1. LA RICERCA CLINICA CONTROLLATA PER I FARMACI Milano 25 Settembre 2014 SILVIO GARATTINI

2. PRE-MARKET ACADEMIA SCIENTIFIC SOCIETIES PHARMACEUTICAL INDUSTRY REGULATORS LEGISLATION

3. PHYSICIANS DRUG STORES PATIENTS CONSUMERS MASS-MEDIA SOCIAL NETWORK ACADEMIA SCIENTIFIC SOCIETIES PHARMACEUTICAL INDUSTRY REGULATORS LEGISLATION PRE-MARKETPOST-MARKET

5. MEDIAN0,097 QALY 51%< 0,1 QALY 12%> 1,0 QALY IMPROVEMENT INDUCED BY 281 NEW MEDICINAL PRODUCTS Basic Clin Pharmacol 2009, 105, Suppl. 1, 032 Walker et al., 2009

6. What innovation? When wrapping up his 10 years as chief of the EMA, Thomas Lönngren criticised the drug industry, saying that of the estimated US$85 billion spent globally each year on drug research and development (R&D), around $60 billion was wasted when one calculated how few new molecular entities were produced. He also pointed out that the industry failed to invest enough effort into developing drugs where there is the greatest need—for key and unmet areas of public health—such as infections with multidrug-resistant bacteria and disorders of the CNS. Lancet Vol 377 January 8, 2011

7. 2000 – 2013 ORPHAN DRUGS DESIGNATEDAPPROVED 985 EXPIRED 9 85 WITHDRAWN 10

8. SCANDALS THAT HAVE DAMAGED THE PRESTIGE OF INDUSTRY, REGULATORY AUTHORITIES AND ACADEMIA COX-2 INHIBITORS INHIBITORS OF 5HT RE-UPTAKE ROSIGLITAZONE SIBUTRAMINE H 1 N 1 VACCINES AND OSELTAMIVIR

9. Scannell et al., 2012

10. Clinical trials in Europe 4400 clinical trials are applied for every year in the EU/EEA. 60% sponsored by the pharmaceutical industry. The number of applications for clinical trials fell by 25% from 2007 to 2011. 24% of all clinical trials are multinational, i.e. performed in at least two Member States. Multinational trials involve 67% of all the subjects enrolled in clinical trials. Based on the figure for 2010. Proposal for a regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC.

12. ITALY N. of studies non-profit 2008 - 2012 - 38 % Position of Italy n. of recluted patients 23 rd Clinical Trial Attractiveness Index > 30 th

13. IT IS TIME FOR ACADEMIA TO BECOME THE LEADER IN THE DEVELOPMENT AND USE OF DRUGS

14. 3 KEYWORDS EVIDENCE

15. PROTOCOLLO REVISIONE SISTEMATICA/METANALISI OBIETTIVO INCLUSIONE/ESCLUSIONE TRATTAMENTI RANDOMIZZAZIONE E CECITA’ END-POINTS (SURROGATI TERAPEUTICI) REAZIONI AVVERSE CALCOLO DELLA NUMEROSITA’ ANALISI STATISTICA

16. EVIDENCE INAPPROPRIATE USE OF PLACEBO

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

18. RCT CARRIED OUT AGAINST PLACEBO CLADRIBINE (2010)DIRUCOTIDE (2011) NATALIZUMAB (2006)TERIFLUNOMIDE (2011) FINGOLIMOD (2010)LAQUINIMOD (2012)

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

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

21. Use of Placebo 33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven intervention(s), except in the following circumstances: Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or DECLARATION OF HELSINKI

22. Where for compelling and scientifically sound methodological reasons the use of any intervention less effective than the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy or safety of an intervention and the patients who receive any intervention less effective than the best proven one, placebo, or no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention. Extreme care must be taken to avoid abuse of this option.

23. EVIDENCE INAPPROPRIATE USE OF PLACEBO DESIGN OF NON INFERIORITY

24. 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

25. 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?

26. QUALITY OF REPORTING NON-INFERIORITY TRIALS (n= 232) ONLY 24 % EXPLAINED HOW THE N.I. MARGIN WAS DETERMINED WANGGE et al., 2010

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

28. EVIDENCE INAPPROPRIATE USE OF PLACEBO DESIGN OF NON INFERIORITY SURROGATE END-POINTS

29. 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

30. Comparison of treatment effect sizes associated with surrogate and final patient relevant outcomes in randomised controlled trials: meta-epidemiological study Oriana Ciani PhD candidate, Marc Buyse chairman, Ruth Garside senior lecturer, Toby Pavey research fellow, Ken Stein professor, Jonathan A C Sterne professor, Rod S Taylor professor Conclusions Trials reporting surrogate primary outcomes are more likely to report larger treatment effects than trials reporting final patient relevant primary outcomes. BMJ 2013;346:f457

31. XIAO et al., 2012 NSCLC and TKI

32. XIAO et al., 2012

34. EVIDENCE INAPPROPRIATE USE OF PLACEBO DESIGN OF NON INFERIORITY SURROGATE END-POINTS COMPOSITE END-POINTS

35. Ferreira-Gonzàlez et al., 2007

36. EVIDENCE INAPPROPRIATE USE OF PLACEBO DESIGN OF NON INFERIORITY SURROGATE END-POINTS COMPOSITE END-POINTS UNDER EVALUATION OF ADVERSE REACTIONS

37. CURRENT RANDOMIZED CLINICAL TRIALS ARE DESIGNED TO MAXIMIZE BENEFITS BUT USUALLY THEY DO NOT HAVE ENOUGH POWER TO DETECT ADVERSE REACTIONS

38. A retrospective cohort study that included 13626 people taking statins and 32 623 controls found a greater incidence of musculoskeletal disorders overall and injuries in those taking statins (odds ratio 1.19, 95% confidence interval 1.08 to 1.3 and 1.13, 1.05 to 1.21, respectively). The NNH for musculoskeletal disorders and injuries in people taking statins were 47 and 37, respectively. Mansi et al., JAMA lut Med, 2013, 73, 1-10

39. Dormuth et al., BMJ, 2013

40. EVIDENCE INAPPROPRIATE USE OF PLACEBO DESIGN OF NON INFERIORITY SURROGATE END-POINTS COMPOSITE END-POINTS UNDER EVALUATION OF ADVERSE REACTIONS FROM CLINICAL TRIALS TO REAL POPULATION

41. Clinical research must include more older people Why are the people who take part in clinical research systematically different from those seen in practice? Marion McMurdo says funders, ethics committees, and journals must stop older people being under- represented Marion McMurdo professor, ageing and health, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK

42. Modified from Bethel et al., 2008

45. 3 KEYWORDS EVIDENCE ETHICS

46. 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

47. ETHICS PARTICIPATION TO PROTOCOL PREPARATION

48. ETHICS PARTICIPATION TO PROTOCOL PREPARATION REGISTRATION OF THE PROTOCOL

49. ETHICS PARTICIPATION TO PROTOCOL PREPARATION REGISTRATION OF THE PROTOCOL INFORMED CONSENT

50. ETHICS PARTICIPATION TO PROTOCOL PREPARATION REGISTRATION OF THE PROTOCOL INFORMED CONSENT PROPERTY OF DATA

51. ETHICS PARTICIPATION TO PROTOCOL PREPARATION REGISTRATION OF THE PROTOCOL INFORMED CONSENT PROPERTY OF DATA ACCESS TO RAW DATA

52. ETHICS PARTICIPATION TO PROTOCOL PREPARATION REGISTRATION OF THE PROTOCOL INFORMED CONSENT PROPERTY OF DATA ACCESS TO RAW DATA PUBLICATION INDEPENDENTLY FROM RESULTS

53. Non-publication was more common among trials that received industry funding (150/468, 32%) than those that did not (21/117, 18%), P=0.003. Of the 171 unpublished trials, 133 (28%) had no results available in ClinicalTrials.gov.

54. Non-publication of large randomized clinical trials: cross sectional analysis Christopher W Jones attending physician, Lara Handler school of medicine liaison librarian, Karen E Crowell clinical information specialist2, Lukas G Keil research assistant, Mark A Weaver assistant professor, Timothy F Platts-Mills assistant professor Of 585 registered trials, 171 (29%) remained unpublished. These 171 unpublished trials had an estimated total enrollment of 299 763 study participants. The median time between study completion and the final literature search was 60 months for unpublished trials. BMJ 2013;347:f6104 doi:

55. ECONOMICO RELIGIOSO(es. Legge 40) COMPETITIVO(es. editori) COMPETENZA CONFLITTO D’INTERESSE

56. ECONOMICO. PERSONALE - AZIONI - DIPENDENTE - CONSULENTE - PROGETTI DI RICERCA CONFLITTO D’INTERESSE

57. ECONOMICO. ISTITUZIONALE - ACCETTAZIONE INCONDIZIONATA - ACCETTAZIONE CON REGOLE CONFLITTO D’INTERESSE

58. 3 KEYWORDS EVIDENCE ETHICS LEGISLATION

59. Regulatory confidentiality The reasons for transparency The industry is not the sole financer of research. Clinical trials require the participation of patients, who take part free of charge. In most European states the drug market is prosperous because it is guaranteed by national health services. Secrecy may be justifiable in connection with information regarding the production of the active principles and the methods utilized for drug discovery. But information on drug development including pre-clinical findings and clinical controlled trials must be available for scrutiny by clinicians and patients.

60. QUALITY, EFFICACY, SAFETY QUALITY, EFFICACY, SAFETY AND THERAPEUTIC ADDED VALUE CHANGE NEEDED IN EUROPEAN LEGISLATION

61. Two pivotal trials needed to support MAA One sponsor-driven RCT One independent RCT

62. PHYSICIANS DRUG STORES PATIENTS CONSUMERS MASS-MEDIA SOCIAL NETWORK ACADEMIA SCIENTIFIC SOCIETIES PHARMACEUTICAL INDUSTRY REGULATORS LEGISLATION PRE-MARKETPOST-MARKET