technical briefing seminar 22-26 september 2008 1 |1 | methods to study medicine safety problems...

Technical Briefing Seminar 22-26 September 20081 |

Methods to study medicine safety problems

Mary R Couper Quality Assurance and Safety of Medicines

Methods to study medicine safety problems

Mary R Couper Quality Assurance and Safety of Medicines


METHODS TO STUDY DRUG SAFETY PROBLEMS

METHODS TO STUDY DRUG SAFETY PROBLEMS

animal experiments

clinical trials

epidemiological methods – spontaneous reporting– Cohort event monitoring

Other epidemiological methods

Phase IV studies – usually carried out by pharmaceutical industry

Case series

Registers

Record linkages

Meta- analysis


Spontaneous reportingSpontaneous reporting

Principle: The alert health professional connects an undesirable medical event with medicine exposure – Suspicion

Report is sent to central database for analysis


Spontaneous reporting - advantagesSpontaneous reporting - advantages

– large population– all medicines– hospital and out-patient care– long perspective– patient analyses possible– inexpensive


Spontaneous reporting - disadvantagesSpontaneous 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


Spontaneous reporting- cornerstone of PVSpontaneous 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.


Cohort Event MonitoringCohort Event Monitoring

Cohort event monitoring (CEM) is a prospective, observational, cohort study of adverse events associated with one or more medicines.


CEMCEM

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


Basic CEM principlesBasic CEM principles

Enroll a cohort of patients

Actively pursue adverse events

(‘Hot pursuit’)


DJ Finney 1965DJ 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.’


The objectives of CEMThe 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 avoidedAge Duration of therapyGender Concomitant diseaseDose Concomitant therapy

Assess safety in pregnancy & lactation


The objectives of CEMThe 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


CohortCohort

PopulationSample

Exposed Outcome

Time


The objectivesThe objectives

Detect inefficacy, which might be due to• Faulty administration• Poor storage conditions• Out of date• Poor quality product• Counterfeit • Interactions

Drug utilization


Reporting requirementsReporting 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


Non-serious eventsNon-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


Special follow-upsSpecial follow-ups

Pregnancies

Deaths

Treatment failures


PregnanciesPregnancies

Pregnant women followed up

Women of child-bearing agePregnancy test or follow-up


PregnancyPregnancy

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


DeathDeath

Procedure for follow-up with specific form

Accurate timing

Try & establish cause– Laboratory results– Autopsy

Confirm drug use


Lack of effectLack 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


Publications on CEMPublications on CEM

Pharmacovigilance for antiretrovirals in resource-poor countries. Geneva 2007

Manual for pharmacovigilance of antimalarials in press

technical briefing seminar 22-26 september 2008 1 |1 | methods to study medicine safety problems...

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