Clinical trial design III

Objective
Different type of trial designs: Parallel design Crossover design Factorial design Hybrid design Sequential Design
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The choice of study design depends on the following factors like.

Hypothesis to be tested Minimize bias Minimize variability of observations, with the aim of obtaining powerful statistical tests and precise estimates

A first and basic classification of experimental has two main objectives:

Designs based on between-subjects comparisons

Designs based on with-in subject comparisons

Parallel Group Design

First a homogenous group of subjects are selected using suitable selection criteria and then subjects from this group are randomly allocated to two or more treatment group. The subjects are studied in parallel

Parallel design

Characteristics of parallel design

Traditional Simple Commonest Compares outcomes between groups Easiest to analyse

When do we employ parallel design?

When we are comparing outcomes between groups The parallel design can be used in broad range of experimental conditions For broad range of applicability and simplicity.

Other consideration for employing parallel design

Include patient characteristics ( e.g. acute, chronic, seriously ill or life threatening) Nature of study medicine ( Potential toxicity and long elimination half -life) Financial consideration

Advantages of using parallel design

The duration of the study is shorter Easiest to analyse as statistical analysis requires fewer assumption It is simpler and thus makes bias free comparison easier to obtain Cost effective

Disadvantages of Parallel design

Requires larger sample size Intra-subject variability cannot be measured

Cross Over trials

A crossover study compares the results of a two treatment on the same group of patients.

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Cross Over trials

Treatment

Cross over

Randomize

Placebo

Time 1

Time 2

Cross over trials

Period 1

Period 2

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Example of Cross over design

A cross-over trial was run to compare the effect of tramadol to placebo in painful polyneuropathy (Sindrup et al., 1999). Forty-five patients were randomized to one of two sequences, tramadol followed by placebo or placebo followed by tramadol. Each treatment was delivered for four weeks. Using 10-point numeric scales, patients rated pain, paresthesia and touch-evoked pain.

Characteristic of crossover design

In this design each subject is treated with two or more treatments successively in random order. Each subject is randomized to one of the possible successions of the treatment called sequences of the study.

Characteristic of crossover design

Each of the time intervals in which one of the study treatment is administered is called a period. There is a wash out period between two successive treatments.

When do we employ crossover design?

When we need to study the intra-subject variability of treatment modalities The study treatment have reversible effect This design is especially useful in doseresponse study (phase-II)

Limitations of a crossover design

Persistence of effect of first treatment
Rapidly changing underlying disease A carryover effect (persistence of a pharmacological or psychological effect of the first treatment into the second period);

Limitations of a crossover design

High dropout rates Crossover designs are generally not used in vaccine trials because the immune system is permanently affected (or at least affected for a long time). Thus, carry over effects are always present

Advantages of Crossover design

Intra-subject variability can be estimated Smaller sample size As the intra-subject variability is reduced the studies have greater statistical power

Disadvantage of crossover design

More complex longer

Factorial design
This design is used to assess simultaneously the effects of multiple independent variables. It is very efficient, instead of conducting series of experiment, it can be effectively be able to combine in one.

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Factorial design

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Two types of factorial design

Parallel group factorial design Cross over factorial design

Applicability of Factorial design

When a primary questions concerns the interaction between treatments, in addition to their individual effects - Fixed dose combinations - When two or more comparators are used and both schedule and dose are tested

Cluster randomization/ Group allocation design

In this design the basic sampling units and units of analysis are groups, not individual participants A group of individuals, patients of a clinic or a community is randomized into particular intervention or control.

Sequential design
In order to approve new beneficial treatments as rapidly as possible and minimizing harm by avoiding giving harmful and less effective treatment to subjects, this design is employed.

Sequential design
The subjects are administered with the new treatment and their response are assessed and analyzed sequentially before administering to the subsequent participant.

Advantages of using sequential treatment

Minimize harm and maximize benefits for the trial participants Do not unnecessarily give harmful or less effective treatment to trial subjects Fewer patients are need on average Sufficient evidence available to be confident in rejecting or accepting a specific hypothesis

Thus Importance of clinical trial design cannot be underestimated because every element in a trial is influenced by its design. Every study team member has contributing role in design development.

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References
Statistics for Biology and Health Antonella Bacchieri and Giovanni Della Cioppa Basic Principles of Clinical Research and Methodology S K Gupta http://www.peri.org/distance_tour/stats/html /parallel.html