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

2. Causality assessment Perspectives patient treating doctor drug manufacturer drug control authority

3. Causality assessment Three 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 assessment First 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 Categories Certain 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 Categories Probable 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 Categories Possible 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 Categories Unlikely 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?