2. CAUSALITY ASSESSMENT OF SUSPECTED AEs Dr. Retesh Kumar Head, Global PhV Department 12/13/2015

3. What is causality ssessment? Causality assessment is the evaluation of the likelihood that a particular treatment is the cause of an observed event. Decrease ambiguity of data, prevent erroneous conclusions and aid data exchange – Structured and harmonized systemdata exchange ~ 34 different methods: falling into 3 broad approaches approaches Why causality assessment?How we do Causality Assessment? 12/13/2015

4. Major uses of causality assessment Risk benefit assessment Signal detection Evaluation of ADR reports Regulatory purposes An essential component of Pharmacovigilance contributing to better: 12/13/2015

5. Causality assessment Three Key Questions Can the drug cause the adverse experience? Has the drug caused the adverse experience? Will the drug cause the adverse experience? 12/13/2015

6. Temporal sequence Previous experience/Drug info Drug Level Alternative aetiological candidates Dechallenge/Rechallenge Plausibility Concomitant drugs Objective evidence Background epidemiological data Assigning Causality: Relevant criteria 12/13/2015

7. Decision based on the information 12/13/2015

8. Quantitative Estimate Confirmation: Experimental Study  APPROVe Thrombotic Events  Risk of thrombotic CV events after 18 months of Tx  Subgroup analyses: Age, hypertension, diabetes, hypercholesterolemia, aspirin use, cigarette smoking, Increased CV risk 12/13/2015

9. Overall Perspective……  Opinion of experts, clinical judgment or global introspection  Algorithm or standardized assessment method  Probabilistic or Bayesian approaches Expert expresses judgment: Considering all available data relevant to suspect ADR- Most widely used Advantages: Similar to clinical diagnosis Straight forward Easy to use Disadvantages: Poor reproducibility Inter & Intra rater disagreements No standardized evaluation Problem specific flowchart / decision table approach- Structured and standardized approach Advantages: Quick and simple to use Higher Inter & Intra rater reliability High degree of consistency and reproducibility Disadvantages: Lacks flexibility Inconsistent use of terminology Specific findings in a case to transform a prior into a posterior probability –Most logical method/ Gold standard Advantages: Open ended Highest reproducibility Disadvantages: Complex and extensive calculations Unavailability of requisite epidemiological data 12/13/2015

10. APPROACHES CAUSALITY ASSESSMENT Opinion of experts, clinical judgment or global introspection Algorithm or standardized assessment method Probabilistic or Bayesian approaches 12/13/2015

11. WHO SCALE OF CAUSALITY ASSESSMENT 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 (pharmacologically, pathologically) Event definitive pharmacologically or phenomenologically Rechallenge satisfactory, if necessary Probable /Likely 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 required 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 may be unclear or lacking Unlikely Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) Disease or other drugs provide plausible explanations Conditional / Unclassified Event or laboratory test abnormality More data for proper assessment needed Additional data under examination Unassessable / Unclassifiable Report suggesting an adverse reaction Cannot be judged because information is insufficient or contradictory Data cannot be supplemented or verified 12/13/2015

12. THE NARANJO ADR PROBABILITY SCALE QuestionsYesNoDon’t Know 1) Are there previous conclusive reports on this reaction? +100 2) Did the ADR appear after the suspected drug was administered? +20 3) Did the ADR improve when the drug was discontinued? +100 4) Did the ADR appear with re-challenge?+20 5) Are there alternative causes for the ADR?+20 6) Did the reaction appear when placebo was given?+10 7) Was the drug detected in blood at toxic levels?+100 8) Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +100 9) Did the patient have a similar reaction to the same or similar drug in any previous exposure? +100 10) Was the ADR confirmed by any objective evidence? +100 12/13/2015

13. What causality assessment can do Decrease disagreement between assessors Classify relationship likelihood (semi-quantitative) Mark individual case reports Education / improvement of scientific assessment 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 12/13/2015

14. Questions?