1. Causality Assessment in postmarketing adverse events Anshu Vashishtha MD PhD Watson Pharmaceuticals

2. Evaluation of causality (Question 3) Pros and ConsPros and Cons Criteria to considerCriteria to consider Examples of methods of assessment- WHO Index cases, PRR, Global Clinical Assessment, broad categorizationExamples of methods of assessment- WHO Index cases, PRR, Global Clinical Assessment, broad categorization Going forwardGoing forward

3. Evaluation of causality Individual levelIndividual level Case CollectionCase Collection Importance of Case definition (confirmation of diagnosis): CIOMS, MSSOImportance of Case definition (confirmation of diagnosis): CIOMS, MSSO Importance of qualityImportance of quality Necessity: reported adverse event maybe related to concomitant medication or coexisting diseaseNecessity: reported adverse event maybe related to concomitant medication or coexisting disease

4. Individual adverse event causality assessment - Pros Better case quality and follow up Surfaces confounding factors and follow- up needs while case is freshSurfaces confounding factors and follow- up needs while case is fresh Allows ongoing signal assessment by number of reports considered probably, possibly or unlikely to be relatedAllows ongoing signal assessment by number of reports considered probably, possibly or unlikely to be related

5. Individual adverse event causality assessment - Pros More meaningful Package insert If reported cases are not considered causally related, may keep those events out of package insertIf reported cases are not considered causally related, may keep those events out of package insert If assessed as causally related, allows true risks to be communicated betterIf assessed as causally related, allows true risks to be communicated better

6. Individual adverse event causality assessment - Cons Takes time and resources - some approaches more conducive to large scale applicationTakes time and resources - some approaches more conducive to large scale application Limited by lack of all relevant data in several instancesLimited by lack of all relevant data in several instances Legal liability of sponsor?Legal liability of sponsor?

7. Criteria to consider for causality assessment positive rechallengepositive rechallenge positive dechallenge (resolution upon stopping suspect drug, in absence of other intervention or treatment)positive dechallenge (resolution upon stopping suspect drug, in absence of other intervention or treatment) known class effectknown class effect biological plausibilitybiological plausibility lack of alternative explanation - concomitant drug or diseaselack of alternative explanation - concomitant drug or disease “typical” adverse drug reaction (low background rate)“typical” adverse drug reaction (low background rate) Reference: Guidelines for preparing Core Clinical Safety Information on Drugs Report of CIOMS Working Group III, 1995

8. Criteria to consider for causality assessment -2 Dose responseDose response Lack of concomitant factors (clean subject eg. child)Lack of concomitant factors (clean subject eg. child) Consistency of time to onset eg. early for immediate hypersensitivity or long term for tumorigenesisConsistency of time to onset eg. early for immediate hypersensitivity or long term for tumorigenesis High frequency of reported casesHigh frequency of reported cases Similar findings in toxicity studiesSimilar findings in toxicity studies Reference: Guidelines for preparing Core Clinical Safety Information on Drugs Report of CIOMS Working Group III, 1995

9. Criteria to consider for causality assessment -3 Positive in vitro test eg. IgE antibodies to allergen and elevated serum serum tryptase in anaphylaxisPositive in vitro test eg. IgE antibodies to allergen and elevated serum serum tryptase in anaphylaxis positive in vivo test eg. Intradermal or prick test for immediate hypersensitivity or patch test for delayedpositive in vivo test eg. Intradermal or prick test for immediate hypersensitivity or patch test for delayed Identified subset at risk or predisposing factorIdentified subset at risk or predisposing factor Reference: Guidelines for preparing Core Clinical Safety Information on Drugs Report of CIOMS Working Group III, 1995

10. Criteria to consider for causality assessment -4 Protopathic bias: drug given to treat early symptoms may appear temporally associated with the subsequent illnessProtopathic bias: drug given to treat early symptoms may appear temporally associated with the subsequent illness Stimulated Reporting- recall bias after publicityStimulated Reporting- recall bias after publicity

11. Methods for causality assessment Evaluating Clinical Differential Diagnosis or algorithms Factors to judge (Lane and Hutchison, 1986)Factors to judge (Lane and Hutchison, 1986) –Repeatability –Explicitness –Explanatory culpability –Completeness –Biological Balancing –No a priori constraints From “Detection of New Adverse Drug Reactions” Editor, MDB Stephens, JCC Talbot, PA Routledge, 4th edition

12. Methods for causality assessment : WHO index cases WHO (Edwards et al, 1990): Three index casesWHO (Edwards et al, 1990): Three index cases “Substantial” Index case has information on all eleven major items and lack of confounding variables (“feasible” on first six)“Substantial” Index case has information on all eleven major items and lack of confounding variables (“feasible” on first six) –Information on source of case, identification of case, description of reaction, name of drug, treatment dates, reaction date, –age, sex, all drugs with doses and dates, indication for treatment/ underlying disease, outcome –1 index case= 2 substantial or 4 feasible cases From “Detection of New Adverse Drug Reactions” Editor, MDB Stephens, JCC Talbot, PA Routledge, 4th edition

13. Probability of 3 cases occurring with 300,000 treated patients (Begaud et al, 1995)

14. Proportional reporting rate PRR AD/ BCPRR AD/ BC Signal (PRR >3) + (Chi -squared >5) +(Number of cases>3)Signal (PRR >3) + (Chi -squared >5) +(Number of cases>3) Remains one aspect of causality assessment subject to usual biases inherent in spontaneous reporting (Waller 1998)Remains one aspect of causality assessment subject to usual biases inherent in spontaneous reporting (Waller 1998)

15. Evaluation of causality- broad categorization Example Category A: Good reasons and sufficient documentation to assume causal relationshipCategory A: Good reasons and sufficient documentation to assume causal relationship Category B: connection uncertain and even doubtful, eg. Because of missing dataCategory B: connection uncertain and even doubtful, eg. Because of missing data Category O: Not assessable because of missing or conflicted dataCategory O: Not assessable because of missing or conflicted data Causality classification at Pharmacovigilance centers in the European Community; Meyboom RHB and Royer RJ, Pharmacoepidemiology and Drug Safety, Vol 1: 87-97(1992)

16. Evaluation of causality- way forward Individual level- research European agencies’ experience (eg. French require causality assessment by sponsors)Individual level- research European agencies’ experience (eg. French require causality assessment by sponsors) Case Collection- necessary for signal evaluation- WHO, algorithms or global introspection as a guideCase Collection- necessary for signal evaluation- WHO, algorithms or global introspection as a guide Importance of Case definition (confirmation of diagnosis), good case qualityImportance of Case definition (confirmation of diagnosis), good case quality Grades of causal likelihood- role of algorithms needs evaluationGrades of causal likelihood- role of algorithms needs evaluation

17. Evaluation of causality- way forward- 2 Need to evaluate existing methods and experience on worldwide basisevaluate existing methods and experience on worldwide basis agree on approach to categorization into broad “zones of likely relationship” of reported adverse eventsagree on approach to categorization into broad “zones of likely relationship” of reported adverse events conduct retrospective evaluation for utility of causal assessment - initially using existing data from FDA databaseconduct retrospective evaluation for utility of causal assessment - initially using existing data from FDA database consider pilot on certain drugsconsider pilot on certain drugs determine overall guidance based on above resultsdetermine overall guidance based on above results