Methods to study medicine

safety problems

Mary R Couper
Quality Assurance and Safety of Medicines

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METHODS TO STUDY DRUG SAFETY PROBLEMS

 animal experiments Other epidemiological methods

Phase IV studies – usually
 clinical trials carried out by pharmaceutical
industry
 epidemiological methods Case series
– spontaneous reporting Registers
– Cohort event monitoring Record linkages
Meta- analysis

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 Spontaneous reporting

 Principle: The alert health professional connects an

undesirable 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 comparative
observational studies

Ref. Drug Safety 2006: An assessment of the publicly disseminated evidence of safety used in
decisions 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 a

prospective, observational, cohort study
of adverse events associated with one
or more medicines.

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 CEM

 Adaptable to any situation and all types of medicine

 Good data on drug utilization and events

 Signals identified early

 Short term, but long term if needed

 Followed up by
– Stimulated Passive Reporting &/or
– Spontaneous reporting

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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 observations

on 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 becomes

suspicious 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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 The objectives of CEM

 Measure risk (including comparative)

 Provide evidence for effective risk management

– Safer prescribing
– Benefit / harm assessment
– Regulatory changes

 Hypothesis generation

 Cohorts for study

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 Cohort

Exposed Outcome

Time
Sample
Population

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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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 Pregnancy

 Diagnosis of pregnancy recorded as an event –pregnancy

register
 Special questionnaire for outcome

 Note outcomes
– During pregnancy
– Of labour
– Of newborn infant
– Of breast-fed infant

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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-poor

countries. Geneva 2007

 Manual for pharmacovigilance of antimalarials in press

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