent.