Drug Safety Matters

#35 Veterinary pharmacovigilance part 2 – James Mount

• Uppsala Monitoring Centre

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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. 

In part 2, you will hear about

  • differences in types of ADRs reported for animals as compared to humans,
  • when humans are accidentally exposed to medicines for animals, and vice versa,
  • how the many species and breeds included in veterinary PV affects the coding of ADR reports, 
  • breed-specific ADRs – what is safe for one breed of e.g. dog or pig, may not be appropriate for another, 
  • the EU Veterinary Big Data Strategy,

... and much more!

 

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Fredrik Brounéus:

Welcome to Drug Safety Matters, a podcast by Uppsala Monitoring Center, where we explore current issues in pharmacovigilance and patient safety. I'm Fredrik Brouneus and you're listening to the second part of our two-part episode on veterinary pharmacovigilance. If you haven't yet listened to the previous part of the interview, I would suggest that you do so first, to get the most out of the discussions. And now let's go back to the studio, where I'm joined by James Mount, veterinary pharmacovigilance assessor at the Swedish Medical Products Agency and EU-elected chair of the Pharmacovigilance Working Party for Veterinary Medicinal Products. Welcome back to the Drug Safety Matters studio, James. We have a lot to cover in the second part of the interview as well, so I say let's dive straight in. Is there a difference in the type of adverse events reported on the vet side compared with the human side?

James Mount:

Yeah, I would say so. There is quite a significant difference. Apart from these suspected adverse events that we've talked about in the first episode, the veterinarians and animal owners are actually actively encouraged, and also stipulated in the legislation, that they should be reporting lack of expected efficacy, and here I mean when a medicine has not had its intended effect in those individuals that you've treated, and then also if you suspect there's an environmental exposure or incident that's happened. These should be reported. Judging by experience, they're quite rare to happen, but this is when large amounts of particularly veterinary medicines are leaked into the environment. This is most common, potentially when you've used dips or baths with production animals, commonly with sheep or with topical preparations in other animals. And then also veterinarians and even animal owners are also potentially encouraged to report residues in meat, eggs and milk which occur potentially when recommended withdrawal periods are not followed. These are the set periods of time, usually just a few days, where meat, eggs and milk should not be used for human consumption.

James Mount:

And also there is the odd scenario, which is very rare, that suspected transmission of an infection agent should also be reported. And, as I said, this is a quite rare scenario and often related to quality defects during manufacture, and often they're detected very early, before even patients get exposed to these

Fredrik Brounéus:

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.

Fredrik Brounéus:

How about user safety with veterinary medicines? Are the risks greater than for human medicines?

James Mount:

With veterinary medicines, I would say that, yes, there is a greater risk for user safety, and this is when you can get exposed to a preparation when you're administrating it.

James Mount:

And, as I said, animals can be quite a moving target, and so there can be a risk for human exposure to a medicine when you're a vet or an animal nurse, or even animal owners when you're administering products at home, if you take the example, as I said, animals are moving target and they can easily shake their head when you're trying to administer a preparation for treating an ear infection, and also I remember that animals can tend to sneeze when you're giving an intranasal vaccine and you can get unintentionally exposed to that vaccine. Also, animal owners and family members at home can also be at risk when pets are treated in the household. If you take the example when owners and their children often stroke and cuddle pets, and if you've recently applied a topical medicine to that individual animal, then there can be a risk for exposure to

Fredrik Brounéus:

Yeah I can relate to both those scenarios.

Fredrik Brounéus:

We have a big slobbery hound back home and when we applied an ear medicine he was shaking and that medicine was flying all over the room.

James Mount:

It just proves the point that you have to be careful with the medicines when you are in the home environment.

James Mount:

Sometimes, administration of some veterinary products are actually discouraged to be handled or used in certain human risk groups. So that's something you have to consider at home if you've got either potentially pregnant women at home or people that with known allergies, then they should definitely not handle these products.

James Mount:

And also then there's advice about the handling of animals for a certain period of time after treatment. So particularly with these spot-on antiparasitic preparations that are used at home, there's often stated in the product information that animals should not be cuddled or touched for a certain amount of time, normally 24 hours or so, but these recommendations are normally clearly stated in the product information and animal owners and vets should consult those product information carefully. And then also there are all sorts of scenarios that can occur and, as we touched on, accidental ingestion potentially can occur with veterinary medicines and often relates to potentially elderly people with poor eyesight, so they mix up their medicines with an animal medicine if they've got them together in the same cupboard, which is obviously discouraged.

James Mount:

And also children can also get in contact and ingest these products due to their normal inquisitive nature. And it's all unintentional exposure but should be tried to to be avoided, mainly by locking away products and separating them out from human products. And then, as as I said, self-injection, which I'm quite familiar with, that you often self-inject yourself a few times as vets, mainly because the animals move and are not that compliant often.

Fredrik Brounéus:

It sounds potentially, as it could be quite serious as well, depending on what kind of medicine you are injecting.

James Mount:

Yeah, absolutely, and one of the most serious cases that I'm familiar with is when you can get accidental ingestion or self-injection with these alpha-2 adrenoreceptor agonists that we use, and these are used to sedate animals in the field most commonly, particularly horses, and even at very, very low dosages you can get sedation and blood pressure changes in humans if they're exposed to it. There now are specific warnings in the product information for these products that contain this active ingredient to instruct vets that if they do suspect that they have exposed themselves either accidentally through ingestion or self-injection, that they should not drive, as obviously this can have a fatal consequence.

Fredrik Brounéus:

So does the opposite happen as well? I mean animals being unintentionally exposed to human medicines.

James Mount:

Yeah, of course that's particularly relevant and it also exposes the crossover that we have between the human and veterinary side, and one of the most topical examples here is exposure to topical hormone replacement therapies, which are commonly used by animal owners, and these products normally contain substances such as testosterone or estrogen, and they can result in quite severe and serious adverse events in pet animals if they get exposed in the same household, and most commonly or what we've observed is most common in dogs and cats, but even guinea pigs are at risk as well, and, I'm sure, other mammals in the household as well, and also here I should mention that even children are at risk.

James Mount:

And we've actually published observations, and very recently, a few weeks ago in fact, the Swedish Medical Products Agency has launched an information campaign in the news and other social media channels and this campaign includes advice to vets, animal owners and prescribing human healthcare professionals in order to try to reduce the risk of exposure in that household, mainly focusing on pets, but also children.

James Mount:

For example, part of the communication indicates that it's important for prescribing human healthcare professionals to inform users of the risk of secondary exposure in their household and actually stipulate that it can be their pets and children that are at risk, and then users themselves should be encouraged to really strictly follow the product information, in particularly where to apply the medicine to avoid secondary exposure in the household. And then also, vets are also then encouraged to both report when they see these events in animals and also consider it as a differential diagnosis, as we call it, when they see these patients come in. But this example, which we have a campaign about now, is a very, very good example of this crossover between veterinary and human pharmacovigilance, I would say.

Fredrik Brounéus:

Yes, and we should mention here that we have a link in the episode show notes for listeners who want to find out more about this. I I read about it in the paper just a couple of days ago actually.

James Mount:

And then there are other scenarios as well.

James Mount:

There has been situations where human products, used both for animals and humans, have caused a simultaneous sudden rise in adverse events, and here I'd like to talk about potentially the most commonly known example, which is the use of human gentamicin in horses, and these observations were made in 2015 and 17.

James Mount:

So a while back, but there was a presence of high levels of histamine in the human gentamicin which caused a sudden spike or sudden increase in hypersensitivity reactions in horses, and obviously the hypersensitivity reactions in horses are quite severe, and these initial serious reactions that you observed in horses actually transpired to be an important indicator for a human health risk. So the risk for hypersensitive reaction in humans as well. And obviously the industry investigated this issue and it turned out that there was a fish peptone which was used as a nutrient during the growth medium process of manufacture. That was the source of this histamine. And so later on, the relevant human and veterinary medicines committees within the EU, specifically the CHMP and the CVMP both made scientific opinions to actually limit the level of histamine in both human and veterinary medicines going forward, to alleviate this risk again.

Fredrik Brounéus:

I think it's very interesting, these examples that you have of the crossover, as you say, between veterinary and human pharmacovigilance and how they sort of enrich each other here. But I would like to go back to where you mentioned "lack of efficacy". I was intrigued when I first saw in the Swedish Medical Products Agency's ADR reporting form for animals, since, as you say, it has no equivalent in the reporting form for humans. And I also noticed in the form for humans that the user is asked to provide information about where the medicine was acquired, if it's at a pharmacy, other vendor, internet, abroad and so on. But I couldn't find the corresponding field in the form for animals. And another difference I noticed is that there are no de-challenge or re-challenge questions in the veterinary form. So I was just wondering if you could comment on these differences.

James Mount:

Yes, these are very good observations. It's good you picked them up. There are quite significant differences of how we report adverse events on the vet side within Europe and we've already addressed these potentially in the first episode that, like we said, that adverse events on the veterinary side can involve both animals and humans that are being exposed to medicine, and also the use of human and veterinary medicines is commonplace in animals themselves, and also that more than one individual can be reported 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 of animals can be reported and, as I said, with these big facilities where you've got pigs and poultry and mink and even the fish tanks full of fish, these facilities, when they form large-scale treatments and vaccinations, can experience lots of animals with adverse events if they report them.

James Mount:

But I know the observation that you made that the Swedish Medical Products Agency does not specifically request information about the source of medicines and also about the specific information of re- and de-challenge.

James Mount:

But in our experience, often the reporter tends to provide this information in their free text narratives that we have in our system.

James Mount:

And if they don't provide it, then normally we contact the reporter for this information and, as we said, the number of reports that are received, we have the ability to do that.

James Mount:

But, to be absolutely honest, the Swedish Medical Products Agency has actually purposely excluded a lot of questions in our specific reporting form in order to make it easier for people, that's vets and animal owners, to actually report. But I'd also say that, on reflection of looking nationally, within Europe there are quite significant differences and some other EU countries have additional questions on their reporting forms and these differences potentially can be explained either through the fact that they have specific national requirements to ask those questions in specific cases, or there might be specific circumstances where there are specific products being used in a disease outbreak and this might mean that you need to pose specific questions, to capture specific information from reporting vets, which then justifies these additional questions. A nd the current disease outbreaks that we have in Europe include blue tongue and avian influenza, and thus you tend to pose specific questions on your reporting form to capture specific information about these ongoing vaccination campaigns.

Fredrik Brounéus:

In the previous episode we also talked about environmental exposure as something that is reported in veterinary pharmacovigilance. Would you say that there's more focus on environmental aspects of medicine safety on the veterinary side?

James Mount:

No, I wouldn't say that the focus is greater on the vet side. I would say that the European experts, on both the human and veterinary side, they equally recognize the significant impact that medicines have, or can have, or are having, on our environment. In fact, and this is really confirmed through the fact that now, prior to authorisation of medicinal products, European legislation specifically requires all human and veterinary medicines to undergo an environmental risk assessment, and we call this an ERA, and it's based on its expected use. But it's one important aspect here to clarify is that on the veterinary side, specifically, if there is an identified environmental risk during the approval stages of any significance, this can be used as a motivation or a reason to actually not approve the authorization of that specific veterinary medicine, which is not yet the case on the human side.

Fredrik Brounéus:

So almost like an eco veto, so to say. I think it's interesting to think back to the One Health perspective, the one health concept that we talked about in the first part of this episode. I mean, looking at the weight that we attribute to human health as compared to the health of animals and the health of the environment, that this is something that we will perhaps need to reconsider or at least widen our views on.

James Mount:

Absolutely, I would agree whole-heartedly with you. If we consider potentially like the environmental part of One Health, I'm aware of many initiatives, within Europe specifically, and even other parts of the world, and this includes cross-governmental groups that have been established and also collaboration between the human and veterinary experts to try to look at ways to reduce the impact of pharmaceuticals in the environment. And here, to plug the Swedish medical products agency again, most recently, the Swedish and the Danish medicine agencies together have embarked on a close collaboration regarding reducing the environmental impact of both medical devices as well as pharmaceuticals, and they've even begun to discuss concrete initiatives to try to reduce this environmental impact, which will be interesting to follow how this collaboration progresses.

Fredrik Brounéus:

Indeed, I was also thinking about the wide variety of stakeholders that are involved in veterinary pharmacovigilance. We've touched on this before. But the veterinarians, the vet nurses, the farmers, the professional owners, the pet owners and so on – it's quite a diverse crowd as compared to the human side.

James Mount:

Yeah, absolutely.

James Mount:

We are a diverse crowd and we have quite a different set of veterinary stakeholders and the engagement and the ability to reach out to the different stakeholders can be a challenge, mainly because we're so diverse.

James Mount:

And apart from contacting stakeholders, as we've said, to encourage adverse event reporting, there's often a need to have established good channels of communication when safety issues are identified, and we normally contact veterinary health care professionals and this is both vets and nurses either directly or through their professional organizations, but distributing sort of important safety information directly to animal owners, as you can imagine, they're quite diverse and we're even talking about farmers here of different animal species. This can be really challenging, although we do sometimes have to rely on our veterinary health care professionals to distribute that information, and that's for the prescription drugs that they prescribe, and then even we try to encourage pharmacists also to provide some safety information, when we're talking about both prescription and non-prescription drugs that we have on the veterinary side. In some cases there's a need to even engage with human healthcare professionals, which we've already talked about with the topical, hormone exposure, and also discussions with human pharmacovigilance experts is also sometimes essential.

Fredrik Brounéus:

Yeah, listening to to you, James, it's apparent, I think, in many ways, that veterinary medicine and veterinary pharmacovigilance is a lot more complex than human medicine. I mean, not only does it involve both human and veterinary products, but it deals with, you know, a myriad of not only mammals but also fish, reptiles, amphibians, birds and so on, and you also have breeds within these many species, and I was wondering a bit how this affects the coding.

James Mount:

Yeah, well, as in that, species and breed coding is obviously probably one of the biggest differences that we have on the veterinary side and, as I said earlier, that we've got the VICH standard and the VICH maintain our global standard list of species and breeds that we use in coding, so it's all really harmonized and standardized and to give you an idea of that list, because it's quite a long one, there are 40 species on that list, so that shows the diversity that we have to deal with and, as an example, there are nearly 400 breeds of dog on that list and over 300 breeds of cattle.

James Mount:

So that just gives an indication of diversity.

James Mount:

The standard practice generally with reports is to only report one species in a report, but you can report as many breeds within that species within those reports. And then in terms of signal detection, we normally perform initial signal detection within the same species, otherwise it becomes very complicated.

Fredrik Brounéus:

So while we're on the topic of breeds here, we have received a question via social media from one of our listeners and this is the question: Hi, I'm curious about the difference in side effects among different dog breeds and other animals as well. I've heard that there are drugs that are safe to use on most dogs, but that they'll get through the blood brain barrier on just a few breeds, causing nasty side effects. Are there many such exceptions that need to be considered?

James Mount:

Thank you for the question and, yes, breed specific adverse events are known to occur on the vet side. There are many examples, but one of the well-known examples that we have is sensitivity to ivermectin in some breeds of dog, and this is commonly associated with collies or sheep dogs or the crosses between collie and sheep dogs, although there are individuals of border collies, sheep dogs, old english sheep dogs and Australian shepherds that have believed to have this sensitivity. And ivermectin itself is commonly used to treat parasitic infections in animals. And the sensitivity in some breeds of dog, or some individuals within breeds, relates to the presence of a deletion gene mutation, and it's the MDR-1 gene to be precise, also known as the multidrug-resistant gene. And this multidrug-resistant gene encodes a large transmembrane protein which is obviously an integral part of the blood-brain barrier. And when these specific dogs have both copies of this deletion mutation, then they can develop signs of neurotoxicity when treated with ivermectin and this can be established as a form of blindness or ataxia and unfortunately, sometimes it can even result in death and this is attributed to a leaky blood- brain barrier in these individuals, and then it means that the high amounts of that ivermectin can accumulate in the brain of the susceptible dog. And then there's other examples of hypersensitivity to certain antibiotics, specifically those that contain sulfonamides, and this relates to the Doberman pinchers, and they can develop a hypersensitivity anywhere between 5 and 12 days after the initiation of treatment, and here the clinical signs can be subtle as a fever or hepatopathy, and they can also develop quite serious neurological signs.

James Mount:

Then, if you consider other breed- specific adverse events, there can be instances where you get a geographical incident of specific adverse events. And here I take the example from Sweden and Denmark, where there were adverse events seen in the landrace breed of Swedish and Danish pigs specifically, and this was following the use of an antibiotic from the pleuromutilin group, quite a specific group, and in this case the pigs were treated for swine dysentry using this antibiotic and these specific pigs from these two regions developed fever and also loss of appetite, incoordination and in some instances there was a death observed as well in some of these pigs. So it's quite dramatic and there has been investigations undergone, but the exact cause has not been really properly established, but it's highly likely it's related to some sort of genetic susceptibility in these specific breeds. And also, there was one interesting case in relation to a species- specific sensitivity, and this is quite dramatic, in some cases, which is the establishment of permethrin toxicosis in cats, a And this product is commonly used to treat ectoparasites and these are those infestations where you get fleas and ticks and mites that live on the skin surface. And it's also, I must say here that this permethrin is also used to in some instances to treat l, to treat head lice in children and also, if scabies develops, in humans as well. So there can be human-containing products here. Permethrin is safe generally to use in most mammals and it's often applied topically, as you can imagine. But cats are really extremely sensitive and this is down to the fact that they have a reduced ability to metabolize the active substance, permethrin, and instead it just accumulates in the body and signs can develop, ranging from restlessness in the cats to hypersalivation, and they can even resort to muscle spasms, seizures, and then also they can die of it as well. And cats are at risk for both veterinary and human products obviously containing this active substance, permethrin, and, as a result, owners should really be extremely careful when using this product, either on their pets, and they potentially mistakenly use it on a cat, or when they're using it within the pet's environment, the cats can be exposed so it should be careful.

Fredrik Brounéus:

So, owners using them on themselves ...

James Mount:

Exactly.

Fredrik Brounéus:

Yeah mind the breed and the species, in other words. And I read that new technologies are being tested to monitor production animals well-being for instance, that you could have cameras connected to an AI to scan or monitor their behavior for signs of stress, and I was wondering if you think that these kinds of solutions could become useful for detecting, and possibly reporting as well, adverse drug reactions.

James Mount:

Yes, you're perfectly right. There are very many advanced monitoring systems specifically for production animals and especially dairy cattle.

James Mount:

There's a lot of systems there for monitoring their well-being, and these comprise of collars and ear tags that the animals wear, and this enables those farmers to monitor activity, to provide information on specifically reproductive behaviour and then, as you said, general health status as well to monitor that. And this activity data that you collect is vast, but the actual way we can use it to detect adverse events is still under investigation, although there are numerous groups looking into it to see if they can elucidate adverse events, but it doesn't have its uses at the moment.

James Mount:

And in terms of other innovations, not just specifically production animals, but within small animal medicine, there are monitoring tools there available as well. Now, one example of them I'm aware of is there is a wearable accelerometer which can be used to detect a puritic activity in dogs and this is where dogs are very prone to developing itchy skin conditions and so that this wearable accelerometer can provide an alert for animal owners to seek early veterinary care before the condition gets really serious. And then there are artificial intelligence tools to help animal owners detect sort of early signs of osteoarthritis in cats as well.

James Mount:

And there are many other examples as well live and also under development, but the ability for these innovations to help us identify adverse events is still very much unclear. Oh, okay, but while we're talking about AI, at the moment, the area that would benefit greatest from the application of artificial intelligence tools is our signal detection in our databases, and I think that's the same with the human side, and AI can assist us there in multiple ways.

James Mount:

Although the use of AI in actual case management and that is when reports are coming in and registering adverse events then I think AI is quite limited there, mainly through the fact that you need to have some degree or some level of manual human review of cases in order to understand them as well as to maintain accuracy in those cases.

Fredrik Brounéus:

We'll get back to AI a little further on in this interview, but this does bring us to the methods used for signal detection in veterinary pharmacovigilance. Would you say that they are the same as in human practice?

James Mount:

Yeah, I would say so. In terms of the use of data from spontaneous reported adverse events, the basic methods that we use for signal detection are very, very much similar between the human and veterinary side. We use similar statistical tools. We use relative odds ratio, which the human side uses, so-called ROR, to support our signal detection. But on the veterinary side, when you're talking about ROR, if you base that on case number, it's not particularly useful for production animal species. As we've said, a single report can contain thousands of animals so it's not so sensitive.

James Mount:

But one thing that I would say is that the use of other sources of data is unfortunately less well developed within the veterinary pharmacovigilance, and again we take the example from the Swedish Medical Product Agency. Within the human pharmacovigilance, they have now successfully used data from other national registers to support signal detection and they've also initiated collaboration with universities to better utilize other data sources. And then also, which is I think most people are familiar with, there is the Darwin project within Europe, now on the human side, which is collating large-scale real-world data or real-world evidence from across Europe, and this is collating data on diseases on the human side, also information on the populations and then also on the use and performance of human medicine. So there's a lot of data being collected on the human side and I think there's very much a need for developments within the veterinary medicine field now as well. But I think budget limitations play an important role. Also, we're waiting for the human systems to develop, as well.

Fredrik Brounéus:

While on the topic of data, duplicates are a challenge here for signal detection in human medicine or pharmacovigilance, what about the vet side?

James Mount:

Duplicates are a challenge for the veterinary reports as well, but I wouldn't say they impact us on the same extent. Most competent authorities encourage those that report, either vets or animal owners, to report to either the national competent authority or to their marketing authorization holder, and not to both, to try to reduce the risk of of duplicates forming. But there are other forms of duplication that can occur, obviously, and other sources globally, and the European Medicines Agency has assisted here by trying to implement algorithms in the union pharmacovigilance database to try to help us detect these duplicate reports. But I would say that despite these measures that have been implemented so far, duplicates can persist in the data set and, as the human side is experiencing, they do impact the data quite significantly. To address this, we've got ongoing discussions between regulators and industry still progressing to try to establish the most optimal approach really for duplicate detection and then also case management afterwards to try to merge these cases that are identified, because often merging can also cause its own issues as well.

Fredrik Brounéus:

Well, now that we are on the topic of algorithms, I was wondering if you could tell us a little about the EU Veterinary Big Data Strategy.

James Mount:

Yeah, the EU Big Data Strategy. That's a strategic vision really towards implementation of new digital solutions in the veterinary regulatory domain. So it's progression towards using other forms of data sources and it focuses on primarily three aspects, which is sustainability and then, obviously, the use of multiple data sources and then also, quite importantly, the maintenance of data accuracy and quality. And I'm personally very interested in this area and I'm actually currently a member of the EU Veterinary Big Data Hub. I know it's a strange name, but it's a group of multidisciplinary experts on the veterinary side who try to support the implementation of the EU Veterinary Big Data Strategy. And just to give you a brief insight and an update, most recently, part of this strategy, the Wagen ingen University in the Netherlands, has performed a landscape analysis for this strategy, looking at veterinary data sources that are available and can be of use for the various veterinary domains, and I believe it was around 650 potential sources of veterinary data that were identified within Europe. And currently the European Medicines Agency are reviewing these sources with the aim to identify which domain of veterinary medicine will benefit greatest from one or more of the data sources.

James Mount:

And obviously I've got some bias here, but I think pharmacovigilance is an obvious choice and can benefit greatly from that data.

James Mount:

And I would say that there is one rich source of data which they did identify as well, which is the information within our veterinary medical record systems, which we've mentioned before, where a few universities, outside of the EU unfortunately, have started to explore. And the advantage of extracting this large amount of data from the veterinary medical record systems is that it will provide us with a very useful background data in order to provide context to our adverse events that are coming in, and that is that we can compare with the actual extent of the use of the products in the field or in a population, which we can't really do at the moment properly, and even we can also derive accurate values of reporting rates and reporting incidences and also look at the general efficiency of the medicines that we're One other importance of the Big Data Strategy, as I said, is to maintain data quality, and this is that we share this kind of value in data quality between the human and veterinary side, because it's fundamental for us to do our analysis.

James Mount:

The Heads of Medicines Agencies, which is the HMA, and also the European Medicines Agency they've recently actually published a data quality framework for EU medicine regulations and the next stage is to create specific chapters for the specific domains, with the next chapter, luckily enough, focusing on human and veterinary adverse events arising from all sources, so adverse event reporting, in other words. And early this year, 2024, there was, in fact, a multi-stakeholder workshop around data quality in adverse event reports, and here we had representation from both the human and veterinary regulators and industry at that workshop, so I was quite pleased that we had that dialogue all together. And I'm eager to see what the results are from those exchanges that we had.

Fredrik Brounéus:

So so is there a timeline for when they will be published and do you know if they will be made publicly available?

James Mount:

Yes, well, drafting is well underway that I've heard and publication on the European Medicines Agency's website is expected during the first half of 2025, so quite soon.

Fredrik Brounéus:

Well, we'll make sure to add that link to the show notes when it's out. And well, if we go back to the Big Data Strategy, do you know if there are similar initiatives in other regions or countries around the world?

James Mount:

No, but I think I've already mentioned in the first episode that the initiatives that I'm aware of and are well known in fact are based in the United Kingdom, although these initiatives have been expanded recently into the US and Australia, only in a small level.

James Mount:

But the two initiatives that I'm aware of are the Small Animal Veterinary Surveillance Network, SAVSNET, which is based at the University of Liverpool in the UK, and then we've got VetCompass, which is a very much a similar system, but that's based at the Royal Veterinary College in London.

James Mount:

But the initiatives involve extraction, anonymization and analysis of information taken directly from veterinary medical record systems, and I guess this is quite comparable with the Darwin project which we've mentioned 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 the extraction of this large amount of data, as we've said before, it will generate a very comprehensive background reference data for us all, irrespective of if we're working in pharmacovigilance or not, and also provide us with more accurate understanding of how products are used and how efficient they are or effective. You can combine information as well with other sources, and Liverpool has done this. They've compared some data with climate data so they can then identify some seasonal patterns, which they've done, and I think that as these veterinarian initiatives advance, they are with pace and they also are continuing to prove their concept, which I think they also already have. There may be a growing interest to establish a similar initiative in Europe, which I hope will happen quite soon.

Fredrik Brounéus:

Yeah well, speaking of that and the future, where do you hope these systems will be in, say, five years' time, or what will they allow us to do and to what effect?

James Mount:

Well, generally, it's quite difficult to predict the development of the current systems, as in mainly because they're developed and maintained by the European Medicines Agency, although there is a natural direction that's been set out in this European Veterinary Big Data Strategy, and that is to begin to use multiple data sources. So I think there'll be a move towards that and obviously, as we said, the most obvious data source to to tap into is that that vast amount of information that's contained within the veterinarian medical records systems, and that could mean the establishment of a similar system to SAVSNET or VetCompass in Europe. To enable us to use efficiently this vast amount of data efficiently and effectively, then you will need other tools to help us, and this is where artificial intelligence probably comes into play. And in fact, this is something that even the European Medicines Agency has started to address, and they've even published recently a reflection paper on the use of AI in the life cycle of medicines, and this paper maps out the current thinking of artificial intelligence to how to support the safe and effective development of medicines, both for human and veterinary use, and there are clear advantages of the use of AI in all the stages of pharmacovigilance.

James Mount:

However, I would say that the goal for each AI innovation that we do develop needs to be clearly set before implementation. It's recently come to my knowledge that the first use of any form of AI in pharmacovigilance dates back actually from the 90s, so it's not really a new concept. concept that in the 90s it was used in prediction models for in relating active substances to expected adverse events, so it's not new, but our computer capacity has now advanced exponentially, so we can do a lot more. The European Medicines Agency has also hosted quite a few multi-stakeholder forums inviting both the veterinary and human side here to discuss AI, and some of the important areas that have been earmarked for further discussion really are around data protection and copyright, data sharing and even GDPR, which is quite important to consider.

James Mount:

And then, at these multi-stakeholder forums, there are many groups that are indicating that they're experimenting with large language models, so-called LLMs, and these look to have some great potential. And, as I said, that AI in pharmacovigilance can be applied at all stages and there's a huge list where it can be applied. I know I said that case management potentially is not one way you would apply it first, but you could potentially have AI tools helping you with automation of case management, potentially using something like a natural language processing of case narratives, and then AI can help us very much with pattern recognition, which we have difficulty doing manually, and then triaging of cases and also triage of drug event combinations that are coming up in our systems, and then predictive modeling can also be very useful, and the list just goes on. on it's important, I think, that we all consider that AI tools are not infallible, so they can make mistakes and there needs to be potentially mitigating measures in place already at the start to compensate and protect from incorrect decision making using AI models. And this is not just unique for pharmacovigilance, but for pharmacovigilance it means that we're really trying to protect patient safety. It may not be a particularly relevant example, but there has been studies where they've tried to assign human MedDRA terms from free text narratives in adverse event reports using a form of large language model, and it's shown that they've had an accuracy of around 80%, and although this is quite high, it may indicate that there still needs to be some sort of manual review of cases in order to maintain the high level of accuracy and data quality that we need. But despite these small, small aspects, this implementation of AI tools in pharmacovigilance is very exciting and, judging by the stakeholder forums, it's a fast-growing area and it does have some clear uses and advantages in pharmacovigilance and I really follow this quite eagerly.

Fredrik Brounéus:

Yes, we live in interesting times, don't we? And with that we've reached the end of this two-episode special on veterinary pharmacovigilance. Thank you so much, James. It's been a pleasure talking to you.

James Mount:

Thank you very much.

Fredrik Brounéus:

And if you'd like to learn, more about differences and similarities between human and veterinary pharmacovigilance, . James has put together a list of links for you in the episode show notes. Apart from these conversations with experts, we offer a series of audio stories from Uppsala Monitoring Centre's pharmacovigilance news site called Uppsala Reports Long Reads, so why not check that out too? That's all for now, but we'll be back soon with more on medicine safety. In the meantime, please feel free to reach out on Facebook, LinkedIn linkedin and X. comments or suggestions for the show or questions for our guests, and visit our website to learn more about what we do to promote safer use of medicines and vaccines for everyone, everywhere. If you like the podcast, please subscribe to make sure you won't miss an episode and spread the word so other listeners can find us too. For Drug Safety Matters, I'm Fredrik Brouneus. Thanks for listening.

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Alexandra Coutinho

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Federica Santoro

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Fredrik Brounéus

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