Clinical causality assessment

1. Clinical causality assessment I. Ralph Edwards R.H.B Meyboom

2. Causality assessmentPerspectives • patient • treating doctor • drug manufacturer • drug control authority

3. Causality assessmentThree Key Questions • Can the drug cause the adverse reaction? • Has the drug caused the adverse reaction? • Will the drug cause the adverse reaction?

4. Causality assessment • how likely is it that this medication is the cause of this problem in this particular patient? • making a differential diagnosis

5. Categories of disease aetiology • Sufficient causes. On exposure to a sufficient cause, the disease will inevitably follow. (Type A effects.) • Necessary causes. Although exclusion of a necessary cause inevitably prevents the disease, exposure is not invariably followed by development of the disease. (Type B effects.) • Contributory causes. Increase the risk of a given disease. Exclusion leads to reduction in frequency but not eradication of the disease. (Type C effects.)

6. Approaches to causality assessment • individual expert • panel of experts • formal algorithm • decrease inter-individual differences • improve validity? • time consuming

7. Causality assessmentFirst step • Make sure you have access to all available details

8. Data elements relevant to causality assessment • Age, sex and medical history • Identified suspected and other drugs, doses, routes, start stop dates and indications for use • Description of adverse event, including clinical data, laboratory results and date of onset (or interval) • Treatment, course and outcome

9. Four assessment criteria • The association in time (place) between drug administration and event • Pharmacology (features, previous knowledge of side effects) • Medical plausibility (characteristic signs and symptoms, laboratory tests, patho-logical findings) • Likelihood or exclusion of other causes

10. Causality assessment • Reasonable time relationship • pharmacokinetics • type of reaction • Site of reaction • Dose-response • effect of dose reduction • effect of re-exposure • Known actions of the drug • Other drugs taken • traditional remedies • Effects of underlying disease or conditions • Main factors to consider

11. Causality assessment • Are there previous conclusive reports on this reaction? • Did the ADR appear after the suspected drug was administered? • Did the ADR improve when the drug was discontinued or a specific antagonist was administered? • Did the ADR reappear when the drug was readministered? • Was the ADR confirmed by objective evidence

12. Causality assessment • Are there alternative causes that could on their own have caused the reaction? • Did the ADR reappear when a placebo was given? • Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? • Was the ADR more severe when the dose was increased or less severe when the dose was decreased? • Did the patient have a similar ADR to the same or similar drugs in any previous exposure?

13. WHO Causality CategoriesCertain • Event or laboratory test abnormality, with plausible time relationship to drug intake, cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmaco-logically, pathologically) • Event definitive pharmacologically or phenomenologically (An objective and specific medical disorder or a recognised pharmacological phenomenon) • Rechallenge (if necessary)

14. WHO Causality CategoriesProbable • Event or laboratory test abnormality, with reasonable time relationship to drug intake, unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not necessary

15. WHO Causality CategoriesPossible • Event or laboratory test abnormality, with reasonable time relationship to drug intake, could also be explained by disease or other drugs • Information on drug withdrawal lacking or unclear

16. WHO Causality CategoriesUnlikely • Event or laboratory test abnormality, with a time to drug that makes a relationship improbable (but not impossible) • Diseases or other drugs provide plausible explanations

17. WHO Causality Categories Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed or additional data under examination

18. WHO Causality Categories Unassessable/Unclassifiable • A report suggesting an adverse reaction • Cannot be judged because of insufficient or contradictory information • Report cannot be supplemented or verified

19. Major uses of causality assessment • Signal detection • Drug regulation • Scientific publications • Data exchange

20. What causality assessment can do • Decrease disagreement between assessors • Classify relationship likelihood (semi-quantitative) • Mark individual case reports • Education / improvement of scientific assessment

21. What causality assessment cannot do • Give accurate quantitative measurement of relationship likelihood • Distinguish valid from invalid cases • Prove the connection between drug and event • Quantify the contribution of a drug to the development of an adverse event • Change uncertainty into certainty

22. Questions for the future • Causality assessment as a routine of all reports, or only in selected cases? • One general system, or special systems adapted to specific adverse reactions?