2. Dr Rob Heerdink Pharmacoepidemiology & Pharmacotherapy Utrecht Institute for Pharmaceutical Sciences Universiteit Utrecht The Netherlands www.pharm.uu.nl/epithera
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4. Drug development 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 preclinical clinical (I-III) phase IV
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9. Study design Past Present Future Retrospective Cohort Prospective Cohort Case-Control (retrospective) Cross-sectional
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11. Source population Randomisation Index group Control group Follow-up Follow-up Outcome Outcome In- and exclusion criteria Method, blinding Prognostically comparable Treatment Double blind Loss-to-follow-up Blinded measurement of outcome
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13. Evaluation of therapy: golden standard Randomised Controlled Clinical Trial (RCT) Randomise: why? Controlgroup: why? Blinding: why? Goal: Only difference between treated and untreated group is the treatment
14. Experiments are often impossible Ethical (e.g. smoking, birth defects) Practical (e.g. rare adverse effects) Non-experimental (observational) research For example: Do animals bite more often during full moon?
15. Do animals bite more during a full moon? Bhattacharjee C et al. BMJ 2000;321:1559-61
19. 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
20. Dwarsdoorsnede onderzoek beschrijft een karakteristieke relatie tussen determinant en uitkomst op 1 moment in de tijd Causaliteit?
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22. Voorbeeld dwardoorsnede onderzoek Polymorphisms of the LEP- and LEPR gene and obesity in patients using antipsychotic medication Gregoor et al J Clin Psychopharmacol (2009) Onderzoeksvraag: zijn polymorfismen in de LEPR geassocieerd met hoger BMI in antipsychotica gebruikers? Studie opzet: dwarsdoorsnede onderzoek
23. Voorbeeld : LEPR onderzoek Populatie: 200 antipsychotica gebruikers Determinanten: LEPR Q223R en LEP promoter 2548G/A SNP polymorfismen Uitkomst: BMI
24. ** p<0.05 Voorbeeld : LEPR onderzoek 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%)
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26. Cohort study / Follow-up study Study population Exposed Non-exposed Disease + Disease + Disease - Disease -
31. Frequency measures cohort study (P1 personyears) (P0 personyears) A1 A0 Exposure No Exposure Disease Disease No disease Time Time No disease (B1) (B0)
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33. Risk disease + | exposure + = A1 / N1 = CI 1 Risk disease + | exposure - = A0 / N0 = CI 0 Frequency measures cohort study Disease No disease Total Exposure + A1 B1 N1 - A0 B0 N0
34. Force of morbidity | exposure + = A1 / P1 = IC 1 Force of morbidity | exposure - = A0 / P0 = IC 0 Frequency measures cohort study Disease Personyears Exposure + A1 P1 - A0 P0
48. Case Control Exposure + a b - c d a+c b+d Exposure odds among cases = a/c Exposure odds among controls = b/d Exposure Odds ratio (OR) = (a/c) / (b/d) = (a*d) / (b*c) RR Calculation OR
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55. Data Collection External Data Sources Internal Data Sources Exposure Hospital records, employers Questionnaires, physical examinations, and/or blood tests, other diagnostic tests Event Disease registries, death certificates, physician and hospital records Questionnaires, physical examinations, and/or blood tests, other diagnostic tests Confounder Hospital records registries Questionnaires, physical examinations
66. The likelihood of observing an adverse drug reaction in 2,000 patients Threshold for ADR Probability 1 / 500 0.98 (Lymphoma From Azathioprine) 1 / 1,00 0.86 (Eye Damage From Practolol) 1 / 10,000 0.18 (Anaphylaxis From Penicillin) 1 / 50,000 0.04 (Aplastic Anemia From Chloramphenicol) Lembit Rägo, WHO Upsala
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72. Case control Time Time Exposure No exposure Exposure No exposure Case (disease) Control (no disease)
