1. Technical Briefing Seminar 22-26 September 2008 1 |1 | Methods to study medicine safety problems Mary R Couper Quality Assurance and Safety of Medicines

2. Technical Briefing Seminar 22-26 September 2008 2 |2 | 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

3. Technical Briefing Seminar 22-26 September 2008 3 |3 | Spontaneous reporting Principle: The alert health professional connects an undesirable medical event with medicine exposure – Suspicion Report is sent to central database for analysis

4. Technical Briefing Seminar 22-26 September 2008 4 |4 | Spontaneous reporting - advantages – large population –all medicines –hospital and out-patient care –long perspective –patient analyses possible –inexpensive

5. Technical Briefing Seminar 22-26 September 2008 5 |5 | 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

6. Technical Briefing Seminar 22-26 September 2008 6 |6 | 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.

7. Technical Briefing Seminar 22-26 September 2008 7 |7 | Cohort Event Monitoring Cohort event monitoring (CEM) is a prospective, observational, cohort study of adverse events associated with one or more medicines.

8. Technical Briefing Seminar 22-26 September 2008 8 |8 |

9. 9 |9 | 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

10. Technical Briefing Seminar 22-26 September 2008 10 | Basic CEM principles Enroll a cohort of patients Actively pursue adverse events (‘Hot pursuit’)

11. Technical Briefing Seminar 22-26 September 2008 11 | 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.’

12. Technical Briefing Seminar 22-26 September 2008 12 | 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 AgeDuration of therapy GenderConcomitant disease DoseConcomitant therapy Assess safety in pregnancy & lactation

13. Technical Briefing Seminar 22-26 September 2008 13 | 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

14. Technical Briefing Seminar 22-26 September 2008 14 | Cohort Population Sample Exposed Outcome Time

15. Technical Briefing Seminar 22-26 September 2008 15 | The objectives Detect inefficacy, which might be due to Faulty administration Poor storage conditions Out of date Poor quality product Counterfeit Interactions Drug utilization

16. Technical Briefing Seminar 22-26 September 2008 16 | 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

17. Technical Briefing Seminar 22-26 September 2008 17 | 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

18. Technical Briefing Seminar 22-26 September 2008 18 | Special follow-ups Pregnancies Deaths Treatment failures

19. Technical Briefing Seminar 22-26 September 2008 19 | Pregnancies Pregnant women followed up Women of child-bearing age  Pregnancy test or  follow-up

20. Technical Briefing Seminar 22-26 September 2008 20 | 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

21. Technical Briefing Seminar 22-26 September 2008 21 | Death Procedure for follow-up with specific form Accurate timing Try & establish cause –Laboratory results –Autopsy Confirm drug use

22. Technical Briefing Seminar 22-26 September 2008 22 | 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

23. Technical Briefing Seminar 22-26 September 2008 23 | Publications on CEM Pharmacovigilance for antiretrovirals in resource-poor countries. Geneva 2007 Manual for pharmacovigilance of antimalarials in press