Transcript Technical Briefing Seminar 22

Methods to study medicine
safety problems
Mary R Couper
Quality Assurance and Safety of Medicines
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Technical Briefing Seminar 22-26 September 2008
METHODS TO STUDY DRUG SAFETY PROBLEMS
 animal experiments
 clinical trials
 epidemiological methods
– spontaneous reporting
– Cohort event monitoring
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Technical Briefing Seminar 22-26 September 2008
Other epidemiological methods
Phase IV studies – usually carried
out by pharmaceutical industry
Case series
Registers
Record linkages
Meta- analysis
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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Technical Briefing Seminar 22-26 September 2008
Spontaneous reporting - advantages
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large population
all medicines
hospital and out-patient care
long perspective
patient analyses possible
inexpensive
Technical Briefing Seminar 22-26 September 2008
Spontaneous reporting - disadvantages
 Underreporting
 Poor quality of reports
 No denominator data
 Reporting varies with
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severity of reaction
time from market introduction
promotional claims
promotion of reporting system
publicity of specific association
Technical Briefing Seminar 22-26 September 2008
Spontaneous reporting- cornerstone of PV
 Eleven products recalled from UK and US during 19992001
 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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Technical Briefing Seminar 22-26 September 2008
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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Technical Briefing Seminar 22-26 September 2008
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Technical Briefing Seminar 22-26 September 2008
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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Technical Briefing Seminar 22-26 September 2008
Basic CEM principles
 Enroll a cohort of patients
 Actively pursue adverse events
(‘Hot pursuit’)
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Technical Briefing Seminar 22-26 September 2008
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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Technical Briefing Seminar 22-26 September 2008
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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Technical Briefing Seminar 22-26 September 2008
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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Technical Briefing Seminar 22-26 September 2008
Cohort
Exposed
Population
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Sample
Technical Briefing Seminar 22-26 September 2008
Time
Outcome
The objectives
 Detect inefficacy, which might be due to
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Faulty administration
Poor storage conditions
Out of date
Poor quality product
Counterfeit
Interactions
 Drug utilization
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Technical Briefing Seminar 22-26 September 2008
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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Technical Briefing Seminar 22-26 September 2008
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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Technical Briefing Seminar 22-26 September 2008
Special follow-ups
 Pregnancies
 Deaths
 Treatment failures
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Technical Briefing Seminar 22-26 September 2008
Pregnancies
 Pregnant women followed up
 Women of child-bearing age
 Pregnancy test or
 follow-up
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Technical Briefing Seminar 22-26 September 2008
Pregnancy
 Diagnosis of pregnancy recorded as an event –pregnancy
register
 Special questionnaire for outcome
 Note outcomes
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During pregnancy
Of labour
Of newborn infant
Of breast-fed infant
Technical Briefing Seminar 22-26 September 2008
Death
 Procedure for follow-up with specific form
 Accurate timing
 Try & establish cause
– Laboratory results
– Autopsy
 Confirm drug use
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Technical Briefing Seminar 22-26 September 2008
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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Technical Briefing Seminar 22-26 September 2008
Publications on CEM
 Pharmacovigilance for antiretrovirals in resource-poor
countries. Geneva 2007
 Manual for pharmacovigilance of antimalarials in press
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Technical Briefing Seminar 22-26 September 2008