An adverse drug reaction is distinguished from an adverse event by the fact that in an adverse drug reaction, a causal relationship is suspected between a drug and an adverse event. Hence, all cases assessed by either the reporting healthcare professional or the sponsor as having a reasonable suspected causal relationship to the drug qualify as adverse drug reactions.
For the purposes of regulatory reporting, if an adverse event is reported spontaneously, even if the relationship is unknown, it meets the criteria of an adverse drug reaction. Hence, all spontaneous reports reported by healthcare professionals or consumers are considered suspected adverse drug reactions since they denote the suspicion of the primary sources, unless the reporters specifically mentions that that a causal relationship can be excluded or they consider the events to be unrelated.
Need for Causality Assessment
A fundamental issue in pharmacovigilance is that many cases concern suspected adverse drug reactions. In real-life situations, a very limited number of adverse reactions qualify as ‘certain’ or ‘unlikely’; most are usually in between, i.e., either ‘possible’ or ‘probable’. To address this issue, many methods have been developed to harmonize causality assessment. However, causality assessment has become a common routine activity in pharmacovigilance.
The advantages of causality assessment includes the following:
Provides uniformity and reduce disagreement between reviewers
Provides likelihood of relationship
Mark individual cases
Improves case evaluation and benefit-risk assessment
Methods of Causality Assessment
There are numerous methods published for causality assessment of adverse events. These fall into the following 3 broad categories: Expert judgement/Global introspection, Algorithms and Probabilistic methods (Bayesian approaches).
The 2 commonly accepted and used methods for causality assessment across the globe are the following:
WHO UMC causality assessment
A method developed by World Health Organization (WHO) and Upsala Monitoring center (UMC) at Sweden as a practical instrument for the assessment of causal relationship. This is a combined assessment considering the clinical-pharmacological aspects of the case and the quality of documentation of the observation.
The main criteria for causality assessment in this method includes temporal relationships between the drug and the adverse event; absence of other confounding factors (e.g., drugs, underlying disease etc.); response to drug withdrawal (dechallenge); and response to drug re-administration (rechallenge).
The various causality categories include the following:
Naranjo causality assessment (Naranjo Scale)
The Naranjo algorithm (Adverse Drug Reaction (ADR) Probability Scale) was developed by Naranjo and coworkers in 1991 to determine the possibility of whether an ADR is due to the drug rather than due to other contributory factors. The probability is assigned using a simple questionnaire to assign scores. There are 10 questions in the questionnaire scale that are answered as either “Yes”, “No”, or “Do not know”. Different point values (-1, 0, +1 or +2) are assigned to each answer.
The total scores in the actual ADR Probability Scale range from -4 to +13; the reaction is considered definite when the score is 9 or higher, probable between 5 to 8, possible between 1 to 4, and doubtful if 0 or less.
Conclusion
Causality assessment to assess the relationship or connection between the drug and adverse events is a key component for benefit-risk assessment and identification / assessment of safety signals. Despite various methods developed and standardized, no specific method is accepted universally, although the expert judgement/global introspective method is most commonly used, as algorithm-based and probabilistic methods have been shown to be tough to reliably implement in real situations.
References
- ICH Topic E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting: European Medicines Agency: June 1995
- The use of the WHO-UMC system for standardised case causality assessment; 06 April 2018. (who-umc-causalityassessment_new-logo.pdf)
- Management of Safety Information from Clinical Trials: Report of CIOMS Working Group VI: Geneva 2005
- Guideline on good pharmacovigilance practices (GVP) Module VI – Management and reporting of adverse reactions to medicinal products: European Medicines Agency: November 20172
- Agbabiaka TB, Savović J, Ernst E. Methods for causality assessment of adverse drug reactions: a systematic review. Drug Saf. 2008;31(1):21-37. doi: 10.2165/00002018-200831010-00003. PMID: 18095744.
- Renata Rezende de Menezes et al: Causality assessment of adverse drug reactions by applying a global introspection method in a high complexity hospital: Exploratory Research in Clinical and Social Pharmacy: Volume 3, September 2021, 100064
- Martin J. Doherty: Algorithms for assessing the probability of an Adverse Drug Reaction: Respiratory Medicine CME Volume 2, Issue 2, 2009, Pages 63-67
Author
Mridula Pant - Sr. Associate-Clinical Safety and Pharmacovigilance (CSPV)
Mridula is Master’s in Pharmacy (Pharmaceutics) with overall 4.4 years of experience in Pharmacovigilance. She had a knowledge of case processing, analyzing different types of AE reporting forms, reviewing the cases with respect to case validity, seriousness, narrative writing for serious and non-serious cases, event coding with the use of MedDRA. Besides she had 1.4 years of experience in Quality Assurance.
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