Federica Santoro 0:15

Welcome to Drug Safety Matters, a podcast by Uppsala Monitoring Center, where we explore current issues in pharmacovigilance and patient safety. As a consequence of the COVID-19 pandemic and the mass vaccination campaigns, the topic of vaccine safety is on everyone's minds. And the same pharmacovigilance systems that until recently had been unknown to many are now the object of intense scrutiny and media attention. But it's not always easy to understand how it all works. So if you've been wondering how side effects are studied, what happens after you report one, or how Uppsala Monitoring Center fits into the picture, this is the episode for you. I'm your host, Federica Santoro, and my guests today are two of my colleagues. Vigi-based manager Helena Schueld, who curates the world's largest collection of data on side effects of medicines and vaccines, and pharmacovigilance scientist Annette Rudolf, who digs into that data to flag any issues we should be concerned about. So follow along as we dive into the world of vaccine pharmacovigilance. It's fun to have not one but two of my colleagues on the show today. I'd like to kick off with the basics, and my first question goes to you, Helena. So let's imagine I've been administered a vaccine. I feel a bit off after that, and I suspect it could be a side effect.

SPEAKER_00 1:59

What should I do then? Yeah, it depends on the setting. If you get a reaction to a vaccination, the vaccination facility would collect that report, especially if it happens in a short time after you got vaccinated. But let's say that you got home and you notice this after a few days or something, then perhaps it's not easy to go back to that facility. Then you would probably seek out your physician instead and have a discussion with them. And I would say it doesn't even have to be that you recognize this as a side effect. It might be that you're experiencing something and then that the physician would ask you whether or not you've been taking any drugs that could cause this. So the physician is expected to capture this information. And with the spontaneous reporting systems in place, this means that the physician would collect information from you. They would fill out either a paper form or send an email to the drug regulatory authority. Or there are even hotlines, or you can send text messages. It's really a number of different ways you can do this. And then the regulator will collect the information from all the different reporters of the country in one database, and they would look at each case to understand what happened and try to figure out if there is a relationship between what you experienced and the drug or vaccine that you took. Also, I would say that it's important that the national regulator that they have the mandate. So in the extended process, having this information may want them to act on something. Let's say they have a lot of these reports coming up from around the country, they would need to have the mandate to act on that, to have a communication with the manufacturer, act through communication, either through sending letters to the physicians or to ask the company or require the company to update their labeling, for example. At the end, then and where we are at, at the Uppsala Monitoring Center, through the WHO program for international drug monitoring, the drug regulator would send their reports onward to Vigibase, which is the WHO's global safety database, to pool all this data together into just one big data pool where we can do other stuff with the data later on. So from patient to doctor to national regulator to Vigibase.

Federica Santoro 4:31

And Vigibase has been maintained by us at UMC since 1978. But what's the advantage of collecting information at a global level in a large database like that when every country with a functional pharmacovigilance system, and I'm glad to say that's most countries in the world, already has its own database. What value does VigiBase add?

SPEAKER_00 4:57

Yes, so as I mentioned, the national responsibility for their own market, of course, is crucial and they need to be able to act on anything that they find. So that's the primary purpose. But when we gather all this data into VigiBase, we can get an additional perspective. For example, if a country records only single events, they wouldn't really raise any concern over this because it's just maybe one, it could be coincidental, or you would look at this as a spurious event. But if we see this same reaction appear in other countries, we understand that they would not see this as anything to consider, but looking at the global picture, you can really see other patterns emerge. So it's a good way to find what's rare and unexpected, basically. And in addition to this, and not only covering the additional value of VigiBase, but additional value of being a member of the WHO program, you also have the benefit of through the tools, you can really utilize the Vigibase data for your own good as well as the national regulator. So I would say that perhaps this is an even bigger value because through the program you can share the signals that you find with others, and others can see what you do, and you can also see what others are doing and what the UMC is doing when it comes to this uh safety data analysis.

Federica Santoro 6:23

So it's a global collection of data that will help you spot patterns, but also a way to collaborate across borders, right? Absolutely, yes. And the WHO program for international drug monitoring encompasses nowadays more than 140 countries, and all of them send data to VigiBase. But how well does the database represent the world's population? In other words, how well does VigiBase portray what's happening with medicines and vaccines in different countries around the world?

SPEAKER_00 6:57

Yeah, that's uh a difficult one. So we know that there is considerable underreporting. There's a lot of ADRs that go unrecognized. And the magnitude of this issue really varies from country to country. It also varies with the reporting culture. In some countries, it can actually be very sensitive to report. Sensitive how? Yeah, you would, as a doctor, you might jeopardize your reputation by letting others know that you've caused harm to your patient. That's a global issue, really, to ensure that the reporting culture can be as open as possible to ensure that that it's no stigma in reporting, so to speak, that you really encourage reporting from doctors and patients. And on the other hand, we have situations where the reporting can actually be boosted by media attention, for example, which would then really increase the number of reports for a specific drug and ADR combination. So it can go both ways. So it's something that you always have to have in mind when you do the analysis. It's something that you always look into. If you find something that you investigate, you really look into these surrounding factors.

Federica Santoro 8:09

And since you mentioned ADRs, we should quickly explain for our audience's sake that that acronym stands for adverse drug reaction. And that's a technical term we tend to use when we talk about side effects. But you said media attention can boost reporting. Do you think that will affect the amount and the kinds of reports that we'll get for COVID-19 vaccines over time?

SPEAKER_00 8:35

Yeah, I would suspect that I'm forwarding this to Annette as well, but I would expect that events that are really picking up attention in media will also be much more reported than than you would have seen otherwise. Would you agree with that, Annette?

SPEAKER_02 8:49

Yes, I can definitely uh confirm that. So there have been already studies done actually a few years back, so it has nothing to do with the COVID-19 vaccines, or it's nothing particular for them, but it's uh it's a known fact that media attention does influence reporting behaviour.

Federica Santoro 9:05

One last thing for you then, Helena. When reports come into Vigibase, or one of the national databases for that matter, they contain information about suspected side effects. How sure must one be of that suspicion before reporting?

SPEAKER_00 9:22

That's a good question. And I would say it varies a little bit between countries and what their guidelines say. In general, it would be encouraged, I would say, to even with very low level of suspicion, you're encouraged to report. In some countries, it's even just the fact that something happened after you took the drug is enough for it to be reported. Um, but other countries may have more strict guidelines. And this is for the national view. And if we look at what we receive in VigiBase, and this is also something that varies, some members they send everything that they have, and others will do a selection and only send cases where they actually have made the causality assessment that's possible or higher. So they've already made that connection that this is something that we think is actually a causal relationship.

Federica Santoro 10:13

Now, Annette, you will tell us some more about that process of causality assessment that Helena just mentioned. And for those who are listening and don't know what that means, that's basically the process through which you try and determine whether a side effect you're seeing was indeed caused by a drug or a vaccine. We'll get back to that in a little bit, but first let's talk about the difference between reporting rate and incidence. And the reason I'm asking about this is that I read an article recently written by the director of the Drug Safety Research Unit, or DSRU, in the UK, where he warned that even public health and pharmacovigilance specialists tend to confuse these two terms. And that's risky. And to understand why, let's take an example. So, say my country has vaccinated one million people against COVID-19, and of these, a hundred people get a headache and report it as a side effect of the vaccine. So one hundred in a million or one in ten thousand is our reporting rate. That's how often headache has been reported as a side effect after vaccination. Why can I not conclude though that one in ten thousand is also the incidence of headaches? In other words, how often I expect headaches to occur as a whole in vaccinated people. Where's the difference, Annette?

SPEAKER_02 11:46

Well, the difference is uh has to do with what uh Helena mentioned earlier with the under-reporting. So basically the reporting rates are just what we see, are just what we get here, for example, at UMC. So we get mostly unsolicited and spontaneous reports. But under-reporting is like one of the biggest limitations we have in pharmacovigilance at all. So you can be quite sure that a lot or a big proportion of patients, also medical doctors or pharmacists or whoever is reporting, they might not report everything they see. And that is that can have various reasons. So, for example, one could say, okay, this is a side effect that is already known. Why should I report it? I don't report it. Okay. That one, for example, is a report we miss. Or someone says, I'm kind of embarrassed. I don't want to share this, I don't want anyone to see it. Another report is gone. Uh so yeah, reporting rates and incidences are two very different things and mustn't be confused, I think.

Federica Santoro 12:45

That's right. And it's important that people understand this distinction because if they see figures of reporting rates, they shouldn't draw the conclusion that that's how often that particular side effect occurs in the vaccinated population. And there's another thing people should remember about reports collected in pharmacovigilance databases, and that's that the side effects listed there are suspected, and as we've said now a few times, can only be confirmed after careful investigation. But really, I feel I cannot stress this enough these days when all our eyes are turned on the COVID vaccines. So once again, just because there's a long list of side effects reported for a vaccine does not mean that the vaccine caused those side effects. And why, you may wonder? Well, some of those reported side effects may have been caused by a medicine that the person was taking at the same time. Other side effects may simply be a health condition that the person manifests after vaccination. Correlation is not causation. So before we can draw any meaningful conclusion on the safety profile of a vaccine, we need to analyze those reported side effects rigorously and exclude any confounding factors. And that's where pharmacovigilant scientists like you, Annette, come into play. So let's talk more about this process of causality assessment. If reported side effects are mere suspicions, how do you go about confirming those suspicions?

SPEAKER_02 14:29

Um well, it's uh it's a whole process behind this. So um what we here do first is uh well in the very first step we would uh apply some statistics to find combinations that are unexpected and maybe not known yet. And once we identified a combination, we would go further and uh have a look on what happened exactly. So what is the drug or the vaccine involved and what is the reaction that happened? And then we would try to, well, one of the first steps is to to check whether anything is already known about this reaction. So for example, do we have already information from clinical studies? Is the reaction maybe already described in the in the drug leaflet? Things like that. Or also go and uh look in the in the scientific literature. If there have been maybe already studies performed or case reports described at least. And then one would get a little bit deeper on the more pharmacological level, and try to see if there is maybe some kind of potential link, potential mechanism linking the the drug and the reaction that occurred. Can it be somehow explained, like on a biological level, for example? This is the rough process, I would say.

Federica Santoro 15:39

It's tricky stuff. Um what do you think are the main challenges of that process? What makes it so complicated?

SPEAKER_02 15:48

Well, it's not always super easy to find this biological link, for example, to find the mechanism, especially when thinking about the the COVID-19 vaccines now, which are very new vaccines. You might not know from the beginning the exact mechanism, how do they work? What is the way of working? What happens to the vaccine once it entered your body, for example? So that is quite some detective work, I would say.

SPEAKER_00 16:13

And also perhaps lack of details in the data. I mean, this is one of the challenges that we face, I guess, with the information that we have to deal with. If we don't get enough information on the reports, it's really difficult to establish any relationship. You need to have as detailed as information as possible on when the event happened and when the drug or vaccine was given. That's really important to be able to establish the time relationship. And I mean other factors that are really helping out in the process. Like the story behind what happened is really important when you do this work as well.

Federica Santoro 16:49

And does that boil down to an issue with the reporting culture then? Are you saying that we shouldn't only convince people to report, but also make sure that when they do report, that they fill in a form as comprehensively as possible?

SPEAKER_00 17:06

That would be definitely a very good situation, but there's also the problem, so to speak, with privacy. We're dealing with health data. So actually, when it comes to sharing information with a global organization like the WHO program, uh there might be situations where the countries simply cannot share data even if they would like to. And in those cases, we need to deal with what we have and hope that we have some index cases that are well documented and that we can have support from other cases as well.

Federica Santoro 17:41

I understand that complication. So, Annette, you and a lot of our colleagues have been working with analyzing side effects of COVID-19 vaccines lately. This has really become your priority. And that was quite a change for us at UMC because really most of the work we've been doing over the years has focused on medicines rather than vaccines. How does monitoring the safety of vaccines differ from that of medicines?

SPEAKER_02 18:14

The first and most apparent difference might be the type of patient or the type of recipient, let's put it like this. I hope not all of them are patients. So while medicines usually are getting administered to patients who suffer from some condition with the aim to treat this condition, a vaccine you would usually administer to a probably healthy person. So that's why adverse events or reactions that occur, especially with vaccines, are way less tolerated than with medicines, for example. So that is something to keep in mind when asking this question. Another difference, of course, is the way of working, a way of mechanism. So drugs and vaccines work pretty differently. They target different things, potentially at least. And well, also the timelines of reporting, especially now during these pandemic conditions, differ a lot. So while with traditional medicines and drugs, we would probably see safety signals emerge. Yes, some might emerge briefly after market authorization, but I think a lot may emerge only like after some some time. Now we are in the unprecedented situation that these vaccines we have now are super new. And even though there have been really, really big studies done already, everything we see might be new. The timelines of reporting, but also of acting, so of the assessment we do, they differ a lot right now at least.

SPEAKER_00 19:43

I would also like to add, because I think in the global sense of vaccine monitoring, you usually have uh different setups in the country. So in most countries, especially in the low middle income countries, you have the setup with an immunization program that's very stable, it's been there for a long time, and they have really robust processes, but they are focused to a large extent because of the difference that Annette mentioned. I mean, vaccines are also often perhaps more sensitive, they require a cold chain, storage facilities, etc. It's also handled by those who give the vaccine, you need to mix it with a dilutant, etc. So there are more steps in the process that can affect the outcome. So a lot of the focus when it comes to the safety of vaccine in that context focuses on the surrounding factors to find the root cause of the problem. And when we end up with the information that we have, we're trying to find the more unexpected things and the things that can't be explained by this situation. But it's really two different complementing processes, I think.

Federica Santoro 20:54

And Anette, more specifically, how have you and the rest of the research team been investigating covet vaccines lately?

SPEAKER_02 21:04

So, what we do right now is to really regularly screen our database to find disproportionately often reported events. And uh we try to maintain the global perspective here. That's to keep in mind. So, what we do is also checking what are the others doing. What is for example the FDA or the EMA doing already? So we don't want to repeat their work. But of course, we are offering collaboration, I guess. But um what we try to do here is really focus on the global issues, as Helena said before, and focus on things that are emerging and unexpected. So, what we do is these regular screenings that are in place right now, they are basically every one or two weeks. We go through the entire database to see if there's anything that we didn't expect yet, that we didn't know about yet or didn't hear about uh from from media, from social media, whatever. And uh we try then to prioritize these combinations and see what do we have to look at in a very timely manner? What is really important and is there anything we can do maybe to minimize risks for patients, for example?

Federica Santoro 22:14

What about you, Helena? How has your work as VigiBase manager changed because of the pandemic?

SPEAKER_00 22:21

Yeah, I can I can mention a few points. I think Aneta describes very well the work that we do, but in complementing that, I would say that we've done also a lot of work to really ensure that the countries can do their work better as well. And to ensure that the WHO guideline that was issued on the safety surveillance of the COVID-19 vaccines, um, that they can, through the tools and the services that we provide from the UNC to the WHO program members, that they can really step up and get improved processes for data collection, for example, because a lot of the countries are really based on a paper, still a paper form system. And this means that they have long lag times from when something happened until the information reaches the regulator or the national immunization program. So by working closely together with WHO headquarters, we've done a lot of work to ensure that we have digital alternatives for them to use. Also, to ensure that they have the possibility to use our analysis tool to do their own national analysis in efficient ways and to document their findings to avoid that they need to look at something again and so on. And also, I mean, as part of the the things that we've done to ensure that that Annette and the team have good data, we have put a lot of effort into manual coding. And this coding of data is really important because when you have a database as big as Vigibase, if things are not structured and coded appropriately, you won't be able to find anything. So from an analytical perspective, it's really important to have that specificity and uh accuracy.

Federica Santoro 24:02

I can imagine. You want data standardized and organized in a certain way, otherwise you're not even sure what you're looking at. Well, okay. It sounds like you're both really busy and have lots of stuff to return to, so I won't keep you any longer. But is there anything either of you would like to add as we wrap up the interview?

SPEAKER_02 24:24

I would say now more than ever, it is really important that everybody, all our listeners and everybody out there should be encouraged to really report what they see because every voice right now is really important and will be heard for sure.

SPEAKER_00 24:37

And I agree with that completely. I think the scale when these vaccines are being rolled out, even a very, very rare reaction occurring in perhaps one in a million or one in ten million people, it has the potential to affect a lot of patients in a short time because of all these people getting vaccinated around the world in so short time. Absolutely.

Federica Santoro 25:00

And I hope our listeners will have also understood that reporting is a crucial part of public health and that everyone has a role to play. Thank you both once again for taking the time to talk to me and joining me on drug safety matters. It was great to have you on the show. Thank you very much. Thank you. That's all for now, but we'll be back soon with more conversations on medicine safety. If you'd like to know more about vaccine pharmacovigilance, check out the episode show notes for useful links. If you like our podcast, subscribe to it in your favorite player so you won't miss an episode. And spread the word on social media so other listeners can find us. Apart from these in-depth conversations with experts, we host a series called Uppsala Reports Long Reads, a selection of audio stories from UMC's pharmacovigilance magazine. So do check those out too. Any comments or suggestions for the show are welcome. Look for Uppsala Monitoring Center on Facebook, LinkedIn, or Twitter, and come talk to us there. For drug safety matters, I'm Federica Santoro. I'd like to thank Helena Huld and Annette Rudolph for their time, Matthew Barwick for production support, and of course you for listening. Till next time!