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Methods to study medicine safety problems Mary R Couper Quality Assurance and Safety of Medicines 1| Technical Briefing Seminar 22-26 September 2008 METHODS TO STUDY DRUG SAFETY PROBLEMS animal experiments clinical trials epidemiological methods – spontaneous reporting – Cohort event monitoring 2| 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 3| Technical Briefing Seminar 22-26 September 2008 Spontaneous reporting - advantages – – – – – – 4| 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 – – – – – 5| 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. 6| 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. 7| Technical Briefing Seminar 22-26 September 2008 8| 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 9| Technical Briefing Seminar 22-26 September 2008 Basic CEM principles Enroll a cohort of patients Actively pursue adverse events (‘Hot pursuit’) 10 | 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.’ 11 | 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 12 | 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 13 | Technical Briefing Seminar 22-26 September 2008 Cohort Exposed Population 14 | Sample Technical Briefing Seminar 22-26 September 2008 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 15 | 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 16 | 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 17 | Technical Briefing Seminar 22-26 September 2008 Special follow-ups Pregnancies Deaths Treatment failures 18 | Technical Briefing Seminar 22-26 September 2008 Pregnancies Pregnant women followed up Women of child-bearing age Pregnancy test or follow-up 19 | Technical Briefing Seminar 22-26 September 2008 Pregnancy Diagnosis of pregnancy recorded as an event –pregnancy register Special questionnaire for outcome Note outcomes – – – – 20 | 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 21 | 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 22 | 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 23 | Technical Briefing Seminar 22-26 September 2008