1e jaars inleiding fase IV geneesmiddelen onderzoek blok FA107 Farmaceutische Wetenschappen

1. Geneesmiddelenonderzoek Fase IV Rob Heerdink 10 juni 2009

2. Dr Rob Heerdink Pharmacoepidemiology & Pharmacotherapy Utrecht Institute for Pharmaceutical Sciences Universiteit Utrecht The Netherlands www.pharm.uu.nl/epithera

4. Ontwikkeling van geneesmiddelen discovery Discovery & screening Proof of Concept first administration to man registration & launch approx. 10-12 years 10,000 Pre-clinical development 15-30 Fase I/IIa 10-15 Fase IIb/III 1 5 preklinisch klinisch (I-III) fase 4

5. Een geneesmiddel komt op de markt

6. Science 2005; 307: 196-8.

9. Verschil tussen RCTs en de praktijk – aantal gebruikers Klinisch onderzoek De markt

12. “ It was easy money during the first trial, but that spinal tap really hurt.”

18. Are Subjects in Pharmacological Treatment Trials of Depression Representative of Patients in Routine Clinical Practice? Mark Zimmerman, M.D., Jill I. Mattia, Ph.D., and Michael A. Posternak, M.D Am J Psychiatry 159:469-473, March 2002 ‘ Van 346 patienten met ‘major depression’ voldoet slechts 14% aan de inclusiecriteria die algemeen gelden voor een trial met antidepressiva.’

21. comparator Heres et al. Am J Psych, Feb 2006 sponsored drug risperidon clozapine ziprasidone ami sulpiride Olanzapine (Lilly) 5 / 0 2 / 1 2 / 0 1 / 0

22. comparator Heres et al. Am J Psych, Feb 2006 sponsored drug olanzapine risperidon clozapine ziprasidone ami sulpiride Olanzapine (Lilly) 5 / 0 2 / 1 2 / 0 1 / 0 Risperidon (Janssen) 3 / 1 1 / 0

23. comparator Heres et al. Am J Psych, Feb 2006 sponsored drug olanzapine risperidon clozapine ziprasidone ami sulpiride Olanzapine (Lilly) 5 / 0 2 / 1 2 / 0 1 / 0 Risperidon (Janssen) 3 / 1 1 / 0 Clozapine (Novartis) 1 / 0 1 / 0

24. comparator Heres et al. Am J Psych, Feb 2006 sponsor drug olanzapine risperidon clozapine ziprasidone ami sulpiride Olanzapine (Lilly) 5 / 0 2 / 1 2 / 0 1 / 0 Risperidon (Janssen) 3 / 1 1 / 0 Clozapine (Novartis) 1 / 0 1 / 0 Ziprasidone (Pfizer) 1 / 1 Amisulpiride (Sanofi) 1 / 0

25. evidence based medicine ?

26. farmaco-epidemiologie medicine based evidence

27. NRC Handelsblad 6 juni 2009

29. Evaluatie van therapie: gouden standaard Randomised Controlled Clinical Trial (RCT) Randomiseren: waarom? Controlegroep: waarom? Blindering: waarom? Doel: Enige verschil tussen behandelde en niet-behandelde groep is de behandeling

30. Een experiment is heel vaak niet mogelijk Ethisch (bv. roken, aangeboren afwijkingen) Praktisch (bv. zeldzame bijwerking) Niet-experimenteel (observationeel) onderzoek Voorbeeld: Bijten dieren vaker tijdens volle maan?

31. Do animals bite more during a full moon? Bhattacharjee C et al. BMJ 2000;321:1559-61

33. Onderzoeks opzetten Case report Cross-sectioneel Case-control Follow-up (cohort) Trial

35. The Lancet, 1961

36. LETTER TO THE EDITOR THALIDOMIDE AND CONGENITAL ABNORMALITIES Sir, Congenital disorders are present in approximately 1.5% of babies. In recent months I have observed that the incidence of multiple severe abnormalities in babies delivered of women who were given the drug thalidomide ('Distaval') during pregnancy,as an anti-emetic or as a sedative, to be almost 20%. Have any of your readers seen similar abnormalities in babies delivered of women who have taken this drug during pregnancy? McBride WG. The Lancet, December 16, 1961: page 1358

37. Example cross-sectional study Polymorphisms of the LEP- and LEPR gene and obesity in patients using antipsychotic medication Gregoor et al J Clin Psychopharmacol (in press) Research question: are LEPR polymorphisms associated with increased BMI in antipsychotic users Study design: cross-sectional

38. Example : LEPR study Population: 200 patients using antipsychotics Determinants: LEPR Q223R and LEP promoter 2548G/A SNP polymorphisms Outcome: BMI

39. Example : LEPR study ** p<0.05 N BMI>30 Males QQ 30 6 (20%) QR 73 16 (21%) RR 31 8 (26%) Females QQ 17 12 (71%) ** QR 39 15 (39%) QR 10 4 (40%)

40. Indexed prevalence and incidence per year of antidepressant use during 1992-2001 (1992=1). Meijer et al. Eur J Clin Pharmacol (2004) 60: 57–61

43. Cohort study / Follow-up study Study population Exposed Non-exposed Disease + Disease + Disease - Disease -

47. Cohort study / Follow-up study Study population Exposed Non-exposed Disease + Disease + Disease - Disease -

48. Case-control study Study Population Cases Controls Exposed Non-exposed Exposed Non-exposed

50. Coogan et al. Am J Epidemiol 2005

51. Meijer et al. Arch Int Med 2004

55. Lanes et al. Pharmacoepidemiol & Drug Saf 2000;9:113-7 Selective prescribing of meloxicam meloxicam ibuprofen n=5000 n=5000 recent use NSAIDs 49.8% 7.9% recent use H2 blockers 12.4% 4.0% recent use proton-pump inh. 11.1% 4.0% history of dyspepsia 38.4% 20.3% history of peptic ulcer 6.1% 3.1%

56. population to be prescribed a NSAID prescribed ibuprofen prescribed meloxicam prescriber’s decision younger healthier no GI history older GI history

58. Risk assessment

60. Registration of a drug is only the beginning of safety research