Drug risk assessment 23 4-2010

faculteit Farmaceutische Wetenschappen

Drug risk assessment & Pharmacoepidemiology

Rob Heerdink 23 April 2010


Dr Rob Heerdink

Pharmacoepidemiology & Pharmacotherapy

Utrecht Institute for Pharmaceutical Sciences

Universiteit UtrechtThe 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-clinicaldevelopment

15-30

Fase I/IIa

10-15Fase IIb/III

15

preclinicalclinical (I-III)

phase IV

faculteit Farmaceutische WetenschappenScience 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)• Only frequent side effects known (small RCTs)• Often not measured (not expected, no

suspicion)• Follow-up period often too short• Other restrictions to trials


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)


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 drugnot dose dependentnot dose dependent- rarerare- all or none phenomenonall or none phenomenon- not predictablenot 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


Clinical trials

A numbers game

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 groupin control group

50% 1425% 7710% 2665% 5821% (liver dysfunction) 3,1040.1% (hepatitis) 31,4830.01% (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

faculteit Farmaceutische WetenschappenHerald 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’


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


sponsored drug

olanzapine risperidon clozapine ziprasidone

amisulpiride

Olanzapine(Lilly)

5 / 0 2 / 1 2 / 0 1 / 0

Risperidon(Janssen)

3 / 1 1 / 0

comparator



sponsored drug


amisulpiride

Olanzapine(Lilly)

5 / 0 2 / 1 2 / 0 1 / 0

Risperidon(Janssen)

3 / 1 1 / 0

Clozapine(Novartis)

1 / 0 1 / 0

comparator



sponsored drug


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



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 standardRandomised 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).

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


Observational studies

Past Present FutureRetrospective Cohort Prospective Cohort

Case-Control (retrospective)

Cross-sectional


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


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

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


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


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 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.


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.


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 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


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

question1. RCT2. Case-control design3. Cohort design


Design

• Formulate research question• Domain / setting• Exposure • Outcome measures• Timing• Association• Financing


Design

• Present your design• Peer review your fellow students

Drug risk assessment 23 4-2010

Health & Medicine

Transcript of Drug risk assessment 23 4-2010