SPEAKER_00 0:16

By hearing their stories, we get a feeling for what matters to patients. And by getting this feeling, we can also set pharmacovigilance center think about how can we address what the patients need. Because they are the ultimate users of drugs.

Federica Santoro 0:31

Welcome to Drug Safety Matters, a podcast by Uppsala Monitoring Center, where we explore current issues in pharmacovigilance and patient safety. In this episode, we'll talk about the role of patients in pharmacovigilance. Why is their input so important? And how can we get them more involved? As the end users of medicines, patients can provide first-hand information on side effects. Yet for many years, patients had little to do with the science of pharmacovigilance. Recognizing and reporting side effects was a job for drug manufacturers or healthcare professionals. But that has changed for the better. And we've been listening more and more to what people have to say about the medicines they take. My name is Federica Santoro, and my guest today is Linda Hermark, Head of Innovations and Projects at the Netherlands Pharmacovigilance Center LAREP. Linda is an expert in pharmacovigilance reporting, especially when it involves patients, so I couldn't miss the opportunity to chat with her and learn how patient stories help make medicine safer for everyone. Now, if you're not familiar with the pharmacovigilance jargon, please note that you're gonna hear the acronym ADR from time to time. That stands for adverse drug reaction and it's just a technical term for a side effect. Let's get started. So let's start with the basics. What do we mean by patient reporting?

SPEAKER_00 2:00

Well, there's been a lot of uh talk about the terminology because some people say um we shouldn't call it patient reporting because not everyone is a patient. Sometimes when you're just a normal person buying a paracetamol because you have some headache and then taking it, are you per definition a patient then? So some people would prefer to say consumer reporting. I personally think that patient reporting is a better term because it does say that someone is using drugs because they need to. And I think consumer sounds very commercial because I don't think people are consumers of drugs because drugs are special products which you don't consume. Sometimes in the English vocabulary we use the term reporting by the general public. That I think is also quite a friendly word to say that you allow everyone to report. What we then mean with a patient report, and I will use this terminology, is that a report is filled in from the perspective of the patient. So it can be the patient themselves that fill it in, and it can be a carer that fills it in, or it can even be a healthcare professional that facilitates the filling in of the form for the patient. But if the healthcare professional fills in the form on behalf of the patients, they only give administrative support. So they don't do their own interpretation of the information. I think that's the key to say what is a real patient information, that the information is coming directly from the patient without interpretation of any healthcare professional.

Federica Santoro 3:24

So traditionally, reports of adverse effects have been submitted by pharmaceutical companies who manufacture the drug and are required by law to report or by healthcare professionals. When did that change? When did we start thinking about allowing patients to report as well?

SPEAKER_00 3:40

If you look in a global perspective, it has been allowed in some countries since the beginning of pharmacovigilance, for example, in the US and in Australia. I don't know how much the systems have been promoted there. I think in Europe, as we are centered in Europe, the change began in the middle of the 2000s. In the Netherlands, we started allowing patient reporting in 2004, and I know Denmark and the UK followed, and Sweden followed in the following years. But then it was very controversial, and I remember it because I just started at LAREP in 2006. And then, well, a lot of people also within LARE were quite negative. We thought, why should we start with this? So patients don't know anything, they just want to complain, and we will not get any useful information because they don't know how to provide information. So also internally it was uh a lot of negative commotion in this. But the our director at that time, Kees van Grotes, he really believed that was the way forward for us as an organization. So he really pushed through and said, Well, I understand all your arguments, but still I think we should give it a try. And today I'm very thankful for him that he made uh this big commitment to allow patient reporting.

Federica Santoro 4:53

So, why did he believe in it so much? Why would we want patients to report?

SPEAKER_00 4:56

I think he believed that patients can also tell us things that other people cannot. So I think that's what's the key.

Federica Santoro 5:03

And that brings me to my follow-up question, which is what is the difference then in the kind of information that patients relay compared to healthcare professionals?

SPEAKER_00 5:12

Well, you can say the difference in very many aspects. If you think about the completeness or the documentation grade of the uh the reports, it's quite similar. Maybe because we at our center use web-based forms, so then you can uh trigger a higher completeness of your information by mandatory fields. Um I think patients more tell their stories. You have a sort of personal commitment to write the report, so it's quite personal. They talk about how the ADR impacts their life, how it impacts their view on using drugs. Sometimes they also tell about how they are treated in healthcare. They are not listened to. As sometimes is just the same as healthcare professionals. Uh, some studies have shown that patients are more prone to report um psychiatric adverse drug reactions or sexual um adverse drug reactions, which is of course sometimes very difficult topics to talk to your healthcare professional. I also noticed that uh while a healthcare professional more often reports a diagnosis, and of course that's their job to put diagnosis, a patient reports more symptoms.

Federica Santoro 6:19

In a paper published last year to celebrate 15 years of patient reporting, Ladeb noted how healthcare professionals nowadays report roughly the same as they did in 2004. While patients send in 20 to 30 times more reports now than they did 15 years ago, and that's a good thing. All pharmacovigilance systems, even the most developed ones, suffer from chronic under-reporting. Healthcare professionals will often say they don't have enough time to report. They might not be interested or forget altogether, and sometimes they will have no idea they should be reporting. So it makes all the sense in the world to try and bring patients on board. Another valuable aspect about patient reports is that they often cover blind spots of pharmacovigilance systems. Products that pharmacovigilance professionals tend to focus a little less on, such as over-the-counter, herbal, and falsified medicines. And in terms of usefulness then to pharmacovigilance and ultimately to the identification of signals, do you find that patient reports have proved just as useful as those submitted through conventional routes?

SPEAKER_00 7:29

Yes, uh, we have done two studies where we have looked what is the value of patient reports in signal detection. And in both studies, they show that they do contribute to signal detection as much as other reports do at our center. But I also think that not maybe the patient reporting from signal detection point of view, but because we now allow patient reporting, we also get their stories. So even though a report isn't a signal in a sense, we get their stories, and by hearing their stories, we get a feeling for what matters to patients. And by getting this feeling, we can also, as a pharmacovigilance center, think about how we can address what the patients need, because they are the ultimate users of drugs. So it's very important that we address their needs. So I think one of the things that we, at least in our center, are thinking a lot about how can we shift the focus a bit from finding signals in the sense in finding the new and unexpected, because these are very often very serious reactions, of course, but also very rare reactions. So a lot of patients don't get it. So how can we shift the focus from the very serious and rare to the more common and severe? Because from the very common adverse drug reactions, a lot of people will experience them and they will be severe, so they will have impact on their quality of life, they will have impact in how they use the drug. And if we can manage to find information that will help patients and healthcare professionals to help patients to manage these adverse drug reactions. For example, when does an ADR occur? Can you expect it in the first week or is it in the second week, or is it after a year? And what do you do when you experience this? Can you continue the drug or will it worsen? Do you need to stop? And if you continue, when can you expect that the ADR disappear? And also how can you treat the ADR? Can you do anything to alleviate the ADR so that you can get a higher quality of life? I think it's important for pharmacovigilance to make that shift, to also see how can we generate information that is useful for patients in their management of their ADRs.

Federica Santoro 9:35

That's really interesting. Do you have an example of a situation where patient reports were instrumental in identifying a problem with a drug?

SPEAKER_00 9:44

Of course they have been used in very many signals that we have brought out through the years, but one that I remember very much is the signal that we wrote about the use of SSRIs and um aggression. When you heard the term aggression, well you think, well, it's very unpleasant. Well, people can get a bit aggressive, but you don't have a good picture about it. You'd think, well, it's not that bad. But then we had a few patient reports that very clearly describe what happened to these patients. And I I remember once, and I also used that in a quote in an article that I written, that they don't recognize themselves, that they can shake their babies, or they can be very aggressive and hit and hurt other people, and then afterwards they are so shocked by their behavior because they don't recognize this violence in themselves. So I think those are stories that really stuck to me, which I have uh really thought about. But on a daily basis, we see things from patients. For example, a few years ago we had problems with the drug liver thyroxine, and then patient reports were very instrumental in identifying that signal. Um yeah, we see it all the time. But for me, what's most interesting is the impact that you have when you read it. So that's the more the stories that stick to me, and not so much the normal signals.

Federica Santoro 10:58

In 2016, UMC staff traveled to the Netherlands to conduct a signal detection sprint, a signal detection exercise together with LADEP staff, and that was focused on patient reports. So I was wondering what came out of that that is noteworthy.

SPEAKER_00 11:15

Well, no, first of all, I think what was very interesting was for us at LAREP site was to get to know more about the UMC's signal detection methodology, so to be able to discuss with the UMC colleagues about signal detection in patient reports. I also think we identified a number of signals which have been published both in the signal document and in the WHO pharmaceutical newsletter. And I think what's different with these signals is that they often conserve very well-used drugs, so very common drugs: levithyroxine, the contraceptive pill, antihistamines, amitrictylene, so drugs that are very commonly used. And also the type of ADRs that we um detected were also not medically serious, but severe, for example, panic attacks, dry eyes, and that kind of thing. So it was a different kind of signal that we uh identified. And we also looked for signals in the wider sense that uh not only is it new but also is it not adequately labeled, so is it not adequately described for patients in the leaflet? So, for example, one of the signals was about amitriptylin and dry eyes, and for everyone in the pharmacovigilance community, that is a very well-known effect. So it's not new in the sense of that. But in the patient information leaflet, it doesn't mention dry ice, it says anticholinergic effects, and dry ice is an anticholinergic effect. But most patients uh wouldn't know that. So we think by raising the awareness that dry ice is a symptom of an anticholinergic effect and make it more explicit, it's very important for patients to understand their ADRs.

Federica Santoro 12:57

That's really interesting, and I think that raises then two points. Like on one hand, that tells us a lot about what healthcare professionals focus on and which adverse reactions they decide to report. And on the other hand, it tells us that there's a problem with our patient information leaflets, right? That perhaps the information they supply is not complete. So let's start with my first point. What does the information you collect from patient reports tell us about the way healthcare professionals report? And how can we convince them then to report more and report more comprehensively?

SPEAKER_00 13:27

I don't think that patient reports in general says anything about how healthcare professional reports. Um I think both reporters are very important for pharmacovigilance because they do contribute to sometimes with a bit different perspectives. What I think is very important is to keep engaging with patients but also keep engaging with healthcare professionals because we do notice that because of lack of time, they do not report as much as I would like to. So I think that's more the challenge to see how you can make pharmacovigilance attractive for healthcare professionals again.

Federica Santoro 14:01

Yeah, so we need both of them, right? It's a complementary approach. Yes, definitely. Yeah, and for my second point, then what do we do about the patient information leaflets?

SPEAKER_00 14:10

I think the key issue here is that the patient information leaflet is a legal document. Of course it's aimed at patient, but still they have to fulfill legal requirements. And I think in this tension between fulfilling the legal requirements and be patient friendly, it's difficult to make a patient information leaflet that is truly informative for the patient.

Federica Santoro 14:33

Studies on the reporting habits of healthcare professionals have shown that people will often report issues that are dear to them. Physicians tend to describe serious problems that require their intervention, while nurses might highlight issues connected to patient care, and pharmacists will often report problems related to the drug's dosage or its interaction with other medicines. So it's not entirely surprising that patients will focus on how medicines impact their quality of life. That's what matters most to them, after all. An interesting aspect that emerged from the UMC Lareb collaboration a few years ago is that by reviewing case narratives, the patient's stories, pharmacovigilance professionals can identify issues that may have been overlooked or misinterpreted by the treating physicians. A patient who taken the contraceptive desogesterol, for example, wrote, I never suspected the drug to have any role in my anxiety or panic attacks before I stopped the drug and realized that my problems went away. What this narrative tells us is that neither the patient nor the physician had recognized that the panic attacks could be caused by the medicine. And that's why it's important to detect and communicate such side effects. So doctors and patients can become aware of the link and stop or change the treatment if required. So we understand that it's important for patients to report. We get really useful information from them. But what do the patients think? Do they report willingly?

SPEAKER_00 16:07

It's difficult to say. The patients that do find us are very happy that they can report. I think in many countries, and also in our country, it's quite unknown that there is a pharmacovigilance center and that you can report to a pharmacovigilance center and what's happening with your report if you report. So sometimes when we do campaigns, we get reports from patients that experienced their ADR maybe 10 years ago. So then you think, hmm, very strange. Why do you report something that happens 10 years ago? But I also think it shows that this ADR has had such an impact on their life. So even though 10 years after the event, at the moment that they know that there is a pharmacovigilance center where they can contribute their report, they are still willing to contribute it. So I think that's very nice. We have also done studies among those who report to ask what is the motivation for you to report? What drives you to report? And there we found out it's very altruistic motive. So people just want to share their stories to prevent that other people will experience the same as they have. And in the Netherlands we get about more than 5,000 patient reports a year. But if you consider that we have a population of 60 million people, still the number of reports is very low. So there's also a huge mass that maybe don't even know that they can report. And if they know, they don't think it's worthwhile. So I think we still can have a lot of more impact if we could also attract those patients to pharmacovigilance.

Federica Santoro 17:42

And do you have strategies to do that? I mean, at LARE, are there strategies to try and reach more patients?

SPEAKER_00 17:47

Well, we are trying constantly. I know last year the UMC, together with the European Union, organized its social media campaign, so we also participated in that. We also tried to publish for patient organizations and also for more general magazines in the Netherlands. So not only scientific publications, but also for magazines where also patients read. Of course, our website, our newsletters. We also go to some conferences for patients and conferences on health to promote pharmacovicness. So we we are trying, but it's a very large and very diverse group, so it's difficult to know where you will have the highest impact.

Federica Santoro 18:27

The social media campaign Linda mentioned is Med Safety Week, an annual appointment where UMC and medicine regulators across the globe come together to spread the word about side effects and how to report them. Last year's campaign took place in over 60 countries and reached more than 10 million people worldwide. But good communication is not only crucial to raise awareness. Once patients have reported and signals have been identified, it's important to communicate the information back to people. But that can't be done via specialist publications that patients don't read or don't understand. In a study conducted last year, LADEB documented their collaboration with an organization for patients with thyroid disorders. The point of the collaboration was to disseminate the information that anxiety and panic attacks can occur with the use of livothyroxine, a drug used to treat thyroid disorders, and that these side effects are often caused by incorrect dosage. By posting the message on the patient organization's news and social media channels, LAREB managed to reach almost 14,000 patients affected by thyroid disorders. A pretty specific audience that would have been difficult to reach otherwise. I know that at LAREB you make a point of giving reporters feedback. So in the case of patients, for example, what kind of information do you give them once they've reported?

SPEAKER_00 19:53

Well, when they have reported, depending on the type of report they have submitted, the complexity, sometimes we only send a nice feedback letter, a general one, because we have done research which shows that patients were also very happy with a nice feedback letter. In the more complex cases, and if they have questions, we make a personal feedback. We try to answer questions as good as we can, but we are not the treating healthcare professionals, so we can never give pharmacotherapeutic advice. So we would never say you can stop this drug or you should continue that drug. So then we would say we think it's wise for you to consult your prescribing physician. So that's what we do when they have submitted a report. And also we provide them with information about the ADR if there is anything known. And then if we find a signal and if their report has contributed to a signal, we send them an email which saying thank you for reporting three years ago, your report has contributed to this signal, and then we send it to us because I think that feedback loop is very important that they see that their report has really contributed to something.

Federica Santoro 20:56

And motivate them perhaps to report again in the future.

SPEAKER_00 20:58

Yes, or at least spread the word among their friends.

Federica Santoro 21:01

Okay, how how widespread are patient reporting systems around the world? We have around 150 countries now between uh full members and associate members in the WHO program for international drug monitoring. But roughly, do you have an idea of how many of them implement patient reporting?

SPEAKER_00 21:16

I have an idea, but uh we have actually done a survey within the program to ask about the status of patient reporting, so that's been published in Drug Safety. I don't know the numbers on top of my head, but I think there are quite a substantial part that accepts patient reports. But accepting patient reports isn't the same as actively promoting the involvement of patients. But I think in many countries all over the world, the interest and the possibilities that patient reports give to pharmacoviginals is being explored. So I think there's a lot of lots going on, but it can, of course, as always still be better.

Federica Santoro 21:51

So let's talk a little bit about countries who don't have a patient reporting system in place. What should they consider when starting to implement one?

SPEAKER_00 21:59

Well, I think. I think patient reporting, of course, is very important, but I think you need to look in each country what are your priorities at the moment. So, what kind of difficulties are you facing and how can we best use the resources that we have? If you think that one of the options would be patient reporting, I think it's first important to liaise with patients to see what would be your preferred mode of reporting. Because the writing and reading skills vary in various parts of the world. The logistics in sending mail, access to computers, access to smartphones, and access to internet also varies. So depending on how your setting looks like and what your patients need, you would have to design reporting modes that fit your population. So some people do telephone reporting, some people do apps, some people do paper forms. But I think that's the important thing to show how can you make reporting accessible to the patients? And also how can you make patients aware that they can report? So, how can you design your communication to raise the awareness among the general population? I think those are key questions. And I actually think that raising the awareness is the most difficult part because making a form is not so difficult. But raising the awareness, it's a difficult one.

Federica Santoro 23:17

And when it comes to the reporting forms, what are the differences between the forms designed for patients compared to those designed for healthcare professionals, for example?

SPEAKER_00 23:26

I think it's different between different countries. Some countries just have the same form. Some countries have the same form with the same fields, but they use different words to describe different fields. For example, in a healthcare professional form, you maybe have the word indication where you want people to fill in the indication. And in a patient form, you might write the drug is used for treating, and then. So it's just two ways of asking the same. And I think in the beginning, at least in our center, we were very we wanted to have the same forms because we wanted to make sure that we didn't create a situation where there was a difference between healthcare professional reports and patient reports, because we were very conscious of that we wanted to measure if patient reports were equal to healthcare professional reports. But I think with time we have realized that patients contribute with other information that healthcare professionals cannot, and also the other way around. So now we have more tailor-made the forms for the both groups. So for patients now, for example, we ask them what the impact is on the quality of life. So how uh how severe did they experience the ADR? That's something that the healthcare professional wouldn't know. I still think that we ask them where they have obtained the drugs, if they, for example, have obtained it through internet, then we ask which website, because that's information that can help us uh identify maybe counterfeit drugs that comes into the country in a more irregular way, and that we don't ask healthcare professionals in general because they would maybe don't know. So now we try to make tailor-made the forms to get the information that each reporter can provide.

Federica Santoro 25:04

And I have one last question. Because the information you get is slightly different than depending on who is reporting, do the signal detection strategies differ then depending on what kind of reports you're doing it on?

SPEAKER_00 25:15

No, we have one um signal detection process in the Netherlands, and it's the same for patient and healthcare professional reports. We are, of course, have a much smaller database than the UMC. We get about 200 to 250 reports every week, and those are looked upon in a case-by-case fashion. So every report is looked at by an assessor, and it doesn't matter if it's a patient report or a healthcare professional report, they are looked at in exactly the same way.

Federica Santoro 25:40

I imagine one difference is that patient reports are richer in case narratives.

SPEAKER_00 25:45

So perhaps that's something that Yes, but by using uh case-by-case signal detection, you can take that into account. So when you read every report before putting it into the database, you can highlight if there is a rich narrative that provides you with extra information. And that's very different to when you rely on the statistical signal detection when you don't look at every report, but you let an algorithm choose to you which reports to look at. So then the narrative is not taken into account. So I think that's one of the things that needs to be improved in statistical signal detection if they want to make best use of patient reports.

Federica Santoro 26:20

How do you see patient reporting developing in the future?

SPEAKER_00 26:23

I think it's a very bright future, not only patient reporting. I think we started a bit with patient reportment, but now we talk more about patient involvement in pharmacovigilance. So not only as reporters, but also that they provide their view on other aspects on drugs, for example, also the benefit-risk assessment, but also in communication that the patient view is taking into account how to communicate. So I think patient reporting is good, and I'm of course it's very important for me, but I think patient involvement in the broader sense in pharmacovigilance is a very important topic. And I think also there is a lot that we can learn and take into account because pharmacovigilance has been quite academic, regulatory, a bit old-fashioned in the way we approach involving patients in our processes. But I think it would be very beneficial for pharmacovigilance to have more patient involvement in our processes.

Federica Santoro 27:16

It is their health after all, right? Yes. Thank you a lot for being with us, Linda. 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 patient reporting, check out the episode show notes for more information. If you like drug safety matters, make sure to subscribe to it via your favorite podcast directory. And don't forget to check out our new series of Uppsala Reports long reads, the best stories from our pharmacovigilance magazine, brought to you in audio format. If you have any comments or suggestions for the show, get in touch with us on social media. We love to hear from our listeners. You'll find Uppsala Monitoring Center on Facebook, LinkedIn, and Twitter, and you can join the conversation there with the hashtag drug safety matters. Thanks for listening and till next time.