Clinical trials

cross over design,factorial design and equivalence design

1. CLINICAL TRIALS : CROSS OVER DESIGN, FACTORIAL DESIGN AND EQUIVALENCE DESIGN 1

2. CLINICAL TRIALS A prospectively planned experiment for the purpose of evaluating potentially beneficial therapies or treatments. Clinical trials are part of clinical research and at the heart of all medical advances. Clinical trials look at new ways to prevent, detect, or treat diseases. Treatments might be new drugs or new combinations of drugs, new surgical procedures or devices, or new ways to use existing treatments. 2

3. TRIAL DESIGN Trials can be further classified by design. This classification is more descriptive in terms of how patients are randomized to treatment. The most common design is the Parallel-Group Trial . Patients are randomized to the new treatment or to the standard treatment and followed-up to determine the effect of each treatment in parallel groups . 3

4. Other trial designs include, Crossover Trials, Factorial Trials, and Cluster Randomized Trials. Crossover trials randomize patients to different sequences of treatments. Factorial trials assign patients to more than one treatment-comparison group. Cluster randomized trials are performed when larger groups are randomized instead of individual patients. 4

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6. CROSS-OVER DESIGN Crossover trials are designed so that each recruited patient receives both active and control treatments in either order for a specified duration, with a ‘washout’ period between treatments when no treatments is administered. In such trials, patients act as their own controls, therefore fewer patients are required to evaluate the effects of different therapies. 6

7. Crossover Designs Randomization Treatment A Treatment B Treatment A Treatment B Evaluation of Outcomes Evaluation of Outcomes Adapt e d from Tinmouth A, Hebe rt P. Interventional trials: an ov erview of d e sign alt e rn atives. Transfusion. 2007;47:565-67. 7

8. In a Crossover Trial, each subject receives more than one treatment in a specified sequence. It is a study that compares two or more treatments or interventions in which subjects, on completion of a course of one treatment, are switched to another. This effectively means that each subject acts as his own control. 8

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10. The fundamental assumptions of crossover trials is that patients usually have a chronically stable condition that will not vary between when they are taking the first and second treatments. Therefore, crossover trials are short-term trials. 10

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12. FACTORIAL DESIGN Factorial design is the evaluation of more than one treatment for safety and/or efficacy compared to a control. It includes conducting a multiple-arm parallel trial or several separate trials to evaluate the effect of each treatment individually. 12

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15. Attempts to evaluate two interventions compared to a control in a single experiment (simplest case ). An important concept for these designs is interaction (sometimes called effect modification ). Interaction : The effect of treatment A differs depending upon the presence or absence of intervention B and vice-versa. 15

16. Advantages: If no interaction, can perform two experiments with less patients than performing two separate experiments. Can examine interactions if this is of interest. Disadvantages : Added complexity. P otential for adverse effects due to “poly-pharmacy ”. 16

17. EQUIVALENCE DESIGN Clinical trials are usually conducted to detect the superiority of one treatment over another. However, compounds often undergo alterations to either their release mechanism, formulation or manufacturing process, and some are modified chemically, resulting in related compounds. It can then become necessary to conduct a trial to compare the altered versus the original compound or drug to demonstrate that there has been no loss of effectiveness or increase in side-effects. Such trials are known as E quivalence T rials . 17

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19. TYPES OF EQUIVALENCE TRIALS CLINICAL EQUIVALENCE They are based on clinical outcomes such as death, stroke, heart attack or hospitalization. Outcomes such as improvement in depression are difficult to measure objectively and reproducibly. BIOEQUIVALENCE An alternative method is to use a pharmacokinetic approach, which compares the PK parameters derived from plasma or blood concentrations of the compound. The outcomes are more objective and measurable. 19

20. Equivalence studies importance in clinical trials: They are used for comparing similar treatment compounds. They are used for comparing the efficacy of the same treatment compound in different formulations. They can have either an equivalence or inferiority endpoint. The outcomes can be clinical or pharmacokinetic. 20

21. REFERENCES Wang D. Clayton T, Bakhai A. (2006c). Confounding. In: D Wang & A Bakhai , ( Ed.s ). Clinical trials: A practical guide to design, analysis and reporting. London: Remedica . 119-304. http ://www.lshtm.ac.uk/study/howto/clinical_trials_leaflet_2011 . https://prsinfo.clinicaltrials.gov/trainTrainer/Factorial-Design-Fiction-Manuscript . h ttp :// medicine.dundee.ac.uk/sites/medicine.dundee.ac.uk/files/page-files/Crossover%20Analysis . 21

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