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

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METHODS TO STUDY DRUG SAFETY PROBLEMS  animal experiments  clinical trials  epidemiological methods – spontaneous reporting – Cohort event monitoring

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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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Spontaneous reporting - advantages – – – – – –

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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 – – – – –

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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 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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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 12 |

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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

Population

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Sample

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Time

Outcome

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 16 |

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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 – – – –

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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 22 |

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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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