Intro

Federica Santoro 0:15

Where do pharmacovigilance experts look for signals? Mostly in spontaneous reports, and sometimes in real-world data, as we discussed in previous episodes. But safety monitoring actually begins with clinical trials before a drug is even placed on the market. So, how much can clinical trials tell us about safety? And what other studies are needed to fill the gaps? My name is Federica Santoro, and this is Drug Safety Matters, a podcast by Uppsala Monitoring Center where we explore current issues in pharmacovigilance and patient safety. Joining me today are Marianne Lunzer from the Austrian Agency for Health and Food Safety and Sania Pirpich from the Croatian Agency for Medicinal Products and Medical Devices. Marianne is a pharmacovigilance and clinical trials safety assessor and also the chair of the European Clinical Trials Coordination Group, while Sania works as principal coordinator for safety assessment of medicines in clinical trials. For this episode, we talked about the pros and cons of different safety studies, the issue of diversity in clinical trial populations, and much more. Enjoy the conversation.

Welcome, Marianne and Sanja!

Federica Santoro 1:54

I'm delighted I could get not just one but two experts on clinical trial safety on the show today. So thanks for agreeing to the interview.

How is safety studied in clinical trials?

Federica Santoro 2:04

Now, throughout the episode, we will be talking about pre- and post-approval safety studies. So that's studies that are conducted either before or after a medicine is placed on the market. But why don't we start from the beginning so we get everyone on the same page? Marianne, how is the safety of medicinal products assessed in clinical trials? And how does that process differ between pre- and post-approval studies?

SPEAKER_00 2:36

Thank you, Federica. First of all, let me start with the definition of a clinical trial so that everyone knows what we are talking about. In a clinical trial, there is a clear definition that the therapeutic strategy is decided in advance and does not fall within normal clinical practice of a specific member state. This might still differ. The decision to prescribe the investigational medicinal product is taken together with the decision to include the subject in the clinical study, and there are diagnostic or monitoring procedures going beyond normal clinical practice. And why is this so relevant to be defined at the beginning? Once we have a clinical trial, the sponsor will have to submit this clinical trial to clinical trial information system, which is a database, a European-wide database where all application dossiers will then be stored. And when it comes to safety assessment in relation to authorized or non-authorized products, I think there is no huge difference other than the amount of data available. So on the one hand, you might end up in a phase one clinical trial where already one single case might alert you heavily and lead to action potentially, while in a post-approval safety study you're dealing with a large amount of data where it's rather a matter of finding the needle in the haystack, and you will have to have proper methodology in place how you try to filter out the irrelevant information in the huge data set that you have at hand.

Strengths and limitations of clinical trials

Federica Santoro 4:22

So, from a safety perspective, what are the strengths and limitations of clinical trials compared to other types of studies?

SPEAKER_00 4:32

Well, one strength I think I mentioned already at the beginning, uh we have this data gathering via an IT infrastructure, which is on the one hand an infrastructure to gather the protocol and the data package that is submitted before authorizing a trial. And on the other hand, we have an IT infrastructure specifically for gathering safety-related information, and this is the uterigilance database. And this is different for clinical trials, where it is reported to a specific part of the uterigilance database, and for all post-marketing information that is gathered in another part of the uterigilance database. And the advantage when it comes to safety-related information is the structured way of gathering data. You have predefined visits where you are actively asking the patient, which is completely the opposite from post-marketing data reporting, where the patient or the healthcare professional takes the decision to actively report because they are alerted and they are not asked for their input. So the structure of data gathering is the huge difference between clinical trials and both post-approval studies, which are not clinical trials, and the post-marketing pharmacovigilance.

Federica Santoro 6:00

And we'll cover other types of post-approval studies later on. But Sania, did you have anything to add about strengths and limitations of clinical trials?

SPEAKER_02 6:10

Yes, just to fill in a little bit on the last part Marianne was talking about, the trials, not clinical trials. So one of these would be the non-interventional studies, where the name itself says there are no interventions, and the ADRs, so adverse drug reactions occurring in these types of studies are then reported in the post-marketing part of the utervigence system. And the flaws of these are very scarce data. But then again, you might have patients with maybe comorbidities or some kind of specificities that you don't get in clinical trials where the inclusion of the patient is very regulated. So then this is a flaw of the clinical trials, but then again, you get something in the non-interventional that you don't see in clinical trials.

Federica Santoro 7:05

So each type of study has different strengths and different drawbacks, and probably you need all of them to see the bigger picture and get as much information as possible. Yes.

Connecting pre- and post-approval studies

Federica Santoro 7:17

Um Sanya, let's continue with you. It's easy to think of pre and post-approval studies as separate entities, and well, I open the episode by making this distinction after all. But I imagine they are connected to a certain extent. How exactly are they connected? And does one type of study help inform the other, for example?

SPEAKER_02 7:44

Yes, I would say yes. And uh the easiest way to explain this would be in an example where you have a drug that is on the market. So the drug has indications approved. The marketing authorization holder then decides this drug will be investigated in a new indication. So in this indication, they conduct clinical trials, and after some years or a certain period, this new indication will also maybe be approved. So in this new indication, you might have information about safety, so a specific new adverse drug reaction you have not seen previously. So this can be informative and new for already approved indications with this same drug. There is also the post-approval study, which also can, of course, follow safety. And you can also have a new safety information with this drug in already approved indications, but you can use this new information to maybe already use it in indications not approved. For example, change something in inclusion or exclusion criteria or add something to the protocol of a clinical trial that will in advance be aware of this possible adverse reaction that you now know about and did not know up to this moment. So, yes, they they communicate pre- and post-approval studies.

Large simple trials

Federica Santoro 9:13

Now, this being a pharmacovigilance podcast, it's probably not surprising that we are most interested in post-approval trials. And they come in different shapes and sizes, as far as I understand. And one type I came across as I was researching the episode is large, simple trials. What are these and what are they best suited for?

SPEAKER_02 9:41

Well, when you say large studies, so this would then mean you get a big number of patients. How big are we talking about? Well, that of course is very hard to say. Depends on the indication of type of therapeutic area we are talking about. But of course, when you say post-approval, you will always maybe easier get bigger number of patients than in clinical trials. Clinical trials, of course, in big majority of cases don't include a very, very big number of patients. And I will now say what is big number of patients with regards to pharmacovigilance, the number enough to detect the very rare adverse drug reactions. So the advantage of a big number of patients would be that you detect these kind of ADRs. The very rare ADRs are extremely rarely detected in clinical trials. So the very rare ones you would then see in spontaneous post-marketing reporting or in these types of trials where you get a big number of patients. So this would be, I think, the from a covigilance perspective, uh, the advantage.

Federica Santoro 10:56

Thank you.

Strengths and limitations of post-authorisation safety studies

Federica Santoro 10:57

Back to you, Marianne. To make matters even more confusing, post-authorization safety studies don't have to be clinical trials at all, as we said. And they can be different types of studies, they can be active surveillance or observational studies. So, again, what advantages do these offer over conventional, so to say, clinical trials?

SPEAKER_00 11:21

Well, uh Federica, I think the advantage of the non-interventional studies, to pick out one example, would be that you cover a broad population. Usually, and typically in a clinical trial, you have your inclusion and exclusion criteria. Usually you don't immediately go into a vulnerable population before you have proven your efficacy. And therefore, the advantage of those late and large and even non-interventional studies would be to cover the whole population across gender, ethnicity, even in vulnerable population, if the treatment is appropriate for this population. And this is a clear advantage to generalize the information that you have gained from your initial safety battery. And the downsides of those trials are point number one, the less structured information gathering, and point number two, uh Sanya already mentioned it, I think, is the increasing number of comorbidities, co-medication, which makes it difficult to interpret when you get a safety signal, whether or not this is really related to the product you are trying to investigate, or whether this is based on the background treatment or based on the background illnesses that the population

Diversity in clinical trial populations

SPEAKER_00 12:47

have.

Federica Santoro 12:48

And Marianne, since you mentioned the lack of diversity in clinical trials, I have a follow-up question. So this is a well-known sore point in clinical trial design. I think it's been discussed extensively in the literature over the years. Men tend to be overrepresented in clinical trial populations, ethnic minorities are often underrepresented, and pregnant or breastfeeding women tend to be excluded altogether. But what does this lack of diversity really mean in terms of safety? How does that affect our understanding of medicinal product safety?

SPEAKER_00 13:32

Well, basically, I think it means that at the point of marketing authorization, we have not a completely clear picture when it comes to safety of this specific population. It's clear that you tend to prefer to go into a population where at least you don't risk to have pregnancies. This is why women overall are underrepresented in clinical trials, because then you have all the problems with demanding contraception to all trial participants. You have to repeatedly do pregnancy tests, for example. And all this you can get rid of if you just confine the population to men. While I have to say that even the clinical trial regulation already says that unless otherwise justified in the protocol, the subjects participating in a clinical trial should represent the population groups when it comes to gender or age groups that are likely to use the medicinal product investigated later on in real life, so to say. And if you don't cover them in your protocol, uh you have to justify it and uh argue why you exclude them or why they are underrepresented in your clinical trials. And finally, it says that the information on age group breakdown and gender breakdown will be reflected in the summary of results and also in the lay summary. So at least what we have at the end of the clinical investigation program, so to say, is we have clarity on who has been covered by the clinical trial. And then after you sufficiently proved your efficacy, then is the point in time, and this might even be before marketing authorization that you go into vulnerable population. And when it comes to pregnant or breastfeeding women, I think there is a lot of information that can even be obtained from pre-clinical studies from the animal model, basically. So I think there is a lot of additional information that can be taken into account when it comes to drawing up your summary of product characteristics or the description and the risks of the product when it comes to marketing authorization. And overall, we are rarely ever really go into the details of the population when it comes to one single trial. We rather expect the sponsor to cover the population or broaden up the population across their investigational plan. So not in one single study. It can be across different studies.

Federica Santoro 16:15

Thanks. Sonia, is there anything you'd like to add to that?

SPEAKER_02 16:19

Yes, I wanted to add that we have tools to impose to the marketing authorization holder. So when it comes to the procedure of approval, and in the data, the assessors see that there is a lack of data in a certain population, but nevertheless decides to approve the drug, they can impose uh post-authorization safety studies in specific populations that are underrepresented. And that's why we have the imposed uh post-authorization safety studies that then the marketing authorization holder has to conduct and get the data and get the information within a specific time frame to the assessors again. So we can better understand the safety profile in this population, not enough covered in clinical trials.

International cooperation

Federica Santoro 17:10

Okay, so we've covered now the lack of diversity. Let's dive into the regulation in a little more detail. Now, you're both based in the European Union, which is investing considerable effort in harmonizing clinical trials regulation across member states. And in January 2022, the new clinical trials regulation came into effect, and also the heads of medicines agencies have a dedicated clinical trials coordination group to synchronize efforts across countries. So, Marianne, my question is: why is international cooperation so important for safety?

SPEAKER_00 17:55

Thank you, Federica. I think I touched already a little bit on the change of modality and on the structured data gathering, which is a European-wide effort. And based on this gathered data, we now use the new way of working that was imposed by the clinical trial regulation and also by an implementing regulation specifically directed towards safety assessment. We were moving from a member state isolated view on safety signals that refer to trials on their territory or even cases on their territory. We are moving to a more coordinated safety assessment where we took the decision to appoint responsibilities to member states that would then do an assessment of all cases in relation to a specific investigational medicinal product, and therefore have the complete overview of all incoming cases, all notifications made by a sponsor which might be safety relevant. So they have really the complete picture. By having this complete picture, we hope for an improved assessment and earlier detection of safety signals. As we are looking at more data, and I think this is a general topic for safety assessment. The more data you have, the earlier you detect signals, and therefore the decision to do safety assessment on a European level is a very good decision and will bring safety assessment in clinical trials in a far better position.

Clinical Trials Regulation

Federica Santoro 19:42

That makes sense. And Sanya, how has the regulation affected safety studies so far in practice?

SPEAKER_02 19:51

Well, the new regulation has introduced many changes, not just for safety studies, for all studies, for all clinical trials. So the way we are working now is as Mariana said, uh we will have division of work and one member state will be in charge of following all available data for a specific active substance. And with this new work, many member states expressed their worries and lack of experience and knowledge in this field because many of them did not have this way of working, and this area was practically non-existing work in their departments of clinical trials. Motivated by this, we had an initiative by the European Commission that secured the funding for a project under the EU for Health Roof, I would say. The project is called Safe CT. And now it's been ongoing for a year, and we have 22 member states in this project. And the aim of the project is to help member states EU-wide to build capacity in this new field of work and to build this network that does the work of safety assessment and clinical trials. So through this project, we helped countries to recruit new safety assessors. Then we organized sort of twinning projects where we merged senior, experienced assessors with the newcomers so they gain experience, and we are trying to establish a network within this field that would exchange experiences and develop this field further. So this is really ongoing, and we are applying the new way of working and gaining more and more experience. And we are relating this field with the post marketing pharmacovigilance because we have the data we. Have, as we mentioned, the user vigilance database where we have data from clinical trials and from postmarketing. So when we look at the active substance, we can access all these data and have a bigger picture and do better assessment.

Federica Santoro 22:16

Do you foresee any more changes in the regulation?

SPEAKER_02 22:20

Well, I think the regulation is something that does not change as very often. But we foresee changes in the way we work to optimize the work. And this is also something we will do in this project. We have a developed best practice document developed by the CTCG, but we will within this project then see if this can be improved, optimized, so we we do the work as efficiently as possible.

Federica Santoro 22:48

Sounds good.

Lessons from the COVID pandemic

Federica Santoro 22:49

Now it's nearly impossible to talk about clinical trials without mentioning COVID-19, and that's because the pandemic showed that we can change our processes when needed to accelerate both development and testing of new medicinal products. Now I'm wondering how that whole pandemic experience has affected how we conduct safety studies even when the health crisis has subsided?

SPEAKER_00 23:23

I have to say, Federica, that it might not have informed us very much when it comes to safety studies. I think the main emphasis at the beginning was to prove the efficacy of both vaccination and treatment. But what it clearly showed is that numbers matter when it comes to safety assessment. And I would really like to hand over to Sanya here because the main achievement here was not safety data gained from clinical trials or studies, it was really the safety signal that was early detected in post-marketing. And this is more Sanya's field, so I would like to hand over to her.

SPEAKER_02 24:03

Yes, I mean this is a topic I'm sure very much discussed, and it showed and now we are benefiting from these experiences that the huge numbers of ADRs we were receiving in I think every European agency, I can say for Croatia, that during the pandemic years we had an increase about 150% increase in the number of ADRs we were receiving. So we had to reorganize the way we work to be able to process all the data and of course not miss anything crucial. So we had to had our work done risk-based. But of course, then this enabled us. Now I'm not speaking about Croatia, but the EU part of the data enabled to detect very rare ADRs very soon. Because in a I would say regular type of following safety reports and post-marketing, sometimes you need years to have the exposure that in this case of vaccines it occurred very, very fast. And not just exposure, but the number of reports is uh unseen up to this pandemic, the numbers that we received in such a short period. And then again, I say this enabled us to see the very, very rare adverse drug reactions very soon. And then we could react and physicians could be more informed how to react in these situations.

Federica Santoro 25:41

Yes, it was a great demonstration of the usefulness and power of post-approval monitoring systems.

Integrating multiple sources of evidence

Federica Santoro 25:50

And well, that leads me nicely into my next and final question. With this episode, we are wrapping up a mini-series we've been running on sources of evidence in pharmacovigilance. So we've discussed spontaneous reporting systems and their strengths and limitations. Then we moved on to real-world data in another episode, and now obviously we are addressing clinical trials and pre- and post-approval safety studies. So I'm just wondering: do you have any reflections on how these sources are best integrated? How do you want the pharmacovigilance community to use these different data sources? Marianne, why don't we start with you?

SPEAKER_00 26:42

Thanks. I think we all agree uh that not one data source will be sufficient to find the whole truth about any specific drug. So there seems to be broad agreement that using all data sources as far as we can uh will give a clearer picture. And we have already discussed the pros and cons of all the different types, and I can say that already now uh we have good opportunities to look at both data sources together because we have this joint database where the partitions are separate, but the output can come together. So you can have an output of the clinical trial-related case reports and of the post-marketing related data sources, where you also cover the non-interventional studies because they have joint reporting with the post-marketing. So we have the ability to look at both data sources at once, and uh we're already doing it right now, and this I think is a huge advantage. So not only looking across all member states in Europe, but also looking across the different data sources enables us to have a better picture when it comes to safety for specific substances, be it used in clinical trials or be it used in the post-marketing setting.

Federica Santoro 28:09

Thank you. Over to you, Sanjay for any final reflections.

SPEAKER_02 28:12

Yes, well, I can say that when we started assessing uh safety in clinical trials in this safety cooperation procedure, some of the countries had, I would say, a bit of an advantage because, for example, Croatia is one of them, where we have this assessment in clinical trials done within the same department as safety in post-marketing. So now we have really great experience assessing in post-marketing, where we can apply some of these concepts to clinical trials, and vice versa. So this is really something actually going on, and safety assessors are now using both sources of data, and uh the assessment then can be very high quality and done much faster when you get the data faster and you have more sources.

Federica Santoro 29:05

Thank you. This is what the other speakers on the previous two episodes concluded as well. But integration of as many data sources is best and is what will lead us to better and faster safety data available. Well, thank you very much for taking the time to talk to me. I'm sure our listeners will find this episode interesting. Thanks again for being with us today.

SPEAKER_00 29:31

Thank you for inviting us. Thank you very much, Frederica. It was a pleasure.

Outro

Federica Santoro 30:04

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 that out too. Uppsala Monitoring Center is on Facebook, LinkedIn, and Twitter. And we'd love to hear from you. Send us comments or suggestions for the show, or send in questions for our guests next time we open up for that. For Drug Safety Matters, I'm Federica Santoro. I'd like to thank Marianne Lunzer and Sania Pirpic for their time, Matthew Barwick for postproduction support, and of course, you for tuning in. Till next time.