February 29, 2024 • 27 mins
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
Want to know more?
Here are the research articles cited in the episode:
- Quality of reporting of adverse events in clinical trials of COVID-19 drugs: systematic review
- Psychiatric disorders and hydroxychloroquine for COVID-19: a VigiBase study
- Hepatic disorders with the use of remdesivir for COVID-19
- Serious bradycardia and remdesivir for COVID-19: a new safety concern
- Oxford-AstraZeneca COVID-19 vaccine-induced cerebral venous thrombosis and thrombocytopaenia: a missed opportunity for a rapid return of experience
- Atypical thrombosis associated with VaxZevria® (AstraZeneca) vaccine: data from the French network of regional pharmacovigilance centres
- Teaching pharmacovigilance to French medical students during the COVID-19 pandemic: interest of distance learning clinical reasoning sessions
If you enjoyed this podcast, check out these related episodes from the Drug Safety Matters archive:
- Reforming pharmacovigilance education
- Lessons in pandemic pharmacovigilance
- Intuition in pharmacovigilance
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Follow us on Facebook, LinkedIn, X, or Bluesky and share your thoughts about the show with the hashtag #DrugSafetyMatters.
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Federica Santoro (00:15):
Adverse drug reactions come in many different
shapes and sizes, but the mostconcerning are those that are
serious and unexpected.
In philosophy, such high-impactevents that are impossible to
predict are known as 'blackswans'.
This expression has existed inhuman culture since the ancient
(00:36):
Romans, but it was economist andstatistician Nassim Nicholas
Taleb who popularised it in theearly 21st century.
Taleb explored black swans infinance, history, and
technology, mainly, but todaywe're hunting for them in drug
safety, a field that isnotoriously c haracterised by
(01:00):
risk and uncertainty.
My name is Federica Santoro andthis is Drug Safety Matters, a
podcast by Uppsala MonitoringCentre, where we explore current
issues in pharmacovigilance andpatient safety.
Joining me today is FrançoisMontastruc, specialist in
(01:21):
clinical pharmacology andpharmacovigilance at the
Toulouse University Hospital inFrance.
François has long beenfascinated by Taleb's theory and
its implications for drugsafety.
What makes an adverse drugreaction a black swan and if
they can't be predicted, howshould pharmacovigilance
(01:43):
professionals deal with them?
You'll learn this and much morein the conversation that
follows.
I hope you enjoy listening.
Hi, François, and welcome toDrug Safety Matters.
I am especially delighted tohave you on the show today
(02:07):
because you contacted me a fewmonths ago with an idea for the
podcast, and I love it whenlisteners approach us with ideas
for content.
So, you came to me with an ideaof drawing a parallel between
the science of pharmacovigilanceand the black swan theory,
(02:27):
which is developed bystatistician Nassim Nicholas
Taleb.
And I found that parallel veryinteresting, so here you are to
tell me all about it.
Now, to begin with, I have toadmit I wasn't familiar with
this theory, and it might be newfor others in our audience.
So let's start with this – whatis the black swan theory?
François Montastruc (02:53):
Hi, Federica.
I'm very pleased to presentthis theory.
So the theory was developed byNassim Nicholas Taleb.
He's a statistician.
He's a former trader,specialist in risk analysis.
Taleb is very famous for hisphilosophical essay on
(03:13):
uncertainty, called 'Incerto'.
In 2007 he published his book'The Black Swan: The Impact of
the Highly Improbable.
"In this book, Taleb explains the
black swan event theory.
So the black swan theory is ametaphor.
This theory describes an eventthat comes as a surprise, with a
(03:38):
major effect, and is ofteninappropriately rationalised
after the fact.
The term 'black swan' is basedon an ancient saying that
presumed black swans did notexist, until they were
discovered in Australia in 1697.
(03:59):
So, to resume, the Taleb blackswan theory refers to
statistically unexpected eventsof large magnitude and
consequences.
Taleb explained that black swanevents have a dominant role in
history.
Black swan events should beconsidered as extreme outliers
(04:22):
that collectively play a largerrole than regular occurrence.
Initially, Taleb explained hisblack swan theory using examples
from the field of finance, butafter he developed this theory
outside the financial marketexample.
And I think we could use thisblack swan metaphor to think the
(04:46):
pharmacovigilance activity.
Federica Santoro (04:51):
And I imagine why you draw that parallel.
I mean, if black swans are rareand hard- to- predict events, I
can see where we're going withthis.
But why don't we spell it outfor our listeners?
So, why do you think Taleb'stheory applies so well to the
world of pharmacovigilance?
François Montastruc (05:11):
Yeah, I think that Taleb's theory
applies perfectly topharmacovigilance because it's a
field of medicine that dealswith the uncertainty of drug
risk and rare or very rareadverse drug reactions.
Sometimes these adverse drugreactions have a major impact on
patients and populationsexposed to drugs and these
(05:35):
adverse drug reactions are asurprise because we were unable
to calculate the probability ofthese rare adverse drug
reactions using the first stepof drug clinical evaluations,
especially clinical trials.
So to illustrate the black swantheory in pharmacovigilance, I
(05:55):
would like to present myresearch I did during the
COVID-19 pandemic.
The first research I would liketo speak it's about the adverse
drug reactions reporting inclinical trials of drugs used to
treat COVID-19.
This research was published inBritish Medical Journal Medicine
(06:17):
and the title is 'Quality ofreporting of adverse events in
clinical trials of COVID-19drugs'.
It's a systematic review.
In this research we found threemajor problems in clinical
trials of drugs for COVID-19.
The first problem wasinadequacy and inconsistency in
(06:40):
quality of reporting adverseevents of drug usage for the
treatment of COVID-19 inpublished articles.
We found that one in threestudies had a very low or low
quality of reporting, accordingto the CONSORT statement, which
is the base of recommendationsfor clinical trials.
(07:05):
And we found also that,compared with serious adverse
events reported in trialsummaries on clinical trials,
about half of serious eventswere not reported in published
clinical trials.
So these studies have differentinterpretations.
One is that some publicationsof clinical trials underreported
(07:31):
adverse events and thereforethe safety evaluation of these
drugs is affected because theassessments of benefit– risk
ratio of these COVID-19 drugsbased on these clinical trials
are not precise.
This study finally highlightsthe limitation of clinical
trials for assessing adversedrug reactions, and particularly
(07:54):
in time of emergency, such asthe COVID-19 pandemic.
So, we understand the role ofpharmacovigilance to identify
adverse drug reactions that havenot been identified in clinical
trials, some of which wereblack swan events.
Federica Santoro (08:15):
So obviously, if adverse events go
underreported in clinical trials, then that makes life more
difficult for those of us whowork in the post-marketing phase
, because if we're lacking thatinformation then that might
delay the identification ofadverse events once the drug is
out there.
But why don't we give theaudience some concrete examples.
(08:38):
What is a good example of ablack swan event for you?
François Montastruc (08:45):
Yeah, the good example of black swan event
in pharmacovigilance during theCOVID-19 pandemic are the cases
of thrombosis andthrombocytopenia with the
AstraZeneca COVID-19 vaccines.
In fact, this adverse drugreaction was a surprise for the
pharmacovigilance system andspecialists.
(09:07):
It was an unexpected event andit was not detected in clinical
trials.
Second, these adverse drugreactions had major effects on
patients because it was veryserious adverse drug reactions
and sometimes patients diedafter these adverse drug
(09:29):
reactions.
And it was also a major effecton the vaccination strategy.
For example, in France theAstraZeneca vaccine was no
longer used in young peopleafter the first reports of these
adverse drug reactions.
And finally, after theidentification of these adverse
(09:53):
drug reactions, the adverse drugreaction was better understood,
in particular its mechanism ofaction, people at risk, and its
clinical management.
For these adverse drugreactions, I took part in two
publications (10:09):
firstly, on the first French case reported to
the French pharmacovigilancenetwork, which was used to
better understand the adversedrug reactions, and also a
publication outlining theimportance of rapid and
widespread communication ofthese black swan events or
(10:31):
serious adverse drug reactionsat national, but better at the
international level, betweenpharmacovigilance specialists
and other clinicians.
Federica Santoro (10:43):
And we will link to all those publications
in the show notes so people cango read in more detail if
they're interested.
But okay, so if we say that ablack swan event is a rare and
unpredictable event, like thethrombosis and thrombocytopenia
syndrome with the AstraZenecaCOVID vaccine, where does that
(11:04):
leave us then with the whiteswans, which presumably
represent the majority ofadverse events that are
identified in PV?
Could you give me some examplesof those and what makes a white
swan?
François Montastruc (11:16):
Yeah, exactly.
From the black swan theory wecan use the metaphor for other
clinical situations inpharmacovigilance and, as you
said, there are probably morewhite swans than black swan
events.
Some adverse drug reactions arewell described and could be
(11:38):
considered as white swans.
To illustrate these white swanevents I'm going to use the
research I did in the worldwidepharmacovigilance database,
VigiBase.
So we performed severalpharmacovigilance studies on
(11:59):
VigiBase and the first study Iperformed was at the beginning
of the pandemic.
During the stressful period oflockdown, some patients were
exposed to hydroxychloroquineand this drug is known to have
adverse cardiac and alsopsychiatric effects.
In the publication of thejournal Drug Safety, we show
(12:24):
that several patientsexperienced psychiatric effects
when taking hydroxychloroquinefor COVID-19.
These adverse drug reactions,these psychiatric adverse drug
reactions, were sometimes veryserious with suicide attempts or
psychotic symptoms.
So this is an example of whiteswan because it was a well-known
(12:49):
adverse drug reaction ofhydroxychloroquine, but we
better characterised thisadverse drug reaction using
pharmacovigilance data fromVigiBase.
Federica Santoro (13:01):
So you're saying there's nothing extremely
new about that observation?
If a drug has a prettyestablished safety profile, then
when you use it for a newindication, you actually should
expect a very similar array ofadverse events.
François Montastruc (13:15):
Yeah.
There are also white swanevents with new drugs when the
adverse drug reaction wasalready described in clinical
trials.
During the COVID-19 pandemic,it was the case of remdesivir,
which was a new drug where inclinical trials they described
(13:35):
hepatic adverse effects.
And we performed, after thefirst use of these drugs, we
performed a pharmacovigilancestudy to corroborate this safety
profile with remdesivir.
Federica Santoro (13:54):
So we've described now the two extremes,
so to say.
So, we have the rareunpredictable events, on one
hand – the black swans – andthen we have the more
predictable ones that in one wayor the other have been
described in trials or in theliterature, and so that we
should really see coming.
(14:14):
But, you know, life is rarelyblack and white, so what about
those in- between cases?
Can we call them grey swans andwhat do those look like?
François Montastruc (14:26):
Yeah, this is the major world of
pharmacovigilance systems.
It's about the grey swans: adverse drug reactions that are (14:31):
undefined
unexpected events because theywere not reported in clinical
trials (because clinical trialshave limitations, as we said
before), but thanks to thepharmacological expertise, we
can anticipate these events.
(14:55):
This expertise ofpharmacovigilance specialists is
based on the different tools ofpharmacology, including drug
mechanism of action, history ofdrugs, pharmacodynamic,
pharmacokinetics, evenpharmacogenetics could help to
(15:15):
identify grey swans.
To illustrate this example ofgrey swans, I would like to
speak about, again aboutremdesivir and the signal of
pharmacovigilance about seriousbradycardia.
In fact, when this drug wasmarketed and used for COVID-19,
(15:40):
we identified this drug was thesimilar family of drugs, of
other anti viral drugs which wecall phosphoramidate drugs.
And these drugs in fact have ahistory of safety in the past,
in clinical trials or when theywere marketed.
(16:00):
For example, remdesivir was thesame family of sofos buvir,
which is known to inducebradycardia and severe
bradycardia when it isassociated with amiodarone.
So we were expecting thatremdesivir could induce serious
(16:21):
bradycardia.
And at the beginning of thepandemic, 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 withremdesivir, and this signal was
(16:45):
corroborated after with anothermore robust study.
So that's an example of greysignal which could illustrate
one major goal ofpharmacovigilance specialists.
Federica Santoro (17:00):
Great, and so we've covered now the full scale
of swans, from black to white.
I'm wondering, whatimplications would you say all
of this has for drug safetyexperts like yourself?
If white and grey swans arerelatively easy to predict, then
(17:22):
why can't we always protectpatients from harm?
François Montastruc (17:27):
Well, in fact, I think a
pharmacovigilance systemspecialist should focus on white
, grey, and black swan events.
And as pharmacovigilancespecialists, we have to better
understand white swan events, tobetter describe the white
(17:49):
events, because they are morecommon in patients, and to
protect them better.
We have to also better detect inpost-marketing the grey swans,
which could be anticipated basedon the pharmacological
knowledge, and that should be apriority for the signal
(18:11):
detection in pharmacovigilance.
But also the pharmacovigilancespecialist and the system should
be flexible, because we knowthat sometimes black swan events
with major impact for publichealth and patients could
emerge, and so we should beflexible.
(18:33):
Nassim Nicholas Taleb namedthat the 'antifragile' concept:
to identify rapidly the blackswan events and also communicate
the pharmacovigilance signalsat the international level to
help physicians and to protectthese patients.
(18:54):
So we need flexibility andreactivity to better protect
patients about black swan events, but also grey and white swans.
In fact, I think we can use themetaphor of black swan theory
(19:16):
and we can call thepharmacovigilance could be as a
bird catcher or, what we say inFrench, the 'oiseleur', which
was a specialist to catch birdsin the past.
So we have to be a bird catcher, catcher of adverse reactions,
(19:39):
and for that we need to use allthe tools of pharmacology,
especially the knowledge ofpharmacovigilance.
Federica Santoro (19:48):
I like that analogy and I think it sounds
way better in French than birdcatcher in English.
But let's expand a little biton that, then.
I mean, the essence of Taleb'stheory is really not that you
can predict black swans, becauseby nature they are
unpredictable, but of coursethat you can prepare and set up
(20:08):
systems, as you say, to beflexible and reactive, so that
then, when the black swan eventappears, you know what to do.
But yeah, back to thepharmacovigilance specialist as
the bird catcher.
Is that a skill you can teach?
How do we get better atidentifying and acting in
(20:31):
response to black swans?
François Montastruc (20:33):
Yeah, to respond to these black swans, or
even if grey and white, we haveto work together.
And so the pharmacovigilancespecialist should work with
other actors ofpharmacovigilance, which are
patients, health professionals,and medical doctors.
For that, we need to learnpharmacovigilance to every actor
(20:59):
around the drugs, especiallymedical doctors, and for that,
during the COVID-19 pandemic, Ideveloped a method to teach
pharmacovigilance to Frenchmedical students.
This method was simulations ofmedical consultations between
one student, which played therole of patients, and another
(21:24):
student or two other studentswhich played the role of doctors
.
And these students should learnhow we ask questions to detect
adverse drug reactions.
We used some examples ofadverse drug reactions induced
by COVID-19 vaccines, and thisexperience was very well
(21:50):
received by French students,because for the first time
during the medical learning,they tried to understand what
are the skills to identifyadverse drug reactions and also
report to the pharmacovigilancesystems.
I explored the method and whatwe did with French medical
(22:13):
students in a publicationrecently published in the
journal Therapies.
Federica Santoro (22:20):
So we can link to that in the show notes as
well.
And for those who areinterested, I can also recommend
a few episodes from the DrugSafety Matters Archive on
teaching pharmacovigilance tohealth care professionals, but
also an episode from the veryfirst year of the podcast on
intuition in pharmacovigilanceand learning to harness that
(22:41):
skill to detect events sooner.
So I can highly recommendlistening to those if you're
curious.
Well, thanks, François.
I think I'll conclude with onefinal question.
You've mentioned nowcollaboration several times and
the need to communicate betteramong different types of
professionals.
(23:01):
This seems to be a recurringtheme in your work.
I couldn't help noticing, whenI was preparing for this
interview, that you did a lot ofwork with other regional
pharmacovigilance centres duringthe pandemic.
That was sort of the hallmarkof the French strategy in
response to the pandemic and theintroduction of the COVID
(23:23):
vaccines.
But also, there's onepublication you released shortly
after the thrombosis andthrombocytopenia syndrome was
linked to the AstraZenecavaccine, where you advocated for
clinicians to share informationfaster and better when these
(23:44):
really serious andlife-threatening adverse events
emerge, and there you suggestedthat pharmacovigilance centres
could play a crucial role.
So, my question is, what didall of that – the pandemic, the
response to the vaccinationcampaigns – teach you really
about how different professionscan come together and how you
(24:08):
can harness collaboration bestfor the safety of patients.
François Montastruc (24:14):
Well, I think the experience of COVID-19
pandemic at different levels ofpharmacology, but especially in
pharmacovigilance, called tobetter communications in a
network of specialists of drugsand between medical doctors,
because we need to share rapidlythe information about drug
(24:38):
safety to better characterisethe signals and also to have a
better treatment for patientswhen they have serious adverse
drug reactions.
So, I think bettercommunication among the network
of pharmacovigilance, at theregional, national, but also at
(25:00):
the international level, shouldimprove the knowledge of drugs
and to improve the flexibilityagainst black swan events.
So we have to work together and, with a global view, should
improve the pharmacovigilanceand protect the patients.
Federica Santoro (25:20):
Well, thank you.
Obviously, as advocates of aninternational programme for drug
monitoring, here at UppsalaMonitoring Centre, we couldn't
agree more on the value ofglobal collaboration.
Thank you very much for yourtime, François, and I hope our
listeners will find thisinspiring and will try to become
(25:43):
better bird catchers.
François Montastruc (25:45):
Thank you, Federica.
Thank you, everybody.
Federica Santoro (25:56):
That's all for now, but we'll be back soon
with more conversations onmedicines safety.
If you'd like to know moreabout the black swan theory and
research, check out the episodeshow notes for useful links.
If you like our podcast,subscribe to it in your
favourite player so you won'tmiss an episode, and spread the
(26:20):
word on social media so otherlisteners can find us.
Apart from these in-depthconversations with experts, we
host a series called UppsalaReports Long Reads, a selection
of audio stories from UMC'spharmacovigilance news site, so
do check that out, too.
Uppsala Monitoring Centre is onFacebook, LinkedIn, and X, and
(26:45):
we'd love to hear from you.
Send us comments or suggestionsfor the show or send in
questions for our guests nexttime we open up for that.
For Drug Safety Matters, I'mFederica Santoro.
I'd like to thank FrançoisMontastruc for his time, Matthew
Barwick for post-productionsupport, and of course you for
(27:08):
tuning in.
Till next time.
Adverse drug reactions come in many different
shapes and sizes, but the mostconcerning are those that are
serious and unexpected.
In philosophy, such high-impactevents that are impossible to
predict are known as 'blackswans'.
This expression has existed inhuman culture since the ancient
(00:36):
Romans, but it was economist andstatistician Nassim Nicholas
Taleb who popularised it in theearly 21st century.
Taleb explored black swans infinance, history, and
technology, mainly, but todaywe're hunting for them in drug
safety, a field that isnotoriously c haracterised by
(01:00):
risk and uncertainty.
My name is Federica Santoro andthis is Drug Safety Matters, a
podcast by Uppsala MonitoringCentre, where we explore current
issues in pharmacovigilance andpatient safety.
Joining me today is FrançoisMontastruc, specialist in
(01:21):
clinical pharmacology andpharmacovigilance at the
Toulouse University Hospital inFrance.
François has long beenfascinated by Taleb's theory and
its implications for drugsafety.
What makes an adverse drugreaction a black swan and if
they can't be predicted, howshould pharmacovigilance
(01:43):
professionals deal with them?
You'll learn this and much morein the conversation that
follows.
I hope you enjoy listening.
Hi, François, and welcome toDrug Safety Matters.
I am especially delighted tohave you on the show today
(02:07):
because you contacted me a fewmonths ago with an idea for the
podcast, and I love it whenlisteners approach us with ideas
for content.
So, you came to me with an ideaof drawing a parallel between
the science of pharmacovigilanceand the black swan theory,
(02:27):
which is developed bystatistician Nassim Nicholas
Taleb.
And I found that parallel veryinteresting, so here you are to
tell me all about it.
Now, to begin with, I have toadmit I wasn't familiar with
this theory, and it might be newfor others in our audience.
So let's start with this – whatis the black swan theory?
François Montastruc (02:53):
Hi, Federica.
I'm very pleased to presentthis theory.
So the theory was developed byNassim Nicholas Taleb.
He's a statistician.
He's a former trader,specialist in risk analysis.
Taleb is very famous for hisphilosophical essay on
(03:13):
uncertainty, called 'Incerto'.
In 2007 he published his book'The Black Swan: The Impact of
the Highly Improbable.
"In this book, Taleb explains the
black swan event theory.
So the black swan theory is ametaphor.
This theory describes an eventthat comes as a surprise, with a
(03:38):
major effect, and is ofteninappropriately rationalised
after the fact.
The term 'black swan' is basedon an ancient saying that
presumed black swans did notexist, until they were
discovered in Australia in 1697.
(03:59):
So, to resume, the Taleb blackswan theory refers to
statistically unexpected eventsof large magnitude and
consequences.
Taleb explained that black swanevents have a dominant role in
history.
Black swan events should beconsidered as extreme outliers
(04:22):
that collectively play a largerrole than regular occurrence.
Initially, Taleb explained hisblack swan theory using examples
from the field of finance, butafter he developed this theory
outside the financial marketexample.
And I think we could use thisblack swan metaphor to think the
(04:46):
pharmacovigilance activity.
Federica Santoro (04:51):
And I imagine why you draw that parallel.
I mean, if black swans are rareand hard- to- predict events, I
can see where we're going withthis.
But why don't we spell it outfor our listeners?
So, why do you think Taleb'stheory applies so well to the
world of pharmacovigilance?
François Montastruc (05:11):
Yeah, I think that Taleb's theory
applies perfectly topharmacovigilance because it's a
field of medicine that dealswith the uncertainty of drug
risk and rare or very rareadverse drug reactions.
Sometimes these adverse drugreactions have a major impact on
patients and populationsexposed to drugs and these
(05:35):
adverse drug reactions are asurprise because we were unable
to calculate the probability ofthese rare adverse drug
reactions using the first stepof drug clinical evaluations,
especially clinical trials.
So to illustrate the black swantheory in pharmacovigilance, I
(05:55):
would like to present myresearch I did during the
COVID-19 pandemic.
The first research I would liketo speak it's about the adverse
drug reactions reporting inclinical trials of drugs used to
treat COVID-19.
This research was published inBritish Medical Journal Medicine
(06:17):
and the title is 'Quality ofreporting of adverse events in
clinical trials of COVID-19drugs'.
It's a systematic review.
In this research we found threemajor problems in clinical
trials of drugs for COVID-19.
The first problem wasinadequacy and inconsistency in
(06:40):
quality of reporting adverseevents of drug usage for the
treatment of COVID-19 inpublished articles.
We found that one in threestudies had a very low or low
quality of reporting, accordingto the CONSORT statement, which
is the base of recommendationsfor clinical trials.
(07:05):
And we found also that,compared with serious adverse
events reported in trialsummaries on clinical trials,
about half of serious eventswere not reported in published
clinical trials.
So these studies have differentinterpretations.
One is that some publicationsof clinical trials underreported
(07:31):
adverse events and thereforethe safety evaluation of these
drugs is affected because theassessments of benefit– risk
ratio of these COVID-19 drugsbased on these clinical trials
are not precise.
This study finally highlightsthe limitation of clinical
trials for assessing adversedrug reactions, and particularly
(07:54):
in time of emergency, such asthe COVID-19 pandemic.
So, we understand the role ofpharmacovigilance to identify
adverse drug reactions that havenot been identified in clinical
trials, some of which wereblack swan events.
Federica Santoro (08:15):
So obviously, if adverse events go
underreported in clinical trials, then that makes life more
difficult for those of us whowork in the post-marketing phase
, because if we're lacking thatinformation then that might
delay the identification ofadverse events once the drug is
out there.
But why don't we give theaudience some concrete examples.
(08:38):
What is a good example of ablack swan event for you?
François Montastruc (08:45):
Yeah, the good example of black swan event
in pharmacovigilance during theCOVID-19 pandemic are the cases
of thrombosis andthrombocytopenia with the
AstraZeneca COVID-19 vaccines.
In fact, this adverse drugreaction was a surprise for the
pharmacovigilance system andspecialists.
(09:07):
It was an unexpected event andit was not detected in clinical
trials.
Second, these adverse drugreactions had major effects on
patients because it was veryserious adverse drug reactions
and sometimes patients diedafter these adverse drug
(09:29):
reactions.
And it was also a major effecton the vaccination strategy.
For example, in France theAstraZeneca vaccine was no
longer used in young peopleafter the first reports of these
adverse drug reactions.
And finally, after theidentification of these adverse
(09:53):
drug reactions, the adverse drugreaction was better understood,
in particular its mechanism ofaction, people at risk, and its
clinical management.
For these adverse drugreactions, I took part in two
publications (10:09):
firstly, on the first French case reported to
the French pharmacovigilancenetwork, which was used to
better understand the adversedrug reactions, and also a
publication outlining theimportance of rapid and
widespread communication ofthese black swan events or
(10:31):
serious adverse drug reactionsat national, but better at the
international level, betweenpharmacovigilance specialists
and other clinicians.
Federica Santoro (10:43):
And we will link to all those publications
in the show notes so people cango read in more detail if
they're interested.
But okay, so if we say that ablack swan event is a rare and
unpredictable event, like thethrombosis and thrombocytopenia
syndrome with the AstraZenecaCOVID vaccine, where does that
(11:04):
leave us then with the whiteswans, which presumably
represent the majority ofadverse events that are
identified in PV?
Could you give me some examplesof those and what makes a white
swan?
François Montastruc (11:16):
Yeah, exactly.
From the black swan theory wecan use the metaphor for other
clinical situations inpharmacovigilance and, as you
said, there are probably morewhite swans than black swan
events.
Some adverse drug reactions arewell described and could be
(11:38):
considered as white swans.
To illustrate these white swanevents I'm going to use the
research I did in the worldwidepharmacovigilance database,
VigiBase.
So we performed severalpharmacovigilance studies on
(11:59):
VigiBase and the first study Iperformed was at the beginning
of the pandemic.
During the stressful period oflockdown, some patients were
exposed to hydroxychloroquineand this drug is known to have
adverse cardiac and alsopsychiatric effects.
In the publication of thejournal Drug Safety, we show
(12:24):
that several patientsexperienced psychiatric effects
when taking hydroxychloroquinefor COVID-19.
These adverse drug reactions,these psychiatric adverse drug
reactions, were sometimes veryserious with suicide attempts or
psychotic symptoms.
So this is an example of whiteswan because it was a well-known
(12:49):
adverse drug reaction ofhydroxychloroquine, but we
better characterised thisadverse drug reaction using
pharmacovigilance data fromVigiBase.
Federica Santoro (13:01):
So you're saying there's nothing extremely
new about that observation?
If a drug has a prettyestablished safety profile, then
when you use it for a newindication, you actually should
expect a very similar array ofadverse events.
François Montastruc (13:15):
Yeah.
There are also white swanevents with new drugs when the
adverse drug reaction wasalready described in clinical
trials.
During the COVID-19 pandemic,it was the case of remdesivir,
which was a new drug where inclinical trials they described
(13:35):
hepatic adverse effects.
And we performed, after thefirst use of these drugs, we
performed a pharmacovigilancestudy to corroborate this safety
profile with remdesivir.
Federica Santoro (13:54):
So we've described now the two extremes,
so to say.
So, we have the rareunpredictable events, on one
hand – the black swans – andthen we have the more
predictable ones that in one wayor the other have been
described in trials or in theliterature, and so that we
should really see coming.
(14:14):
But, you know, life is rarelyblack and white, so what about
those in- between cases?
Can we call them grey swans andwhat do those look like?
François Montastruc (14:26):
Yeah, this is the major world of
pharmacovigilance systems.
It's about the grey swans: adverse drug reactions that are (14:31):
undefined
unexpected events because theywere not reported in clinical
trials (because clinical trialshave limitations, as we said
before), but thanks to thepharmacological expertise, we
can anticipate these events.
(14:55):
This expertise ofpharmacovigilance specialists is
based on the different tools ofpharmacology, including drug
mechanism of action, history ofdrugs, pharmacodynamic,
pharmacokinetics, evenpharmacogenetics could help to
(15:15):
identify grey swans.
To illustrate this example ofgrey swans, I would like to
speak about, again aboutremdesivir and the signal of
pharmacovigilance about seriousbradycardia.
In fact, when this drug wasmarketed and used for COVID-19,
(15:40):
we identified this drug was thesimilar family of drugs, of
other anti viral drugs which wecall phosphoramidate drugs.
And these drugs in fact have ahistory of safety in the past,
in clinical trials or when theywere marketed.
(16:00):
For example, remdesivir was thesame family of sofos buvir,
which is known to inducebradycardia and severe
bradycardia when it isassociated with amiodarone.
So we were expecting thatremdesivir could induce serious
(16:21):
bradycardia.
And at the beginning of thepandemic, 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 withremdesivir, and this signal was
(16:45):
corroborated after with anothermore robust study.
So that's an example of greysignal which could illustrate
one major goal ofpharmacovigilance specialists.
Federica Santoro (17:00):
Great, and so we've covered now the full scale
of swans, from black to white.
I'm wondering, whatimplications would you say all
of this has for drug safetyexperts like yourself?
If white and grey swans arerelatively easy to predict, then
(17:22):
why can't we always protectpatients from harm?
François Montastruc (17:27):
Well, in fact, I think a
pharmacovigilance systemspecialist should focus on white
, grey, and black swan events.
And as pharmacovigilancespecialists, we have to better
understand white swan events, tobetter describe the white
(17:49):
events, because they are morecommon in patients, and to
protect them better.
We have to also better detect inpost-marketing the grey swans,
which could be anticipated basedon the pharmacological
knowledge, and that should be apriority for the signal
(18:11):
detection in pharmacovigilance.
But also the pharmacovigilancespecialist and the system should
be flexible, because we knowthat sometimes black swan events
with major impact for publichealth and patients could
emerge, and so we should beflexible.
(18:33):
Nassim Nicholas Taleb namedthat the 'antifragile' concept:
to identify rapidly the blackswan events and also communicate
the pharmacovigilance signalsat the international level to
help physicians and to protectthese patients.
(18:54):
So we need flexibility andreactivity to better protect
patients about black swan events, but also grey and white swans.
In fact, I think we can use themetaphor of black swan theory
(19:16):
and we can call thepharmacovigilance could be as a
bird catcher or, what we say inFrench, the 'oiseleur', which
was a specialist to catch birdsin the past.
So we have to be a bird catcher, catcher of adverse reactions,
(19:39):
and for that we need to use allthe tools of pharmacology,
especially the knowledge ofpharmacovigilance.
Federica Santoro (19:48):
I like that analogy and I think it sounds
way better in French than birdcatcher in English.
But let's expand a little biton that, then.
I mean, the essence of Taleb'stheory is really not that you
can predict black swans, becauseby nature they are
unpredictable, but of coursethat you can prepare and set up
(20:08):
systems, as you say, to beflexible and reactive, so that
then, when the black swan eventappears, you know what to do.
But yeah, back to thepharmacovigilance specialist as
the bird catcher.
Is that a skill you can teach?
How do we get better atidentifying and acting in
(20:31):
response to black swans?
François Montastruc (20:33):
Yeah, to respond to these black swans, or
even if grey and white, we haveto work together.
And so the pharmacovigilancespecialist should work with
other actors ofpharmacovigilance, which are
patients, health professionals,and medical doctors.
For that, we need to learnpharmacovigilance to every actor
(20:59):
around the drugs, especiallymedical doctors, and for that,
during the COVID-19 pandemic, Ideveloped a method to teach
pharmacovigilance to Frenchmedical students.
This method was simulations ofmedical consultations between
one student, which played therole of patients, and another
(21:24):
student or two other studentswhich played the role of doctors
.
And these students should learnhow we ask questions to detect
adverse drug reactions.
We used some examples ofadverse drug reactions induced
by COVID-19 vaccines, and thisexperience was very well
(21:50):
received by French students,because for the first time
during the medical learning,they tried to understand what
are the skills to identifyadverse drug reactions and also
report to the pharmacovigilancesystems.
I explored the method and whatwe did with French medical
(22:13):
students in a publicationrecently published in the
journal Therapies.
Federica Santoro (22:20):
So we can link to that in the show notes as
well.
And for those who areinterested, I can also recommend
a few episodes from the DrugSafety Matters Archive on
teaching pharmacovigilance tohealth care professionals, but
also an episode from the veryfirst year of the podcast on
intuition in pharmacovigilanceand learning to harness that
(22:41):
skill to detect events sooner.
So I can highly recommendlistening to those if you're
curious.
Well, thanks, François.
I think I'll conclude with onefinal question.
You've mentioned nowcollaboration several times and
the need to communicate betteramong different types of
professionals.
(23:01):
This seems to be a recurringtheme in your work.
I couldn't help noticing, whenI was preparing for this
interview, that you did a lot ofwork with other regional
pharmacovigilance centres duringthe pandemic.
That was sort of the hallmarkof the French strategy in
response to the pandemic and theintroduction of the COVID
(23:23):
vaccines.
But also, there's onepublication you released shortly
after the thrombosis andthrombocytopenia syndrome was
linked to the AstraZenecavaccine, where you advocated for
clinicians to share informationfaster and better when these
(23:44):
really serious andlife-threatening adverse events
emerge, and there you suggestedthat pharmacovigilance centres
could play a crucial role.
So, my question is, what didall of that – the pandemic, the
response to the vaccinationcampaigns – teach you really
about how different professionscan come together and how you
(24:08):
can harness collaboration bestfor the safety of patients.
François Montastruc (24:14):
Well, I think the experience of COVID-19
pandemic at different levels ofpharmacology, but especially in
pharmacovigilance, called tobetter communications in a
network of specialists of drugsand between medical doctors,
because we need to share rapidlythe information about drug
(24:38):
safety to better characterisethe signals and also to have a
better treatment for patientswhen they have serious adverse
drug reactions.
So, I think bettercommunication among the network
of pharmacovigilance, at theregional, national, but also at
(25:00):
the international level, shouldimprove the knowledge of drugs
and to improve the flexibilityagainst black swan events.
So we have to work together and, with a global view, should
improve the pharmacovigilanceand protect the patients.
Federica Santoro (25:20):
Well, thank you.
Obviously, as advocates of aninternational programme for drug
monitoring, here at UppsalaMonitoring Centre, we couldn't
agree more on the value ofglobal collaboration.
Thank you very much for yourtime, François, and I hope our
listeners will find thisinspiring and will try to become
(25:43):
better bird catchers.
François Montastruc (25:45):
Thank you, Federica.
Thank you, everybody.
Federica Santoro (25:56):
That's all for now, but we'll be back soon
with more conversations onmedicines safety.
If you'd like to know moreabout the black swan theory and
research, check out the episodeshow notes for useful links.
If you like our podcast,subscribe to it in your
favourite player so you won'tmiss an episode, and spread the
(26:20):
word on social media so otherlisteners can find us.
Apart from these in-depthconversations with experts, we
host a series called UppsalaReports Long Reads, a selection
of audio stories from UMC'spharmacovigilance news site, so
do check that out, too.
Uppsala Monitoring Centre is onFacebook, LinkedIn, and X, and
(26:45):
we'd love to hear from you.
Send us comments or suggestionsfor the show or send in
questions for our guests nexttime we open up for that.
For Drug Safety Matters, I'mFederica Santoro.
I'd like to thank FrançoisMontastruc for his time, Matthew
Barwick for post-productionsupport, and of course you for
(27:08):
tuning in.
Till next time.
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