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Identifying early signals

Understand the concept of signals in clinical practice, learn how to recognize and assess signals effectively, exploring key methods such as clinical assessment and review. Delve into examples and principles essential for detecting early signals in adverse drug reactions.

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Identifying early signals

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  1. David Coulter Identifying early signals Dar es Salaam

  2. Summary of content • What is a signal? • Recognising a signal • What can be achieved by you? • Clinical assessment of individual events • Clinical review of collated events • Principles of signal detection • Ta Dar es Salaam

  3. Definition 1 A signal refers to‘reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously’. WHO Dar es Salaam

  4. Definition 2 • In practice it means, a strong suspicion of an adverse reaction that has not been recognised previously Dar es Salaam

  5. Recognising a signal Dar es Salaam

  6. Signal identification • Record • Collate • Look!! Dar es Salaam

  7. Recognition of a signal 1 How do we know when events are not recognised reactions? • Martindale* • DrugDex* • Physicians Desk Reference (PDR). All available on website of Micromedex Healthcare Series www.thomsonhc.com Dar es Salaam

  8. Recognition of a signal 2 • You don’t need to do data mining (BCPNN), or proportional reporting ratios (PRR), or disproportionality analysis to identify signals • Careful clinical assessment of your own events data is the quickest and most satisfying way. Dar es Salaam

  9. Recognition of a signal 3 • Routine clinical appraisal facilitates the earliest possible generation of hypotheses • Automated signal detection • good for testing hypotheses • identifying missed signals • still needs clinical confirmation Dar es Salaam

  10. Recognition of a signal 4 Clinical review the quickest method • careful • informed • systematic • standardised • clinical review • In your centre Dar es Salaam

  11. Dar es Salaam

  12. What can be achieved –by you? Dar es Salaam

  13. What can be achieved? Example: IMMP -omeprazole • Hyponatraemia • Dry mouth • Taste disturbance • Interstitial nephritis • Polydypsia / polyuria • Polymyositis Dar es Salaam

  14. Omeprazole • Hepatitis • Angioedema / urticaria • Bone marrow depression • Carcinoid tumour • Gastric polyps • Diarrhoea Dar es Salaam

  15. Omeprazole • Hallucinations • Amnesia / confusion • Headache • Myalgia • Gynaecomastia / galactorrhoea Dar es Salaam

  16. Omeprazole • Paraesthesia • Pruritus • Rash • Extrapyramidal symptoms • Blood dyscrasias Dar es Salaam

  17. Clinical assessment of individual events Dar es Salaam

  18. COX-2 inhibitors and disturbance of vision Example 1 Dar es Salaam

  19. Example 1 • M 78 • Shoulder pain • Rofecoxib 50 mg once • Woke next morning with • no vision right eye • 6/18 left eye • Recovered next day Dar es Salaam

  20. Example 1 • M 81 • Osteoarthritis knee • Celecoxib100mg daily • Central loss of vision • Onset after each morning dose, recovering after a few hours • No recurrence after withdrawal Dar es Salaam

  21. Example 1 • These 2 case reports can be called the INDEX CASES • Contain good information • close time relationship • positive dechallenge • one had rechallenge Dar es Salaam

  22. Example 1 Now we look for information that may strengthen the signal: • Other case reports • WHO database (Vigibase) • Literature • Mechanism Dar es Salaam

  23. Example 1Other reports of eye problems-blurred vision Dar es Salaam

  24. Example 1WHO reports • Celecoxib • Blindness 12 • Temporary blindness 4 • Vision abnormal 181 • Rofecoxib • Blindness 22 • Temporary blindness 5 • Vision abnormal 167 Dar es Salaam

  25. Example 1Literature search • One case report with celecoxib • Orange spots in both visual fields. (Lund & Neiman, 2001) • No reports with rofecoxib • Visual field defects have been reported rarely with the traditional NSAIDs Dar es Salaam

  26. Example 1Mechanism • Interference with retinal blood flow by inhibition of prostaglandins and related substances. Dar es Salaam

  27. Example 1Conclusion • Two good index cases • Several supporting cases • Supporting cases in WHO database • Similar reports for related drugs • A plausible mechanism • Only one similar report in the literature • We have a signal! Dar es Salaam

  28. Clinical review of collated events Dar es Salaam

  29. COX-2 inhibitors and prothrombotic disorders Example 2 Dar es Salaam

  30. Demo • Cluster of events Dar es Salaam

  31. Dar es Salaam

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  34. Prothromboticevents Summary of findings • No difference in rates of IHD / stroke between rofecoxib & celecoxib • Higher rate of prothrombotic events than comparators • Shorter time to onset of death than comparators • Differences in death rates due to prothrombotis events • Higher rate of cardiac dysrythmias with celecoxib Dar es Salaam

  35. Principles of signal detection Dar es Salaam

  36. Remember • Treatment dates -starting date & ending • Date of onset of event • Was the patient on the drug when the event began? • Calculate onset time • Effect of dechallenge / rechallenge Dar es Salaam

  37. Signal assessment Other questions • Could the problems be caused by a disease? • The disease being treated • A co-morbid condition • Could the problems be caused by another drug? • Are the events caused by related drugs? • Is it relevant or important? Dar es Salaam

  38. Look for non-random features • Gender • Age • Duration to onset • Survival / life table analysis Dar es Salaam

  39. Non-random features • Differences in means • Patients with reaction v patients in cohort • t-test • Differences in rates • RR with CI • Survival or life table analysis • Clustering around a certain duration • Differences between medicines • Multiple logistic regression Dar es Salaam

  40. Collate reports clinically • By Clinical Category (CC) • Then in clinically related groups • Anatomical functional change • Clinical sub-group • Primary event term • Secondary event term • Motto: Sort & see & pursue Dar es Salaam

  41. Identifying early signals Report your signals to: • your advisory committee &/or regulatory authority • local health practitioners • the Uppsala Monitoring Centre • local ADR bulletin • medical journal Dar es Salaam

  42. Signal identification • Record • Collate • Look!! Dar es Salaam

  43. Dar es Salaam

  44. Thank You Merci beaucoup Dar es Salaam

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