drug risk assessment 23 4-2010
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Drug risk assessment & Pharmacoepidemiology
Rob Heerdink 23 April 2010
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Dr Rob Heerdink
Pharmacoepidemiology & Pharmacotherapy
Utrecht Institute for Pharmaceutical Sciences
Universiteit UtrechtThe Netherlands
www.pharm.uu.nl/epithera
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Drug development
discovery
Discovery & screening
Proof of Concept
first administration to man
registration& launch
approx. 10-12 years
10,000
Pre-clinicaldevelopment
15-30
Fase I/IIa
10-15Fase IIb/III
15
preclinicalclinical (I-III)
phase IV
faculteit Farmaceutische WetenschappenScience 2005; 307: 196-8.
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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)• Only frequent side effects known (small RCTs)• Often not measured (not expected, no
suspicion)• Follow-up period often too short• Other restrictions to trials
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2 types of side effectsType A side effectsType 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)
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2 types of side effectsType A side effectsType B side effects
Typical type B side effectTypical type B side effect
- not resulting from primary action of the drugnot resulting from primary action of the drug- not dose dependentnot dose dependent- rarerare- all or none phenomenonall or none phenomenon- not predictablenot predictable
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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
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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
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Clinical trials
A numbers game
Market
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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
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Sample size requirement in RCT
baseline risk number required side effect in each groupin control group
50% 1425% 7710% 2665% 5821% (liver dysfunction) 3,1040.1% (hepatitis) 31,4830.01% (cholestatic jaundice) 315,268
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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
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Too short
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faculteit Farmaceutische WetenschappenHerald Tribune 30-09-96
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“It was easy money during the first trial, but that spinal tap really hurt.”
Herald Tribune 30-09-96
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Real patients
• Age
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Real patients
• Age• Pharmacokinetics
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Real patients
• Age• Pharmacokinetics• Adherence
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Real patients
• Age• Pharmacokinetics• Adherence• Comorbidity
Nemesis:
geen
1
>1
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Real patients
• Age• Pharmacokinetics• Adherence• Comorbidity• Comedication
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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’
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sponsored drug
risperidon clozapine ziprasidone
amisulpiride
Olanzapine(Lilly)
5 / 0 2 / 1 2 / 0 1 / 0
comparator
Heres et al. Am J Psych, Feb 2006
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sponsored drug
olanzapine risperidon clozapine ziprasidone
amisulpiride
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
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sponsored drug
olanzapine risperidon clozapine ziprasidone
amisulpiride
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
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sponsored drug
olanzapine risperidon clozapine ziprasidone
amisulpiride
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
comparator
Heres et al. Am J Psych, Feb 2006
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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
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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
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evidence based medicine
?
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pharmacoepidemiology
medicine based evidence
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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
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Evaluation of therapy: golden standardRandomised Controlled Clinical Trial (RCT)
Randomise: why?
Controlgroup: why?
Blinding: why?
Goal:Only difference between treated and untreated group is the treatment
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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?
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Do animals bite more during a full moon?
Bhattacharjee C et al. BMJ 2000;321:1559-61
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DOMAIN
Determinant(s) Endpoint(s)time
• yes / no comparison
• experimental or observational
• retrospective or prospective
Study design
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Pharmacoepidemiological designs•Descriptive methods (Signal detection, hypothesis generating).
Identifying previously unrecognised safety issues – Case reports, – Case series, – Cross-sectional study
•Analytical methods (quantifying + risk factors, hypothesis testing). Investigating possible hazards (hypothesis-testing in order to substantiate a causal association)
– Observational • Cohort studies, • Case-control studies, • Case-crossover studies
– Intervention • Experimental Clinical trial
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Observational studies
Past Present FutureRetrospective Cohort Prospective Cohort
Case-Control (retrospective)
Cross-sectional
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Case Report / Case series
Describes characteristic association in one / somepatient(s) between determinant en outcome
examples:
• serious liverdamage following use of XTC
• birth defects after use of Thalidomide (Softenon)
• etcetera, etcetera, etcetera
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The Lancet, 1961
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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
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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
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Example: LEPR study
Population: 200 patients using antipsychotics
Determinants: LEPR Q223R and LEP promoter 2548G/A SNP polymorphisms
Outcome: BMI
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Example: LEPR study
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%)
** p<0.05
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0,0
1,0
2,0
3,0
4,0
5,0
6,0
7,0
8,0
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001
Prevalence SSRI
Incidence SSRI
Prevalence TCAIncidence TCA
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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Observational Cohort
Group of individuals with common inclusion criteria is followed over time until an endpoint occurs.
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Cohort study / Follow-up study
Study population
Exposed
Non-exposed
Disease +
Disease +
Disease -
Disease -
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A cohort studyRR (myocardial
infarction)*
Untreated normotensive and hypertensive men 1.0 (reference)Treated hypertensive men DBP90 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.
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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;12:339-344.
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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
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Cohort study / Follow-up study
Study population
Exposed
Non-exposed
Disease +
Disease +
Disease -
Disease -
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Case-control study
Study Population
Cases
Controls
Exposed
Non-exposed
Exposed
Non-exposed
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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
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Coogan et al. Am J Epidemiol 2005
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Meijer et al. Arch Int Med 2004
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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”.
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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
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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
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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
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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)
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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
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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
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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
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Data CollectionExternal Data
SourcesInternal 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
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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
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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
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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
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Risk assessment
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Registration of a drug is only the beginning of safety research
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Practical exercise
• Analysis and discussion of paper• Study design
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N Engl J Med 2006;354:579-87
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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?
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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
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Methods:
• Case-control study• Cases: mothers of newborns with PPHN• Controls: mothers of health newborns• Exposure:SSRI use during pregancy
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Methode:
Exposure assessment:• Telephoneinterview within 6 months• Backgroundvariables• Medical history• Drug use• Antidepressant use during pregnancy
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Practical exercise
• Study design
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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
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Design
• Form subgroups• What is the research question?• Design a study answering the research
question1. RCT2. Case-control design3. Cohort design
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Design
• Formulate research question• Domain / setting• Exposure • Outcome measures• Timing• Association• Financing
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Design
• Present your design• Peer review your fellow students