Drug risk assessment 23 4-2010
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  • 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

Drug risk assessment 23 4-2010 Drug risk assessment 23 4-2010 Presentation Transcript

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