Drug Safety Matters

#28 Catching black swans – François Montastruc

February 29, 2024 Uppsala Monitoring Centre
Drug Safety Matters
#28 Catching black swans – François Montastruc
Show Notes Transcript Chapter Markers

Serious and unexpected adverse drug reactions – the ‘black swans’ of pharmacovigilance – can place enormous strain on safety monitoring systems. Drawing examples from the COVID-19 pandemic, François Montastruc from Toulouse University Hospital explains how we can get better at dealing with the unpredictable.

Tune in to find out:

  • What Nassim Nicholas Taleb’s ‘black swan’ theory has to do with pharmacovigilance
  • What makes an adverse drug reaction a black, white, or grey swan
  •  Why flexibility and communication are key to patient safety

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Federica Santoro:

Adverse drug reactions come in many different shapes and sizes, but the most concerning are those that are serious and unexpected. In philosophy, such high-impact events that are impossible to predict are known as 'black swans'. This expression has existed in human culture since the ancient Romans, but it was economist and statistician Nassim Nicholas Taleb who popularised it in the early 21st century. Taleb explored black swans in finance, history, and technology, mainly, but today we're hunting for them in drug safety, a field that is notoriously c haracterised by risk and uncertainty.

Federica Santoro:

My name is Federica Santoro and this is Drug Safety Matters, a podcast by Uppsala Monitoring Centre, where we explore current issues in pharmacovigilance and patient safety. Joining me today is François Montastruc, specialist in clinical pharmacology and pharmacovigilance at the Toulouse University Hospital in France. François has long been fascinated by Taleb's theory and its implications for drug safety. What makes an adverse drug reaction a black swan and if they can't be predicted, how should pharmacovigilance professionals deal with them? You'll learn this and much more in the conversation that follows. I hope you enjoy listening.

Federica Santoro:

Hi, François, and welcome to Drug Safety Matters. I am especially delighted to have you on the show today because you contacted me a few months ago with an idea for the podcast, and I love it when listeners approach us with ideas for content. So, you came to me with an idea of drawing a parallel between the science of pharmacovigilance and the black swan theory, which is developed by statistician Nassim Nicholas Taleb. And I found that parallel very interesting, so here you are to tell me all about it. Now, to begin with, I have to admit I wasn't familiar with this theory, and it might be new for others in our audience. So let's start with this – what is the black swan theory?

François Montastruc:

Hi, Federica. I'm very pleased to present this theory. So the theory was developed by Nassim Nicholas Taleb. He's a statistician. He's a former trader, specialist in risk analysis. Taleb is very famous for his philosophical essay on uncertainty, called 'Incerto'. In 2007 he published his book 'The Black Swan: The Impact of the Highly Improbable."

François Montastruc:

In this book, Taleb explains the black swan event theory. So the black swan theory is a metaphor. This theory describes an event that comes as a surprise, with a major effect, and is often inappropriately rationalised after the fact. 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. So, to resume, the Taleb black swan theory refers to statistically unexpected events of large magnitude and consequences. Taleb explained that black swan events have a dominant role in history. Black swan events should be considered as extreme outliers that collectively play a larger role than regular occurrence. Initially, Taleb explained his black swan theory using examples from the field of finance, but after he developed this theory outside the financial market example. And I think we could use this black swan metaphor to think the pharmacovigilance activity.

Federica Santoro:

And I imagine why you draw that parallel. I mean, if black swans are rare and hard- to- predict events, I can see where we're going with this. But why don't we spell it out for our listeners? So, why do you think Taleb's theory applies so well to the world of pharmacovigilance?

François Montastruc:

Yeah, I think that Taleb's theory applies perfectly to pharmacovigilance because it's a field of medicine that deals with the uncertainty of drug risk and rare or very rare adverse drug reactions. Sometimes these adverse drug reactions have a major impact on patients and populations exposed to drugs and these adverse drug reactions are a surprise because we were unable to calculate the probability of these rare adverse drug reactions using the first step of drug clinical evaluations, especially clinical trials. So to illustrate the black swan theory in pharmacovigilance, I would like to present my research I did during the COVID-19 pandemic. The first research I would like to speak it's about the adverse drug reactions reporting in clinical trials of drugs used to treat COVID-19. This research was published in British Medical Journal Medicine and the title is 'Quality of reporting of adverse events in clinical trials of COVID-19 drugs'. It's a systematic review.

François Montastruc:

In this research we found three major problems in clinical trials of drugs for COVID-19. The first problem was inadequacy and inconsistency in quality of reporting adverse events of drug usage for the treatment of COVID-19 in published articles. We found that one in three studies had a very low or low quality of reporting, according to the CONSORT statement, which is the base of recommendations for clinical trials. And we found also that, compared with serious adverse events reported in trial summaries on clinical trials, about half of serious events were not reported in published clinical trials. So these studies have different interpretations. One is that some publications of clinical trials underreported adverse events and therefore the safety evaluation of these drugs is affected because the assessments of benefit– risk ratio of these COVID-19 drugs based on these clinical trials are not precise. This study finally highlights the limitation of clinical trials for assessing adverse drug reactions, and particularly in time of emergency, such as the COVID-19 pandemic. So, we understand the role of pharmacovigilance to identify adverse drug reactions that have not been identified in clinical trials, some of which were black swan events.

Federica Santoro:

So obviously, if adverse events go underreported in clinical trials, then that makes life more difficult for those of us who work in the post-marketing phase, because if we're lacking that information then that might delay the identification of adverse events once the drug is out there. But why don't we give the audience some concrete examples. What is a good example of a black swan event for you?

François Montastruc:

Yeah, the good example of black swan event in pharmacovigilance during the COVID-19 pandemic are the cases of thrombosis and thrombocytopenia with the AstraZeneca COVID-19 vaccines. In fact, this adverse drug reaction was a surprise for the pharmacovigilance system and specialists. It was an unexpected event and it was not detected in clinical trials.

François Montastruc:

Second, these adverse drug reactions had major effects on patients because it was very serious adverse drug reactions and sometimes patients died after these adverse drug reactions. And it was also a major effect on the vaccination strategy. For example, in France the AstraZeneca vaccine was no longer used in young people after the first reports of these adverse drug reactions. And finally, after the identification of these adverse drug reactions, the adverse drug reaction was better understood, in particular its mechanism of action, people at risk, and its clinical management. For these adverse drug reactions, I took part in two publications: firstly, on the first French case reported to the French pharmacovigilance network, which was used to better understand the adverse drug reactions, and also a publication outlining the importance of rapid and widespread communication of these black swan events or serious adverse drug reactions at national, but better at the international level, between pharmacovigilance specialists and other clinicians.

Federica Santoro:

And we will link to all those publications in the show notes so people can go read in more detail if they're interested. But okay, so if we say that a black swan event is a rare and unpredictable event, like the thrombosis and thrombocytopenia syndrome with the AstraZeneca COVID vaccine, where does that leave us then with the white swans, which presumably represent the majority of adverse events that are identified in PV? Could you give me some examples of those and what makes a white swan?

François Montastruc:

Yeah, exactly. From the black swan theory we can use the metaphor for other clinical situations in pharmacovigilance and, as you said, there are probably more white swans than black swan events. Some adverse drug reactions are well described and could be considered as white swans. To illustrate these white swan events I'm going to use the research I did in the worldwide pharmacovigilance database, VigiBase. So we performed several pharmacovigilance studies on VigiBase and the first study I performed was at the beginning of the pandemic. During the stressful period of lockdown, some patients were exposed to hydroxychloroquine and this drug is known to have adverse cardiac and also psychiatric effects. In the publication of the journal Drug Safety, we show that several patients experienced psychiatric effects when taking hydroxychloroquine for COVID-19. These adverse drug reactions, these psychiatric adverse drug reactions, were sometimes very serious with suicide attempts or psychotic symptoms. So this is an example of white swan because it was a well-known adverse drug reaction of hydroxychloroquine, but we better characterised this adverse drug reaction using pharmacovigilance data from VigiBase.

Federica Santoro:

So you're saying there's nothing extremely new about that observation? If a drug has a pretty established safety profile, then when you use it for a new indication, you actually should expect a very similar array of adverse events.

François Montastruc:

Yeah. There are also white swan events with new drugs when the adverse drug reaction was already described in clinical trials. During the COVID-19 pandemic, it was the case of remdesivir, which was a new drug where in clinical trials they described hepatic adverse effects. And we performed, after the first use of these drugs, we performed a pharmacovigilance study to corroborate this safety profile with remdesivir.

Federica Santoro:

So we've described now the two extremes, so to say. So, we have the rare unpredictable events, on one hand – the black swans – and then we have the more predictable ones that in one way or the other have been described in trials or in the literature, and so that we should really see coming. But, you know, life is rarely black and white, so what about those in- between cases? Can we call them grey swans and what do those look like?

François Montastruc:

Yeah, this is the major world of pharmacovigilance systems.

François Montastruc:

It's about the grey swans: adverse drug reactions that are unexpected events because they were not reported in clinical trials (because clinical trials have limitations, as we said before), but thanks to the pharmacological expertise, we can anticipate these events.

François Montastruc:

This expertise of pharmacovigilance specialists is based on the different tools of pharmacology, including drug mechanism of action, history of drugs, pharmacodynamic, pharmacokinetics, even pharmacogenetics could help to identify grey swans.

François Montastruc:

To illustrate this example of grey swans, I would like to speak about, again about remdesivir and the signal of pharmacovigilance about serious bradycardia. In fact, when this drug was marketed and used for COVID-19, we identified this drug was the similar family of drugs, of other anti viral drugs which we call phosphoramidate drugs. And these drugs in fact have a history of safety in the past, in clinical trials or when they were marketed. For example, remdesivir was the same family of sofos buvir, which is known to induce bradycardia and severe bradycardia when it is associated with amiodarone. So we were expecting that remdesivir could induce serious bradycardia. And at the beginning of the pandemic, only two months after remdesivir was used in the US, based on the pharmacovigilance data, especially VigiBase data, we were able to detect early the signal of serious with remdesivir, and this signal was corroborated after with another more robust study. So that's an example of grey signal which could illustrate one major goal of pharmacovigilance specialists.

Federica Santoro:

Great, and so we've covered now the full scale of swans, from black to white. I'm wondering, what implications would you say all of this has for drug safety experts like yourself? If white and grey swans are relatively easy to predict, then why can't we always protect patients from harm?

François Montastruc:

Well, in fact, I think a pharmacovigilance system specialist should focus on white, grey, and black swan events. And as pharmacovigilance specialists, we have to better understand white swan events, to better describe the white events, because they are more common in patients, and to protect them better.

François Montastruc:

We have to also better detect in post-marketing the grey swans, which could be anticipated based on the pharmacological knowledge, and that should be a priority for the signal detection in pharmacovigilance. But also the pharmacovigilance specialist and the system should be flexible, because we know that sometimes black swan events with major impact for public health and patients could emerge, and so we should be flexible. Nassim Nicholas Taleb named that the 'antifragile' concept: to identify rapidly the black swan events and also communicate the pharmacovigilance signals at the international level to help physicians and to protect these patients. So we need flexibility and reactivity to better protect patients about black swan events, but also grey and white swans. In fact, I think we can use the metaphor of black swan theory and we can call the pharmacovigilance could be as a bird catcher or, what we say in French, the 'oiseleur', which was a specialist to catch birds in the past. So we have to be a bird catcher, catcher of adverse reactions, and for that we need to use all the tools of pharmacology, especially the knowledge of pharmacovigilance.

Federica Santoro:

I like that analogy and I think it sounds way better in French than bird catcher in English. But let's expand a little bit on that, then. I mean, the essence of Taleb's theory is really not that you can predict black swans, because by nature they are unpredictable, but of course that you can prepare and set up systems, as you say, to be flexible and reactive, so that then, when the black swan event appears, you know what to do. But yeah, back to the pharmacovigilance specialist as the bird catcher. Is that a skill you can teach? How do we get better at identifying and acting in response to black swans?

François Montastruc:

Yeah, to respond to these black swans, or even if grey and white, we have to work together. And so the pharmacovigilance specialist should work with other actors of pharmacovigilance, which are patients, health professionals, and medical doctors. For that, we need to learn pharmacovigilance to every actor around the drugs, especially medical doctors, and for that, during the COVID-19 pandemic, I developed a method to teach pharmacovigilance to French medical students. This method was simulations of medical consultations between one student, which played the role of patients, and another student or two other students which played the role of doctors. And these students should learn how we ask questions to detect adverse drug reactions. We used some examples of adverse drug reactions induced by COVID-19 vaccines, and this experience was very well received by French students, because for the first time during the medical learning, they tried to understand what are the skills to identify adverse drug reactions and also report to the pharmacovigilance systems. I explored the method and what we did with French medical students in a publication recently published in the journal Therapies.

Federica Santoro:

So we can link to that in the show notes as well. And for those who are interested, I can also recommend a few episodes from the Drug Safety Matters Archive on teaching pharmacovigilance to health care professionals, but also an episode from the very first year of the podcast on intuition in pharmacovigilance and learning to harness that skill to detect events sooner. So I can highly recommend listening to those if you're curious. Well, thanks, François. I think I'll conclude with one final question.

Federica Santoro:

You've mentioned now collaboration several times and the need to communicate better among different types of professionals. This seems to be a recurring theme in your work. I couldn't help noticing, when I was preparing for this interview, that you did a lot of work with other regional pharmacovigilance centres during the pandemic. That was sort of the hallmark of the French strategy in response to the pandemic and the introduction of the COVID vaccines. But also, there's one publication you released shortly after the thrombosis and thrombocytopenia syndrome was linked to the AstraZeneca vaccine, where you advocated for clinicians to share information faster and better when these really serious and life-threatening adverse events emerge, and there you suggested that pharmacovigilance centres could play a crucial role. So, my question is, what did all of that – the pandemic, the response to the vaccination campaigns – teach you really about how different professions can come together and how you can harness collaboration best for the safety of patients.

François Montastruc:

Well, I think the experience of COVID-19 pandemic at different levels of pharmacology, but especially in pharmacovigilance, called to better communications in a network of specialists of drugs and between medical doctors, because we need to share rapidly the information about drug safety to better characterise the signals and also to have a better treatment for patients when they have serious adverse drug reactions. So, I think better communication among the network of pharmacovigilance, at the regional, national, but also at the international level, should improve the knowledge of drugs and to improve the flexibility against black swan events. So we have to work together and, with a global view, should improve the pharmacovigilance and protect the patients.

Federica Santoro:

Well, thank you. Obviously, as advocates of an international programme for drug monitoring, here at Uppsala Monitoring Centre, we couldn't agree more on the value of global collaboration. Thank you very much for your time, François, and I hope our listeners will find this inspiring and will try to become better bird catchers.

François Montastruc:

Thank you, Federica. Thank you, everybody.

Federica Santoro:

That's all for now, but we'll be back soon with more conversations on medicines safety. If you'd like to know more about the black swan theory and research, check out the episode show notes for useful links. If you like our podcast, subscribe to it in your favourite player so you won't miss an episode, and spread the word on social media so other listeners can find us. Apart from these in-depth conversations with experts, we host a series called Uppsala Reports Long Reads, a selection of audio stories from UMC's pharmacovigilance news site, so do check that out, too. Uppsala Monitoring Centre is on Facebook, LinkedIn, and X, and we'd love to hear from you. Send us comments or suggestions for the show or send in questions for our guests next time we open up for that. For Drug Safety Matters, I'm Federica Santoro. I'd like to thank François Montastruc for his time, Matthew Barwick for post-production support and, of course, you for tuning in. Till next time.

Intro
Black swan theory
Relevance to pharmacovigilance
Black swan events
White swan events
Grey swan events
The pharmacovigilance 'oiseleur'
Teaching bird-catching
Collaboration is crucial
Outro