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Drug Safety Matters
Drug Safety Matters brings you the best stories from the world of pharmacovigilance. Through in-depth interviews with our guests, we cover new research and trends, and explore the most pressing issues in medicines safety today. Produced by Uppsala Monitoring Centre, the WHO Collaborating Centre for International Drug Monitoring.
Drug Safety Matters
#34 Veterinary pharmacovigilance, Part I – James Mount
Human and veterinary pharmacovigilance (PV) share many goals, challenges and approaches. But there are also significant differences, such as the numerous species and breeds 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:
- What are the similarities and differences between veterinary and human pharmacovigilance?
- How is animal health connected to public health?
- What types of adverse events are reported on the veterinary side compared with the human side?
- What can be found in the EU veterinary pharmacovigilance database?
Want to know more?
- The new veterinary medicines regulation (Regulation (EU) 2019/6) can be found here.
- The public portal of the European Union Veterinary Pharmacovigilance Database.
- WHO's information page on One Health, an integrated approach to the well-being of people, animals and the environment.
- A survey of veterinary professionals in Sweden, about current practices and attitudes in relation to adverse events reporting and the accessibility of product safety information.
- A review of adverse events in animals and children after secondary exposure to transdermal hormone-containing medicinal products.
- A study looking at suspected adverse drug reaction reporting in veterinary free‐text clinical narratives.
- The EMA Big Data strategy for veterinary medicines in the EU.
- Data quality framework for medicines regulation | European Medicines Agency (EMA)
- Small Animal Veterinary Surveillance Network (SAVSNET) - University of Liverpool
- VetCompass - Royal Veterinary College, RVC
- Reflection paper on the use of artificial intelligence in the lifecycle of medicines | European Medicines Agency (EMA)
- The Swedish Medical Products Agency's online reporting form for suspected adverse drug reactions in animals (In Swedish).
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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 today I'm looking forward to learning more about veterinary pharmacovigilance, including its differences and similarities to the human side. Human and veterinary pharmacovigilance share many goals, challenges and approaches, but there are also significant differences, such as the numerous species and breeds that need to be considered in veterinary pharmacovigilance. In this two-part episode, I will be joined in the studio 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.
Fredrik Brounéus:Hi, James, and welcome to the Drug Safety Matters studio.
James Mount:Thank you very much. Thank you for the invitation.
Fredrik Brounéus:So, veterinary pharmacovigilance; this is something that's quite new to me and I was hoping we could start off with sort of the broader picture here, James. How similar would you say that veterinary pharmacovigilance is to human pharmacovigilance?
James Mount:Well, I would say they're very similar, but before I develop that point further, I'd just like to say that the views that I express in this podcast will be the ones of my role as veterinarian and pharmacovigilance assessor at the Swedish Medical Products Agency and are not an EU view or opinion, despite my current role as elected chair of the European Union's Veterinary Pharmacovigilance Working Party. But if we go back to your question now, actually there is an enormous amount of similarity and crossover between human and veterinary pharmacovigilance, and I would say, above all, we share the same goal, which is to maintain the supply of safe and effective medicines for use, and obviously this simultaneously sort of maintains animal and public health and also even protects our environment as well. In terms terms of challenges, we share the same ones there, with trying to encourage healthcare professionals, and this is whether they're vets or human healthcare professionals and even the general public, to actually report suspected adverse events when they occur. After all, these reports are actually the fundamental source of information that we use both for human and veterinary pharmacovigilance, and I would say that the basic approaches, even for surveillance and signal detection, are very similar, although we do have different digital systems, of course, and also we have quite different volumes of data available to us.
James Mount:But then also there's an increasing use on the veterinary side with polypharmacy and that's the use of multiple drugs in an individual, or "multimodal treatment, you might call them and human and veterinary pharmacovigilance share more and more now the same challenges in relation to trying to establish a causal relationship when many drugs are used at the same time, and also trying to establish any product association with any potential interaction if you suspect one. There's also an increase in the number of advanced therapies as well, and many of these are already available on the human side, but they are being introduced on the veterinary side and if we take some examples that we've got a number of stem cell therapies on the veterinary side, now there's quite a number of monoclonal antibody therapies marketed as well, and then gene therapies are coming along as well, and all these pose their own unique challenges which I think the human side really are familiar with in terms of pharmacovigilance
Fredrik Brounéus:So very similar would perhaps sum it up then. I mean, mean at least with regards to the bigger picture of aims and goals and challenges that we are talking about here.
James Mount:Yeah, very much similar, and I know that we're focusing on similarities here, but I think I should mention one significant regulatory difference within Europe, and that's been implemented in the new veterinary medicines regulation, which actually only came into force in January 2022, which is relatively recently, and that is that the traditional PSURs, or the periodic safety update reports that you still have on the human side, and these are when the marketing authorization holder submits an evaluation of their benefit risk balance on defined time points, and these are usually every three years or so, or even longer, on the human side as well.
James Mount:But now on the veterinary side, these have been replaced with a more continuous signal management process, as we've called it, now and here. Now, these marketing authorization holders, which are the responsible pharmaceutical companies, should notify any competent authority of any changes in the benefit risk balance of their product, or, if they see any new risks emerge, they should report these within 30 days, so it becomes more of a continuous process, and then also, these responsible companies should be providing a conclusion of their general benefit risk balance assessment on an annual basis instead.
Fredrik Brounéus:But then this annual report or conclusion would be less comprehensive than the PSUR?
James Mount:Yes, it is definitely much less comprehensive, but the veterinary side now has really instead become more focused on trying to identify new risks when they emerge and then quickly establishing any mitigating measures in a timely fashion, and the overall aim of the veterinary medicines regulation in terms of pharmacovigilance is to reduce the administrative burden for all concerned parties and then make us more efficient and focused, which I think it does. Obviously, the implementation of this new process moving away from those traditional PSURs is still ongoing in Europe, despite being implemented in 2022. And there have been obvious challenges, mainly because it's quite a different approach traditionally, and also we've had to make some significant adjustments to our IT systems, which does take some time.
Fredrik Brounéus:Now you mentioned both animal and public health. Could you perhaps go a little bit deeper into how animal health is connected to public health, because there is a quite intimate connection, isn't there?
James Mount:There is a significant interconnection as animal health does impact public health in many ways and even I should say that even impacts our environment together. And I think this interaction is quite well recognized in this establishment of the One Health concept, which is well established globally and that tries to integrate approaches to contribute to better human, animal and environmental health simultaneously, and I should also mention it also tries to improve our food safety.
Fredrik Brounéus:Yes, I must say that One Health is an intriguing concept and I think we will need to have a separate episode on that on the pod next year, but in the meantime, we will add a link to the show notes for those who want to find out more.
James Mount:And then, in relation to this interconnection with animal and public health, one ongoing focus is to reduce the need for antibiotics to treat animals, and also minimizing the emergence of resistance through alternative methods such as efficient disease control, and this is through either use of more vaccination or applying better farm management and animal husbandry, or even improving biosecurity, which is particularly important in in terms of trying to prevent infections from coming in in the first place. Apart from the changes to pharmacovigilance, another goal of the veterinary medicines regulation is actually to reduce the development of antimicrobial resistance. For example, there's been a ban on the prophylactic use of antibiotics introduced, and then also there's a clear restriction being introduced to reserve certain antibiotics for only human use, and this has caused a generation of a list of reserved antimicrobials for human use, and the overall aim of that list is that it reduces the risk of developmental resistance because you're limiting the use of it, and that means that effective antibiotics will be available for humans when they're really needed. And also, on top of this, all member states now are obliged to actually report sales and use of antimicrobials in their member states, so that this information can then be compiled centrally within Europe and then that means that we can closely monitor the situation and take action when necessary.
James Mount:And if I may, there are other initiatives as well. I'd like to mention one from the European Medicines Agency where they've introduced a ranking scheme of antibiotics as well to support the decision-making of vets, and that considers what level of risk their use of a certain product in animals has on the public health through the possible development of antimicrobial resistance. And they also actually consider the absolute necessity to use these antibiotics in veterinary medicine as well. And they've introduced a classification scheme with four categories, and there's antibiotics to absolutely avoid in animals, restrictive use, cautious use and then the prudent use category as well. This advice from the European Medicines Agency also indicates that the route of administration in animals should be considered, because, if you take the example of group medication in feed and drinking water, which is quite commonplace in large animal species, also called metaphylaxis, this has been shown to be a considerable driver of resistance and this type of treatment should only be considered if it's really fully justified in those cases.
Fredrik Brounéus:So in human medicine, some side effects can be clinically discovered or observed from the outside, so to say, such as skin rashes, heart palpitations or impaired liver or kidney function, whereas the discovery of other effects are dependent on patients experiencing and describing them, such as headaches, nausea, blurred vision. In veterinary medicine, we are only dealing with side effects that can be observed from the outside by a human, so I was wondering, could this mean that animals plausibly experience side effects that are never actually discovered? Reported?
James Mount:I think this is quite a relevant reflection on many levels, as in if we take the level of adverse event reporting first, human and veterinary pharmacovigilance share a significant level of underreporting generally and it's estimated that around 90 percent of our adverse events that occur are not reported, and that's documented both on the vet and human side.
James Mount:And I should mention here, in fact, that there has been actually a recent study at the University of Liverpool in the United Kingdom that actually has confirmed this degree of underreporting on the vet side. And they actually did this through a new sort of tool that they've established where they've identified and quantified the mention of unreported adverse events in the free text within veterinary medical record systems, and they've analysed data that they extract from these veterinary medical record systems through the Small Animal Veterinary Surveillance Network, and that's also known as SAVSNET, and it collects data from a proportion of small animal veterinary practices in the UK and it's a promising system really. But if we go back to the aspect of your question regarding adverse events going undiscovered, if you take companion animal species and here we're talking about dogs, cats, rabbits and horses these individual animals tend to live relatively close, in close contact with their animal owners and I would say then that the adverse events are normally observed quite readily, although there are some species of domestic animals, such as cats particularly, which often tend to hide systemic clinical disease quite well, probably due to their survival instinct, I would have thought.
Fredrik Brounéus:So as not to show signs of weakness or vulnerability to possible enemies.
James Mount:Yes, exactly, that would be the case and I think it's an evolutionary sort of holdover from their sort of wild ancestry that they have. But generally speaking, the signs of illness and injury in cats is generally quite subtle and often overlooked if you're not careful. But despite cats and those other companion animals, adverse events can also go undiscovered in production animal species, and here we're talking about cattle, pigs, poultry, mink and even aquaculture. So that's fish we're talking there. So it's quite diverse, and these animals are often kept and treated in very large groups and the daily contact with an animal owner is relatively limited, although it does occur – that's a legal requirement, in fact.
James Mount:But adverse events can then go unnoticed in these species unless the adverse events are really severe, or they're fatal, obviously, or they affect many animals in the group, so it's very, very obvious that there is a an issue. And the other aspect, apart from adverse events not being really detected, it can also be the case that the known adverse events are not reported. And here when I when I say known adverse events, these are those adverse events that are already listed in the product information and it's assumed that many vets and animal owners don't realize that they can, or even in fact should, report these known adverse events in order to help us, both as regulators and also industry, to facilitate the monitoring of the overall safety of medicines. And it's often the case that animal owners particularly tend to report suspected adverse events through their vets, and then unfortunately the vets don't have time to complete that task.
Fredrik Brounéus:Right. Just roughly during a normal year in Sweden, how many or how big a proportion of the incoming reports are from pet owners and how many are from professionals, say, you know, veterinarians?
James Mount:Well, I can say on an average, as in during a normal year, um, we receive roughly 70 to 80 percent of our adverse event reports from veterinarians in Sweden, and the rest come from animal owners, but we also get a few from veterinary nurses and pharmacists. To give you an idea of the entire volume in Sweden of reports, this year so far we've received 1,140 adverse event reports totally, and just over 50 percent have been handled by the Swedish Medical Products Agency and the rest have come via the marketing authorization holders.
Fredrik Brounéus:Okay. Going back to what you said about production animals and side effects often being harder to detect in those larger populations, could that mean that the level of underreporting could be even higher than the 90 percent that you mentioned that were found in the Liverpool study, as those unnoticed events among production animals wouldn't appear in the medical records?
James Mount:Absolutely I would agree with you, but I would say that the Liverpool study did only use data from small companion animals. But there are similar systems to SAVSNET and actually Liverpool own them, for data extraction from both equine and production animal systems as well. These are the record systems, but they're not as well developed at this moment in time, but they're coming along. And apart from the fact that these adverse events in production animals go unnoticed, potentially due to this limited contact with their animal owner, there can be other potential reasons for the limited degree of adverse event reporting, and these could vary from a general lack of awareness, which we try to increase. There can be time limitations, both from the animal owners themselves as, particularly farmers, they're particularly busy and vets themselves, and even there can be an instance where there's a potential reluctance to report, and this could be the scenario when a product is potentially sort of used off label in some scenarios.
Fredrik Brounéus:Well, under- reporting is a quite a challenge, isn't it?
Fredrik Brounéus:So are there, or have there been, initiatives or innovations to stimulate more reporting on the veterinary side?
James Mount:Yeah, numerous. Within the European Union, which I can only really speak for, there are many initiatives in place to both encourage and then also to try to facilitate the adverse event reporting, and this is mainly done at a member state level.
James Mount:But of course, when you're talking about these initiatives, it really is highly dependent on the budgets available and then also the resources at member state level.
James Mount:So there is quite a diversity of options available within member states, and I should mention here that there have been several surveys performed amongst the veterinary health care professionals in order to try to elucidate the main hinders or the issues that they have with adverse event reporting, and from surveys conducted by the FVE, which is the Federation of Veterinarians of Europe, and even the Swedish Medical Products Agency, there have been a number of factors that have been identified, and this includes that, potentially, vets have a limited time to report.
James Mount:As I said, they are very busy individuals and they have to prioritize other activities, and also the presence of some of the inefficient methods of reporting that we have doesn't really help them. And there's also a need for further or continued educational interventions to keep the level of awareness up, of course, and then also we need to try to encourage other veterinary healthcare professionals, such as veterinary nurses, to even report. In the new veterinary medicines regulation, which I've mentioned a number of times now, it's possible for national competent authorities to impose specific legal requirements on vets and other veterinary healthcare professionals to report suspected adverse events. And if you look at Europe, most reporting is still voluntary, but in a few member states, including Sweden, it is obligatory for veterinarians to actually report.
Fredrik Brounéus:So when did it become mandatory and did it increase the level of reporting?
James Mount:Well, this mandatory option is not a new thing, and the ability to impose this specific requirement on vets to report was available in the previous EU directive related to medicinal products from 2001.
James Mount:And this requirement has been imposed on vets since then, such as 2001 and obviously then adopted in our national legislation, of course, but whether it's had an impact on reporting rates is difficult to determine, but I would say that Swedish vets appear to be very aware of this obligation, and I would also say that even reminding vets of this obligation can be a useful tool in generally raising awareness.
James Mount:We have actually considered, in Sweden, to expand the obligation of reporting adverse events to include even qualified veterinary nurses, and this is based on evidence we saw in our survey that veterinary nurses tend to have more contact time with animals in the clinic. They also have more contact time with animal owners as well to actually receive information on adverse events. And if you do apply this specific requirement to nurses, it will signal to them that they can actually report themselves and they don't have to go through their vets, which they tend to do at the moment. And also I think that, potentially, nurses may have more time to actually report or complete the task. And if you look at the human side, in some of the studies that have been done and I think some of them have actually been done in Sweden they have shown that if you encourage nursing staff to actually report, there can be quite a significant improvement in reporting rates, so that's something to take into account. Other initiatives to raise awareness have been run by the European Medicines Agency, and I'd just like to say here that, like in recent years, they've tried to hold regular veterinary focus groups in order to discuss adverse event reporting with veterinarians from specific veterinary sectors.
James Mount:e recently they've targeted poultry and aquaculture sectors, and these are quite substantial sectors on their own. And these kinds of forums that they've had have generally been welcomed by all parties involved and they form a basis to raise awareness and also to try to understand the hurdles more and to have generally just an active dialogue with vets in the field, really, and the European Medicines Agency plan to hold these next year as well with other sectors – it's not yet known which ones. But as a spinoff, I'd just like to say that a spinoff to this is that the European Medicines Agency has discussed and indicated that they potentially will establish a yearly campaign which is very similar to the Uppsala Monitoring Centre's #Med Safety Week, in order to try to promote and raise awareness.
Fredrik Brounéus:Nice! As part of the #Med Safety Week planning team, I'm very happy to hear that.
James Mount:Good, and we'll probably get some tips from you going forward. But if we go back to the EU, some national competent authorities have invested quite substantially in trying to improve their electronic reporting forms. Some of them have developed mobile apps to cater for the vets that are out in the field more than they are in the clinic. And then also there are a number of member states that are quite active in engaging with educational initiatives and specifically targeting even veterinary students and veterinary nursing students as well, and obviously this then means that they ingrain the importance of adverse event reporting early on in the career. And I also should mention here, otherwise I might get into trouble, that even the Swedish Medical Products Agency has recently launched an online reporting form, and this should hopefully, not hopefully, but it will, as in, facilitate the reporting by vets and animal owners in Sweden okay, so it's.
Fredrik Brounéus:It's one form for both pet owners and and veterinaries, and you find this form via the agency's website
James Mount:Yeah, absolutely, it's up and running.
James Mount:And yeah, it's one form, but there are different sorts of ways in, if you're an animal owner or a vet, but it's relatively straightforward and it's all up and running, and it's been popular. Actually, most of our reports now are coming in through that online reporting form, which is encouraging, and some of the advantages of this reporting form is that particularly the veterinary products that are concerned can be searched for within our national product register, and this means that then some of the information can be auto-populated in the form for you which then obviously facilitates and reduces the time to report.
James Mount:But while we're on reporting forms, if we consider the new initiatives or new innovations around, one of the most significant innovations around trying to facilitate adverse event reporting is the generation of a so-called adverse event reporting button, which is in the SAVSNET system, which I've already mentioned, the SAVSNET data collection system, and here this button allows veterinarians to send information about an adverse event directly from their medical record system to the national competent authority. In this case, because the system's in the UK, this is the Veterinary Medicines Directorate and this method has actually anecdotally cut down reporting times to as little as five minutes in the the most uncomplicated of cases, and there's still ongoing refinements to improve this and I've had engagement with industry around it and there's also ongoing investigation to see if reports can actually be extracted more passively from this vast array of information in the veterinary medicine record systems.
Fredrik Brounéus:That's a very interesting approach to integrate the reporting button into the medical record system. I was also wondering about this: when you say passively, do you mean by some kind of automated process like data mining and so on?
James Mount:Yeah, that's correct, but it's very much in its infancy within this system. But I would say that in fact there are numerous studies on the human side which have used different methods of data mining, including regular expression and regression techniques, to try to identify adverse events in electronic health records, as you call them, within the human healthcare service, and they've been quite promising. In fact, with those studies, and here, to promote the Swedish Medical Products Agency again, as in, we've actively engaged with providers of these veterinary medical record systems in Sweden to try to discuss the potential development of adverse event reporting tools which could be integrated within the veterinary medical record systems and there seems to be a demand for that from the vets in the field and currently, uniquely, I think, there are only two providers that dominate the market in Sweden and we're quite interested in continuing these discussions in the near future with those with those parties.
Fredrik Brounéus:So, taking a small step back here perhaps in the discussion, going back to the side effects experienced by animals; are we in general tolerating more side effects from veterinary medical treatments than we do for human medical treatments? Is there a difference in the benefit-risk balance?
James Mount:That's an interesting reflection and question.
James Mount:But generally speaking, when veterinary medicinal products are authorized, the benefits must always outweigh the risks following the use of that product in a particular target species.
James Mount:And that is the case with authorisation of human medicines as well, that the benefits should always outweigh the risks.
James Mount:In some instances there might be a degree of tolerance for some types of adverse events, and these are normally restricted to the non-serious adverse events when you're using these veterinary medicinal products. But I think that a tolerance of adverse events is also seen within human medicine and can depend heavily on the indication of that medicine, both for human and veterinary use. So, regardless of whether you're talking about a human or veterinary medicine, it fundamentally depends on the situation or the indication of that medicine which dictates how much risk is allowed to outweigh the benefit. And if you take one of the extreme examples of chemotherapy treatment, which we do use in animals and is available for human use, these treatments often cause quite significant adverse events that we all know about, which are tolerated as the substantial benefit of the treatment is considered to outweigh the risk of these adverse events occurring. I
Fredrik Brounéus:guess it's the the question of balance is both on the regulatory side and on the side of the individual patient. so I mean, what risks or side effects are acceptable to the system and to me also as the patient, given sort of the prospect of a certain benefit? And the same for animals, of course. But here the decision always needs to be made by the owner, and in a way I think this also touches on the question of animal protection regulations, as they can also be quite different in different parts of the world. Are are these differences reflected in the veterinary pharmacovigilance practices as well?
James Mount:Yeah no, think so. I don't think I have a concrete answer, but animal protection regulations are quite different around the globe.
James Mount:If you take the case of the European Union, which I'm most familiar with, we do have substantial animal welfare legislation and there's been recent updates to that regarding transportation of animals that I'm aware of and also breeding of dogs and cats.
James Mount:But all the welfare regulation that's around is based on the five freedoms, which is the freedom from hunger and thirst, freedom from discomfort, pain and injury, freedom for disease and freedom to express normal behavior, and also freedom from fear and distress. And, and although people around the world are heavily reliant on their animals for their survival and I do generally believe that they care for animal welfare, it's often the case that it's the economic and social cultural differences which cause countries to kind of vary on their animal-related values. And if you bring this into the context of pharmacovigilance, this would potentially have an impact on any veterinary pharmacovigilance system, assuming a country has an established system in place on the veterinary side, which very few have, potentially, the impact being that there'll be potentially reduced awareness, even reduced funding, and also a decreased motivation of the general public to actually report adverse events. But I don't think it would be a major challenge and it wouldn't be totally impossible to kind of overcome these economic and social cultural differences in these countries to establish a fully functional veterinary pharmacophysic system.
Fredrik Brounéus:Okay, so let's talk a bit about that system aspect now that you mentioned it. How and where are veterinary reports collected and stored? Locally, internationally, managed by whom, and so on? How big is the veterinary database? If we could sort of start pulling the threads out of that sort of snake's nest of questions ...
James Mount:Yeah absolutely, and I'm going to mainly focus on the european situation because that's the one I'm most familiar with.
James Mount:But before we delve into the details, I'd just like to sort of clarify again that veterinarians have the right to use and prescribe human medicines as well as veterinary medicines, and as long as it's possible to guarantee that it's safe for the consumer when you're actually treating food- producing animals, so that means that, both veterinary and human medicines can be used to treat animals. That's something to consider and that's quite unique to our side.
Fredrik Brounéus:Yeah, I'm sorry, but I need need to insert another question: does this include any and all human medicines?
James Mount:No, not all human medicines are allowed to be used in in animals. Of course, as I said earlier that there is a list of antimicrobials that are only reserved for human use, and then I'm also aware of some other active substances, such as these antiviral medicines which are restricted for human use and shouldn't be used in animals. However, I should probably say now that, before human products are actually used in animals, vets should always follow what we call the cascade, which is a risk-based decision tree, which has been actually set out in the veterinary medicines regulation and that should always be applied on a case-by-case basis. Now, I'll try to summarize the cascade.
James Mount:There are different scenarios where it's implemented, but the idea is that the first treatment choice of a vet should always be a veterinary medicinal product which is authorized in a member state, so here we're talking about the EU mainly, and it should be for a specific indication in that specific target species. And if that first choice is not available, then a vet can then use, potentially on license, a veterinary medicinal product authorized in another EU member state for use in that same species, or it could be another species, and ideally it should be for the same indication, but you could also choose a product that has a slightly different indication, but in the absence of any of those veterinary medicinal products that are authorized, then you can then consider a medical product for human use. But this summary is quite simplistic and I wouldn't take it as formal guidance for me.
Fredrik Brounéus:Apologies again: so, this is leading us further away from the original question on the system, but I have to ask. The reason for human products not being authorized for animal use when they are apparently being used in veterinary medicine, is that because the market authorization holders have no incentive to seek veterinary approval, so to say?
James Mount:Yeah, it's mainly the economic and practical reasons really, I think, which explain that there are some products that are not available for veterinary use, and it's down to the fact that the veterinary sector is simply just not a big enough market and the margins are just so small that it makes it really very uncertain for companies to invest in the development of veterinary medicines. And I would say even that often you find that there's a practice or a routine established around the use of human medicines in veterinary clinics and thus then it conceivably makes it unnecessary to spend large amounts of money or invest large amounts of money and time in applying for the approval of medicines for a specific veterinary use. And in some cases, when you're talking about specialist treatments for the use of unusual conditions, so it's a very few individuals involved, it can be very challenging even to actually design and carry out studies or relevant studies in those target species to actually even justify or support that. And actually, I would say here that the new veterinary medicines regulation has been quite good in fact, by introducing specific authorization routes for medicines which are intended for these kinds of limited markets on the veterinary side and for sort of these special circumstances or exceptional circumstances as they call them in the legislation, and that the aim here is to try to further stimulate the development of veterinary medicinal products for these small markets and mainly to focus on increasing the availability of treatments for really these serious and life-threatening diseases but also focus on these other unmet needs from the veterinary side. And this means these aspects that are stipulated in the legislation means that medicines can actually be approved with less comprehensive data than normal, so the process is more straightforward.
James Mount:The other reasons potentially for the use of human medicines in animals can also be due to the problem of availability of veterinary medicines. Some anesthetics for animals are also authorized for human use and that can sometimes cause a level of competition for supply, and I would say that this was most notable during our COVID pandemic that we had, when vets then were encouraged to identify alternatives to some anesthetics that they commonly use, and one of these that's most commonly used is propofol. And it was there during the COVID pandemic, it was critical to ensure that there was a steady supply of propofol specifically to human patients and obviously in this scenario, with the reliance on some human medicines in veterinary clinics, then a reduced availability of human medicines can have quite an impact on the veterinary side. And I should mention here, actually, we have a live example in place here where there is an ongoing availability issue related to a human inhaler which contains a form of cortisone, and this inhaler is primarily used to treat asthma in very small children, but this same substance is also used on license in cats and horses and, due to the ongoing availability issue and the very important fact that there are very few alternatives to treat these small children, the Swedish Medical Products Agency has now appealed to vets to limit the use of this product in animals for the time being.
Fredrik Brounéus:ctually actually read about that in the paper – the shortage of the medicine, but I didn't see any mention of the use in veterinary medicine.
James Mount:This crossover is quite significant occasionally, and all these examples that we've talked about now really do emphasize that. There is a need to have an efficient communication strategy that crosses over between the veterinary and human medical disciplines so that we can consider both supply and availability of medicines, we can mutually sort of raise each other's awareness and, in terms of pharmacovigilance, we should be together minimizing the risk of adverse events that occur from any medicinal product, whether it's used in animals or humans, or even both.
Fredrik Brounéus:Yeah, communication is key, as is often the case, perhaps. Well, now let's turn the ship around and go back to that original question on the reporting infrastructure. Sorry James, so let's start again. How and where are veterinary adverse drug reactions reported, collected, stored and so on?
James Mount:Well, first of all, I'd just like to stress the point that the suspected adverse events are reported both for veterinary and human medicines when they're used in animals, and within Europe, which I can only have the picture of, really, these suspected adverse events are mostly reported by veterinarians or animal owners, with the reports being submitted either to the national comptent authority within that EU member state or to the marketing authorization holder themselves and, as I said, these are the responsible pharmaceutical companies for their particular products. And, in accordance with the new veterinary medicines regulation, these adverse events should be recorded within 30 days now, which is a slight change from previously, and they should be recorded in the Union Pharmacovigilance Database, and this is also known as EudraVigilance Veterinary, or EVVet for short, and this system is maintained and managed by the European Medicines Agency in Amsterdam, and within this database there are even reports from countries outside of the EU, in fact. So this does provide, in some way, a very broad data set for signal detection.
Fredrik Brounéus:So, does that mean that you could report side effects from anywhere in the world to the EVVet database?
James Mount:No, not really, as in the EV Vet system is not a global veterinary pharmacovigilance database, although I should say that we potentially do need one soon and perhaps a UMC or a similar organization might want to help us here. But the only national competent authorities within the EU and the pharmaceutical companies which have a marketing authorization or products marketed within the EU have access to EVVet, and this means that they then have the ability to register their adverse event reports and also perform some form of signal detection in the dashboards that are available there. The reports that I mentioned, that come from outside of the EU, are actually recorded by the MAHs within Europe which have the same veterinary medicinal products marketed or and authorized in countries, or maybe several countries, outside of the EU, so it comes from their global sales and use. But while we're touching on the database, I could give you an idea of the size of the EU database and currently, when I last looked, there was roughly 950,000 reports or cases in the database.
James Mount:And that's in total, which obviously is significantly dwarfed by the volume of cases in the human equivalent database, and from what I've heard they've got around 12 million cases there.
James Mount:But if you consider the cases that we have on the vet side, the 950,000 within the EU database, currently, these contain about 300 million animals that have experienced an adverse event. And that's if the data is correct, but it roughly is, and this is because more than one animal can be reported per case. And if you talk about production animals and these large facilities that hold animals on a production scale, like pigs and poultry and mink, these are the extreme ones, where you can have thousands of individuals reacting to a medicine and can be reported in one single case. I don't know what the record is, but I've seen cases of 5,000 individuals reported. And this is where you've performed large-scale vaccination in these individuals or some form of large-scale treatment. But I also should mention that, like with the UMC system, where part of it is publicly available, I should mention here that there is a public portal available in the European Union pharmacovigilance database and that's open to anyone to go in there if anyone's interested.
Fredrik Brounéus:Right, so well, 300 million animals. So if we're comparing numbers of individuals instead of reports in the databases, the veterinary side is in a league of its own, really. Is there a difference in reporting due to the quantities of veterinary medicines that are used when it comes to treating individuals versus masses, if I mean, for example, a companion animal versus the mass treatment of livestock, poultry, aquaculture and so on?
James Mount:Yes, I would say so. And we do have a diverse array of animals that are treated in different ways. And just to emphasize the point that I've already made, is that most of the events in companion animals and here we're talking about pets and horses, these are reported on an individual basis or a small group.
James Mount:But, as we've just mentioned, when you're talking about pigs, poultry, mink and aquaculture and here I should even mention beehive owners, there can be like thousands of individuals that are treated and this could be either through drinking water, mass vaccination campaign, waterborne medicines for the aquaculture, and even we do have specific beehive treatments. And in these scenarios, as I mentioned, it's quite difficult to observe the adverse events unless a large number of animals are affected, and this means that there may be a significant number that die potentially and you normally have to take this in consideration to the normal fatality rate within that population. But the differences in what is reported on the vet side is also due to different types of handling that we have within veterinary medicine compared to human medicine and, as you've alluded to, there is large quantities of medicine that can be administrated in veterinary practice and in quite different ways to human medicine,
James Mount:Which can lead, if you consider the environment and exposure to the environment, when environmental exposure does occur, and if you compare veterinary and human side, different compartments of the environment tend to be exposed. With veterinary medicines, which are used in production animals, these medicines tend to end up in the soil through the manure, whereas with human medicine, they tend to end up most always in the wastewater instead.
Fredrik Brounéus:We'll get back to that eco aspect of pharmacovigilance in a little while. But first, how does the EudraVigilance veterinary database compare to other veterinary pharmacovigilance databases around the world? You mentioned that there's no global database as of yet, but are there similar systems in place in other regions?
James Mount:Well, I don't have a complete picture of all the systems that are available around the world, but those that I am aware of are very similar to the European Union's pharmacovigilance database. And here I'm talking about databases that are used by both regulators and industry, because sometimes they have separate systems, and the similarity with them is that mainly through the adherence to the same electronic standards to transfer data and here it's called the VICH standard that we use globally, or most of us use globally, and, if I may, that VICH stands for the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products.
James Mount:It's a rather long-winded title so it's often easier to refer to VICH, but it's very much comparable with the ICH standard on the the human side, and here there are VICH guidelines that cover all the different areas.
James Mount:For example, you've got standards on the construction of a single electronic message, the management of adverse events generally, and also one specific unique aspect is these controlled lists of terms that we have on the vet side, which include the global species list and the global breeds list and also other veterinary pharmacovigilance databases similar to the EU. One also use what we call VeDDRA terminology to code the clinical signs which are described in adverse event reports and to define VeDDRA as in that stands for the Veterinary Dictionary for Drug Related Affairs, and here it's very much similar to the MeDDRA terminology which you use on the human side, although there are quite some significant differences. Most notably is the total number of terms available. On the vet side, we have roughly 2,900 lower level terms, as we call them, or LLTs, and these are mainly the terms that describe the clinical signs that you report in an adverse event report. And if you compare this to the human side, in MeDDRA they have currently 88,000. So there's a lot more there.
James Mount:And also MeDDRA is a bit more of a complex list, being multi-axial, so there's several interconnections within the list, whereas VeDDRA is just a straightforward, simple Excel list.
Fredrik Brounéus:Thank you very much, James. That concludes the first part of this two-part episode on veterinary pharmacovigilance, and next time we will talk about differences in types of adverse events reported on the veterinary and human sides, methods and new technology, including AI, being used in veterinary pharmacovigilance, and user safety in veterinary medicine. As a veterinarian, I know you have some hands-on experience of so-called self-injection, James.
James Mount:Unfortunately, yes. Working as a vet, our patients tend to be not so compliant at times. Often we're working with moving targets, which can add an element of risk.
Fredrik Brounéus:Yes, I look forward to hearing more about that. Until next time.
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.
Fredrik Brounéus: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?
Fredrik Brounéus:That's all for now, but we'll be back soon with the second part of the Veterinary Pharmacovigilance episode. In the meantime, please feel free to reach out on Facebook, LinkedIn and X, send 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.
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Fredrik Brounéus:For Drug Safety Matters. I'm Fredrik Brouneus. Thanks for listening. Thank
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