Top 6: What is EU HTA and why should statisticians care?

Anders Gorst-Rasmussen

Senior Director, Head HTA Data Science at Novo Nordisk

He received his PhD in statistics from Aalborg University in 2011 and worked with pharmacoepidemiology and RWE in academia prior to joining the Development organization in Novo Nordisk in 2015. At Novo Nordisk, he has held roles as project statistical lead on various late-phase projects. For the last 2 years, has been working in the HTA area as functional lead for a small team of dedicated HTA statisticians. He is an active member of the PSI/EFSPI HTA Special Interest Group.

Lara J. Wolfson

AVP & Head HTA Statistics at MSD | Co-chair PSI/EFSPI HTA Special Interest Group

She is Executive Director and Head, Health Technology Assessment (HTA) Statistics in the Biostatistics and Research Decision Sciences (BARDS) organization at MSD Switzerland.    Lara holds a PhD in Statistics from Carnegie Mellon University in the US, and an undergraduate degree from Simon Fraser University in Canada.   Lara has held academic appointments at University of Waterloo in Canada and Brigham Young University in the US, and has previously worked as a scientist covering health economics, epidemiology, and statistics at the World Health Organization, as well as in the pharmaceutical industry in outcomes research and Market Access at both the Janssen Pharmaceutical Companies of Johnson & Johnson in Belgium and the Merck Center for Observational Research and Real-World Evidence in the US.   Lara has authored more than 70 peer-reviewed journal articles, and currently chairs the HTA European Special Interest Group of EFSPI/PSI (a professional organization for Statisticians in the Pharmaceutical Industry).   Lara currently lives in the Greater Zurich Area with her husband, skiing-obsessed twin sons, and a cat named Hokey Pokey. 

Transcript

546_Replay EU HTA

[00:00:00] Alexander: You are listening to the Effective Statistician Podcast, the weekly podcast with Alexander Schacht and Benjamin Piske designed to help you reach your potential lead great science and serve patients while having a great [00:00:15] work life balance.

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[00:01:27] Alexander: Welcome to another episode of The [00:01:30] Effective Statistician, and this is a release. Special one because it is the starting episode. Also little series of a couple of episodes that I’m doing together with the [00:01:45] HTA special interest group. I’m really happy to have Lara and others here today to speak about this and let’s first, little bit of an introduction.

[00:01:57] Alexander: Lara, do you wanna start? 

[00:01:58] Lara: My name’s Lara [00:02:00] Wolfson and I work for MSD based in Zurich, Switzerland. I lead the HTA Statistics Group at MSD, A group of about 80 dedicated statisticians who work with an equal number of programmers, specifically to reanalyze [00:02:15] clinical data for health technology assessment submissions.

[00:02:18] Lara: I’ve been in this role for about four years. I have a PhD in statistics from Carnegie Mellon University in the us, but I’m actually Canadian and I’ve been working in the pharma industry for about 10 years. [00:02:30] Prior to that, I spent 10 years with the World Health Organization and also time in academic positions in the US and Canada.

[00:02:36] Alexander: Very good. 80 statistician dedicated statistician status. Far the biggest number that I’ve ever heard. And of [00:02:45] course, MSD is not a small company. So that a little bit into perspective. Probably other companies that have less than 80 substitutions overall, but that’s quite significant department. Okay.

[00:02:57] Alexander: Anders, what about you? 

[00:02:58] Anders: I’m part of [00:03:00] the HTA Sik and I’m working as an HTA statistician within Nova Nordic, based in Copenhagen, Denmark, where I’m part of a smaller group. I think we’re about five people now working within the HTA statistics. It’s something that I think my [00:03:15] group was established soon be two years ago.

[00:03:17] Anders: And my background, I’ve been within Pharma for seven years and actually before I started working, more dedicated within share, I was working as a regulatory statist station. So I have five years of experience also working. [00:03:30] Before that, I was actually working somewhere completely different, which was more academia within Pharmaco epidemiology, so a bit of exposure also to real world evidence.

[00:03:39] Anders: And I have a PhD from Univers here in Denmark. 

[00:03:43] Alexander: Cool. Very good. Yeah, [00:03:45] it’s actually quite helpful to have this mixed background in terms of both HTA and clinical. And yes, this episode will actually speak quite a lot about this, so let’s talk [00:04:00] about. European, HTA, EU HTA, because there’s a couple of really significant changes going on that have started some time ago.

[00:04:12] Alexander: And yeah. Rah, do you [00:04:15] wanna give a little bit of an high level intro in terms of what’s happening here at the moment? 

[00:04:21] Lara: So I think here it’s helpful to take a step back and say what’s going on with HT Health Technology Assessment itself. One of the challenges we’re [00:04:30] facing in our world is that there’s all these fantastic new medicines of vaccines that pharma companies are developing and bringing to bear.

[00:04:36] Lara: Health systems have challenges and saying. How do we choose between them? How do we afford them? And so they started making this more and more [00:04:45] formal as there’s more and more options on the table. And so regulatory approval, which is where we start in the pharma world, says, is this product safe and effective?

[00:04:54] Lara: Is it suitable for use in humans compared to, there’s other options on there. Is it at least as [00:05:00] safe and as effective as everything else out there in HTA? We’re asking a different question. We’re trying to use the same data. How good is it? That’s a different question. And so we actually need to look at the data in a different way.

[00:05:12] Lara: More and more countries around the [00:05:15] world have started saying, how are we gonna interrogate the data to ask these questions and not just interrogate the clinical data, but you’ve got your regulatory or pivotal trial that you’ve used to get regulatory approval. What other sources of data do they need to bring into the [00:05:30] picture?

[00:05:30] Lara: How do we decide if this is worth paying for? How much it’s worth paying for? You start to look at things like, are there particular subgroup or subpopulations who benefit more than others? How do you financially value some of the trade-offs between some of the side effects? With health [00:05:45] technology assessment, we’re asking a different question than we ask in the regulatory context, not just is it safe and effective?

[00:05:51] Lara: How safe, how effective is it? How does it compare to the other alternatives we have? Can we quantify that? Can we add some [00:06:00] economic dimension so that we can determine how much we’re willing as a society to pay for it? And are there particular subpopulations who benefit from a new treatment more than others or less than others?

[00:06:12] Lara: And so we start to segment it a lot more. And [00:06:15] sometimes as statisticians, we talk about over interrogating it because. We design these studies to get medicines to patients as fast as possible. We think there’s a new treatment that could benefit people. So we design a regulatory trial to [00:06:30] demonstrate that it’s safe and effective, get that regulatory approval and make it available to patients.

[00:06:33] Lara: But then on the health technology assessment side, we’re taking it apart in a different way, and maybe we’re bringing in alternative sources of data, real world evidence data from other trials where we might have to do indirect [00:06:45] treatment comparison. Putting it all together to answer questions, and then this becomes very contextual.

[00:06:51] Lara: In the European context, we have the Europeans Medicine Agency, which does a pan-European regulatory approval. Most of the countries in Europe [00:07:00] have developed their own processes to evaluate whether this medicine should be reimbursed and at what level it should be reimbursed at, and that has to be contextualized in terms of.

[00:07:10] Lara: What they’ve approved before. You’re looking at the standard of care and you’re saying, how does [00:07:15] this compare to the other treatments that are available? And so maybe there’s a treatment where there’s a guideline, for example, that says if you’re under 75 years of age, this is not your first route of treatment, but if you’re over 75 it is.

[00:07:28] Lara: Now the [00:07:30] data has to be analyzed that way because we have to look at how does it perform in over 75 versus under 70 shot. This varies across Europe. It could be that in one country that split is at 75. In another country that split isn’t 65, and [00:07:45] so you have 27 member states in the European Union. Each of them has their own standards of care.

[00:07:50] Lara: Different medicines are reimbursed in different countries, and they’ve all evolved different rules and regulations. This has been [00:08:00] evolving quite intensely for the last 20 years at the European level, they’ve been discussing does this make. Complete sense. Do we want it this way? Is it fair that just because you live a hundred miles apart across, or a hundred kilometers apart across [00:08:15] the border, one person can get access to a medicine and another person can’t?

[00:08:19] Lara: There’s a question of could we make this simpler as well? There’s also huge delays in timing of access. You’ll find that there’s some markets where as soon as there’s a regulatory approval, for [00:08:30] example, in Germany, they have a process that says, as soon as that opinion comes out from European Medicines Agency, they’re immediately going into discussions That medicine is immediately available, and a year later a price is set because of the HTA process, [00:08:45] other countries have a process where the timing is not as close to regulatory approval and it can take a few years.

[00:08:53] Lara: So there’s been lots of discussions. Can you harmonize the processes across Europe? Can you speed up access [00:09:00] so that there’s a quality of access in timing across Europe? And so there’s been these voluntary cooperations that people have tried to experiment with and there’s been this series of different joint actions [00:09:15] sponsored by the European Commission we hear them talked about is unita.

[00:09:19] Lara: But in December, 2021, they actually passed a regulation that said, starting in 2025, we are gonna have a common E-U-H-T-A assessment, and this [00:09:30] will form the basis of the country assessments that will follow. Each country has its own standards of care, its own reimbursement pathways, different ability and willingness to pay in different countries.

[00:09:42] Lara: So there’s still gonna be a national HTA [00:09:45] process, but. At least starting from a common foundation. It’s interesting watching the evolution of this and the amount of data reanalysis of the clinical data has changed dramatically in the last [00:10:00] 20 years. There’s also a lot of economic modeling and the economic modeling part of this will still sit at the country level.

[00:10:07] Lara: That won’t be part of the joint assessment. They did pass this regulation in December, 2021 over the next two or three years. [00:10:15] They’re gonna be shaping how this regulation takes shape. Exactly what analysis need to be done. How are they gonna do the joint clinical evaluations starting in 2025 at first with novel cancer molecules [00:10:30] and A TMP products?

[00:10:31] Lara: It’s going to start, it’ll take five years to fully take effect to cover all medicinal products and vaccines. By 2030, there’s gonna be a joint clinical assessment that feeds into the subsequent national assessments, [00:10:45] and it’s a huge undertaking, but lots of opportunities, particularly in the next 18 months to say what’s the right statistical way to do this challenge is today we don’t design the trials to meet HTA needs.

[00:10:59] Lara: [00:11:00] If you think about the pathways of clinical development, the trials that are already in progress, that will start to read out in 2025, those trials have already been designed, have first patients enrolled, but there’s gonna be a lot of questions that come up later in the [00:11:15] game, which is that now that we know this process gonna be taking place, will it change the way we design some of those trials?

[00:11:22] Lara: So as statisticians. There’s all these different dimensions of how you wanna get involved. One is [00:11:30] what’s the advice we can give about how they shape what should be in the joint clinical assessment? How are we gonna build capacity to do this type of assessment? Not only within pharmaceutical companies, but all the assessors who have to [00:11:45] be involved.

[00:11:46] Lara: The assessors are gonna come from the national agencies and then work together at the EU level. I don’t think there’s enough of them. This is something we’ve talked a lot about this capacity issue and how do you develop it overall? I think it’s an [00:12:00] interesting challenge because there’s gonna be this huge emphasis on statistical analysis of clinical data, re-analysis that the studies weren’t designed for.

[00:12:10] Lara: Do we actually have enough statisticians in Europe? 

[00:12:12] Alexander: In the different companies, we have [00:12:15] just seen that there’s a huge discrepancy between the different companies like RO and Novartis and Pfizer. They have all different organizations. Some have local people, some have regionals, some have global people.

[00:12:28] Alexander: It’s very diverse. Some [00:12:30] people don’t even report to the same organizations as reporting to. R and Ds. Sometimes they report into commercial, sometimes they report into affiliates. There’s all kind of different things going on and that doesn’t make it easier. [00:12:45] The number is one thing, the clear of complexity of the organizations themselves, another hurdle.

[00:12:51] Alexander: And there’s, in terms of capacity, that is one thing, and timing is yet another thing. As Lara just mentioned, timing will change as well. [00:13:00] How will it change? 

[00:13:01] Anders: So one of the things that will happen here is that the way it’s laid out in the regulation is that we will process that hack to the email timelines.

[00:13:11] Anders: So basically what will happen is that once you do your submission to email [00:13:15] for a new medicinal product, you will also certify it. The coordination group of UHTA and they will set up this process of going out and asking the member of countries via Western Air. Okay. What are the that is interested for you [00:13:30] from perspective of your healthcare system?

[00:13:32] Anders: What kind of population would you be interested in that and what vary between countries? Exactly. What does the intervention look like? Are you adding this on top of some kind of background therapy that we should be aware of? What would be the relevant [00:13:45] comparators? Again, as I think you’re also alluding to Lara, that might again be different between different countries.

[00:13:50] Anders: What kind of outcomes are we interested in? We might have countries that are more interested in heart clinical outcomes. You might have some that can make do, for example, with surrogate type [00:14:00] outcomes. All of this will be put together within this information group with the ancestors and the cover sense that be appointed to overseeing this.

[00:14:07] Anders: Then a member of countries will send this information back and you’ll ask a help technology developer. At some point, I think it’s around when we [00:14:15] receive 120 days from email, you receive the scope with information about what is relevant to look at here. And of course there’s a concern that has been discussed quite a lot where we see 27 different questions that we need to address as technology developers.[00:14:30] 

[00:14:31] Anders: 21 is trying to reassure us that this is not how it will happen. And I think irrespective of how things will probably get more than just one question and it’s, they’re not just to be able to predict that. You could say also well in advance because we will not [00:14:45] have a lot of time. Then we need to go into production and have the dacia ready for submission, collating all these different analysis, both based on clinical trials, and maybe we need to do network meta-analysis.

[00:14:57] Anders: Maybe we need to do real world evidence [00:15:00] registry studies, and we need to have all that ready. For submission no later than 45 days before CHMP opinion, if you do the math, that’s about a nine week duration and have to, it’s quite intense in terms of putting all this together. An important [00:15:15] factor here to bear in mind is that it could also be.

[00:15:17] Anders: Despite the challenge for the people that will then subsequently do the as system of the data that we’re providing, we should basically, with breadth of evidence that we might include data from clinical trials. It’ll be [00:15:30] anma, be real world studies. That will also be a lot of pressure on the people that will do the assessment afterwards because all of this needs to be done a hundred percent, 30 days post marketing authorization in Europe, where the final.

[00:15:43] Anders: Joint clinical assessment [00:15:45] report needs to be done. So there’s also a lot of pressure on the assessors and the Coors and the statisticians that will be sitting the other end of the table actually looking through this and assessing the evidence that we’ve submitted as health technology developers. So I think this really calls for [00:16:00] statisticians also.

[00:16:01] Anders: Just a lot of statisticians, but I think also for statisticians also, those working in the regulatory space to have maybe increase their understanding also of the HT A mindset and the way that you need to approach evidence when you think in terms of [00:16:15] HCA, which I think is different as Laro also explain and what to do from a regulatory perspective.

[00:16:19] Alexander: Yeah. And it will mean you need to work very closely together. This is what I’ve seen across lots of different companies. We first take care of the regulatory [00:16:30] submission. And you get access to the other data. 

[00:16:33] Lara: So the dilemmas here, there’s a funny story. One of my first encounters with health technology assessment was when I worked at the World’s Health Organization.

[00:16:41] Lara: I worked primarily in the vaccines area. And there [00:16:45] were some questions about the, we worked a lot with Gabi, the Global Alliance for Vaccines and Immunizations, and Gabi was basically functioning a little bit as a health technology assessment agency because they were making decisions about how were they gonna allocate billions of dollars, [00:17:00] which vaccines were they gonna give it to?

[00:17:01] Lara: Were they gonna give it to measles control? Were they gonna use it to support novel vaccines for pneumococcal rotavirus vaccines? And this is one of the big challenges of shelf technology assessment is that on the surface it [00:17:15] seems really simple. It’s, oh, we wanna fund the most cost effective intervention, but it turns out a lot of other values come into it.

[00:17:22] Lara: One of the funny things when I did this work with Gavi was that we started reanalyzing all kinds of data. It wasn’t so much focused on the clinical data because [00:17:30] the effectiveness of these different vaccines was well understood. But the question then became linking it to how many patients were you targeting?

[00:17:39] Lara: And in this case, you weren’t targeting people who had a disease, right? Vaccines are preventative. So what was the [00:17:45] potential number of kids that you could vaccinate? It’s the number of kids that are being born each year. How likely were they to get the disease and potentially suffer severe consequences?

[00:17:54] Lara: And so you started mapping all of this out. What’s the morbidity? What’s the mortality [00:18:00] outcomes? Which outcomes are most important? And then you start to bring in some things that aren’t obvious because it also had to do with, wait a minute, measles vaccines, they’ve been around for 40, 50 years, right?

[00:18:12] Lara: They’re not novel. They’re being [00:18:15] produced. You don’t need to incentivize that. But at this time, it was 2004, 2005, rotavirus and Pneumococcal vaccines were just coming into play, and there were other values that came into play, like wanting diverse new supply, wanting to encourage manufacturers. [00:18:30] One of the things you saw was that the people who were making the decisions thought they knew what they wanted, what information they wanted.

[00:18:35] Lara: And so they gave us these table shells and said, do all of these analyses, fill these all out? And I started working on them and putting ’em together. And I kept thinking, how on earth is anyone going [00:18:45] to be able to make sense of this? How and pages of tables, like who can process that kind of information?

[00:18:52] Lara: And then you produce it all and you start to systematically evaluated it and it kept pointing to. Invest in measles [00:19:00] control, and everyone kept resisting it because they’d already made up their mind. They really wanted to make sure they were allocating money to rotavirus and pneumococcal vaccines because one of the core values was stimulating production of new vaccines.

[00:19:13] Lara: This was a global context, not a [00:19:15] country specific context. They wanted to make sure they brought developing country manufacturers in and created incentives for them, but the analyses they asked for were never designed to answer the question. This takes it back to one of the critical [00:19:30] things about statisticians really starting to understand the health technology assessment system you’re working in.

[00:19:36] Lara: It turned out they fundamentally had a utility function that they weren’t expressed, and so HTA, whether it’s gonna be European, HTA, or the country specific [00:19:45] HTAs, a lot of it is about articulating or interrogating that utility function. What is it that you’re really trying to assess and how are you defining value in the regulatory context?

[00:19:57] Lara: We have a utility function that [00:20:00] is implicitly well understood in the HTA context. I think that utility function is gonna continue to evolve and we’re gonna have to work with the national HTA agencies and with the European HTA agencies [00:20:15] to understand the information that really helps them make their decision.

[00:20:19] Lara: But their challenge also is that they haven’t fully articulated a utility function and so they go after everyth. We’re likely to see a system that’s very [00:20:30] similar to the OG system in Germany. People are still submitting them as PDF F files and if you actually printed them, which I’m sure some people are doing, worry about the environmental impact of that, you need to cut some trees for that.

[00:20:43] Lara: I have been involved [00:20:45] and dog dossey that run to thousands of pages, and again, I struggle with. How do you really make sense of this much information and what information is actually driving the final decisions? And over time, can we [00:21:00] work with these systems to focus the analyses they need on what really impacts their decisions?

[00:21:08] Lara: Because I think right now these HTA systems have a challenge that they know there’s all these different aspects they wanna [00:21:15] go after, so they just ask for everything. 

[00:21:18] Alexander: All subgroups versus all endpoints, versus all time points, versus all analysis methodologies by study and combined study and everything, then you end up easily with.[00:21:30] 

[00:21:31] Alexander: As you said, thousands and thousands of tables. 

[00:21:33] Lara: And how cognitively, how do you process that? How do you say, how did I get to a decision? How am I sure that my decision is reproducible and traceable and [00:21:45] people can understand it? And so on the one hand, as statisticians, we’re going to have to meet the needs of these systems.

[00:21:53] Lara: But then there’s this other question, which is, how can we help to make these systems. Better and more effective and really understand what they’re [00:22:00] trying to get at. 

[00:22:01] Alexander: That’s a really good point, and the HD ASIC has really started to get involved there. Do you wanna. Talk a little bit about what you have done already there and what’s currently [00:22:15] going on there in terms of how the H dik helps there.

[00:22:19] Anders: Yeah, so I just want, before we go onto that, I think I want to also add a comment to what RO was speaking about and this idea that we have this utility function lying around on the different member [00:22:30] states that they’re not always very explicit about. And basically I think as she also started out, Lara, this is really about assessing the value of new treatments.

[00:22:38] Anders: And I think in that respect. It’s also a massive undertaking what is going on with the UHTA, right? Because the [00:22:45] regulation is quite specific that the joint clinical assessments of the, that will be producing, the actual assessment that will come afterwards is not something that will in any way dictate how the value should be looked at on the individual.

[00:22:58] Anders: That will be up to the member [00:23:00] states themselves also, because that will be very much dependent on how the health system is set up. So basically what is signed up now is that we need to produce an assessment broad enough to fit into the value perception of all the different member states. It should be fully objective [00:23:15] only about the validity, and then put the value assessment out with the member states.

[00:23:19] Anders: I think it’ll be interesting to see how this actually goes on in practice. I think it also very much easily can end. In the situation where it becomes quite a bit of information overload, right? Because there’s so [00:23:30] many different perspectives on this. I think this aspect of trying to make a clean cut between value and validity, it’s really difficult.

[00:23:37] Anders: I think we also see it in steps of what we see some of the draft methodological guidelines coming out. Now, whether you making a [00:23:45] value judgment, when is it just a case of validity? I think that’s also a place where statisticians have something to say. In terms of what’s going on in the HTA, you can see what’s happening right now in the preparatory phase leading up to the implementation [00:24:00] of the HT A regulation.

[00:24:01] Anders: So until 25, there’s agreement of the tender agreement with the involvement of the unit set that are, that Laro was alluding to the beginning, but we had this unit at 21 Consortium. That’s basically looking into doing even more preparations and [00:24:15] making sure that we’re in good shape for actually being able to implement the regulation from 2025.

[00:24:20] Anders: And one of the things that they’ve been doing is grafting, extensive methodological guidelines for how the processes should look, what kind of, if you do, for example, a [00:24:30] network analysis. What are methods for doing that? What should the census look forward through the, if you do a registry study, what should they look for and so forth?

[00:24:40] Anders: So we’ve actually been quite busy over the last couple of months. I think [00:24:45] the United 21 Consortium has been even busier. There’s been a commenting going on. So public consultations, basically, where there’s been input also from industry organizations. We also come within the HTA sector. Apart from that, we’re also [00:25:00] doing things like, for example, participating on your podcast Alexander, but we’re also looking into various other venues of really getting some engagement also within the statistician community, and also making people that are not necessarily deeply involved in HCA [00:25:15] statistics realize that this is something.

[00:25:17] Anders: That will also thank them that this is really about being able to end on with faster patient access. We really need to think about how do we integrate the HCA perspective also into our trials so that we’re not, when we [00:25:30] get at around the same time as the email 120 day questions, we get the scope that we’re not completely surprised by what we see.

[00:25:37] Anders: But it is, to a certain extent, it’s predictable. 

[00:25:40] Alexander: I noticed that, for example, at PSI conference in 2022, there was [00:25:45] a this lunch meeting where there were lots of different people sitting together and talking about this topic. Yeah, I can absolutely encourage people, check out the HTA special interest group homepage, check out if you’re a PSI members.

[00:25:59] Alexander: [00:26:00] There a newsletter that is coming out. There’s also, or has very often things coming out. Watch out for that. If you are. Company is not yet involved. Make sure someone that is involved there. If you [00:26:15] don’t know who is in your company as a statistician involved, reach out to them. That will be really important for if you work on phase two, phase three, absolutely important.

[00:26:26] Alexander: Yeah, really critical. If you are surprised by what you’ll [00:26:30] get, then it’s too late. You should be a higher level understanding of disease will be the critical points is then, oh, here’s another H cut point like Lara mentioned, or here’s another kind of co medication to take into account. If you can’t cut your data because [00:26:45] you haven’t collected these covar, then you are in trouble.

[00:26:48] Alexander: Then maybe millions of billions of dollars that your company has invested, it’s at risk. So really an absolutely important point. [00:27:00] As I said, this is just the first of a series of episodes with this one where they’re not recording them in sequential order, so I can already tell you that will be really good.

[00:27:12] Alexander: So real, no [00:27:15] knockout for them, Lara and us. Any kinda final points you wanna make and the key takeaways for the listener? 

[00:27:22] Lara: Following on what you signed. If you go to our state webpage, you’ll see that there’s the schedule of all these deliverables that [00:27:30] the UNITA 21 Consortium is producing. These are the first drafts.

[00:27:34] Lara: They’re not just first drafts. These are the guidelines that they’re going to use for the assessments they do in 2023 and 2024. They’re the foundation of what they call the implementing [00:27:45] ads of the E-U-H-T-A regulation, and so they’ll be coming back next year. In 2024 for finalization, we post the links to the deliverables as well as coordinating input across all these companies under deliverables.

[00:27:59] Lara: One [00:28:00] other angle that you’ll have available to you within your company is that most pharmaceutical companies are participating in FPA, the European. Federation of pharmaceutical companies and industry. We work closely with FPF. We provide input to them. We [00:28:15] look at are there statistical issues that we need to particularly emphasize in our feedback to the consortium.

[00:28:20] Lara: This process is going on for the next three years. It’s incredibly important to understand it, to shape it, to bring it back into your own company in terms of how you’re thinking [00:28:30] about the design of your trials and looking at all these different dimensions. One thing we didn’t talk that much about, but.

[00:28:36] Lara: Quality of life measures. We collect them in our studies, we summarize them in our regulatory dossey. They play a huge role in [00:28:45] HTA Ments. They come in much more there. Now there’s gonna be this European level scrutiny. And one thing to also realize about E-U-H-T-A and what are the reasons you wanna get involved and think about it, even if you’re a regulatory statistician.

[00:28:58] Lara: Is that the [00:29:00] E-U-H-T-A assessments are most likely gonna be in the public domain. So a lot more of the data and the way that you’re gonna have to take it apart is going to become much more transparent over the next five to 10 years. And so again, thinking about what [00:29:15] does that mean for the design of your trials, what does it mean for your choices, methods, and analysis?

[00:29:21] Lara: One thing I wanna give a brief plug for is that on November 14th, 2022, we’re gonna have a webinar with a panel discussion with some of the people [00:29:30] who are the architects of the E-U-H-T-A system and talk about some of the statistical issues and ways for the statistical community to get more involved.

[00:29:38] Lara: How do we contribute? How do we upskill ourselves? How do we upskill within our companies? How do we contribute [00:29:45] to the bank of knowledge among the assessors and where are the methodologic gaps? Because there are some, there are places where there’s no clean cut answer. It’s a great opportunity, it’s gonna bring some of the statistical issues to the forefront.

[00:29:59] Lara: In [00:30:00] our conversation today, we focused a lot about the joint clinical assessment. There’s also gonna be joint scientific consultations where you can get input on the HTA aspects of the design. It is incredible to see how much of this European HTA system [00:30:15] is founded in statistical analysis and principles.

[00:30:19] Lara: Huge opportunity for statisticians to be involved in shaping the future of the healthcare system in Europe. We’re really looking forward to getting more and more people [00:30:30] involved, more smart people that think about this and contribute to this, the more successful the overall system will be. And I think we all want to see a successful European healthcare system.

[00:30:39] Alexander: Yeah. As you point out, lots of other countries are looking into this, as we have [00:30:45] seen with kind of Nice. And how has impacted globally how HTA has done? Pretty sure that lots of other. The world, including he will have a look into this. Who said jobs? That’s [00:31:00] Europe. Don’t think that way. That’s true.

[00:31:03] Lara: Completely agree. 

[00:31:04] Alexander: Yeah. And this, how about you? What are your key takeaways for the listener? 

[00:31:09] Anders: Yeah, I can only echo Larry’s call for involvement. I think a bit of confusion also around [00:31:15] what can we do. Now that the methodological guidelines are being developed once they’re done and finalized from a 21 perspective, does that mean set in stone?

[00:31:24] Anders: I think the answer to that question is probably not. At some point there will be implementing parts [00:31:30] of this and answering discussion of that. Once the coordination group gets work, a coordination group of the UHTA will comprise. All of the 27 different member countries are very large representation of some of the German institutions.

[00:31:42] Anders: But once that declination group gets into work, I think [00:31:45] things will also continue to evolve. We will have the implementation starting in 2025, but come 2028, they’ll also be a review of, okay, has it actually where. Does it help out in the individual countries? I think there’s, it’s not just, okay, it’s [00:32:00] 2022 and then everything is on and over with, and then we just wait for the implementation.

[00:32:05] Anders: I think there’s actually also a longer window of opportunity where we can raise engagement and where statisticians can really raise the voice in terms of making sure that we have a good system [00:32:15] and important that we ensure faster access for patients to a new treatments in era. 

[00:32:21] Alexander: Yeah, completely agree.

[00:32:22] Alexander: If you see, think about. Or if you think about GBA and T quick, they have continually evolved [00:32:30] their guidelines. I don’t know, in Germany, I think we are now at methods paper number six. If you look into the nice technical summary documents they have grown and evolved. There’s lots of different versions of these, so I don’t think this will be [00:32:45] done and finished when people see how that actually implements and how these dos, look and feel.

[00:32:53] Alexander: The volume of them. I’m pretty sure that will evolve. People will see, maybe we [00:33:00] underestimated to the complexity or we underestimated how much pressure that will put into the system. And as Lara mentioned, maybe we’re underestimated how many statisticians we actually need for it. I think there will be a lot of learning both on the [00:33:15] HTA, the EMA side and the company side.

[00:33:19] Alexander: I also think that other parties, patient advocacy groups will get more involved because they will potentially drive these kind of. Utility [00:33:30] functions that you mentioned with saying, oh, for us this endpoint is much, 

[00:33:34] Anders: I think you’re touching on a very important point. Will it just be a massive PDF file with lots of super complex statistics?

[00:33:40] Anders: It’ll be super transparent, and that’s also something built into the HCA regulation. We need to think, how [00:33:45] about the statisticians? How do we make this with super complex statistics? It’s not accessible in any way for anyone without a PhD degree in statistics. Is that being transparent? Just coordinate that into 50,000 pages of analysis.

[00:33:58] Anders: I think there’s also an opportunity here [00:34:00] to think a bit about how do we actually succeed with transparency, because transparency is not necessarily just putting a lot of stump out there is also thinking carefully about the presentation. 

[00:34:09] Alexander: Yeah, completely agree. 

[00:34:11] Lara: I worry. I think the transparency initiatives are [00:34:15] great, but then I put myself in the position of a cancer patient.

[00:34:18] Lara: I’m diagnosed and I start Googling things and it takes me to this HTA assessment filled with hundreds of pages of PDF tables. What happens if I get confused about whether or not [00:34:30] the treatment my physician is recommending is actually right for me? That’s also something we have to think about. How do we make this information digestible too?

[00:34:39] Alexander: Completely agree. That is so much of an important area. We need to learn [00:34:45] not to just speak to other experts, but to treating physicians, patients, parents, or the kids of the patients because they might take care of their grandparents or parents that are really old and have [00:35:00] dementia. So all these things really play a role.

[00:35:03] Alexander: Thanks so much. That was an outstanding discussion and it’s such an important point. Head over to the HTA special interest group [00:35:15] on the PSI homepage at psiweb.org and find all the other things and also show notes are in the block here on the effective statistician.com. Check that out as well. Thanks so much. [00:35:30] Have a great time and it was an honor to have you on the show.

[00:35:39] Alexander: This show was created in association with PS I, thanks to Reine and to her team [00:35:45] at VVS who works in the background. And thank you for listening. Reach your potential lead great science and serve patients. Just be an effective [00:36:00] statistician.