2. Dr Rob Heerdink Pharmacoepidemiology & Pharmacotherapy Utrecht Institute for Pharmaceutical Sciences Universiteit Utrecht The Netherlands www.pharm.uu.nl/epithera
3. 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
13. The likelihood of observing an adverse drug reaction employing numbers usually studied in premarketing trials Number of Patients Threshold for ADR Probability 2,000 1 / 500 0.98 (Lymphoma From Azathioprine) 1 / 1,000 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
17. “ It was easy money during the first trial, but that spinal tap really hurt.” Herald Tribune 30-09-96
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23. 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 ‘ Of 346 patients with ‘major depression’ only 14% are eligible according to inclusioncriteria for trials with antidepressants’
24. 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
25. 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
26. 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
34. 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
35. 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?
36. Do animals bite more during a full moon? Bhattacharjee C et al. BMJ 2000;321:1559-61
42. 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
43. 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
44. Example : LEPR study Population: 200 patients using antipsychotics Determinants: LEPR Q223R and LEP promoter 2548G/A SNP polymorphisms Outcome: BMI
45. 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%)
46. 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
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49. Cohort study / Follow-up study Study population Exposed Non-exposed Disease + Disease + Disease - Disease -
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53. Cohort study / Follow-up study Study population Exposed Non-exposed Disease + Disease + Disease - Disease -
Scok door de wereld Rozen ook doornen Final trigger betekende echter niet het einde
A cohort study is a study where a group of individuals are followed. The study population is defined on basis on the presence or absence of exposure to a suspected risk factor for a disease. The cohort studies is either classified as a prospective or a retrospective study. The definition is based on the time of occurrence of the disease according to the initiation of the study. In the prospective studies the disease of interest is never occurred at initiation, the exposure are either presence at the beginning of the study or it can occur later. The prospective cohort you have to follow over time. In the retrospective cohort study, all the relevant events disease and exposure have occurred before the initiation of the study. outcome follow- up retrospective/prospective Protocol: study objectives, design choices, performance goals, monitoring and analysis procedures Manual of procedures/log book Centralised training of key personnel
A cohort study is a study where a group of individuals are followed. The study population is defined on basis on the presence or absence of exposure to a suspected risk factor for a disease. The cohort studies is either classified as a prospective or a retrospective study. The definition is based on the time of occurrence of the disease according to the initiation of the study. In the prospective studies the disease of interest is never occurred at initiation, the exposure are either presence at the beginning of the study or it can occur later. The prospective cohort you have to follow over time. In the retrospective cohort study, all the relevant events disease and exposure have occurred before the initiation of the study. outcome follow- up retrospective/prospective Protocol: study objectives, design choices, performance goals, monitoring and analysis procedures Manual of procedures/log book Centralised training of key personnel
Population based: All subjects with the disease in the study base or a random sample
Start med side 137 H&B Controls should be a part of the study base, not represent the entire non diseased population but the population of individuals who would have been identified and included as cases had they also developed the disease. Principles of Control selection Study base: Controls can be used to characterise the distribution of exposure Comparable-accuracy Equal reliability in the information obtained from cases and controls no differential misclassification Deconfounding Elimination of confounding through control selection matching or stratified sampling Those principles should not be regarded as absolute, but rather as points to consider in choosing a control group
About interviews se side 143 H&B,
The prospective study is time consuming and therefore expensive on the other hand it is possible to have valid information on exposure, because it isn.t
