Cover -- Contents -- Abbreviations -- Acknowledgements -- A. Introduction -- 1. Pharmacovigilance -- 1.1 Definition -- 1.2 Explanation -- 1.3 General aims -- 1.4 Specific aims -- 1.5 Pharmacovigilance of antiretrovirals -- 2. Pharmacovigilance centre -- B. Passive or active pharmacovigilance? -- 1. Passive pharmacovigilance -- 2. Active pharmacovigilance -- C. Spontaneous reporting -- 1. Introduction -- 1.1 Background -- 1.2 Adverse reactions -- 2. Objectives -- 2.1 The purpose of spontaneous reporting -- 2.2 Background to the methodology -- 2.3 Serious reactions -- 3. Minimum reporting requirements -- 3.1 WHO criteria -- 3.2 Other practical conditions -- 4. How to report -- 4.1 Reporting form -- 4.2 Other options for reporting -- 5. Where to report -- 6. What to report -- 6.1 Essential data elements -- 6.2 Advice to reporters -- 6.3 Follow-up when necessary -- 7. When to report -- 8. Who should report -- 9. Sharing the results -- 9.1 Individual, immediate -- 9.2 Relevant summaries or reviews -- 9.3 Regular transmission to the WHO database -- 10. Data entry -- 10.1 Options -- 10.2 VigiFlow -- D. Cohort Event Monitoring -- 1. Introduction -- 1.1 Event monitoring -- 1.2 Description -- 1.3 Objectives -- 1.4 Selection of drugs to monitor -- 1.5 Basic processes -- 1.6 Programme duration -- 2. Epidemiology -- 2.1 Observational -- 2.2 Prospective -- 2.3 Inceptional -- 2.4 Dynamic -- 2.5 Longitudinal -- 2.6 Descriptive -- 3. First step - Implementation -- 3.1 First action -- 3.2 Pilot exercise -- 3.3 Sites and training -- 3.4 Advocacy -- 3.5 Reasons for monitoring -- 3.6 Approaches to advocacy -- 4. Second step - establishing the cohort(s) -- 4.1 Numbers of patients -- 4.2 Selection of patients -- 4.3 Patient identification -- 4.4 Other patient data -- 4.5 Background data -- 4.6 Controls or comparators -- 5. Third step - acquiring the data.

The medicines -- 5.1 Details of administration of ARVs -- 5.2 Concomitant medicines -- The events -- 5.3 Principles of event reporting -- 5.4 What kind of events? -- 5.5 Recording event details -- 5.6 Reporting forms (questionnaires) -- 5.7 Logistics of data recording -- 5.8 Frequency and duration of monitoring -- 5.9 Reasons for lack of adherence -- 5.10 How and where to send the completed questionnaires -- 5.11 Record linkage -- 6. Database for CEM -- 6.1 Choice of database -- 6.2 Data elements/fields -- 7. Maximizing the reporting rate -- 7.1 Prepare the ground -- 7.2 Removing barriers to reporting -- 7.3 Other health facilities -- 7.4 Feedback -- 8. General advice and information -- 8.1 Don't ask for too much -- 8.2 Non-serious events -- 8.3 Be open-minded -- 8.4 Privacy -- 9. Fourth step - Clinical review -- 9.1 The event should be specific to be acceptable for recording -- 9.2 Determining the event term -- 9.3 The events dictionary -- 9.4 Dictionary maintenance -- 9.5 Seriousness -- 9.6 Severity -- 9.7 Outcome of the event -- 9.8 Relationship to the medicine/regimen -- E. Data processing -- 1. Data entry -- 1.1 Requirements -- 1.2 Standard formats -- 2. Quality control -- 2.1 Control at entry -- 2.2 Systematic checks -- 3. Coding of medicines and diseases -- 3.1 WHO Drug Dictionary -- 3.2 ICD-10 -- 3.3 Standardized recording of event details -- 4. Using CemFlow -- 5. Collating and summarizing the events -- F. Special types of event -- 1. Serious events -- 2. Pregnancies -- 2.1 Background -- 2.2 CEM of pregnancy -- 2.3 Pregnancy register -- 2.4 Expectations from CEM monitoring of pregnancies -- 2. 5 Verfication of drug-effect -- 2.6 WHO pregnancy registry -- 3. Lactation exposure -- 4. Deaths -- 5. Lack of efficacy -- 5.1 Event terms -- 5.2 Reasons for lack of efficacy -- 6. Late onset reactions -- 7. Concomitant morbid conditions.

G. Relationship/Causality assessment -- 1. Background -- 1.1 Two basic questions -- 1.2 Objective and subjective assessments -- 1.3 General understanding -- 2. Factors to consider when assessing the relationship between drug and event -- 2.1 Did the event begin before the patient commenced the medicine? -- 2.2 Is there any other possible cause for the event? -- 2.3 Is the duration to onset of the event plausible? -- 2.4 Did the event occur after the commencement of some other medicine? -- 2.5 Did the event occur after the onset of some new illness? -- 2.6 What is the response to withdrawal of the medicine (dechallenge)? -- 2.7 What is the response to rechallenge? -- 3. Categories of relationship -- 4. Requirements for inclusion of an event in a specific category -- 4.1 Certain -- 4.2 Probable -- 4.3 Possible -- 4.4 Unlikely -- 4.5 Unclassified or conditional -- 4.6 Unassessable -- 5. Processes for establishing the relationship -- 5.1 Result of dechallenge -- 5.2 Result of rechallenge with the same medicine by itself -- 5.3 Outcome of the event -- 5.4 Clinical details -- 5.5 Logic check -- 5.6 Reactions and incidents -- H. Signal identification -- 1. Introduction -- 1.1 General approach -- 1.2 Definition of a signal -- 1.3 Reference sources on adverse reactions -- 2. Good data are essential -- 3. Selection criteria for events to investigate -- 4. Methods of signal identification -- 4.1 Clinical assessment of individual events -- 4.2 Clinical review of collated events -- 4.3 Record linkage -- 4.4 Automated signal detection -- 5. Comment -- I. Strengthening the signal -- 1. General approach -- 2. Other experience -- 3. Search for non-random patterns -- 3.1 Onset times -- 3.2 Mean dose -- 3.3 Mean age -- 3.4 Sex differences -- 4. Comparison with control events -- 5. Pharmacology -- 6. Investigative epidemiological studies -- 7. Communication.

J. Identifying risk factors -- 1. Introduction -- 1.1 Definition -- 1.2 Risk factors associated with the patient -- 1.3 Risk factors linked to the medicine -- 1.4 Risk factors linked to the culture or environment -- 2. Identification -- 2.1 Pharmacology -- 2.2 Clinical trials -- 2.3 Clinical experience -- 2.4 Spontaneous reporting -- 2.5 Cohort event monitoring -- K. Analyses -- 1. Data manipulation -- 1.1 Tabular -- 1.2 Graphic -- 2. Statistical analyses -- 2.1 The calculation of risk -- 2.2 Attributable risk -- 2.3 Relative risk (RR) with confidence intervals (CI) -- 2.4 t-test for the comparison of means -- 2.5 Life-table analysis (survival analysis) -- 2.6 Multiple logistic regression -- L. Differences between spontaneous reporting and CEM -- 1. Cohort event monitoring -- 1.1 Advantages -- 1.2 Disadvantages -- 2. Spontaneous reporting -- 2.1 Advantages -- 2.2 Disadvantages -- M. Organization -- 1. Legislation -- 1.1 Legal authorization -- 1.2 Conditional registration -- 1.3 Regulation of professional standards -- 2. Ethical issues -- 2.1 Introduction -- 2.2 Prerequisites to collecting patient data -- 2.3 Training of staff -- 2.4 Security issues -- 2.5 Use of data -- 2.6 Confidentiality -- 2.7 Informed consent -- 3. Structure -- 3.1 Pharmacovigilance centre -- 3.2 Centre staff -- 3.3 Field staff for CEM -- N. Communication -- O. Annexes -- Annex 1. Ghanaian Reporting Form for ARV medicines -- Annex 2. Power and sample size analysis for comparison of cohorts -- Annex 3. Abbreviations for ARV medicines and regimens for ART -- Annex 4. Monitoring questionnaires -- Annex 5. Patient card - suggested content -- Annex 6. Coding sheet for reviewing of events before data entry -- Annex 7. Major clinical categories in events dictionary -- Annex 8. Example of events collation -- Annex 9. Comparative events profiles.

Annex 10. Pregnancy questionnaires A, B & C -- Annex 11. Example of collation of deaths (as events) -- Annex 12. Example of collation of eye events with COX-2 inhibitors -- Annex 13. Example of collation of concomitant drug events with celecoxib -- Annex 14. Advice on communication -- Annex 15. Resources -- Annex 16. Suggested standard operating procedures for CEM -- Glossary -- A -- C -- D -- E -- I -- L -- M -- N -- P -- R -- S -- T -- U -- V -- W.