1. CLINICAL TRIALS: Fra MITO e REALTÀ Palermo 13 Aprile 2012 SILVIO GARATTINI

2. To test Randomisation as the only scientific and ethical way to solve uncertainty True uncertainty What’s best for the patients? Not to treat in any case To deny possible benefits To treat in any case To expose to possible risks

3. METHODOLOGICAL REQUIREMENTS FOR CLINICAL TRIALS Ask important questions… …answer them reliably The objective is the patient, the goal is his benefit Yusuf S, Collins R, Peto R. Why do we need some large, simple randomized trials? Stat Med 1984; 3: 409-420

4. PATIENTS CAN BE INVOLVED IN CLINICAL TRIALS ONLY IF THERE IS A REASONABLE POTENTIAL ADVANTAGE. FOR THEM OR FOR FUTURE PATIENTS THE ADVANTAGE COULD BE INCREASED EFFICACY, DECREASED TOXICITY, DIFFERENT TOXIC PROFILES, BETTER COMPLIANCE. LONGER DURATION OF ACTION, etc.

5. MEDIANA0,097 QALY 51%< 0,1 QALY 12%> 1,0 QALY MIGLIORAMENTI INDOTTI DA 281 NUOVI FARMACI Basic Clin Pharmacol 2009, 105, Suppl. 1, 032 Walker et al., 2009

7. THE EXCESSIVE USE OF PLACEBO

8. PLACEBO SHOULD BE USED ONLY WHEN THERE ARE NO EFFECTIVE DRUGS FOR A GIVEN INDICATION INAPPROPIATE USE OF PLACEBO MAY LEAD TO AN OPTIMISTIC EVALUATION OF A NEW DRUG

9. DENOSUMAB (ANTI-RANK LIGAND MAB) HAS BEEN TESTED AGAINST PLACEBO IN POST-MENOPAUSAL WOMEN WHEN THERE ARE AVAILABLE SEVERAL ANTI-OSTEOPOROTIC AGENTS Scrip 19/9/08

11. Giovannoni et al., 2010

13. Kappos et al., 2010

14. Placebo-Controlled Trial of Oral Laquinimod for Multiple Sclerosis Giancarlo Comi, M.D., Douglas Jeffery, M.D., Ludwig Kappos, M.D., Xavier Montalban, M.D., Alexey Boyko, M.D., Maria A. Rocca, M.D., and Massimo Filippi, M.D., for the ALLEGRO Study Group* CONCLUSIONS In this phase 3 study, oral laquinimod administered once daily slowed the progression of disability and reduced the rate of relapse in patients with relapsing–remitting multiple sclerosis. (Funded by Teva Pharmaceutical Industries; ClinicalTrials.gov number, NCT00509145.) N ENGL J MED 2012. 366;11 - 1000

15. Comi et al., 2012

16. RELATIVE RISK REDUCTION OF RELAPSES IN RESPECT TO PLACEBO INF  -1b28 %(1995) INF  -1a32 %(1996) GLATIRAMER29 %(1995)

17. EXCESS OF RELAPSES THAT COULD BE AVOIDED IF A COMPARATOR WOULD HAVE BEEN USED INSTEAD OF PLACEBO CLADRIBINE79DIRUCOTIDE21 NATALIZUMAB138TERIFLUNOMIDE123 FINGOLIMOD100LAQUIMOD130 TOTAL RELAPSES 591 Bertelè et al., 2012

18. ADD-ON DESIGN NEW DRUGPLACEBO BASIC TREATMENT ++

19. Zinman et al., 2007

21. A FAIR COMPARISON WOULD HAVE BEEN TO USE INSTEAD OF PLACEBO ONE OF THE MANY ANTIDIABETIC AGENTS AVAILABLE ON THE MARKET

22. Pratley et al., 2010

23. Effect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, Weight Gain, and Hypoglycemia in Type 2 Diabetes Olivia J. Phung, PharmD Jennifer M. Scholle, PharmD Mehak Talwar, BS Craig I. Coleman, PharmD Conclusion When added to maximal metformin therapy, all noninsulin antidiabetic drugs were associated with similar HbA1c reductions but differed in their associations with weight gain and risk of hypoglycemia. JAMA. 2010;303(14):1410-1418

24. Phung et al., 2010

25. DESIGN OF CLINICAL TRIALS

26. CLINICAL TRIALS MAY BE DESIGNED TO DEMONSTRATE SUPERIORITY EQUIVALENCE NON INFERIORITY

27. IN THE NON-INFERIOR TYPE OF TRIAL WITH AN ACTIVE CONTROL, INVESTIGATORS ARE TESTING THE NULL HYPOTHESIS THAT A NEW DRUG IS WORSE THAN THE ACTIVE CONTROL (STANDARD) AND WHEN THEY CAN REJECT THE NULL HYPOTHESIS THEY ACCEPT THE ALTERNATIVE, THAT THE NEW DRUG IS NOT WORSE THAN THE ACTIVE CONTROL. ARAS, 2001 DRUG INFORMATION J.35,1157

28. SUPERIORITY EQUIVALENCE NON INFERIORITY CONTROL BETTERNEW AGENT BETTER0 - +

29. Are there specific reasons for allowing a non-inferiority approach? There may be non-responders to current treatments and products with comparable activity may offer a useful alternative. If the target is non-responders to current treatments, why not test their superiority over drugs with little effect in this subset of patients?

30. 18ANTICANCER AGENTS 21INDICATIONS 12ONLY PHASE II 9PHASE III 6EQUIVALENCE OR NON INFERIORITY 3SUPERIORITY

31. Fueglistaler et al., 2007 ABC Therapy Efficacy %

32. OUT OF 383 CLINICAL TRIALS 64 % COULD DETECT A DIFFERENCE > 50 % 84 % COULD DETECT A DIFFERENCE > 25 % MOHER et al., 1994

33. Between 2002 and 2009, of 43 NDAs containing data from at least one noninferiority trial, the FDA approved 18 on the basis of pivotal evidence from noninferiority trials but found nine NDAs had poorly designed noninferiority trials that could not be used to establish the efficacy of the new drug. Nature Medicine 2010, 16, 1049

34. THE DESIGN OF N.I. TRAILS REQUIRES ALWAYS THE USE OF STANDARD AND PLACEBO WILE A SUPERIORITY DESIGN REQUIRES ONLY THE USE OF STANDARD.

35. Garattini S, Bertele’ V. How can research ethics committees protect patients better? BMJ 2003; 326:1199-201 Draft informed consent “Let us treat you with something that at best is the same as what you would have had before, but might also reduce - though this is unlikely - most of the advantages previously attained in your condition. It might even benefit you more than any current therapy but, should that actually happen, we shall not be able to prove it. Nor have we enough chance to let you know whether the new treatment may somehow bother or even harm you more than the standard one”.

36. NON-INFERIORITY TRIALS FEW PATIENTS WOULD AGREE TO PARTICIPATE IF THIS MESSAGE IS CLEAR IN THE INFORMED CONSENT FORM.

37. THREE ARM TRIAL RANDOMIZATION PLACEBO COMPARATORNEW DRUG PLACEBO IS NOT NECESSARY IN THE DESIGN OF SUPERIORITY

38. INADEQUATE COMPARATOR

39. ACUTE RENAL REJECTIONS ARE MINIMIZED WHEN TROUGH LEVELS ARE KEPT BETWEEN 330 - 430 ng/ml MARGREITER et al., 2002 TRIAL CYCLOSPORINE < 300 ng/ml TACROLIMUS VS CYCLOSPORINE 32.5 %51.3 % ACUTE REJECTIONS

40. Favours atypical Favours haloperidol Drop out rates by dose of comparator drug in trials of patients with schizophrenia or related disorders (risk difference and 95 % confidence intervals) Geddes et al., 2000 ≤ 12 mg haloperidol > 12 mg haloperidol -0.5-0.4-0.3-0.2-0.100.1

41. CARDIOVASCULAR TOXICITY DICLOFENAC1 COXIBs0.92 * (0.81-1.05) * 26 RCT Psaty and Weiss, 2007

42. CARDIOVASCULAR TOXICITY NAPROXEN1 COXIBs1.57 * (1.21-2.03) * 42 RCT Psaty and Weiss, 2007

43. SURROGATE END POINTS

44. QUALITY OF LIFE, MORBILITY, MORTALITY SHOULD BE THE FINAL OBJECTIVES OF CLINICAL TRIALS

45. ENCAINIDE AND FLECAINIDE DECREASE ARRHYTHMIAS BUT INCREASE MORTALITY OESTROGENS INCREASE HDL-CHOLESTEROL BUT DO NOT PREVENT CARDIOVASCULAR EVENTS TORCETRAPIB INCREASES HDL-CHOLESTEROL BUT INCREASES MORTALITY

46. HbA1c IS NOT A SURROGATE END-POINT FOR CARDIOVASCULAR DISEASES IN TYPE 2 DIABETES SULFONYLUREASHbA 1C MYOCARDIAL INFARCTION ROSIGLITAZONEHbA 1C HEART FAILURE NEED TO EVALUATE PARAMETERS IMPORTANT FOR PATIENTS

47. Arguedas et al., 2009

48. RIMONABANT antagonist of cannabinoid-1 receptor DECREASE OF BODY WEIGHT INCREASE OF HDL, ADIPONECTIN DECREASE OF TRIGLYCERIDES, BLOOD GLUCOSE, FASTING INSULIN, LEPTIN DECREASE OF TOTAL VOLUME ATHEROMA

49. Topol et al., 2010 CRESCENDO TRIAL

50. UTILIZATION OF COMPOSITE END-POINTS

51. Lapostolle et al., 2007

52. Ferreira-Gonzàlez et al., 2007

53. SELECTIVE PUBLICATIONS

54. OF 5 SSRI 21 STUDIES SHOW DRUG BETTER THAN PLACEBO 19 PRIMARY PUBLICATIONS IN TOTAL 42 STUDIES Sweedish Drug Regulatory Authority Melander et al., BMJ 2003

55. SELECTIVE PUBLICATIONS OF 5 SSRI 21 STUDIES SHOW DRUG BETTER THAN PLACEBO 19 PRIMARY PUBLICATIONS IN TOTAL 42 STUDIES 21 STUDIES SHOW NEGATIVE RESULTS 6 PRIMARY PUBLICATIONS Sweedish Drug Regulatory Authority Melander et al., BMJ 2003

56. SELECTIVE PUBLICATIONS OF 5 SSRI 21 STUDIES SHOW DRUG BETTER THAN PLACEBO 19 PRIMARY PUBLICATIONS EVIDENCE B(I)ASED MEDICINE IN TOTAL 42 STUDIES 21 STUDIES SHOW NEGATIVE RESULTS 6 PRIMARY PUBLICATIONS Sweedish Drug Regulatory Authority Melander et al., BMJ 2003

57. Kirsch et al., 2008

59. Eyding et al., 2010

61. SELECTIVE REPORTING OF CLINICAL TRIALS MAY BIAS META-ANALYSES AND MISDIRECT GUIDE-LINE. IN A RETROSPECTIVE REVIEW OF 130 TRIALS, THOSE WITH POSITIVE RESULTS WERE THREE TIMES MORE LIKELY TO BE PUBLISHED WITH A SIGNIFICANT SHORTER TIME TO PUBLICATION THAN THOSE WITH NEGATIVE RESULTS. STERN, SIMES, 1997