8. Causality assessment: scales and methods Multi-partner training package on active TB drug safety monitoring and management (aDSM) July 2016

Objectives of the presentation By the end of this presentation, the participant is expected to be able to: describe the main principles of causality assessment identify the different levels of certainty when attributing an event to a suspected exposure

Causality assessment (1) one of the main reasons we collect aDSM data Programme indicators Causality assessment Signal detection Drug-safety profiles

Causality assessment (2) an integral part of clinical management Evaluating the likelihood that a TB medicine was the causative agent of an observed adverse reaction forms part of clinical evaluation. While the details of the systematic method of conducting causality assessment may not be familiar to the practitioner, the overall approach is not too different from the clinical practice followed when evaluating any patient on treatment.

Causality assessment (3) attribution The attribution (relationship or causality or drug related assessment) must be made A physician or any other health care professional who has the right expertise describes the relationship between the adverse event and an exposure This determination must be recorded both in the medical record as well as in the case report form For aDSM, causality assessment should be made primarily at the country level and by consulting the relevant data sources close to where the event occurred

Causality assessment (4) Is there a convincing relationship between the medicine and the event ? Did the medicine actually cause the event ? OR Other TB medicines ? Medicines for other diseases ? Effect of the TB disease itself or co-morbidities?

Causality assessment (5) reaction versus event Adverse drug reactions (ADR): a response to a medicine which is noxious and unintended, and which occurs at doses normally used in humans Adverse events (AE): Any untoward medical occurrence that may present during treatment with a pharmaceutical product, but which does not necessarily have a causal relationship with this treatment

Causality assessment (6) main things to look out for Is the time to onset of the event compatible with the suspected cause (plausible time-frame) ? Did the event occur after the start of some other medicine or new illness? Is the event plausible given what is known about the drug? Is there any other possible cause for the event? What is the response to withdrawal of the medicine (dechallenge)? What is the response to rechallenge, if applicable?

Causality assessment (7) key data elements for causality assessment Medical history (incl. concomitant disease) Other risk factors (social factors, alcohol use, substance abuse, etc.) Details of drugs taken : names, doses, routes Start and stop dates and indications for use Description of adverse event, including clinical description, laboratory results, and date of onset / end Evolution of event, severity, seriousness, outcome

Causality assessment (8) classification of level of relationship Time to event plausible? Other explanation excluded? Recovery after withdrawal? Recurrence after rechallenge? notes Certain Yes Rechallenge not needed in case of an anaphylactic reaction Probable No or ? Possible ? Unlikely No Suggestive if event resolves despite continued exposure

Causality assessment (9) inference on the grade of the relationship Definite – Clearly caused by the exposure Probable – Likely to be related to the exposure Possible – May be related to the exposure Unlikely – Doubtfully related to the exposure Unrelated – Clearly not related to the exposure

Causality assessment (10) inference on the grade of the relationship Category Definition Definite / certain There is clear evidence to suggest a causal relationship and other possible contributing factors can be ruled out. Probable There is evidence to suggest a likely causal relationship and the influence of other factors is unlikely. Possible There is some evidence to suggest a causal relationship (e.g. because the event occurs within a reasonable time after administration of the trial medication). However, the influence of other factors may have contributed to the event (e.g. the patient’s clinical condition, other concomitant treatments). Unlikely There is little evidence to suggest there is a causal relationship (e.g. the event did not occur within a reasonable time after administration of the study regimen). There is another reasonable explanation for the event (e.g. the patient’s clinical condition, other concomitant treatment). Not related There is no evidence of any causal relationship . Unclassifiable There is insufficient information about the ADRs to allow for an assessment of causality.

Causality assessment (11) Naranjo ADR probability scale (items and score) Source: Naranjo CA et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30: 239 - 245.

Causality assessment (12) WHO-UMC system Practical tool for the assessment of case reports Combined assessment taking into account clinical-pharmacological aspects of the case history the quality of the documentation Other criteria such as previous knowledge and statistical chance play a less prominent role as to facilitate detection of unknown and unexpected adverse drug reactions Source: http://who-umc.org/Graphics/24734.pdf

Causality assessment (13) approaches to test hypotheses Method Principles + / - Reproducibility Expert opinion Based on judgment of individual experts Subjective Low Algorithms Follows a decision tree defined by experts / pharmacology More standardized than expert opinion Low (subjective) Probability assessment Bayesian approach Need special skills; numeric data Considered «gold standard» Adapted from R Benkirane (WHO-CC Morocco; 2014)

Causality assessment (14) who does the causality assessment ?

Conclusion An attempt to attribute an event to a cause is a basic principle of monitoring and clinical management in aDSM Attributing a relationship requires a systematic process and is one of the main reasons why data are collected in aDSM. The exercise is done by experts who are competent in therapeutics and toxicity The causality assessment once done attributes a level of certainty between the event and the exposure, ranging from certain to unrelated