How can the ‘Black Swan Theory’ help us Prevent Adverse Drug Reactions?

Perspective / 23 September 2024

How does an economics theory apply to drug safety, and how can we use it to better manage rare, unexpected, and serious adverse drug reactions?


Any prescription and/or administration of a drug exposes the patient to the risk of mild or serious adverse drug reactions of varying frequency. The role of the pharmacovigilance specialist is to prevent, manage, and monitor adverse drug reactions. This pharmacovigilance activity is applied both collectively through public health initiatives and individually through clinical practice involving patients and prescribing doctors. The prevention and management of both frequent and serious adverse drug reactions, for example bleeding with anticoagulants, or falls with psychotropic drugs, are part of the day-to-day management of drug prescribing and the priority of modern pharmacovigilance, as they have a major impact on patients in terms of mortality, morbidity, quality of life, and economy.

However, serious, unexpected adverse drug reactions are often more difficult to manage on an individual or collective scale, as they occur very rarely. As a result, they sometimes cause considerable concern for patients and decision-makers and have a major impact on prescribing recommendations. Therefore, thinking about the management of rare, unexpected adverse drug reactions with a high social and/or individual impact should be a priority for pharmacovigilance specialists in the 21st century.

Black Swan Theory

In philosophy, such high-impact events that are impossible to predict are known as 'black swans'. The black swan theory is a metaphor popularised in the early 21st century by the economist and statistician Nassim Nicholas Taleb. The term 'black swan' is based on an ancient saying that presumed black swans did not exist until they were discovered in Australia in 1697. This theory describes an event that comes as a surprise, has a major effect, and is often inappropriately rationalised after the fact. Taleb mainly explored black swans in finance, history, and technology, but we could hunt black swans in drug safety, a field that is notoriously characterised by risk and uncertainty.

Some adverse drug reactions can be characterised as black swans because they have a major impact on patients and populations, yet come as a surprise because we have not been able to calculate the probability of these rare adverse reactions using clinical drug evaluations or data from clinical trials.

 

The "Black Swan" theory was originally applied to finance, history, and technology

White, Grey, and Black Swans

Based on this theory, we could classify adverse drug reactions as white, grey, or black swans. Let’s take an example from pharmacovigilance studies conducted during the COVID-19 pandemic. Well-described and known adverse drug reactions could be considered as white swans. During the stressful period of lockdown during the COVID-19 pandemic, some patients were exposed to hydroxychloroquine, which is known to have adverse psychiatric effects. Our publication in Drug Safety described several cases where patients experienced psychiatric effects when taking hydroxychloroquine for COVID-19. This is a nice example of a white swan because it is an already well-known adverse drug reaction of hydroxychloroquine but was better characterised using pharmacovigilance data from VigiBase in the specific context of COVID-19.

An example of a black swan event in pharmacovigilance during the COVID-19 pandemic is the risk of thrombosis and thrombocytopenia with non-replicating adenovirus vector-based COVID-19 vaccines. This adverse drug reaction was a surprise to pharmacovigilance specialists and clinical specialists, as it was not previously detected in clinical trials. These adverse drug reactions had major effects on patients because they resulted in ‘serious’ outcomes, such as death, and had a major impact on the global COVID-19 vaccination strategy.

Between unpredictable effects (black swans) and those that are already described (white swans), one can also distinguish grey swans. Adverse drug reactions considered as grey swans are unexpected because they were not reported in clinical trials, but thanks to pharmacological expertise such as pharmacodynamics of the drug effects, drug mechanism of action, history of drugs, pharmacokinetics, and pharmacogenetics, can be anticipated. The example of remdesivir and serious bradycardia is a good example of a grey swan event. When this drug was marketed and used for COVID-19, we anticipated that this drug could induce serious bradycardia as it was pharmacologically close to other anti-viral drugs called phosphoramidate drugs, and another drug in this class, sofosbuvir, is known to induce severe bradycardia when associated with amiodarone.

Predicting the unexpected

The classification of adverse drug reactions into white, grey, and black swan events could be very useful to the pharmacovigilance specialist, as they help pharmacovigilance systems remain flexible. Knowledge of which adverse drug reactions are “white swans” should enable pharmacovigilance specialists to manage frequent adverse drug reactions in patients on a day-to-day basis, and thus better protect them. Better characterisation of post-marketing “grey swans”, which could be anticipated based on pharmacological knowledge, would help predict and prioritise potential pharmacovigilance signals. This gives our pharmacovigilance systems the space to be able to handle these “black swan” events with a major impact on public health and patients.

The Pharmacovigilance specialist as a bird catcher

Based on the metaphor of the black swan theory, we could characterise pharmacovigilance specialists as a bird catcher or, as we say in French, the “oiseleur”. Much like an “oiseleur”, pharmacovigilance specialists need extensive theoretical training, field experience working with patients, and knowledge of the modern tools of pharmacology (clinical experience, pharmaco-epidemiology, and machine learning) to be able to tame the uncertainty and unpredictability of black swans.

François Montastruc @montastrucf
Medical Doctor and Associate Professor Department of Clinical and Medical Pharmacology and Regional Pharmacovigilance Centre Faculty of Medicine and Toulouse University Hospital

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