Clinical trial The Way We Make Progress Against Disease

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

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 clinicaltrial • 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 O U T C O M E Intervention Ref. Pop. Sample Control

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. A Treat. B Treat. B 1st treatment period 2nd treatment period washout period

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

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 onInitial probability of the outcome.

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

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-Number Needed to Treat (NNT):NNT = 1/ ARR = 1 / 0.165 = 6.06 =6 patientsYou 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 • Risk (timolol) = 98/945 = 0.104 (10.4%) • Risk (placebo) = 152/939 = 0.162 (16.2%) • ARR = 0.162 – 0.104 = 0.058 95% CI (0.028, 0.089) • NNT = 1/0.058 [100/5.8] = 17 people

45. Thank you