Clinical trial design

1. CLINICAL TRIAL DESIGN Dr Urmila M. Aswar Department of Pharmacology, SIOP, Narhe

2. Classification of CT study Proof of concept/Feasibility: < 5 subjects or patients; one site, safety and some effectiveness, usually investigator-sponsored study Pilot study: 20-30 subjects; initial effectiveness and safety; two sites, usually investigator-sponsored study Pivotal study: 50 - 500 subjects; multiple sites; main supporting study for claims

3. Observational Studies Cohort (Incidence, Longitudinal) Case-Control Cross-Sectional (Prevalence) Case Series Case Report

4. Clinical Trial Design: Experimental

5. Experimental trials Uncontrolled Controlled Non randomized Randomized Cross-over Factorial Latin square

6. 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

7. 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)

8. 8 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

9. With control non randomised studies

10. 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:

11. 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)

12. 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.

13. 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

14. Randomized Controlled trials

15. 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

16. 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.

17. 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 .

18. Advantages Maximize statistical power , especially in subgroup analyses . Minimize selection bias Minimize allocation bias   

19. Disadvantages 1. Recruitment Hard 2. Acceptability of Randomization Process Some physicians will refuse Some participants will refuse 3. Administrative Complexity 4.Generalizable Results? Participants studied may not represent general study population.

20. 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 .

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

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

23. 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).

24. 5. Latin Square Design

25. Summary

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