January 28, 2025 • 41 mins
Human and veterinary pharmacovigilance (PV) share many goals, challenges and approaches. But there are also significant differences, such as the numerous animal species that veterinary PV needs to take into account. In this two-part episode of Drug Safety Matters, James Mount, Veterinary Pharmacovigilance assessor at the Swedish Medical Products Agency, and EU elected chair of the Pharmacovigilance Working Party for veterinary medicinal products, joins the show to talk about veterinary PV practice and its differences and similarities to human PV.
Tune in to find out
- How the types of ADRs reported for animals and humans differ
- How the many species and breeds included in veterinary PV affect the ADR coding
- What the Veterinary Big Data Strategy is
... and much more!
Want to know more?
- The public portal of the European Union Veterinary Pharmacovigilance Database.
- One Health – an integrated approach to the well-being of people, animals and the environment.
- A survey of veterinary professionals in Sweden, about practices and attitudes in relation to ADR reporting.
- A review of adverse events in animals and children after secondary exposure to transdermal hormone-containing medicines.
- The EMA Big Data strategy for veterinary medicines and Data quality framework for medicines regulation
- Small Animal Veterinary Surveillance Network (SAVSNET) - University of Liverpool
- VetCompass - Royal Veterinary College, RVC
- Veterinary good pharmacovigilance practices (VGVP) | European Medicines Agency (EMA)
- Veterinary Dictionary for Drug Regulatory Activities (VeDDRA) | European Medicines Agency (EMA)
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About UMC
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Fredrik Brounéus (00:15):
Welcome to Drug Safety Matters, a podcast
by Uppsala Monitoring Center,where we explore current issues
in pharmacovigilance and patientsafety.
I'm Fredrik Brouneus and you'relistening to the second part of
our two-part episode onveterinary pharmacovigilance.
If you haven't yet listened tothe previous part of the
interview, I would suggest thatyou do so first, to get the most
(00:38):
out of the discussions.
And now let's go back to thestudio, where I'm joined by
James Mount, veterinarypharmacovigilance assessor at
the Swedish Medical ProductsAgency and EU-elected chair of
(01:02):
the Pharmacovigilance WorkingParty for Veterinary Medicinal
Products.
Welcome back to the Drug SafetyMatters studio, James.
We have a lot to cover in thesecond part of the interview as
well, so I say let's divestraight in.
Is there a difference in thetype of adverse events reported
on the vet side compared withthe human side?
James Mount (01:18):
Yeah, I would say so.
There is quite a significantdifference.
Apart from these suspectedadverse events that we've talked
about in the first episode, theveterinarians and animal owners
are actually activelyencouraged, and also stipulated
in the legislation, that theyshould be reporting lack of
expected efficacy, and here Imean when a medicine has not had
its intended effect in thoseindividuals that you've treated,
(01:38):
and then also if you suspectthere's an environmental
exposure or incident that'shappened.
These should be reported.
Judging by experience, they'requite rare to happen, but this
is when large amounts ofparticularly veterinary
medicines are leaked into theenvironment.
This is most common,potentially when you've used
dips or baths with productionanimals, commonly with sheep or
(02:00):
with topical preparations inother animals.
And then also veterinarians andeven animal owners are also
potentially encouraged to reportresidues in meat, eggs and milk
which occur potentially whenrecommended withdrawal periods
are not followed.
These are the set periods oftime, usually just a few days,
(02:21):
where meat, eggs and milk shouldnot be used for human
consumption.
And also there is the oddscenario, which is very rare,
that suspected transmission ofan infection agent should also
be reported.
And, as I said, this is a quiterare scenario and often related
to quality defects duringmanufacture, and often they're
detected very early, before evenpatients get exposed to these
Fredrik Brounéus (02:44):
A t the end of the first part of this episode
on veterinary pharmacovigilance,we had a teaser about user
safety and the mention of"self-injection.
How about user safety withveterinary medicines?
Are the risks greater than forhuman medicines?
James Mount (03:03):
With veterinary medicines, I would say that, yes
, there is a greater risk foruser safety, and this is when
you can get exposed to apreparation when you're
administrating it.
And, as I said, animals can bequite a moving target, and so
there can be a risk for humanexposure to a medicine when
you're a vet or an animal nurse,or even animal owners when
you're administering products athome, if you take the example,
(03:26):
as I said, animals are movingtarget and they can easily shake
their head when you're tryingto administer a preparation for
treating an ear infection, andalso I remember that animals can
tend to sneeze when you'regiving an intranasal vaccine and
you can get unintentionallyexposed to that vaccine.
Also, animal owners and familymembers at home can also be at
(03:50):
risk when pets are treated inthe household.
If you take the example whenowners and their children often
stroke and cuddle pets, and ifyou've recently applied a
topical medicine to thatindividual animal, then there
can be a risk for exposure to
Fredrik Brounéus (04:04):
Yeah I can relate to both those scenarios.
We have a big slobbery houndback home and when we applied an
ear medicine he was shaking andthat medicine was flying all
over the room.
James Mount (04:16):
It just proves the point that you have to be
careful with the medicines whenyou are in the home environment.
Sometimes, administration ofsome veterinary products are
actually discouraged to behandled or used in certain human
risk groups.
So that's something you have toconsider at home if you've got
either potentially pregnantwomen at home or people that
with known allergies, then theyshould definitely not handle
(04:37):
these products.
And also then there's adviceabout the handling of animals
for a certain period of timeafter treatment.
So particularly with thesespot-on antiparasitic
preparations that are used athome, there's often stated in
the product information thatanimals should not be cuddled or
touched for a certain amount oftime, normally 24 hours or so,
(04:58):
but these recommendations arenormally clearly stated in the
product information and animalowners and vets should consult
those product informationcarefully.
And then also there are allsorts of scenarios that can
occur and, as we touched on,accidental ingestion potentially
can occur with veterinarymedicines and often relates to
potentially elderly people withpoor eyesight, so they mix up
(05:22):
their medicines with an animalmedicine if they've got them
together in the same cupboard,which is obviously discouraged.
And also children can also getin contact and ingest these
products due to their normalinquisitive nature.
And it's all unintentionalexposure but should be tried to
to be avoided, mainly by lockingaway products and separating
them out from human products.
(05:43):
And then, as as I said,self-injection, which I'm quite
familiar with, that you oftenself-inject yourself a few times
as vets, mainly because theanimals move and are not that
compliant often.
Fredrik Brounéus (05:56):
It sounds potentially, as it could be
quite serious as well, dependingon what kind of medicine you
are injecting.
James Mount (06:03):
Yeah, absolutely, and one of the most serious
cases that I'm familiar with iswhen you can get accidental
ingestion or self-injection withthese alpha-2 adrenoreceptor
agonists that we use, and theseare used to sedate animals in
the field most commonly,particularly horses, and even at
very, very low dosages you canget sedation and blood pressure
changes in humans if they'reexposed to it.
(06:24):
There now are specific warningsin the product information for
these products that contain thisactive ingredient to instruct
vets that if they do suspectthat they have exposed
themselves either accidentallythrough ingestion or
self-injection, that they shouldnot drive, as obviously this
can have a fatal consequence.
Fredrik Brounéus (06:44):
So does the opposite happen as well?
I mean animals beingunintentionally exposed to human
medicines.
James Mount (06:52):
Yeah, of course that's particularly relevant and
it also exposes the crossoverthat we have between the human
and veterinary side, and one ofthe most topical examples here
is exposure to topical hormonereplacement therapies, which are
commonly used by animal owners,and these products normally
contain substances such astestosterone or estrogen, and
(07:13):
they can result in quite severeand serious adverse events in
pet animals if they get exposedin the same household, and most
commonly or what we've observedis most common in dogs and cats,
but even guinea pigs are atrisk as well, and, I'm sure,
other mammals in the householdas well, and also here I should
mention that even children areat risk.
And we've actually publishedobservations, and very recently,
(07:34):
a few weeks ago in fact, theSwedish Medical Products Agency
has launched an informationcampaign in the news and other
social media channels and thiscampaign includes advice to vets
, animal owners and prescribinghuman healthcare professionals
in order to try to reduce therisk of exposure in that
household, mainly focusing onpets, but also children.
(07:57):
For example, part of thecommunication indicates that
it's important for prescribinghuman healthcare professionals
to inform users of the risk ofsecondary exposure in their
household and actually stipulatethat it can be their pets and
children that are at risk, andthen users themselves should be
encouraged to really strictlyfollow the product information,
in particularly where to applythe medicine to avoid secondary
(08:20):
exposure in the household.
And then also, vets are alsothen encouraged to both report
when they see these events inanimals and also consider it as
a differential diagnosis, as wecall it, when they see these
patients come in.
But this example, which we havea campaign about now, is a very
, very good example of thiscrossover between veterinary and
(08:42):
human pharmacovigilance, Iwould say.
Fredrik Brounéus (08:44):
Yes, and we should mention here that we have
a link in the episode shownotes for listeners who want to
find out more about this.
I I read about it in the paperjust a couple of days ago
actually.
James Mount (08:58):
And then there are other scenarios as well.
There has been situations wherehuman products, used both for
animals and humans, have causeda simultaneous sudden rise in
adverse events, and here I'dlike to talk about potentially
the most commonly known example,which is the use of human
gentamicin in horses, and theseobservations were made in 2015
(09:19):
and 17.
So a while back, but there was apresence of high levels of
histamine in the humangentamicin which caused a sudden
spike or sudden increase inhypersensitivity reactions in
horses, and obviously thehypersensitivity reactions in
horses are quite severe, andthese initial serious reactions
that you observed in horsesactually transpired to be an
(09:39):
important indicator for a humanhealth risk.
So the risk for hypersensitivereaction in humans as well.
And obviously the industryinvestigated this issue and it
turned out that there was a fishpeptone which was used as a
nutrient during the growthmedium process of manufacture.
(10:00):
That was the source of thishistamine.
And so later on, the relevanthuman and veterinary medicines
committees within the EU,specifically the CHMP and the
CVMP both made scientificopinions to actually limit the
level of histamine in both humanand veterinary medicines going
forward, to alleviate this riskagain.
Fredrik Brounéus (10:20):
I think it's very interesting, these examples
that you have of the crossover,as you say, between veterinary
and human pharmacovigilance andhow they sort of enrich each
other here.
But I would like to go back towhere you mentioned "lack of
efficacy".
I was intrigued when I firstsaw in the Swedish Medical
(10:41):
Products Agency's ADR reportingform for animals, since, as you
say, it has no equivalent in thereporting form for humans.
And I also noticed in the formfor humans that the user is
asked to provide informationabout where the medicine was
acquired, if it's at a pharmacy,other vendor, internet, abroad
(11:02):
and so on.
But I couldn't find thecorresponding field in the form
for animals.
And another difference Inoticed is that there are no
de-challenge or re-challengequestions in the veterinary form
.
So I was just wondering if youcould comment on these
differences.
James Mount (11:22):
Yes, these are very good observations.
It's good you picked them up.
There are quite significantdifferences of how we report
adverse events on the vet sidewithin Europe and we've already
addressed these potentially inthe first episode that, like we
said, that adverse events on theveterinary side can involve
both animals and humans that arebeing exposed to medicine, and
also the use of human andveterinary medicines is
(11:42):
commonplace in animalsthemselves, and also that more
than one individual can bereported per report and if you
compare this to the human side,only one human can be reported
per report on that side.
So we have many thousands ofanimals can be reported and, as
I said, with these bigfacilities where you've got pigs
and poultry and mink and eventhe fish tanks full of fish,
(12:04):
these facilities, when they formlarge-scale treatments and
vaccinations, can experiencelots of animals with adverse
events if they report them.
But I know the observation thatyou made that the Swedish
Medical Products Agency does notspecifically request
information about the source ofmedicines and also about the
(12:26):
specific information of re- andde-challenge.
But in our experience, often thereporter tends to provide this
information in their free textnarratives that we have in our
system.
And if they don't provide it,then normally we contact the
reporter for this informationand, as we said, the number of
reports that are received, wehave the ability to do that.
(12:50):
But, to be absolutely honest,the Swedish Medical Products
Agency has actually purposelyexcluded a lot of questions in
our specific reporting form inorder to make it easier for
people, that's vets and animalowners, to actually report.
But I'd also say that, onreflection of looking nationally
, within Europe there are quitesignificant differences and some
(13:12):
other EU countries haveadditional questions on their
reporting forms and thesedifferences potentially can be
explained either through thefact that they have specific
national requirements to askthose questions in specific
cases, or there might bespecific circumstances where
there are specific productsbeing used in a disease outbreak
and this might mean that youneed to pose specific questions,
(13:35):
to capture specific informationfrom reporting vets, which then
justifies these additionalquestions.
A nd the current diseaseoutbreaks that we have in Europe
include blue tongue and avianinfluenza, and thus you tend to
pose specific questions on yourreporting form to capture
specific information about theseongoing vaccination campaigns.
Fredrik Brounéus (13:56):
In the previous episode we also talked
about environmental exposure assomething that is reported in
veterinary pharmacovigilance.
Would you say that there's morefocus on environmental aspects
of medicine safety on theveterinary side?
James Mount (14:11):
No, I wouldn't say that the focus is greater on the
vet side.
I would say that the Europeanexperts, on both the human and
veterinary side, they equallyrecognize the significant impact
that medicines have, or canhave, or are having, on our
environment.
In fact, and this is reallyconfirmed through the fact that
now, prior to authorisation ofmedicinal products, European
(14:33):
legislation specificallyrequires all human and
veterinary medicines to undergoan environmental risk assessment
, and we call this an ERA, andit's based on its expected use.
But it's one important aspecthere to clarify is that on the
veterinary side, specifically,if there is an identified
environmental risk during theapproval stages of any
(14:55):
significance, this can be usedas a motivation or a reason to
actually not approve theauthorization of that specific
veterinary medicine, which isnot yet the case on the human
side.
Fredrik Brounéus (15:05):
So almost like an eco veto, so to say.
I think it's interesting tothink back to the One Health
perspective, the one healthconcept that we talked about in
the first part of this episode.
I mean, looking at the weightthat we attribute to human
health as compared to the healthof animals and the health of
(15:27):
the environment, that this issomething that we will perhaps
need to reconsider or at leastwiden our views on.
James Mount (15:46):
Absolutely, I would agree whole-heartedly with you.
If we consider potentially likethe environmental part of One
Health, I'm aware of manyinitiatives, within Europe
specifically, and even otherparts of the world, and this
includes cross-governmentalgroups that have been
established and alsocollaboration between the human
and veterinary experts to try tolook at ways to reduce the
impact of pharmaceuticals in theenvironment.
And here, to plug the Swedishmedical products agency again,
most recently, the Swedish andthe Danish medicine agencies
(16:07):
together have embarked on aclose collaboration regarding
reducing the environmentalimpact of both medical devices
as well as pharmaceuticals, andthey've even begun to discuss
concrete initiatives to try toreduce this environmental impact
, which will be interesting tofollow how this collaboration
progresses.
Fredrik Brounéus (16:28):
Indeed, I was also thinking about the wide
variety of stakeholders that areinvolved in veterinary
pharmacovigilance.
We've touched on this before.
But the veterinarians, the vetnurses, the farmers, the
professional owners, the petowners and so on – it's quite a
diverse crowd as compared to thehuman side.
James Mount (16:50):
Yeah, absolutely.
We are a diverse crowd and wehave quite a different set of
veterinary stakeholders and theengagement and the ability to
reach out to the differentstakeholders can be a challenge,
mainly because we're so diverse.
And apart from contactingstakeholders, as we've said, to
encourage adverse eventreporting, there's often a need
(17:11):
to have established goodchannels of communication when
safety issues are identified,and we normally contact
veterinary health careprofessionals and this is both
vets and nurses either directlyor through their professional
organizations, but distributingsort of important safety
information directly to animalowners, as you can imagine,
they're quite diverse and we'reeven talking about farmers here
(17:33):
of different animal species.
This can be really challenging,although we do sometimes have
to rely on our veterinary healthcare professionals to
distribute that information, andthat's for the prescription
drugs that they prescribe, andthen even we try to encourage
pharmacists also to provide somesafety information, when we're
talking about both prescriptionand non-prescription drugs that
(17:54):
we have on the veterinary side.
In some cases there's a need toeven engage with human
healthcare professionals, whichwe've already talked about with
the topical, hormone exposure,and also discussions with human
pharmacovigilance experts isalso sometimes essential.
Fredrik Brounéus (18:09):
Yeah, listening to to you, James, it's
apparent, I think, in manyways, that veterinary medicine
and veterinary pharmacovigilanceis a lot more complex than
human medicine.
I mean, not only does itinvolve both human and
veterinary products, but itdeals with, you know, a myriad
(18:29):
of not only mammals but alsofish, reptiles, amphibians,
birds and so on, and you alsohave breeds within these many
species, and I was wondering abit how this affects the coding.
James Mount (18:43):
Yeah, well, as in that, species and breed coding
is obviously probably one of thebiggest differences that we
have on the veterinary side and,as I said earlier, that we've
got the VICH standard and theVICH maintain our global
standard list of species andbreeds that we use in coding, so
it's all really harmonized andstandardized and to give you an
idea of that list, because it'squite a long one, there are 40
(19:04):
species on that list, so thatshows the diversity that we have
to deal with and, as an example, there are nearly 400 breeds of
dog on that list and over 300breeds of cattle.
So that just gives an indicationof diversity.
The standard practice generallywith reports is to only report
one species in a report, but youcan report as many breeds
(19:28):
within that species within thosereports.
And then in terms of signaldetection, we normally perform
initial signal detection withinthe same species, otherwise it
becomes very complicated.
Fredrik Brounéus (19:39):
So while we're on the topic of breeds here, we
have received a question viasocial media from one of our
listeners and this is thequestion: Hi, I'm curious about
the difference in side effectsamong different dog breeds and
other animals as well.
I've heard that there are drugsthat are safe to use on most
dogs, but that they'll getthrough the blood brain barrier
(20:00):
on just a few breeds, causingnasty side effects.
Are there many such exceptionsthat need to be considered?
James Mount (20:09):
Thank you for the question and, yes, breed
specific adverse events areknown to occur on the vet side.
There are many examples, butone of the well-known examples
that we have is sensitivity toivermectin in some breeds of dog
, and this is commonlyassociated with collies or sheep
dogs or the crosses betweencollie and sheep dogs, although
(20:29):
there are individuals of bordercollies, sheep dogs, old english
sheep dogs and Australianshepherds that have believed to
have this sensitivity.
And ivermectin itself iscommonly used to treat parasitic
infections in animals.
And the sensitivity in somebreeds of dog, or some
individuals within breeds,relates to the presence of a
(20:50):
deletion gene mutation, and it'sthe MDR-1 gene to be precise,
also known as themultidrug-resistant gene.
And this multidrug-resistantgene encodes a large
transmembrane protein which isobviously an integral part of
the blood-brain barrier.
And when these specific dogshave both copies of this
deletion mutation, then they candevelop signs of neurotoxicity
(21:14):
when treated with ivermectin andthis can be established as a
form of blindness or ataxia andunfortunately, sometimes it can
even result in death and this isattributed to a leaky blood-
brain barrier in theseindividuals, and then it means
that the high amounts of thativermectin can accumulate in the
brain of the susceptible dog.
And then there's other examplesof hypersensitivity to certain
(21:35):
antibiotics, specifically thosethat contain sulfonamides, and
this relates to the Dobermanpinchers, and they can develop a
hypersensitivity anywherebetween 5 and 12 days after the
initiation of treatment, andhere the clinical signs can be
subtle as a fever or hepatopathy, and they can also develop
quite serious neurological signs.
(21:57):
Then, if you consider otherbreed- specific adverse events,
there can be instances where youget a geographical incident of
specific adverse events.
And here I take the examplefrom Sweden and Denmark, where
there were adverse events seenin the landrace breed of Swedish
and Danish pigs specifically,and this was following the use
(22:19):
of an antibiotic from thepleuromutilin group, quite a
specific group, and in this casethe pigs were treated for swine
dysentry using this antibioticand these specific pigs from
these two regions developedfever and also loss of appetite,
incoordination and in someinstances there was a death
observed as well in some ofthese pigs.
(22:39):
So it's quite dramatic andthere has been investigations
undergone, but the exact causehas not been really properly
established, but it's highlylikely it's related to some sort
of genetic susceptibility inthese specific breeds.
And also, there was oneinteresting case in relation to
a species- specific sensitivity,and this is quite dramatic, in
(23:01):
some cases, which is theestablishment of permethrin
toxicosis in cats, a And thisproduct is commonly used to
treat ectoparasites and theseare those infestations where you
get fleas and ticks and mitesthat live on the skin surface.
And it's also, I must say herethat this permethrin is also
(23:22):
used to in some instances totreat l, to treat head lice in
children and also, if scabiesdevelops, in humans as well.
So there can behuman-containing products here.
Permethrin is safe generally touse in most mammals and it's
often applied topically, as youcan imagine.
But cats are really extremelysensitive and this is down to
(23:44):
the fact that they have areduced ability to metabolize
the active substance, permethrin, and instead it just
accumulates in the body andsigns can develop, ranging from
restlessness in the cats tohypersalivation, and they can
even resort to muscle spasms,seizures, and then also they can
die of it as well.
(24:04):
And cats are at risk for bothveterinary and human products
obviously containing this activesubstance, permethrin, and, as
a result, owners should reallybe extremely careful when using
this product, either on theirpets, and they potentially
mistakenly use it on a cat, orwhen they're using it within the
(24:24):
pet's environment, the cats canbe exposed so it should be
careful.
Fredrik Brounéus (24:28):
So, owners using them on themselves .
.
.
James Mount (24:31):
Exactly.
Fredrik Brounéus (24:31):
Yeah mind the breed and the species, in other
words.
And I read that newtechnologies are being tested to
monitor production animalswell-being for instance, that
you could have cameras connectedto an AI to scan or monitor
their behavior for signs ofstress, and I was wondering if
you think that these kinds ofsolutions could become useful
(24:54):
for detecting, and possiblyreporting as well, adverse drug
reactions.
James Mount (24:59):
Yes, you're perfectly right.
There are very many advancedmonitoring systems specifically
for production animals andespecially dairy cattle.
There's a lot of systems therefor monitoring their well-being,
and these comprise of collarsand ear tags that the animals
wear, and this enables thosefarmers to monitor activity, to
(25:20):
provide information onspecifically reproductive
behaviour and then, as you said,general health status as well
to monitor that.
And this activity data that youcollect is vast, but the actual
way we can use it to detectadverse events is still under
investigation, although thereare numerous groups looking into
it to see if they can elucidateadverse events, but it doesn't
(25:42):
have its uses at the moment.
And in terms of otherinnovations, not just
specifically production animals,but within small animal
medicine, there are monitoringtools there available as well.
Now, one example of them I'maware of is there is a wearable
accelerometer which can be usedto detect a puritic activity in
dogs and this is where dogs arevery prone to developing itchy
(26:07):
skin conditions and so that thiswearable accelerometer can
provide an alert for animalowners to seek early veterinary
care before the condition getsreally serious.
And then there are artificialintelligence tools to help
animal owners detect sort ofearly signs of osteoarthritis in
cats as well.
And there are many otherexamples as well live and also
(26:28):
under development, but theability for these innovations to
help us identify adverse eventsis still very much unclear.
Oh, okay, but while we'retalking about AI, at the moment,
the area that would benefitgreatest from the application of
artificial intelligence toolsis our signal detection in our
databases, and I think that'sthe same with the human side,
(26:51):
and AI can assist us there inmultiple ways.
Although the use of AI in actualcase management and that is
when reports are coming in andregistering adverse events then
I think AI is quite limitedthere, mainly through the fact
that you need to have somedegree or some level of manual
human review of cases in orderto understand them as well as to
(27:13):
maintain accuracy in thosecases.
Fredrik Brounéus (27:15):
We'll get back to AI a little further on in
this interview, but this doesbring us to the methods used for
signal detection in veterinarypharmacovigilance.
Would you say that they are thesame as in human practice?
James Mount (27:29):
Yeah, I would say so.
In terms of the use of datafrom spontaneous reported
adverse events, the basicmethods that we use for signal
detection are very, very muchsimilar between the human and
veterinary side.
We use similar statisticaltools.
We use relative odds ratio,which the human side uses,
so-called ROR, to support oursignal detection.
But on the veterinary side,when you're talking about ROR,
(27:52):
if you base that on case number,it's not particularly useful
for production animal species.
As we've said, a single reportcan contain thousands of animals
so it's not so sensitive.
But one thing that I would sayis that the use of other sources
of data is unfortunately lesswell developed within the
veterinary pharmacovigilance,and again we take the example
(28:14):
from the Swedish Medical ProductAgency.
Within the humanpharmacovigilance, they have now
successfully used data fromother national registers to
support signal detection andthey've also initiated
collaboration with universitiesto better utilize other data
sources.
And then also, which is I thinkmost people are familiar with,
(28:36):
there is the Darwin projectwithin Europe, now on the human
side, which is collatinglarge-scale real-world data or
real-world evidence from acrossEurope, and this is collating
data on diseases on the humanside, also information on the
populations and then also on theuse and performance of human
medicine.
So there's a lot of data beingcollected on the human side and
(28:58):
I think there's very much a needfor developments within the
veterinary medicine field now aswell.
But I think budget limitationsplay an important role.
Also, we're waiting for thehuman systems to develop, as
well.
Fredrik Brounéus (29:09):
While on the topic of data, duplicates are a
challenge here for signaldetection in human medicine or
pharmacovigilance, what aboutthe vet side?
James Mount (29:21):
Duplicates are a challenge for the veterinary
reports as well, but I wouldn'tsay they impact us on the same
extent.
Most competent authoritiesencourage those that report,
either vets or animal owners, toreport to either the national
competent authority or to theirmarketing authorization holder,
and not to both, to try toreduce the risk of of duplicates
(29:42):
forming.
But there are other forms ofduplication that can occur,
obviously, and other sourcesglobally, and the European
Medicines Agency has assistedhere by trying to implement
algorithms in the unionpharmacovigilance database to
try to help us detect theseduplicate reports.
But I would say that despitethese measures that have been
(30:03):
implemented so far, duplicatescan persist in the data set and,
as the human side isexperiencing, they do impact the
data quite significantly.
To address this, we've gotongoing discussions between
regulators and industry stillprogressing to try to establish
the most optimal approach reallyfor duplicate detection and
then also case managementafterwards to try to merge these
(30:24):
cases that are identified,because often merging can also
cause its own issues as well.
Fredrik Brounéus (30:30):
Well, now that we are on the topic of
algorithms, I was wondering ifyou could tell us a little about
the EU Veterinary Big DataStrategy.
James Mount (30:40):
Yeah, the EU Big Data Strategy.
That's a strategic visionreally towards implementation of
new digital solutions in theveterinary regulatory domain.
So it's progression towardsusing other forms of data
sources and it focuses onprimarily three aspects, which
is sustainability and then,obviously, the use of multiple
(31:03):
data sources and then also,quite importantly, the
maintenance of data accuracy andquality.
And I'm personally veryinterested in this area and I'm
actually currently a member ofthe EU Veterinary Big Data Hub.
I know it's a strange name, butit's a group of
multidisciplinary experts on theveterinary side who try to
(31:23):
support the implementation ofthe EU Veterinary Big Data
Strategy.
And just to give you a briefinsight and an update, most
recently, part of this strategy,the Wagen ingen University in
the Netherlands, has performed alandscape analysis for this
strategy, looking at veterinarydata sources that are available
(31:46):
and can be of use for thevarious veterinary domains, and
I believe it was around 650potential sources of veterinary
data that were identified withinEurope.
And currently the EuropeanMedicines Agency are reviewing
these sources with the aim toidentify which domain of
veterinary medicine will benefitgreatest from one or more of
(32:08):
the data sources.
And obviously I've got some biashere, but I think
pharmacovigilance is an obviouschoice and can benefit greatly
from that data.
And I would say that there isone rich source of data which
they did identify as well, whichis the information within our
veterinary medical recordsystems, which we've mentioned
before, where a fewuniversities, outside of the EU
(32:32):
unfortunately, have started toexplore.
And the advantage of extractingthis large amount of data from
the veterinary medical recordsystems is that it will provide
us with a very useful backgrounddata in order to provide
context to our adverse eventsthat are coming in, and that is
that we can compare with theactual extent of the use of the
(32:54):
products in the field or in apopulation, which we can't
really do at the moment properly, and even we can also derive
accurate values of reportingrates and reporting incidences
and also look at the generalefficiency of the medicines that
we're One other importance ofthe Big Data Strategy, as I said
, is to maintain data quality,and this is that we share this
(33:18):
kind of value in data qualitybetween the human and veterinary
side, because it's fundamentalfor us to do our analysis.
The Heads of Medicines Agencies,which is the HMA, and also the
European Medicines Agencythey've recently actually
published a data qualityframework for EU medicine
regulations and the next stageis to create specific chapters
(33:42):
for the specific domains, withthe next chapter, luckily enough
, focusing on human andveterinary adverse events
arising from all sources, soadverse event reporting, in
other words.
And early this year, 2024,there was, in fact, a
multi-stakeholder workshoparound data quality in adverse
event reports, and here we hadrepresentation from both the
(34:04):
human and veterinary regulatorsand industry at that workshop,
so I was quite pleased that wehad that dialogue all together.
And I'm eager to see what theresults are from those exchanges
that we had.
Fredrik Brounéus (34:15):
So so is there a timeline for when they will
be published and do you know ifthey will be made publicly
available?
James Mount (34:22):
Yes, well, drafting is well underway that I've
heard and publication on theEuropean Medicines Agency's
website is expected during thefirst half of 2025, so quite
soon.
Fredrik Brounéus (34:32):
Well, we'll make sure to add that link to
the show notes when it's out.
And well, if we go back to theBig Data Strategy, do you know
if there are similar initiativesin other regions or countries
around the world?
James Mount (34:46):
No, but I think I've already mentioned in the
first episode that theinitiatives that I'm aware of
and are well known in fact arebased in the United Kingdom,
although these initiatives havebeen expanded recently into the
US and Australia, only in asmall level.
But the two initiatives that I'maware of are the Small Animal
Veterinary Surveillance Network,SAVSNET, which is based at the
(35:08):
University of Liverpool in theUK, and then we've got
VetCompass, which is a very mucha similar system, but that's
based at the Royal VeterinaryCollege in London.
But the initiatives involveextraction, anonymization and
analysis of information takendirectly from veterinary medical
record systems, and I guessthis is quite comparable with
(35:30):
the Darwin project which we'vementioned on the human side, but
it's not yet to that same scale, but that's really the emphasis
on the word "yet.
So it's coming, and with theextraction of this large amount
of data, as we've said before,it will generate a very
comprehensive backgroundreference data for us all,
irrespective of if we're workingin pharmacovigilance or not,
and also provide us with moreaccurate understanding of how
(35:52):
products are used and howefficient they are or effective.
You can combine information aswell with other sources, and
Liverpool has done this.
They've compared some data withclimate data so they can then
identify some seasonal patterns,which they've done, and I think
that as these veterinarianinitiatives advance, they are
with pace and they also arecontinuing to prove their
(36:14):
concept, which I think they alsoalready have.
There may be a growing interestto establish a similar
initiative in Europe, which Ihope will happen quite soon.
Fredrik Brounéus (36:25):
Yeah well, speaking of that and the future,
where do you hope these systemswill be in, say, five years'
time, or what will they allow usto do and to what effect?
James Mount (36:38):
Well, generally, it's quite difficult to predict
the development of the currentsystems, as in mainly because
they're developed and maintainedby the European Medicines
Agency, although there is anatural direction that's been
set out in this EuropeanVeterinary Big Data Strategy,
and that is to begin to usemultiple data sources.
So I think there'll be a movetowards that and obviously, as
(36:59):
we said, the most obvious datasource to to tap into is that
that vast amount of informationthat's contained within the
veterinarian medical recordssystems, and that could mean the
establishment of a similarsystem to SAVSNET or VetCompass
in Europe.
To enable us to use efficientlythis vast amount of data
efficiently and effectively,then you will need other tools
(37:21):
to help us, and this is whereartificial intelligence probably
comes into play.
And in fact, this is somethingthat even the European Medicines
Agency has started to address,and they've even published
recently a reflection paper onthe use of AI in the life cycle
of medicines, and this papermaps out the current thinking of
artificial intelligence to howto support the safe and
(37:43):
effective development ofmedicines, both for human and
veterinary use, and there areclear advantages of the use of
AI in all the stages ofpharmacovigilance.
However, I would say that thegoal for each AI innovation that
we do develop needs to beclearly set before
implementation.
It's recently come to myknowledge that the first use of
any form of AI inpharmacovigilance dates back
(38:05):
actually from the 90s, so it'snot really a new concept.
concept that in the 90s it wasused in prediction models for in
relating active substances toexpected adverse events, so it's
not new, but our computercapacity has now advanced
exponentially, so we can do alot more.
(38:25):
The European Medicines Agencyhas also hosted quite a few
multi-stakeholder forumsinviting both the veterinary and
human side here to discuss AI,and some of the important areas
that have been earmarked forfurther discussion really are
(38:46):
around data protection andcopyright, data sharing and even
GDPR, which is quite importantto consider.
And then, at thesemulti-stakeholder forums, there
are many groups that areindicating that they're
experimenting with largelanguage models, so-called LLMs,
and these look to have somegreat potential.
(39:10):
And, as I said, that AI inpharmacovigilance can be applied
at all stages and there's ahuge list where it can be
applied.
I know I said that casemanagement potentially is not
one way you would apply it first, but you could potentially have
AI tools helping you withautomation of case management,
potentially using something likea natural language processing
of case narratives, and then AIcan help us very much with
(39:33):
pattern recognition, which wehave difficulty doing manually,
and then triaging of cases andalso triage of drug event
combinations that are coming upin our systems, and then
predictive modeling can also bevery useful, and the list just
goes on.
on it's important, I think,that we all consider that AI
(39:54):
tools are not infallible, sothey can make mistakes and there
needs to be potentiallymitigating measures in place
already at the start tocompensate and protect from
incorrect decision making usingAI models.
And this is not just unique forpharmacovigilance, but for
pharmacovigilance it means thatwe're really trying to protect
patient safety.
It may not be a particularlyrelevant example, but there has
(40:16):
been studies where they've triedto assign human MedDRA terms
from free text narratives inadverse event reports using a
form of large language model,and it's shown that they've had
an accuracy of around 80%, andalthough this is quite high, it
may indicate that there stillneeds to be some sort of manual
(40:37):
review of cases in order tomaintain the high level of
accuracy and data quality thatwe need.
But despite these small, smallaspects, this implementation of
AI tools in pharmacovigilance isvery exciting and, judging by
the stakeholder forums, it's afast-growing area and it does
have some clear uses andadvantages in pharmacovigilance
(41:00):
and I really follow this quiteeagerly.
Fredrik Brounéus (41:02):
Yes, we live in interesting times, don't we?
And with that we've reached theend of this two-episode special
on veterinary pharmacovigilance.
Thank you so much, James.
It's been a pleasure talking toyou.
James Mount (41:16):
Thank you very much .
Fredrik Brounéus (41:24):
And if you'd like to learn, more about
differences and similaritiesbetween human and veterinary
pharmacovigilance, .
James has put together a list oflinks for you in the episode
show notes.
Apart from these conversationswith experts, we offer a series
of audio stories from UppsalaMonitoring Centre's
pharmacovigilance news sitecalled Uppsala Reports Long
Reads, so why not check that outtoo?
(41:49):
That's all for now, but we'llbe back soon with more on
medicine safety.
In the meantime, please feelfree to reach out on Facebook,
LinkedIn linkedin and X.
comments or suggestions forthe show or questions for our
guests, and visit our website tolearn more about what we do to
promote safer use of medicinesand vaccines for everyone,
everywhere.
If you like the podcast, pleasesubscribe to make sure you
(42:11):
won't miss an episode and spreadthe word so other listeners can
find us too.
For Drug Safety Matters, I'mFredrik Brouneus.
Thanks for listening.
Welcome to Drug Safety Matters, a podcast
by Uppsala Monitoring Center,where we explore current issues
in pharmacovigilance and patientsafety.
I'm Fredrik Brouneus and you'relistening to the second part of
our two-part episode onveterinary pharmacovigilance.
If you haven't yet listened tothe previous part of the
interview, I would suggest thatyou do so first, to get the most
(00:38):
out of the discussions.
And now let's go back to thestudio, where I'm joined by
James Mount, veterinarypharmacovigilance assessor at
the Swedish Medical ProductsAgency and EU-elected chair of
(01:02):
the Pharmacovigilance WorkingParty for Veterinary Medicinal
Products.
Welcome back to the Drug SafetyMatters studio, James.
We have a lot to cover in thesecond part of the interview as
well, so I say let's divestraight in.
Is there a difference in thetype of adverse events reported
on the vet side compared withthe human side?
James Mount (01:18):
Yeah, I would say so.
There is quite a significantdifference.
Apart from these suspectedadverse events that we've talked
about in the first episode, theveterinarians and animal owners
are actually activelyencouraged, and also stipulated
in the legislation, that theyshould be reporting lack of
expected efficacy, and here Imean when a medicine has not had
its intended effect in thoseindividuals that you've treated,
(01:38):
and then also if you suspectthere's an environmental
exposure or incident that'shappened.
These should be reported.
Judging by experience, they'requite rare to happen, but this
is when large amounts ofparticularly veterinary
medicines are leaked into theenvironment.
This is most common,potentially when you've used
dips or baths with productionanimals, commonly with sheep or
(02:00):
with topical preparations inother animals.
And then also veterinarians andeven animal owners are also
potentially encouraged to reportresidues in meat, eggs and milk
which occur potentially whenrecommended withdrawal periods
are not followed.
These are the set periods oftime, usually just a few days,
(02:21):
where meat, eggs and milk shouldnot be used for human
consumption.
And also there is the oddscenario, which is very rare,
that suspected transmission ofan infection agent should also
be reported.
And, as I said, this is a quiterare scenario and often related
to quality defects duringmanufacture, and often they're
detected very early, before evenpatients get exposed to these
Fredrik Brounéus (02:44):
A t the end of the first part of this episode
on veterinary pharmacovigilance,we had a teaser about user
safety and the mention of"self-injection.
How about user safety withveterinary medicines?
Are the risks greater than forhuman medicines?
James Mount (03:03):
With veterinary medicines, I would say that, yes
, there is a greater risk foruser safety, and this is when
you can get exposed to apreparation when you're
administrating it.
And, as I said, animals can bequite a moving target, and so
there can be a risk for humanexposure to a medicine when
you're a vet or an animal nurse,or even animal owners when
you're administering products athome, if you take the example,
(03:26):
as I said, animals are movingtarget and they can easily shake
their head when you're tryingto administer a preparation for
treating an ear infection, andalso I remember that animals can
tend to sneeze when you'regiving an intranasal vaccine and
you can get unintentionallyexposed to that vaccine.
Also, animal owners and familymembers at home can also be at
(03:50):
risk when pets are treated inthe household.
If you take the example whenowners and their children often
stroke and cuddle pets, and ifyou've recently applied a
topical medicine to thatindividual animal, then there
can be a risk for exposure to
Fredrik Brounéus (04:04):
Yeah I can relate to both those scenarios.
We have a big slobbery houndback home and when we applied an
ear medicine he was shaking andthat medicine was flying all
over the room.
James Mount (04:16):
It just proves the point that you have to be
careful with the medicines whenyou are in the home environment.
Sometimes, administration ofsome veterinary products are
actually discouraged to behandled or used in certain human
risk groups.
So that's something you have toconsider at home if you've got
either potentially pregnantwomen at home or people that
with known allergies, then theyshould definitely not handle
(04:37):
these products.
And also then there's adviceabout the handling of animals
for a certain period of timeafter treatment.
So particularly with thesespot-on antiparasitic
preparations that are used athome, there's often stated in
the product information thatanimals should not be cuddled or
touched for a certain amount oftime, normally 24 hours or so,
(04:58):
but these recommendations arenormally clearly stated in the
product information and animalowners and vets should consult
those product informationcarefully.
And then also there are allsorts of scenarios that can
occur and, as we touched on,accidental ingestion potentially
can occur with veterinarymedicines and often relates to
potentially elderly people withpoor eyesight, so they mix up
(05:22):
their medicines with an animalmedicine if they've got them
together in the same cupboard,which is obviously discouraged.
And also children can also getin contact and ingest these
products due to their normalinquisitive nature.
And it's all unintentionalexposure but should be tried to
to be avoided, mainly by lockingaway products and separating
them out from human products.
(05:43):
And then, as as I said,self-injection, which I'm quite
familiar with, that you oftenself-inject yourself a few times
as vets, mainly because theanimals move and are not that
compliant often.
Fredrik Brounéus (05:56):
It sounds potentially, as it could be
quite serious as well, dependingon what kind of medicine you
are injecting.
James Mount (06:03):
Yeah, absolutely, and one of the most serious
cases that I'm familiar with iswhen you can get accidental
ingestion or self-injection withthese alpha-2 adrenoreceptor
agonists that we use, and theseare used to sedate animals in
the field most commonly,particularly horses, and even at
very, very low dosages you canget sedation and blood pressure
changes in humans if they'reexposed to it.
(06:24):
There now are specific warningsin the product information for
these products that contain thisactive ingredient to instruct
vets that if they do suspectthat they have exposed
themselves either accidentallythrough ingestion or
self-injection, that they shouldnot drive, as obviously this
can have a fatal consequence.
Fredrik Brounéus (06:44):
So does the opposite happen as well?
I mean animals beingunintentionally exposed to human
medicines.
James Mount (06:52):
Yeah, of course that's particularly relevant and
it also exposes the crossoverthat we have between the human
and veterinary side, and one ofthe most topical examples here
is exposure to topical hormonereplacement therapies, which are
commonly used by animal owners,and these products normally
contain substances such astestosterone or estrogen, and
(07:13):
they can result in quite severeand serious adverse events in
pet animals if they get exposedin the same household, and most
commonly or what we've observedis most common in dogs and cats,
but even guinea pigs are atrisk as well, and, I'm sure,
other mammals in the householdas well, and also here I should
mention that even children areat risk.
And we've actually publishedobservations, and very recently,
(07:34):
a few weeks ago in fact, theSwedish Medical Products Agency
has launched an informationcampaign in the news and other
social media channels and thiscampaign includes advice to vets
, animal owners and prescribinghuman healthcare professionals
in order to try to reduce therisk of exposure in that
household, mainly focusing onpets, but also children.
(07:57):
For example, part of thecommunication indicates that
it's important for prescribinghuman healthcare professionals
to inform users of the risk ofsecondary exposure in their
household and actually stipulatethat it can be their pets and
children that are at risk, andthen users themselves should be
encouraged to really strictlyfollow the product information,
in particularly where to applythe medicine to avoid secondary
(08:20):
exposure in the household.
And then also, vets are alsothen encouraged to both report
when they see these events inanimals and also consider it as
a differential diagnosis, as wecall it, when they see these
patients come in.
But this example, which we havea campaign about now, is a very
, very good example of thiscrossover between veterinary and
(08:42):
human pharmacovigilance, Iwould say.
Fredrik Brounéus (08:44):
Yes, and we should mention here that we have
a link in the episode shownotes for listeners who want to
find out more about this.
I I read about it in the paperjust a couple of days ago
actually.
James Mount (08:58):
And then there are other scenarios as well.
There has been situations wherehuman products, used both for
animals and humans, have causeda simultaneous sudden rise in
adverse events, and here I'dlike to talk about potentially
the most commonly known example,which is the use of human
gentamicin in horses, and theseobservations were made in 2015
(09:19):
and 17.
So a while back, but there was apresence of high levels of
histamine in the humangentamicin which caused a sudden
spike or sudden increase inhypersensitivity reactions in
horses, and obviously thehypersensitivity reactions in
horses are quite severe, andthese initial serious reactions
that you observed in horsesactually transpired to be an
(09:39):
important indicator for a humanhealth risk.
So the risk for hypersensitivereaction in humans as well.
And obviously the industryinvestigated this issue and it
turned out that there was a fishpeptone which was used as a
nutrient during the growthmedium process of manufacture.
(10:00):
That was the source of thishistamine.
And so later on, the relevanthuman and veterinary medicines
committees within the EU,specifically the CHMP and the
CVMP both made scientificopinions to actually limit the
level of histamine in both humanand veterinary medicines going
forward, to alleviate this riskagain.
Fredrik Brounéus (10:20):
I think it's very interesting, these examples
that you have of the crossover,as you say, between veterinary
and human pharmacovigilance andhow they sort of enrich each
other here.
But I would like to go back towhere you mentioned "lack of
efficacy".
I was intrigued when I firstsaw in the Swedish Medical
(10:41):
Products Agency's ADR reportingform for animals, since, as you
say, it has no equivalent in thereporting form for humans.
And I also noticed in the formfor humans that the user is
asked to provide informationabout where the medicine was
acquired, if it's at a pharmacy,other vendor, internet, abroad
(11:02):
and so on.
But I couldn't find thecorresponding field in the form
for animals.
And another difference Inoticed is that there are no
de-challenge or re-challengequestions in the veterinary form
.
So I was just wondering if youcould comment on these
differences.
James Mount (11:22):
Yes, these are very good observations.
It's good you picked them up.
There are quite significantdifferences of how we report
adverse events on the vet sidewithin Europe and we've already
addressed these potentially inthe first episode that, like we
said, that adverse events on theveterinary side can involve
both animals and humans that arebeing exposed to medicine, and
also the use of human andveterinary medicines is
(11:42):
commonplace in animalsthemselves, and also that more
than one individual can bereported per report and if you
compare this to the human side,only one human can be reported
per report on that side.
So we have many thousands ofanimals can be reported and, as
I said, with these bigfacilities where you've got pigs
and poultry and mink and eventhe fish tanks full of fish,
(12:04):
these facilities, when they formlarge-scale treatments and
vaccinations, can experiencelots of animals with adverse
events if they report them.
But I know the observation thatyou made that the Swedish
Medical Products Agency does notspecifically request
information about the source ofmedicines and also about the
(12:26):
specific information of re- andde-challenge.
But in our experience, often thereporter tends to provide this
information in their free textnarratives that we have in our
system.
And if they don't provide it,then normally we contact the
reporter for this informationand, as we said, the number of
reports that are received, wehave the ability to do that.
(12:50):
But, to be absolutely honest,the Swedish Medical Products
Agency has actually purposelyexcluded a lot of questions in
our specific reporting form inorder to make it easier for
people, that's vets and animalowners, to actually report.
But I'd also say that, onreflection of looking nationally
, within Europe there are quitesignificant differences and some
(13:12):
other EU countries haveadditional questions on their
reporting forms and thesedifferences potentially can be
explained either through thefact that they have specific
national requirements to askthose questions in specific
cases, or there might bespecific circumstances where
there are specific productsbeing used in a disease outbreak
and this might mean that youneed to pose specific questions,
(13:35):
to capture specific informationfrom reporting vets, which then
justifies these additionalquestions.
A nd the current diseaseoutbreaks that we have in Europe
include blue tongue and avianinfluenza, and thus you tend to
pose specific questions on yourreporting form to capture
specific information about theseongoing vaccination campaigns.
Fredrik Brounéus (13:56):
In the previous episode we also talked
about environmental exposure assomething that is reported in
veterinary pharmacovigilance.
Would you say that there's morefocus on environmental aspects
of medicine safety on theveterinary side?
James Mount (14:11):
No, I wouldn't say that the focus is greater on the
vet side.
I would say that the Europeanexperts, on both the human and
veterinary side, they equallyrecognize the significant impact
that medicines have, or canhave, or are having, on our
environment.
In fact, and this is reallyconfirmed through the fact that
now, prior to authorisation ofmedicinal products, European
(14:33):
legislation specificallyrequires all human and
veterinary medicines to undergoan environmental risk assessment
, and we call this an ERA, andit's based on its expected use.
But it's one important aspecthere to clarify is that on the
veterinary side, specifically,if there is an identified
environmental risk during theapproval stages of any
(14:55):
significance, this can be usedas a motivation or a reason to
actually not approve theauthorization of that specific
veterinary medicine, which isnot yet the case on the human
side.
Fredrik Brounéus (15:05):
So almost like an eco veto, so to say.
I think it's interesting tothink back to the One Health
perspective, the one healthconcept that we talked about in
the first part of this episode.
I mean, looking at the weightthat we attribute to human
health as compared to the healthof animals and the health of
(15:27):
the environment, that this issomething that we will perhaps
need to reconsider or at leastwiden our views on.
James Mount (15:46):
Absolutely, I would agree whole-heartedly with you.
If we consider potentially likethe environmental part of One
Health, I'm aware of manyinitiatives, within Europe
specifically, and even otherparts of the world, and this
includes cross-governmentalgroups that have been
established and alsocollaboration between the human
and veterinary experts to try tolook at ways to reduce the
impact of pharmaceuticals in theenvironment.
And here, to plug the Swedishmedical products agency again,
most recently, the Swedish andthe Danish medicine agencies
(16:07):
together have embarked on aclose collaboration regarding
reducing the environmentalimpact of both medical devices
as well as pharmaceuticals, andthey've even begun to discuss
concrete initiatives to try toreduce this environmental impact
, which will be interesting tofollow how this collaboration
progresses.
Fredrik Brounéus (16:28):
Indeed, I was also thinking about the wide
variety of stakeholders that areinvolved in veterinary
pharmacovigilance.
We've touched on this before.
But the veterinarians, the vetnurses, the farmers, the
professional owners, the petowners and so on – it's quite a
diverse crowd as compared to thehuman side.
James Mount (16:50):
Yeah, absolutely.
We are a diverse crowd and wehave quite a different set of
veterinary stakeholders and theengagement and the ability to
reach out to the differentstakeholders can be a challenge,
mainly because we're so diverse.
And apart from contactingstakeholders, as we've said, to
encourage adverse eventreporting, there's often a need
(17:11):
to have established goodchannels of communication when
safety issues are identified,and we normally contact
veterinary health careprofessionals and this is both
vets and nurses either directlyor through their professional
organizations, but distributingsort of important safety
information directly to animalowners, as you can imagine,
they're quite diverse and we'reeven talking about farmers here
(17:33):
of different animal species.
This can be really challenging,although we do sometimes have
to rely on our veterinary healthcare professionals to
distribute that information, andthat's for the prescription
drugs that they prescribe, andthen even we try to encourage
pharmacists also to provide somesafety information, when we're
talking about both prescriptionand non-prescription drugs that
(17:54):
we have on the veterinary side.
In some cases there's a need toeven engage with human
healthcare professionals, whichwe've already talked about with
the topical, hormone exposure,and also discussions with human
pharmacovigilance experts isalso sometimes essential.
Fredrik Brounéus (18:09):
Yeah, listening to to you, James, it's
apparent, I think, in manyways, that veterinary medicine
and veterinary pharmacovigilanceis a lot more complex than
human medicine.
I mean, not only does itinvolve both human and
veterinary products, but itdeals with, you know, a myriad
(18:29):
of not only mammals but alsofish, reptiles, amphibians,
birds and so on, and you alsohave breeds within these many
species, and I was wondering abit how this affects the coding.
James Mount (18:43):
Yeah, well, as in that, species and breed coding
is obviously probably one of thebiggest differences that we
have on the veterinary side and,as I said earlier, that we've
got the VICH standard and theVICH maintain our global
standard list of species andbreeds that we use in coding, so
it's all really harmonized andstandardized and to give you an
idea of that list, because it'squite a long one, there are 40
(19:04):
species on that list, so thatshows the diversity that we have
to deal with and, as an example, there are nearly 400 breeds of
dog on that list and over 300breeds of cattle.
So that just gives an indicationof diversity.
The standard practice generallywith reports is to only report
one species in a report, but youcan report as many breeds
(19:28):
within that species within thosereports.
And then in terms of signaldetection, we normally perform
initial signal detection withinthe same species, otherwise it
becomes very complicated.
Fredrik Brounéus (19:39):
So while we're on the topic of breeds here, we
have received a question viasocial media from one of our
listeners and this is thequestion: Hi, I'm curious about
the difference in side effectsamong different dog breeds and
other animals as well.
I've heard that there are drugsthat are safe to use on most
dogs, but that they'll getthrough the blood brain barrier
(20:00):
on just a few breeds, causingnasty side effects.
Are there many such exceptionsthat need to be considered?
James Mount (20:09):
Thank you for the question and, yes, breed
specific adverse events areknown to occur on the vet side.
There are many examples, butone of the well-known examples
that we have is sensitivity toivermectin in some breeds of dog
, and this is commonlyassociated with collies or sheep
dogs or the crosses betweencollie and sheep dogs, although
(20:29):
there are individuals of bordercollies, sheep dogs, old english
sheep dogs and Australianshepherds that have believed to
have this sensitivity.
And ivermectin itself iscommonly used to treat parasitic
infections in animals.
And the sensitivity in somebreeds of dog, or some
individuals within breeds,relates to the presence of a
(20:50):
deletion gene mutation, and it'sthe MDR-1 gene to be precise,
also known as themultidrug-resistant gene.
And this multidrug-resistantgene encodes a large
transmembrane protein which isobviously an integral part of
the blood-brain barrier.
And when these specific dogshave both copies of this
deletion mutation, then they candevelop signs of neurotoxicity
(21:14):
when treated with ivermectin andthis can be established as a
form of blindness or ataxia andunfortunately, sometimes it can
even result in death and this isattributed to a leaky blood-
brain barrier in theseindividuals, and then it means
that the high amounts of thativermectin can accumulate in the
brain of the susceptible dog.
And then there's other examplesof hypersensitivity to certain
(21:35):
antibiotics, specifically thosethat contain sulfonamides, and
this relates to the Dobermanpinchers, and they can develop a
hypersensitivity anywherebetween 5 and 12 days after the
initiation of treatment, andhere the clinical signs can be
subtle as a fever or hepatopathy, and they can also develop
quite serious neurological signs.
(21:57):
Then, if you consider otherbreed- specific adverse events,
there can be instances where youget a geographical incident of
specific adverse events.
And here I take the examplefrom Sweden and Denmark, where
there were adverse events seenin the landrace breed of Swedish
and Danish pigs specifically,and this was following the use
(22:19):
of an antibiotic from thepleuromutilin group, quite a
specific group, and in this casethe pigs were treated for swine
dysentry using this antibioticand these specific pigs from
these two regions developedfever and also loss of appetite,
incoordination and in someinstances there was a death
observed as well in some ofthese pigs.
(22:39):
So it's quite dramatic andthere has been investigations
undergone, but the exact causehas not been really properly
established, but it's highlylikely it's related to some sort
of genetic susceptibility inthese specific breeds.
And also, there was oneinteresting case in relation to
a species- specific sensitivity,and this is quite dramatic, in
(23:01):
some cases, which is theestablishment of permethrin
toxicosis in cats, a And thisproduct is commonly used to
treat ectoparasites and theseare those infestations where you
get fleas and ticks and mitesthat live on the skin surface.
And it's also, I must say herethat this permethrin is also
(23:22):
used to in some instances totreat l, to treat head lice in
children and also, if scabiesdevelops, in humans as well.
So there can behuman-containing products here.
Permethrin is safe generally touse in most mammals and it's
often applied topically, as youcan imagine.
But cats are really extremelysensitive and this is down to
(23:44):
the fact that they have areduced ability to metabolize
the active substance, permethrin, and instead it just
accumulates in the body andsigns can develop, ranging from
restlessness in the cats tohypersalivation, and they can
even resort to muscle spasms,seizures, and then also they can
die of it as well.
(24:04):
And cats are at risk for bothveterinary and human products
obviously containing this activesubstance, permethrin, and, as
a result, owners should reallybe extremely careful when using
this product, either on theirpets, and they potentially
mistakenly use it on a cat, orwhen they're using it within the
(24:24):
pet's environment, the cats canbe exposed so it should be
careful.
Fredrik Brounéus (24:28):
So, owners using them on themselves .
.
.
James Mount (24:31):
Exactly.
Fredrik Brounéus (24:31):
Yeah mind the breed and the species, in other
words.
And I read that newtechnologies are being tested to
monitor production animalswell-being for instance, that
you could have cameras connectedto an AI to scan or monitor
their behavior for signs ofstress, and I was wondering if
you think that these kinds ofsolutions could become useful
(24:54):
for detecting, and possiblyreporting as well, adverse drug
reactions.
James Mount (24:59):
Yes, you're perfectly right.
There are very many advancedmonitoring systems specifically
for production animals andespecially dairy cattle.
There's a lot of systems therefor monitoring their well-being,
and these comprise of collarsand ear tags that the animals
wear, and this enables thosefarmers to monitor activity, to
(25:20):
provide information onspecifically reproductive
behaviour and then, as you said,general health status as well
to monitor that.
And this activity data that youcollect is vast, but the actual
way we can use it to detectadverse events is still under
investigation, although thereare numerous groups looking into
it to see if they can elucidateadverse events, but it doesn't
(25:42):
have its uses at the moment.
And in terms of otherinnovations, not just
specifically production animals,but within small animal
medicine, there are monitoringtools there available as well.
Now, one example of them I'maware of is there is a wearable
accelerometer which can be usedto detect a puritic activity in
dogs and this is where dogs arevery prone to developing itchy
(26:07):
skin conditions and so that thiswearable accelerometer can
provide an alert for animalowners to seek early veterinary
care before the condition getsreally serious.
And then there are artificialintelligence tools to help
animal owners detect sort ofearly signs of osteoarthritis in
cats as well.
And there are many otherexamples as well live and also
(26:28):
under development, but theability for these innovations to
help us identify adverse eventsis still very much unclear.
Oh, okay, but while we'retalking about AI, at the moment,
the area that would benefitgreatest from the application of
artificial intelligence toolsis our signal detection in our
databases, and I think that'sthe same with the human side,
(26:51):
and AI can assist us there inmultiple ways.
Although the use of AI in actualcase management and that is
when reports are coming in andregistering adverse events then
I think AI is quite limitedthere, mainly through the fact
that you need to have somedegree or some level of manual
human review of cases in orderto understand them as well as to
(27:13):
maintain accuracy in thosecases.
Fredrik Brounéus (27:15):
We'll get back to AI a little further on in
this interview, but this doesbring us to the methods used for
signal detection in veterinarypharmacovigilance.
Would you say that they are thesame as in human practice?
James Mount (27:29):
Yeah, I would say so.
In terms of the use of datafrom spontaneous reported
adverse events, the basicmethods that we use for signal
detection are very, very muchsimilar between the human and
veterinary side.
We use similar statisticaltools.
We use relative odds ratio,which the human side uses,
so-called ROR, to support oursignal detection.
But on the veterinary side,when you're talking about ROR,
(27:52):
if you base that on case number,it's not particularly useful
for production animal species.
As we've said, a single reportcan contain thousands of animals
so it's not so sensitive.
But one thing that I would sayis that the use of other sources
of data is unfortunately lesswell developed within the
veterinary pharmacovigilance,and again we take the example
(28:14):
from the Swedish Medical ProductAgency.
Within the humanpharmacovigilance, they have now
successfully used data fromother national registers to
support signal detection andthey've also initiated
collaboration with universitiesto better utilize other data
sources.
And then also, which is I thinkmost people are familiar with,
(28:36):
there is the Darwin projectwithin Europe, now on the human
side, which is collatinglarge-scale real-world data or
real-world evidence from acrossEurope, and this is collating
data on diseases on the humanside, also information on the
populations and then also on theuse and performance of human
medicine.
So there's a lot of data beingcollected on the human side and
(28:58):
I think there's very much a needfor developments within the
veterinary medicine field now aswell.
But I think budget limitationsplay an important role.
Also, we're waiting for thehuman systems to develop, as
well.
Fredrik Brounéus (29:09):
While on the topic of data, duplicates are a
challenge here for signaldetection in human medicine or
pharmacovigilance, what aboutthe vet side?
James Mount (29:21):
Duplicates are a challenge for the veterinary
reports as well, but I wouldn'tsay they impact us on the same
extent.
Most competent authoritiesencourage those that report,
either vets or animal owners, toreport to either the national
competent authority or to theirmarketing authorization holder,
and not to both, to try toreduce the risk of of duplicates
(29:42):
forming.
But there are other forms ofduplication that can occur,
obviously, and other sourcesglobally, and the European
Medicines Agency has assistedhere by trying to implement
algorithms in the unionpharmacovigilance database to
try to help us detect theseduplicate reports.
But I would say that despitethese measures that have been
(30:03):
implemented so far, duplicatescan persist in the data set and,
as the human side isexperiencing, they do impact the
data quite significantly.
To address this, we've gotongoing discussions between
regulators and industry stillprogressing to try to establish
the most optimal approach reallyfor duplicate detection and
then also case managementafterwards to try to merge these
(30:24):
cases that are identified,because often merging can also
cause its own issues as well.
Fredrik Brounéus (30:30):
Well, now that we are on the topic of
algorithms, I was wondering ifyou could tell us a little about
the EU Veterinary Big DataStrategy.
James Mount (30:40):
Yeah, the EU Big Data Strategy.
That's a strategic visionreally towards implementation of
new digital solutions in theveterinary regulatory domain.
So it's progression towardsusing other forms of data
sources and it focuses onprimarily three aspects, which
is sustainability and then,obviously, the use of multiple
(31:03):
data sources and then also,quite importantly, the
maintenance of data accuracy andquality.
And I'm personally veryinterested in this area and I'm
actually currently a member ofthe EU Veterinary Big Data Hub.
I know it's a strange name, butit's a group of
multidisciplinary experts on theveterinary side who try to
(31:23):
support the implementation ofthe EU Veterinary Big Data
Strategy.
And just to give you a briefinsight and an update, most
recently, part of this strategy,the Wagen ingen University in
the Netherlands, has performed alandscape analysis for this
strategy, looking at veterinarydata sources that are available
(31:46):
and can be of use for thevarious veterinary domains, and
I believe it was around 650potential sources of veterinary
data that were identified withinEurope.
And currently the EuropeanMedicines Agency are reviewing
these sources with the aim toidentify which domain of
veterinary medicine will benefitgreatest from one or more of
(32:08):
the data sources.
And obviously I've got some biashere, but I think
pharmacovigilance is an obviouschoice and can benefit greatly
from that data.
And I would say that there isone rich source of data which
they did identify as well, whichis the information within our
veterinary medical recordsystems, which we've mentioned
before, where a fewuniversities, outside of the EU
(32:32):
unfortunately, have started toexplore.
And the advantage of extractingthis large amount of data from
the veterinary medical recordsystems is that it will provide
us with a very useful backgrounddata in order to provide
context to our adverse eventsthat are coming in, and that is
that we can compare with theactual extent of the use of the
(32:54):
products in the field or in apopulation, which we can't
really do at the moment properly, and even we can also derive
accurate values of reportingrates and reporting incidences
and also look at the generalefficiency of the medicines that
we're One other importance ofthe Big Data Strategy, as I said
, is to maintain data quality,and this is that we share this
(33:18):
kind of value in data qualitybetween the human and veterinary
side, because it's fundamentalfor us to do our analysis.
The Heads of Medicines Agencies,which is the HMA, and also the
European Medicines Agencythey've recently actually
published a data qualityframework for EU medicine
regulations and the next stageis to create specific chapters
(33:42):
for the specific domains, withthe next chapter, luckily enough
, focusing on human andveterinary adverse events
arising from all sources, soadverse event reporting, in
other words.
And early this year, 2024,there was, in fact, a
multi-stakeholder workshoparound data quality in adverse
event reports, and here we hadrepresentation from both the
(34:04):
human and veterinary regulatorsand industry at that workshop,
so I was quite pleased that wehad that dialogue all together.
And I'm eager to see what theresults are from those exchanges
that we had.
Fredrik Brounéus (34:15):
So so is there a timeline for when they will
be published and do you know ifthey will be made publicly
available?
James Mount (34:22):
Yes, well, drafting is well underway that I've
heard and publication on theEuropean Medicines Agency's
website is expected during thefirst half of 2025, so quite
soon.
Fredrik Brounéus (34:32):
Well, we'll make sure to add that link to
the show notes when it's out.
And well, if we go back to theBig Data Strategy, do you know
if there are similar initiativesin other regions or countries
around the world?
James Mount (34:46):
No, but I think I've already mentioned in the
first episode that theinitiatives that I'm aware of
and are well known in fact arebased in the United Kingdom,
although these initiatives havebeen expanded recently into the
US and Australia, only in asmall level.
But the two initiatives that I'maware of are the Small Animal
Veterinary Surveillance Network,SAVSNET, which is based at the
(35:08):
University of Liverpool in theUK, and then we've got
VetCompass, which is a very mucha similar system, but that's
based at the Royal VeterinaryCollege in London.
But the initiatives involveextraction, anonymization and
analysis of information takendirectly from veterinary medical
record systems, and I guessthis is quite comparable with
(35:30):
the Darwin project which we'vementioned on the human side, but
it's not yet to that same scale, but that's really the emphasis
on the word "yet.
So it's coming, and with theextraction of this large amount
of data, as we've said before,it will generate a very
comprehensive backgroundreference data for us all,
irrespective of if we're workingin pharmacovigilance or not,
and also provide us with moreaccurate understanding of how
(35:52):
products are used and howefficient they are or effective.
You can combine information aswell with other sources, and
Liverpool has done this.
They've compared some data withclimate data so they can then
identify some seasonal patterns,which they've done, and I think
that as these veterinarianinitiatives advance, they are
with pace and they also arecontinuing to prove their
(36:14):
concept, which I think they alsoalready have.
There may be a growing interestto establish a similar
initiative in Europe, which Ihope will happen quite soon.
Fredrik Brounéus (36:25):
Yeah well, speaking of that and the future,
where do you hope these systemswill be in, say, five years'
time, or what will they allow usto do and to what effect?
James Mount (36:38):
Well, generally, it's quite difficult to predict
the development of the currentsystems, as in mainly because
they're developed and maintainedby the European Medicines
Agency, although there is anatural direction that's been
set out in this EuropeanVeterinary Big Data Strategy,
and that is to begin to usemultiple data sources.
So I think there'll be a movetowards that and obviously, as
(36:59):
we said, the most obvious datasource to to tap into is that
that vast amount of informationthat's contained within the
veterinarian medical recordssystems, and that could mean the
establishment of a similarsystem to SAVSNET or VetCompass
in Europe.
To enable us to use efficientlythis vast amount of data
efficiently and effectively,then you will need other tools
(37:21):
to help us, and this is whereartificial intelligence probably
comes into play.
And in fact, this is somethingthat even the European Medicines
Agency has started to address,and they've even published
recently a reflection paper onthe use of AI in the life cycle
of medicines, and this papermaps out the current thinking of
artificial intelligence to howto support the safe and
(37:43):
effective development ofmedicines, both for human and
veterinary use, and there areclear advantages of the use of
AI in all the stages ofpharmacovigilance.
However, I would say that thegoal for each AI innovation that
we do develop needs to beclearly set before
implementation.
It's recently come to myknowledge that the first use of
any form of AI inpharmacovigilance dates back
(38:05):
actually from the 90s, so it'snot really a new concept.
concept that in the 90s it wasused in prediction models for in
relating active substances toexpected adverse events, so it's
not new, but our computercapacity has now advanced
exponentially, so we can do alot more.
(38:25):
The European Medicines Agencyhas also hosted quite a few
multi-stakeholder forumsinviting both the veterinary and
human side here to discuss AI,and some of the important areas
that have been earmarked forfurther discussion really are
(38:46):
around data protection andcopyright, data sharing and even
GDPR, which is quite importantto consider.
And then, at thesemulti-stakeholder forums, there
are many groups that areindicating that they're
experimenting with largelanguage models, so-called LLMs,
and these look to have somegreat potential.
(39:10):
And, as I said, that AI inpharmacovigilance can be applied
at all stages and there's ahuge list where it can be
applied.
I know I said that casemanagement potentially is not
one way you would apply it first, but you could potentially have
AI tools helping you withautomation of case management,
potentially using something likea natural language processing
of case narratives, and then AIcan help us very much with
(39:33):
pattern recognition, which wehave difficulty doing manually,
and then triaging of cases andalso triage of drug event
combinations that are coming upin our systems, and then
predictive modeling can also bevery useful, and the list just
goes on.
on it's important, I think,that we all consider that AI
(39:54):
tools are not infallible, sothey can make mistakes and there
needs to be potentiallymitigating measures in place
already at the start tocompensate and protect from
incorrect decision making usingAI models.
And this is not just unique forpharmacovigilance, but for
pharmacovigilance it means thatwe're really trying to protect
patient safety.
It may not be a particularlyrelevant example, but there has
(40:16):
been studies where they've triedto assign human MedDRA terms
from free text narratives inadverse event reports using a
form of large language model,and it's shown that they've had
an accuracy of around 80%, andalthough this is quite high, it
may indicate that there stillneeds to be some sort of manual
(40:37):
review of cases in order tomaintain the high level of
accuracy and data quality thatwe need.
But despite these small, smallaspects, this implementation of
AI tools in pharmacovigilance isvery exciting and, judging by
the stakeholder forums, it's afast-growing area and it does
have some clear uses andadvantages in pharmacovigilance
(41:00):
and I really follow this quiteeagerly.
Fredrik Brounéus (41:02):
Yes, we live in interesting times, don't we?
And with that we've reached theend of this two-episode special
on veterinary pharmacovigilance.
Thank you so much, James.
It's been a pleasure talking toyou.
James Mount (41:16):
Thank you very much .
Fredrik Brounéus (41:24):
And if you'd like to learn, more about
differences and similaritiesbetween human and veterinary
pharmacovigilance, .
James has put together a list oflinks for you in the episode
show notes.
Apart from these conversationswith experts, we offer a series
of audio stories from UppsalaMonitoring Centre's
pharmacovigilance news sitecalled Uppsala Reports Long
Reads, so why not check that outtoo?
(41:49):
That's all for now, but we'llbe back soon with more on
medicine safety.
In the meantime, please feelfree to reach out on Facebook,
LinkedIn linkedin and X.
comments or suggestions forthe show or questions for our
guests, and visit our website tolearn more about what we do to
promote safer use of medicinesand vaccines for everyone,
everywhere.
If you like the podcast, pleasesubscribe to make sure you
(42:11):
won't miss an episode and spreadthe word so other listeners can
find us too.
For Drug Safety Matters, I'mFredrik Brouneus.
Thanks for listening.
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