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Adverse Event Causality Assessment: The absence of a gold standard
A brief look into the history of causality assessment of adverse events shows that a lot of research was done to find that gold standard which would be used as a standardized scale to access causality.
Many algorithms have been developed and published in the last forty years (from Irey’s algorithm-1972, Karch and Lasanga’s Method- 1977, to the WHO causality scale and the Naranjo scale more recently). These algorithms ranged from 8 questions to 72 questions. Anyone who has had the opportunity to use an algorithm of 30 questions or above would appreciate the thought process and effort made to formulate that gold standard for assessing causality.
What happened next? Why were these algorithms not used?
Unfortunately, none of these algorithms has reached the status of gold standard for causality assessment.
The key reasons why no gold standard algorithm has been recommended by regulatory authorities is because, Algorithms are very time consuming and cannot do away with subjectivity. At present the WHO causality scale and the Naranjo scale are commonly used due to their practicality. There is no gold international standard that is followed by all regulatory authorities. Different causality assessment scales are appropriate for different study protocols. The WHO scale is appropriate for bioequivalence and bioavailability (BA/BE) studies, open labeled clinical trials and post marketing surveillance. The “certain” category in the WHO causality assessment scale may not mean much in a phase one or double blinded clinical trial. Different sponsors use different causality assessment scales in different protocols. They may vary from a simple binary classification: Suspected and Unsuspected, Related and Unrelated, or Multiple categories (certain, probable, possible and unlikely), as in the WHO causality assessment scale.
The fact that no gold standard for causality assessment has been recommended after 40 years of effort requires the assessor (for causality) to have a good understanding of the fundamentals (temporal association, alternate etiology, dechallenge, rechallenge and confounding factors) to make a meaningful causal assessment for an adverse event which could contribute to a potential signal, which in the big picture is an important goal for Pharmacovigilance.
This article written by Dr. Shoba Rajagopal Krishnakumar is the first in a series of pharmacovigilance blogs. Dr. Shoba is the head of Pharmacovigilance and Medical Affairs at NCS. NCS handles approximately 750 molecules in 3 major regions of the world (US, Europe and APAC) through our PV department. We’d love to hear what you have to say about adverse event causality assessment.
Norwich Clinical Services’ (NCS') pharmacovigilance and drug safety support services cover the entire product life cycle from development, through pre and post-marketing stages. The NCS team is your reliable partner in reaching compliance and maximal effectiveness of your pharmacovigilance system and covering the complex regulatory requirements. Our Pharmacovigilance activities are in compliance with the FDA and the latest EU Guidance.