1. Clinical trial The Way We Make Progress Against Disease Prof. Ashry Gad Mohamed Prof. of Epidemiology College of Medicine & KKUH

3. Definition a clinical trial is defined as a planned experiment on humans. the setting is in health institutions environment and it usually involves patients. Rationale Before a new treatment method is made available to the public it must be studied and tested for safety and effectiveness.

4. Each treatment must be tested in increasingly larger numbers of people to determine the effects in a large range of people. (Phases) Each study must follow a rigorous study plan with protections for participants. (protocol) RCT is the gold standard for evidence.

5. Fields of clinical trials Quality of life Therapy Prognosis Prevention Diagnosis Compliance Clinical trial

6. Treatment Trials What new treatments can help people with a particular disease? What is the most effective treatment for people with that disease?

7. Treatment Trials Many treatment trials compare two or more different approaches to treating a disease Participants will take either: –The best accepted treatment –A new treatment

8. Prevention Trials What approaches can prevent healthy people from developing disease?

9. Prevention Trials Two kinds, that ask participants to either: 1. Do something 2. Take something

10. Basic terms in clinical trial Investigators Participants Intervention Outcome

11. Phases of clinical trial

13. Phase 1 Prerequisite: In vitro data support the hypothesis Who? Healthy volunteers or hopeless cases How many? Small group (20 – 80) Why? To determine the best way to give people the drug. How often should be given? What is the safest dose? (Safety & metabolism in human)

14. Phase 2 Why? Drug effectiveness in particular indication.(How well the drug works?) Short term common side effects. Therapeutic pilot study WHO? Larger group of patients (100- 300).

15. Phase 3 Why? Confirm effectiveness. Short & long term side effects. Double blind randomized placebo controlled trials How many? Hundreds or thousands patients. Approval

16. Phase 4 When? Post marketing surveillance. Why? Different populations. Long term side effects. Never end.

17. Steps of clinical trial 1-Formulation of the hypothesis. Hormone replacement treatment (HRT) and Breast cancer. Trial of Vitamin D and calcium supplementation and hip fracture. Use of statins for the prevention of Myocardial Infarction. Use of the oral contraceptive pill and deep vein thrombosis (DVT).

18. 2-Definition of Reference population. Experimental population. Necessary sample size. inclusion criteria. exclusion criteria.

19. 3- Informed consent A process by which a subject voluntarily confirms his/her willingness to participate in a particular trial after having been informed of all aspects of the trial that are relevant the subjects decision to participate.

20. Protecting Patients’ Safety Informed Consent Before agreeing to take part, patients have the right to understand all that is involved in a clinical trial: Procedures and treatments Tests Possible risks and benefits

21. Protecting Patients’ Safety Institutional Review Board Committee made up of experts

22. Benefits of Taking Part Possible benefits: Patients will receive, at a minimum, the best standard treatment If the new approach is proven to work, patients may be among the first to benefit Patients have a chance to help others and improve health care

23. Risks of Taking Part Possible risks: Unknown side effects or other risks New treatment may not help every participant Costs

24. 4-Allocation of regimens Intervention versus Placebo Current treatment Nothing Randomization Aim Methods

25. Variants of clinical trials: 1-Parallel design: Parallel groups design: each patient receives only one treatment. Follow up Ref. Pop. Sample Intervention Control OUTCOMEOUTCOME

26. 2-Crossover design : each patient receives all/both treatments in random order, often with a washout period between treatments Disease: Chronic, incurable stable disease. Intervention: rapid onset & short duration Treat. A Treat. B Treat. A Treat. B washout period 1 st treatment period 2 nd treatment period

27. 3-Factorial Design Sample Drug A Placebo Drug B Placebo Drug B Placebo

28. Clinical trial & number of participants 1-Mega Trial Thousands of patients Multiple centers Statistical power Generalization 2-Sequential trial No specified sample size Continuous recruitment Clear benefit / no difference

29. 3- Fixed size trial Most common Study power 4- N of one Every physician Routine work

30. Blinding One or more of the people involved in the trial is unaware of the intervention. 1- Open trial 2- Single- blind trial 3- Double blind trial 4-Double blind double dummy trial 5- Triple and quadruple blind

31. Collection of baseline data Disease, medical & demographic characteristics. Similarity in all aspect except intervention. Follow up Quantity Quality Compliance

32. Outcome Objective Vs subjective. Surrogate Vs hard outcome.

33. Analysis 60 45 15 Intension to treat analysis. 15/ 60 =0.25 =25% Protocol analysis. 15/45 = 0.33 =33%

34. Relative Risk TotaloutcomeGroup Negativepositive a +bbaIntervention c +ddcControl

35. Measures of effect size 1-Relative risk (RR) – Is the ratio of the risk of a given event in one group of subjects compared to another group Experimental Event Rate (EER) ----------------------------------------------- Control Event Rate (CER ) EER: The percentage of intervention group who experienced outcome in question. ( a/(a + b)) CER: The percentage of control group who experienced outcome in question. (c /( c + d))

36. 2 -Relative risk reduction (RRR) – The proportion of the initial or baseline risk which was eliminated by a given treatment/intervention or by avoidance of exposure to a risk factor –RRR= (CER – EER) / CER 3-Absolute risk reduction (ARR) – The difference in risk of a given event, between two groups –ARR= CER - EER

37. 4-Number Needed to Treat (NNT) – It is defined as the number needed to treat in order to prevent one additional adverse event (e.g. death) –NNT = 1/ ARR –Its clinical importance depends on Initial probability of the outcome.

38. RR=(18/64) / (29/65) = 0.281/0.446 =0.63 =63% 95% CI= 0.39 – 1.01 Source: N Engl J Med 1992; 326: 1527-1532. InterventionOutcomeTotal Deathsurvival Ligation184664 sclerotherapy293665

39. 2 - Absolute Risk Reduction (ARR): ARR= CER - EER =(29/65) – (18/64) = 0.446 – 0.281 = 0.165 = 16.5% 3-Relative Risk Reduction (RRR) RRR= (CER – EER) / CER =(0.446 – 0.281) / 0.446 =0.165 / 0.446 = 0.37 = 37% i.e. Legation decreases the risk of death by 37%

40. 4-N umber Needed to Treat (NNT): NNT = 1/ ARR = 1 / 0.165 = 6.06 =6 patients You have to treat 6 patients by ligation to save one life

42. Example A multi-centre, randomised placebo-controlled trial of the beta blocking drug Timolol, reported the number of deaths in 18 months of follow-up among patients who had recently suffered a myocardial infarction. (New England Journal of Medicine. 1981;304: 801-7).

43. Calculations 1)Risk (timolol) = 98/945 = 0.104 (10.4%) 2)Risk (placebo) = 152/939 = 0.162 (16.2%) 1)ARR = 0.162 – 0.104 = 0.058 95% CI (0.028, 0.089) 6)NNT = 1/0.058 [100/5.8] = 17 people diedsurvived timolol98847945 placebo152787939