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Methods to study medicinesafety problems

Mary R CouperQuality Assurance and Safety of Medicines

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METHODS TO STUDY DRUG SAFETY PROBLEMS

animal experiments

clinical trials

epidemiological methods

spontaneous reporting Cohort event monitoring

Other epidemiological methodsPhase IV studies usually

carried out by pharmaceutical

industry

Case series

Registers

Record linkages

Meta- analysis

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Spontaneous reporting

Principle: The alert health professional connects anundesirable medical event with medicine exposure

Suspicion

Report is sent to central database for analysis

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Spontaneous reporting - advantages

large population all medicines

hospital and out-patient care

long perspective

patient analyses possible

inexpensive

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Spontaneous reporting - disadvantages

Underreporting

Poor quality of reports

No denominator data

Reporting varies with severity of reaction

time from market introduction

promotional claims

promotion of reporting system

publicity of specific association

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Spontaneous reporting- cornerstone of PV

Eleven products recalled from UK and US during 1999-2001

Basis for recall Eight products (73%) were recalled on the basis of spontaneous

reports Two products (18%) recalled on basis of RCTs

Two products (18%) recalled on basis of comparativeobservational studies

Ref. Drug Safety 2006: An assessment of the publicly disseminated evidence of safety used indecisions to withdraw medicinal products from the UK and US markets. Clarke A, Deeks JJ,Shakir SA.

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Cohort Event Monitoring

Cohort event monitoring (CEM) is aprospective, observational, cohort study

of adverse events associated with one

or more medicines.

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Basic CEM principles

Enroll a cohort of patients

Actively pursue adverse events

(Hot pursuit)

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DJ Finney 1965

The purpose of monitoring is to ensure that observationson a large number of persons who receive a new drug are

collated and used effectively; only so can a warning of any

untoward consequences be given as early as possible.

.a reporter is not required to judge whether an event

was drug-induced, though he may usefully express an

opinion.

a skilled medical scrutineer at the centre becomessuspicious much earlier than anyone else.

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The objectives of CEM

Characterize known reactions

Detect signals of unrecognized reactions

Interactions with

Other medicines

Complementary and alternative medicines

Foods

Identify risk factors so that they can be avoided

Age Duration of therapy

Gender Concomitant disease

Dose Concomitant therapy

Assess safety in pregnancy & lactation

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Cohort

PopulationSample

Exposed Outcome

Time

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The objectives

Detect inefficacy, which might be due to Faulty administration

Poor storage conditions

Out of date

Poor quality product Counterfeit

Interactions

Drug utilization

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Reporting requirements

All new events even if common & minor

Change in a pre-existing condition

Abnormal changes in laboratory tests

Accidents

All deaths with date & cause

Possible interactions

NB alcohol, OCs, CAMs

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Non-serious events

May indicate serious problem

May affect compliance nausea

Extreme lethargy

diarrhoea

May be more important than serious reactions

Recording all events is easier than being selective

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Special follow-ups

Pregnancies

Deaths

Treatment failures

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Pregnancies

Pregnant women followed up

Women of child-bearing age

Pregnancy test or

follow-up

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Death

Procedure for follow-up with specific form

Accurate timing

Try & establish cause

Laboratory results

Autopsy

Confirm drug use

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Lack of effect

Adherence to instructions

Did not retain medication vomiting

diarrhoea

Incorrect diagnosis

Batch

Quality / counterfeit issue?

Resistance issue?

Specific enquiry if numbers of cases

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Publications on CEM

Pharmacovigilance for antiretrovirals in resource-poorcountries. Geneva 2007

Manual for pharmacovigilance of antimalarials in press