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Drug risk assessment 23 4-2010


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Drug risk assessment 23 4-2010

  1. 1. Drug risk assessment & Pharmacoepidemiology Rob Heerdink 23 April 2010
  2. 2. Dr Rob Heerdink Pharmacoepidemiology & Pharmacotherapy Utrecht Institute for Pharmaceutical Sciences Universiteit Utrecht The Netherlands
  3. 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
  4. 4. Science 2005; 307: 196-8.
  5. 5. Phase I to III research not very informative on safety <ul><li>Very few RCTs primarily aimed at side effects </li></ul><ul><li>Pre-registration period (phase I to III studies) </li></ul><ul><li>O nly frequent side effects known (small RCTs) </li></ul><ul><li>O ften not measured (not expected , no suspicion) </li></ul><ul><li>F ollow-up period often too short </li></ul><ul><li>Other restrictions to trials </li></ul>
  6. 6. 2 types of side effects <ul><li>Type A side effects </li></ul><ul><li>Type B side effects </li></ul><ul><li>Typical type A side effect </li></ul><ul><li>- result of primary action of the drug </li></ul><ul><li>dose dependent </li></ul><ul><li>relatively common </li></ul><ul><li>gradual, incremental </li></ul><ul><li>possibly predictable (determinants known) </li></ul>
  7. 7. 2 types of side effects <ul><li>Type A side effects </li></ul><ul><li>Type B side effects </li></ul><ul><li>Typical type B side effect </li></ul><ul><li>not resulting from primary action of the drug </li></ul><ul><li>not dose dependent </li></ul><ul><li>rare </li></ul><ul><li>all or none phenomenon </li></ul><ul><li>not predictable </li></ul>
  8. 8. Pre-occupation with type B side effects (“tabloids”) <ul><li>In every-day practice (the much more frequently occurring and less often life-threatening) type A side effects are of major importance </li></ul><ul><ul><li>impotence </li></ul></ul><ul><ul><li>orthostatic hypotension </li></ul></ul><ul><ul><li>sleeping disorders </li></ul></ul><ul><ul><li>diarrhea </li></ul></ul><ul><ul><li>etcetera </li></ul></ul>
  9. 9. Why do we know so little about side effects of drugs? <ul><li>1. Lack of motivation among relevant parties </li></ul><ul><ul><li>in particular pharmaceutical companies </li></ul></ul><ul><li>2. Methodological constraints </li></ul><ul><ul><li>efficacy studies: RCT paradigm  “consensus” </li></ul></ul><ul><ul><li>studies on side effects: “always” controversial </li></ul></ul>
  10. 10. A numbers game Clinical trials Market
  11. 11. Too small <ul><li>Number of patients required in an RCT to assess </li></ul><ul><li>a relative risk of 2.0. </li></ul><ul><li>alpha=0.05; beta=0.10, randomization ratio = 1:1 </li></ul><ul><li>E.g. hepatotoxicity of (yet another) novel NSAID </li></ul>
  12. 12. Sample size requirement in RCT <ul><li>baseline risk number required </li></ul><ul><li>side effect in each group </li></ul><ul><li>in control group </li></ul><ul><li>50% 14 </li></ul><ul><li>25% 77 </li></ul><ul><li>10% 266 </li></ul><ul><li>5% 582 </li></ul><ul><li>1% (liver dysfunction) 3,104 </li></ul><ul><li>0.1% (hepatitis) 31,483 </li></ul><ul><li>0.01% (cholestatic jaundice) 315,268 </li></ul>
  13. 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
  14. 14. Too short
  15. 16. Herald Tribune 30-09-96
  16. 17. “ It was easy money during the first trial, but that spinal tap really hurt.” Herald Tribune 30-09-96
  17. 18. Real patients <ul><li>Age </li></ul>
  18. 19. Real patients <ul><li>Age </li></ul><ul><li>Pharmacokinetics </li></ul>
  19. 20. Real patients <ul><li>Age </li></ul><ul><li>Pharmacokinetics </li></ul><ul><li>Adherence </li></ul>
  20. 21. Real patients <ul><li>Age </li></ul><ul><li>Pharmacokinetics </li></ul><ul><li>Adherence </li></ul><ul><li>Comorbidity </li></ul><ul><li>Nemesis: </li></ul>geen 1 >1
  21. 22. Real patients <ul><li>Age </li></ul><ul><li>Pharmacokinetics </li></ul><ul><li>Adherence </li></ul><ul><li>Comorbidity </li></ul><ul><li>Comedication </li></ul>
  22. 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’
  23. 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
  24. 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
  25. 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
  26. 27. 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 Ziprasidone (Pfizer) 1 / 1 Amisulpiride (Sanofi) 1 / 0
  27. 28. RCTs <ul><li>In most trials into the effectiveness of new antipsychotics haloperidol is used in too high a dosis. </li></ul><ul><li>Hugenholtz et al, J Clin Psych 2006 </li></ul>
  28. 29. RCTs <ul><li>Include selected patients </li></ul><ul><li>Have sometimes flawed design </li></ul><ul><li>Are not investigating relevant questions </li></ul><ul><li>There is a lack of well-designed trials into the effect of drugs in the management of aggression in psychiatric patients </li></ul><ul><li>Goedhard et al, J Clin Psych 2006 </li></ul>
  29. 30. evidence based medicine ?
  30. 31. pharmacoepidemiology medicine based evidence
  31. 33. Relevant questions in practice following registration <ul><li>effect on hard endpoints </li></ul><ul><li>long term (side)effects </li></ul><ul><li>value compared to other drugs </li></ul><ul><li>effect in populations that were not studied </li></ul><ul><ul><li>children </li></ul></ul><ul><ul><li>elderly </li></ul></ul><ul><ul><li>pregnant </li></ul></ul><ul><ul><li>multiple pathology / drug use </li></ul></ul><ul><li>who benefits and who does not </li></ul><ul><li>less frequently seen adverse effects </li></ul>
  32. 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
  33. 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?
  34. 36. Do animals bite more during a full moon? Bhattacharjee C et al. BMJ 2000;321:1559-61
  35. 37. DOMAIN Determinant(s) Endpoint(s) time <ul><ul><li>yes / no comparison </li></ul></ul><ul><ul><li>experimental or observational </li></ul></ul><ul><ul><li>retrospective or prospective </li></ul></ul>Study design
  36. 38. Pharmacoepidemiological designs <ul><li>Descriptive methods (Signal detection, hypothesis generating). I dentifying previously unrecognised safety issues </li></ul><ul><ul><li>Case reports, </li></ul></ul><ul><ul><li>Case series, </li></ul></ul><ul><ul><li>Cross-sectional study </li></ul></ul><ul><li>Analytical methods (quantifying + risk factors, hypothesis testing). I nvestigating possible hazards (hypothesis-testing in order to substantiate a causal association) </li></ul><ul><ul><li>Observational </li></ul></ul><ul><ul><ul><li>Cohort studies, </li></ul></ul></ul><ul><ul><ul><li>Case-control studies, </li></ul></ul></ul><ul><ul><ul><li>Case-crossover studies </li></ul></ul></ul><ul><ul><li>Intervention </li></ul></ul><ul><ul><ul><li>Experimental Clinical trial </li></ul></ul></ul>
  37. 39. Observational studies Past Present Future Retrospective Cohort Prospective Cohort Case-Control (retrospective) Cross-sectional
  38. 40. <ul><li>Case Report / Case series </li></ul><ul><li>Describes characteristic association in one / some </li></ul><ul><li>patient(s) between determinant en outcome </li></ul><ul><li>examples: </li></ul><ul><li>serious liverdamage following use of XTC </li></ul><ul><li>birth defects after use of Thalidomide (Softenon) </li></ul><ul><li>etcetera, etcetera, etcetera </li></ul>
  39. 41. The Lancet, 1961
  40. 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
  41. 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
  42. 44. Example : LEPR study Population: 200 patients using antipsychotics Determinants: LEPR Q223R and LEP promoter 2548G/A SNP polymorphisms Outcome: BMI
  43. 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%)
  44. 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
  45. 47. Observational Cohort <ul><li>Group of individuals with common inclusion criteria is followed over time until an endpoint occurs. </li></ul>
  46. 49. Cohort study / Follow-up study Study population Exposed Non-exposed Disease + Disease + Disease - Disease -
  47. 50. A cohort study <ul><li>RR (myocardial infarction)* </li></ul><ul><li>Untreated normotensive and hypertensive men 1.0 (reference) </li></ul><ul><li>Treated hypertensive men DBP  90 mmHg 3.8 (1.3-11.0) </li></ul><ul><li>Treated hypertensive men DBP>90 mmHg 1.1 (0.5-2.6) </li></ul><ul><li>* adjusted for previous MI, CVA, IHD, IC, diabetes, SBP, duration of antihypertensive therapy, hypercholesterolemia, hypertriglyceridaemia, creatinin, obesity, use of cardiac glycosides, smoking. </li></ul><ul><li>Conclusion: In men treated for hypertension, DBP should not be reduced to lower than 90 mmHg </li></ul>Merlo J, et al. BMJ 1996;313:457-61.
  48. 51. Another cohort study <ul><li>RR (stroke) </li></ul><ul><li>Untreated “Candidates”* for treatment 1.0 (reference) </li></ul><ul><li>Treated Crude RR 0.49 (0.32-0.76) </li></ul><ul><li>Adjusted RR* 0.61 (0.39-0.97) </li></ul><ul><li>** Adjusted for age, sex, diabetes, total cholesterol, BMI, smoking, history of CVD </li></ul><ul><li>* Candidates for treatment defined according to Dutch guidelines on treatment of hypertension taking into account multifactorial risk of cardiovascular disease </li></ul>Klungel et al. Epidemiology 2001;12:339-34 4.
  49. 52. Follow up study versus RCT <ul><li>Similarities </li></ul><ul><ul><li>Use of same measures of frequency and association (RR, RD, AR, RRR, NNT, NNH) </li></ul></ul><ul><ul><li>Use of same analytical techniques (“survival” analysis: Kaplan Meier curves and Cox proportional hazard) </li></ul></ul><ul><li>Differences </li></ul><ul><ul><li>Follow-up vs. RCT: no randomisation and no blinding </li></ul></ul><ul><ul><ul><li>(outcome measurement sometimes blinded) </li></ul></ul></ul>Follow-up studies more vulnerable to bias
  50. 53. Cohort study / Follow-up study Study population Exposed Non-exposed Disease + Disease + Disease - Disease -
  51. 54. Case-control study Study Population Cases Controls Exposed Non-exposed Exposed Non-exposed
  52. 55. Example case-control study <ul><li>What is the risk on breast cancer with the use of SSRI antidepressants? </li></ul><ul><li>Cases: women with breastcancer </li></ul><ul><li>Controles: women with no breastcancer </li></ul><ul><li>Exposure: SSRIs </li></ul>
  53. 56. Coogan et al. Am J Epidemiol 2005
  54. 57. Meijer et al. Arch Int Med 2004
  55. 58. Selection of cases <ul><li>Establish strict diagnostic criteria for the outcome: </li></ul><ul><ul><li>Examples: </li></ul></ul><ul><ul><li>Type 1 diabetes in children: severe symptoms, very high BG, marked glycosuria, and ketonuria. </li></ul></ul><ul><ul><li>Type 2 diabetes: few if any symptoms, Slightly elevated BG, diagnosis “complicated”. </li></ul></ul>
  56. 59. Selection of cases <ul><li>Population-based cases: include all subjects or a random sample of all subjects with the disease at a single point or during a given period of time in the defined population: </li></ul><ul><ul><li>Disease registers </li></ul></ul><ul><li>Hospital-based cases: </li></ul><ul><li>All patients in a hospital department at a given time </li></ul>
  57. 60. Selection of Controls <ul><li>Principles of Control Selection: </li></ul><ul><li>Study base: </li></ul><ul><ul><li>Controls can be used to characterise the distribution of exposure </li></ul></ul><ul><li>Comparable-accuracy </li></ul><ul><ul><li>Equal reliability in the information obtained from cases and controls  no systematic misclassification </li></ul></ul><ul><li>Overcome confounding </li></ul><ul><ul><li>Elimination of confounding through control selection  matching or stratified sampling </li></ul></ul>
  58. 61. Selection of Controls <ul><li>General population controls: </li></ul><ul><ul><li>registries, households, telephone sampling </li></ul></ul><ul><ul><li>costly and time consuming </li></ul></ul><ul><ul><li>recall bias </li></ul></ul><ul><ul><li>eventually high non-response rate </li></ul></ul><ul><li>Hospitalised controls: </li></ul><ul><ul><li>Patients at the same hospital as the cases </li></ul></ul><ul><ul><li>Easy to identify </li></ul></ul><ul><ul><li>Less recall bias </li></ul></ul><ul><ul><li>Higher response rate </li></ul></ul>
  59. 62. Ascertainment of outcome and exposure status <ul><li>External sources: </li></ul><ul><ul><li>Death certificates, disease registries, Hospital and physicians records etc. </li></ul></ul><ul><li>Internal sources: </li></ul><ul><ul><li>Questionnaires and interviews, information from a surrogate (spouses or mother of children), biological sampling( e.g. antibody) </li></ul></ul>
  60. 63. Prospective vs. retrospective Cohort Studies <ul><li>Prospective Cohort Studies </li></ul><ul><ul><li>Time consuming, expensive </li></ul></ul><ul><ul><li>More valid information on exposure </li></ul></ul><ul><ul><li>Measurements on potential confounders </li></ul></ul><ul><li>Retrospective Cohort Studies </li></ul><ul><ul><li>Quick, cheap </li></ul></ul><ul><ul><li>Appropriate to examine outcome with long latency periods </li></ul></ul><ul><ul><li>Admission to exposure data </li></ul></ul><ul><ul><li>Difficult to obtain information of exposure </li></ul></ul><ul><ul><li>Risk of confounding </li></ul></ul>
  61. 64. Selection of the Exposed Population <ul><li>Sample of the general population: </li></ul><ul><ul><li>Geographically area, special age groups, birth cohorts (Framingham Study) </li></ul></ul><ul><li>A group that is easy to identify: </li></ul><ul><ul><li>Nurses health study </li></ul></ul><ul><li>Special population (often occupational epidemiology): </li></ul><ul><ul><li>Rare and special exposure </li></ul></ul><ul><ul><li>Permits the evaluation of rare outcomes </li></ul></ul>
  62. 65. Selection of the Comparison Population <ul><li>Internal Control Group </li></ul><ul><ul><li>Exposed and non-exposed in the same Study population (Framingham study, Nurses health study) </li></ul></ul><ul><ul><ul><li>Minimise the differences between exposed and non-exposed </li></ul></ul></ul><ul><li>External Control Group </li></ul><ul><ul><li>Chosen in another group, another cohort (Occupational epidemiology: Asbestosis vs. cotton workers) </li></ul></ul><ul><li>The General Population </li></ul>
  63. 66. 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
  64. 67. Bias <ul><li>Selection bias: </li></ul><ul><ul><li>Non-response during data collection </li></ul></ul><ul><ul><li>Losses to follow up </li></ul></ul><ul><ul><li>Healthy worker effect </li></ul></ul><ul><li>Misclassification on exposure or event </li></ul><ul><ul><li>Random </li></ul></ul><ul><ul><li>Systematic </li></ul></ul><ul><li>Confounder </li></ul><ul><ul><li>Difference in other risk factors between exposed and non-exposed </li></ul></ul>
  65. 68. Strengths in Cohort vs. Case-control? <ul><li>Cohort study </li></ul><ul><li>Rare exposure </li></ul><ul><li>Examine multiple effects of a single exposure </li></ul><ul><li>Minimizes bias in the in exposure determination </li></ul><ul><li>Direct measurements of incidence of the disease </li></ul><ul><li>Case-control study </li></ul><ul><li>Quick, inexpensive </li></ul><ul><li>Well-suited to the evaluation of diseases with long latency period </li></ul><ul><li>Rare diseases </li></ul><ul><li>Examine multiple etiologic factors for a single disease </li></ul>
  66. 69. Limitations in Cohort vs. Case-control? <ul><li>Cohort study </li></ul><ul><li>Not rare diseases </li></ul><ul><li>Prospective: Expensive and time consuming </li></ul><ul><li>Retrospective: in adequate records </li></ul><ul><li>Validity can be affected by losses to follow-up </li></ul><ul><li>Case-control study </li></ul><ul><li>Not rare exposure </li></ul><ul><li>Incidence rates cannot be estimated unless the study is population based </li></ul><ul><li>Selection Bias and recall bias </li></ul>
  67. 70. Risk assessment
  68. 72. Registration of a drug is only the beginning of safety research
  69. 73. Practical exercise <ul><li>Analysis and discussion of paper </li></ul><ul><li>Study design </li></ul>
  70. 74. N Engl J Med 2006;354:579-87
  71. 75. <ul><li>What is known? </li></ul><ul><li>Incidence: 1-2 per 1000 newborn </li></ul><ul><li>Pathogenesis: unclear </li></ul><ul><li>Maternal riskfactors: diabetes, UTI, smoking, NSAIDs </li></ul><ul><li>Use of fluoxetine in the last trimester associated with ‘complications child’ </li></ul><ul><li>Research question: </li></ul><ul><li>What is the risk on PPHN in newborns associated with use of SSRIs in late phase pregnancy of the mother? </li></ul>
  72. 76. <ul><li>Methods: </li></ul><ul><li>Data from 97 hospitals in the US in 4 large cities </li></ul><ul><li>ICU in large hospitals, weekly telephonecontact with smaller hospitals </li></ul><ul><li>Permission from the mothers </li></ul><ul><li>Response 69% cases, 68% controls </li></ul>
  73. 77. <ul><li>Methods: </li></ul><ul><li>Case-control study </li></ul><ul><li>Cases: mothers of newborns with PPHN </li></ul><ul><li>Controls: mothers of health newborns </li></ul><ul><li>Exposure:SSRI use during pregancy </li></ul>
  74. 78. <ul><li>Methode: </li></ul><ul><li>Exposure assessment: </li></ul><ul><li>Telephoneinterview within 6 months </li></ul><ul><li>Backgroundvariables </li></ul><ul><li>Medical history </li></ul><ul><li>Drug use </li></ul><ul><li>Antidepressant use during pregnancy </li></ul>
  75. 82. Practical exercise <ul><li>Study design </li></ul>
  76. 83. Practical exercise <ul><li>Your company has a new atypical antipsychotic on the market: Enabladon  </li></ul><ul><li>Comparable effectiveness, less weight gain </li></ul><ul><li>3 case reports: arrhythmias in elderly patients </li></ul><ul><li>EMEA demands a safety review </li></ul>
  77. 84. Design <ul><li>Form subgroups </li></ul><ul><li>What is the research question? </li></ul><ul><li>Design a study answering the research question </li></ul><ul><ul><li>RCT </li></ul></ul><ul><ul><li>Case-control design </li></ul></ul><ul><ul><li>Cohort design </li></ul></ul>
  78. 85. Design <ul><li>Formulate research question </li></ul><ul><li>Domain / setting </li></ul><ul><li>Exposure </li></ul><ul><li>Outcome measures </li></ul><ul><li>Timing </li></ul><ul><li>Association </li></ul><ul><li>Financing </li></ul>
  79. 86. Design <ul><li>Present your design </li></ul><ul><li>Peer review your fellow students </li></ul>