speaker-0: Biopharma is a rapidly changing space, and a lot of important conversations and decisions happen every day in response. This is Pharma Unscripted from RTI Health Solutions, where we bring those conversations forward. I'm Peter Wirth, Senior Director of Business Development and Growth Strategy at RTI Health Solutions. Today, I'm joined by Caroline Ling, Vice President, and Vijay D'Souza, Associate Director in our European Value and Access Team. In this episode, we'll be taking a closer look at the first EU Joint Clinical Assessment Report, which was published on June 9th, focusing on Toborefinib, or TOBO, for pediatric low-grade glioma submitted by IPSIN. We'll discuss the scale and complexity of the submission in the report, the methodological insights emerging from this first JCA experience. And what it could mean for future evidence generation and access decisions across Europe. Enjoy my conversation with Caroline and VJ. So Caroline, welcome. Give us a brief overview of the key themes of the first JCA report.
speaker-1: Thanks, Peter. So firstly, this is a real major milestone for ⁓ EU HGA regulation. This has been several years incoming, but they've demonstrated that the the process that they've developed and the methodologies are possible and have completed the first submission. However, there are some caveats to that. So this first report is limited because it was for an orphan indication with very limited evidence available. There's been a lot of interest in it because it's the first one published, but we still need to wait for additional reports to be published for more meaningful insights, particularly for broader disease areas where there is much more data available, RCTs, multiple comparators. Until we have those ⁓ future JCA reports, this current report for Tovarafanib gives us some great insights for orphan diseases in particular. So in terms of the PICOs and the ITC methodology, this is the first time we've seen how the coordination group and the assessors and co-assessors have actually interpreted the methodology and put it into practice for an indication. And we'll talk a bit more about that. In addition, it's clear that the coordination group are committed to transparency. So they've published all aspects of the review. So their re full report is about 150 pages. They've also published a summary. of the full report. They've it and then also the company submission is published along with all of the appendices that haven't been redacted. So there's a huge amount of information available that everybody is able to appraise and take insights from. So we can take some great learnings for future submissions. One important thing to note for JCA is that the report does not make any value statements. So they don't give any rating or overall conclusions in terms of the comparative efficacy of the product or how national HGAs should use that information. However, they do highlight the uncertainties in the data and it'll be really interesting to see how the national HGAs use this first JCA report.
speaker-0: Thanks, Caroline. Now let's focus on the methodological and evidence insights. We all know there's been a major focus on the now famous PICOS. So Vijay, tell us how they were handled and what were the learnings.
speaker-2: Thank you, Peter. To start with, there were eight PICOs in scope covering three distinct populations or subpopulations. Ips in the manufacturer provided evidence on two of them, but interestingly, one of those wasn't actually considered by the SSS. So this shows an early critical mismatch between the evidence submitted and the evidence reviewed. Another thing that stood out was the lack of transparency around the PICO consolidation process itself. That makes it difficult to understand the rationale behind the final set of PICOs. And it will be interesting to see if this lack of clarity gets addressed going forward. So when you look at the four PICOs for the full label indication, two of them involved individualized treatment, with PICO 2 actually being a subset of PICO1. Then there were two further PICOs, each carrying one of the specific treatment options. From PICOS 1 and 2. Because these weren't properly ⁓ outlined in the final report, we are sort of left in the dark about what exactly the assessors and co-assessors expect to see when it comes to individualized treatment PICOs. So clear guidance in this regard is definitely needed. So it is becoming clear that the PICOs are driven heavily by individual member states rather than by the available clinical evidence. And that raises a really important question. If for the majority of PICOs no evidence was actually presented, does it make sense to keep defining them based on local treatment patterns? Or should they be defined on the basis of treatment guidelines arrived by expert consensus in the disease area? Arguably, the consensus guidelines better reflect what actually guides clinical practice, and that might be a far more practical and ⁓ defensible basis for PICOS going forward.
speaker-0: Great. Thanks, VJ. And I'm sure we'll see this continue to ⁓ to evolve. so let's shift gears a little bit around the SLR systematic lit literature review, often the foundation for our evidence that we start to build up, right? ⁓ so Caroline, what are your thoughts or around some of the SLR methodologies?
speaker-1: Yep, so Ibsen presented SLRs for both clinical trials, ⁓ RCTs and single arm trials, and also observational studies. ⁓ they did receive some criticism in the JCA report in terms of some of the methodology and the transparency of their reporting. So one of the clear take homes is that all SLRs need to be really robust, thoroughly reported and and entirely transparent. so they did criticize some of the the searches and the approach to screening. in particular in terms of how they identified studies for these individu individualized therapy ⁓ PICOs. Although it appears they they actually redid some of those searches, it doesn't look like it changed the outcome. So Ibsen didn't identify any relevant studies and nor did the assessors when they re-ran the searches. And so bearing in mind again that this was for an orphan disease with limited data available. This needs then be translated for those JCAs in much larger indications, potentially with multiple comparators with RCT data available. So starting that work on the SLRs early, making sure you're really recording everything all the way through, and then doing regular updates as you approach your JCA submissions submission is going to be really key. Another aspect that was key to this first appraisal that VJ noted that. Although Ibsen presented data for two studies, the coordination group actually rejected the data on one of those PICOs because it was only available in conference materials. Now this is something that had been outlined in the methodological guidance that has come out over the last couple of years that they wouldn't be accepting conference materials. But we were unclear how that would actually be implemented. So for this specific ⁓ appraisal, it's clear that they rejected that one trial because it was only available in conference format. And their ⁓ rationale for that was there wasn't enough information on the methodology of the trial and the patient characteristics and the sort of conduct of the trial in order to use the information. So that could set a precedent that we don't include any conference material in JCAs going forward. We do still wonder how they would accept the data if the conference materials were a secondary publication. So if we already had a full ⁓ published article with all the methodology and the patient characteristics and things, but we had a secondary article that maybe presented an additional outcome, whether JCA would consider that appropriate. For now, our assumption is that we shouldn't submit any conference material to the JCA. ⁓ And that's important to note because that does differ to what we usually do for national HDAs. And obviously all work for JCA is meant to be sort of reducing the work of the national HDAs. But here it means we might then need to submit additional work that's only been presented at conferences to national HDAs that we know the JCA won't consider. So that's still an area we're looking into, making sure our systematic reviews meet those requirements, but making sure we're being careful in terms of any conference. ⁓ information that we may not present it to JCA or if we present it we know it may not be considered. So that's really useful learnings for all our work that we've got ongoing on future submissions. Again, the current evidence is really just for an orphan indication. It'll be interesting to see the first full indication with multiple PICOs and and lots of evidence available.
speaker-0: Great. ⁓ and as we all know, those SLRs really start to feed into the ITC and other evidence generation work. What are some of the insights that we are seeing on the on the ITC side as it relates to Tovo?
speaker-1: Yeah, so as Vijay mentioned, only one PICO was actually considered by ⁓ the assessors for this specific ⁓ appraisal. And that was because they have a single-arm trial, they couldn't do any standard NMA approaches and they used ⁓ unanchored matching adjusted indirect comparison or MAIC. ⁓ and from the critique of it, we can see that the coordination group really don't favour unanchored ITCs. But in this case it was all that was possible based on the data available. And a lot of the criticism of the analysis does come down to that unanchored nature. So that's really very important for other ⁓ manufacturers that have got orphan drugs available or orphan diseases with drugs coming through JCA. And if they've got single arm trials, the more they can ensure that they're designed thinking of these comparisons that are going to be needed for JCA and to ensure that any comparisons are as robust as possible. Will be really helpful. Then, in terms of the match adjusting indirect comparison, one of the other key criticisms that the assessors had was the lack of clear reporting on the identification and selection of treatment effect modifiers and prognostic variables. So the methodological guidance does say they want to see a systematic literature review identifying TEMs and PVs, and Ibsen had done that. But they were criticized that although they'd done an SLR, it wasn't clearly reported how they'd gone from their long list of potential treatment effect modifiers identified down to the ones that they actually talked about within the submission and aimed to adjust for in their analysis. They did mention they'd done an advisory board, but again, there were no detailed notes in terms of what the advice given at that advisory board was. So a key learning here is make sure you do the systematic literature review of your treatment effect modifiers and prognostic variables. make sure you report it transparently, clearly. And if you do get external input from clinicians, again, you need to report that in a clear, unbiased way to demonstrate how you identified the TEMs that you've included in your analysis. And then a second criticism was that they were unable to adjust for all the treatment effect modifiers. And again, this is going to be a risk with orphan diseases or really any disease where if your comparators haven't published any data by those Characteristics, then you can't adjust for them. So again, things to consider for all companies that have got products coming through that are going to be based on single-arm trials or need any form of adjusted indirect comparison, to do make sure you're very robust in your assessment of the TEMs. So, and I guess a key thing from the indirect treatment comparison was that their main outcome, which was progression-free survival or PFS, The matching adjusted indirect comparison actually demonstrated that the comparator was more effective than TOVO with a hazard ratio of 4.88. So although in the report they don't draw any conclusions about that, they do mention that obviously it looks like TOVO is less effective in that outcome than the comparator. So this really shows that if you've got data, you know, you need to be prepared that the JCA will publish those findings, but equally they won't take into account any of your explanations or narratives around those outcomes. or why they might be less robust. So that's key that whatever you put into your report to the JCA may well end up in the published JCA report. Another criticism that they had was that although Ipson had had a SAP to identify the analyses they planned to conduct to support the JCA submission, they didn't include any primary analysis or any hypothesis testing. So all of the analyses were given equal footing and there was no clear primary analysis. And equally, although they did multiple analyses, they didn't ⁓ do any controls for that multiplicity. So obviously, if they were doing tens of of analyses, there's an assumption that some would appear to be significant just on the basis of the numbers done. So the assessors wanted to have seen some adjustment to allow for the fact that they were conducting multiple analyses, and the and Ibsen was criticized for not having done that.
speaker-0: Fix Caroline, these insights really provide some ⁓ key learnings that support the need for strategic planning, time, ⁓ expertise in the methods, et cetera, to help prepare for this JCA submission. So shifting gears a little bit on the overall implications for orphan drugs and evidence generation based on the first report. What are your thoughts there, VJ?
speaker-2: Well Peter, although orphan medicines don't formally fall under the joint clinical assessment mandate until twenty twenty eight, ⁓ approximately half of the JCS currently underway are actually for orphan medicines, the torofenib being the prime example here. So in practice, this is already very much an orphan rac conversation. So what particularly striking is that the HTA coordination group made no allowances whatsoever for the fact that this is a rare disease with a significant unmet need. That sends a pretty clear signal to other ⁓ health technology developers. You will be expected to follow the exact same methodology, and small single arm studies are unlikely to provide sufficient evidence for ⁓ robust conclusions. So that's a massive challenge. Now for ultra-rare diseases specifically, the reality is that you simply can't always run a large trial or a randomized controlled trial. There just aren't enough patients. And that problem isn't going to go away. So the practical takeaway here is that ⁓ manufacturers of orphan drugs need to design the most rigorous trials they possibly can and critically plan far ahead ⁓ for where the evidence gaps will be, because they will exist as we've seen in this case. So one thing that stood out in the assessment itself is the assessors didn't independently evaluate. The Firefly One single arm trial. As Firefly One is a non-comparative study, no no direct comparative data are available to inform any of the PICOS, and ⁓ no data are available to inform an analysis within a connected network of evidence, as Caroline has ⁓ already mentioned. Given how important single arm evidence often is in orphan evaluations, that's notable. It effectively leaves individual member states To interpret and assess those non-comparative endpoints on their own. And finally, that brings us to perhaps the most pressing question for this discussion. Evidence was only provided for a single PICO, covering something in the region of less than 20% of the indicated population. So, what does that mean for the majority of the population, the other 80%? How should member states approach decisions? For that vast majority of the patients, where there is no direct evidence. That feels like a massive open question that this report simply hasn't answered yet.
speaker-0: Thanks for those insights, VJ. So I noticed that they had not included any value statements in the JCA. So how use it and what is the possible impact for the national HTAs? Caroline, what are your thoughts?
speaker-1: Yeah, so although no value statements were made, the report conclusions were quite damning. ⁓ and as Vijay just mentioned, they didn't allow for any leeway due to the rare nature of LGG in the resulting evidence base. So throughout the report, there are statements such as major general uncertainties and bias of unknown magnitude and direction in the resulting treatment effect estimates. So As Vijay said, it's really unclear what the implications are now for the national HTAs and the reimbursement in the twenty seven EU member states. Because generally most countries do allow some leeway for rare diseases and will consider other factors than just the indirect comparisons with the available treatments. So it now will come to the in the separate national HTAs and how they then take the JCA report and implement it within their own framework. to allow for reimbursement of these products. So again, as well as waiting for for additional JCA reports, seeing what happens to this first product in terms of the national EHTAs is going to be key moving forward and for for companies to think about as they're preparing for JCA. Another key change that's happened this week has been that two more of the ongoing JCAs have actually been discontinued. And that's something else we're looking out for. that relates to this point because they've been rejected based on the companies not having submitted all the evidence that were requested by the assessors, co assessors. So here again, we're not clear what's going to happen for those in terms of national HGAs and that's going to be an important point as well.
speaker-0: Great. Thanks for that insight. so as we wrap this up, can each of you offer three quick tips for drug developers when it comes to generation analysis and communication for future JCA reports? Kind of the do's and don'ts. Carol?
speaker-1: Why? Yep. So the number one, and I think everyone's been hearing this now for the last couple of years, is plan early. So both in terms of your clinical trials, maybe getting JSC input before your phase three trial, but even if you don't get JSC input, then making sure you're designing your trial with JCA in mind, whether that's a single arm trial and making sure you've considered the possible treatment landscape, what indirect comparisons you're likely to need in the future, and how you're going to be able to provide evidence for those. ⁓ but then also your synthesis later on. So really early planning in terms of JCA and thinking about the PICOs if possible. I mean, we know often the work's already been done and people are having to pick up with with what they can when the phase three trials are already ongoing. But again, the earlier you plan, looking at your likely PICOs, working out your evidence synthesis, the better. Then as we mentioned earlier, the in terms of your evidence synthesis, making sure you're clearly and accurately reporting all of your gathering of evidence, so your systematic literature reviews and how you're synthesizing that evidence in your indirect treatment comparisons is really important. In the current report, the IPSI were criticized in a number of places because it was unclear what they'd done. And that's also going to be important as you go into your national HTA. So Making sure you're designing your systematic reviews to meet the needs of both JCA and the national HTAs, clearly reporting all steps that will really help with both the JCA and the national HTAs that follow. And then my final one is in terms of your statistical analysis plan for JCA, make sure that you design your SAP based on the anticipated PICOs, think about what analyses you're going to need and pre-specify them within your SAP. But also make sure you've got a primary analysis and hypothesis testing and that you account for the multiplicity of analyses that you're conducting.
speaker-0: Great, thanks Caroline. Vijay, what are your thoughts?
speaker-2: ⁓ I mean if anybody still has doubt, this process is intense. It doesn't stop at a dossier submission. HTDs need to make sure they are prepared for multiple additional information requests and very short timelines. ⁓ the second one is that JCA is very process driven and ⁓ manufacturers can't assume that factors such as rarity, unmet need, ⁓ lack of comparator evidence will be considered in the decision making. As they are by the national HDAs. And finally, we shouldn't forget that this is the first report and in a rare disease, as Caroline touched upon earlier. So we can only learn so much from one report in a rare disease. We cannot extrapolate too much or assume precedent. So it is important to keep monitoring as additional GCA reports are published, as they will continue to provide insights, particularly for non-rare products.
speaker-0: Great, to be continued, right? so thanks for listening to Pharma Unscripted from RTI Health Solutions, where knowledge leads to understanding and strategy drives impact. As we've discussed, the first EU Joint Clinical Assessment Report offers an important early look at how evidence may be evaluated under the new EU HDA framework. From PICOS and systematic reviews to indirect treatment comparisons and single arm studies. First report on Toborefinib for pediatric low-grade glioma highlights both the complexity and the evolving expectations for evidence generation. It also raises important questions for manufacturers, especially in rare diseases, around how evidence is generated, communicated, and ultimately used to inform future access and reimbursement decisions. And from this conversation, it is clear that manufacturers need technically strong agencies to With deep methodological expertise and capacity to support this process. A big thank you to Caroline Lang and VJ D'Souza for sharing their insights and practical guidance for future JCA submissions. Thanks for listening.
speaker-1: Thanks, Peter. So firstly, this is a real major milestone for ⁓ EU HGA regulation. This has been several years incoming, but they've demonstrated that the the process that they've developed and the methodologies are possible and have completed the first submission. However, there are some caveats to that. So this first report is limited because it was for an orphan indication with very limited evidence available. There's been a lot of interest in it because it's the first one published, but we still need to wait for additional reports to be published for more meaningful insights, particularly for broader disease areas where there is much more data available, RCTs, multiple comparators. Until we have those ⁓ future JCA reports, this current report for Tovarafanib gives us some great insights for orphan diseases in particular. So in terms of the PICOs and the ITC methodology, this is the first time we've seen how the coordination group and the assessors and co-assessors have actually interpreted the methodology and put it into practice for an indication. And we'll talk a bit more about that. In addition, it's clear that the coordination group are committed to transparency. So they've published all aspects of the review. So their re full report is about 150 pages. They've also published a summary. of the full report. They've it and then also the company submission is published along with all of the appendices that haven't been redacted. So there's a huge amount of information available that everybody is able to appraise and take insights from. So we can take some great learnings for future submissions. One important thing to note for JCA is that the report does not make any value statements. So they don't give any rating or overall conclusions in terms of the comparative efficacy of the product or how national HGAs should use that information. However, they do highlight the uncertainties in the data and it'll be really interesting to see how the national HGAs use this first JCA report.
speaker-0: Thanks, Caroline. Now let's focus on the methodological and evidence insights. We all know there's been a major focus on the now famous PICOS. So Vijay, tell us how they were handled and what were the learnings.
speaker-2: Thank you, Peter. To start with, there were eight PICOs in scope covering three distinct populations or subpopulations. Ips in the manufacturer provided evidence on two of them, but interestingly, one of those wasn't actually considered by the SSS. So this shows an early critical mismatch between the evidence submitted and the evidence reviewed. Another thing that stood out was the lack of transparency around the PICO consolidation process itself. That makes it difficult to understand the rationale behind the final set of PICOs. And it will be interesting to see if this lack of clarity gets addressed going forward. So when you look at the four PICOs for the full label indication, two of them involved individualized treatment, with PICO 2 actually being a subset of PICO1. Then there were two further PICOs, each carrying one of the specific treatment options. From PICOS 1 and 2. Because these weren't properly ⁓ outlined in the final report, we are sort of left in the dark about what exactly the assessors and co-assessors expect to see when it comes to individualized treatment PICOs. So clear guidance in this regard is definitely needed. So it is becoming clear that the PICOs are driven heavily by individual member states rather than by the available clinical evidence. And that raises a really important question. If for the majority of PICOs no evidence was actually presented, does it make sense to keep defining them based on local treatment patterns? Or should they be defined on the basis of treatment guidelines arrived by expert consensus in the disease area? Arguably, the consensus guidelines better reflect what actually guides clinical practice, and that might be a far more practical and ⁓ defensible basis for PICOS going forward.
speaker-0: Great. Thanks, VJ. And I'm sure we'll see this continue to ⁓ to evolve. so let's shift gears a little bit around the SLR systematic lit literature review, often the foundation for our evidence that we start to build up, right? ⁓ so Caroline, what are your thoughts or around some of the SLR methodologies?
speaker-1: Yep, so Ibsen presented SLRs for both clinical trials, ⁓ RCTs and single arm trials, and also observational studies. ⁓ they did receive some criticism in the JCA report in terms of some of the methodology and the transparency of their reporting. So one of the clear take homes is that all SLRs need to be really robust, thoroughly reported and and entirely transparent. so they did criticize some of the the searches and the approach to screening. in particular in terms of how they identified studies for these individu individualized therapy ⁓ PICOs. Although it appears they they actually redid some of those searches, it doesn't look like it changed the outcome. So Ibsen didn't identify any relevant studies and nor did the assessors when they re-ran the searches. And so bearing in mind again that this was for an orphan disease with limited data available. This needs then be translated for those JCAs in much larger indications, potentially with multiple comparators with RCT data available. So starting that work on the SLRs early, making sure you're really recording everything all the way through, and then doing regular updates as you approach your JCA submissions submission is going to be really key. Another aspect that was key to this first appraisal that VJ noted that. Although Ibsen presented data for two studies, the coordination group actually rejected the data on one of those PICOs because it was only available in conference materials. Now this is something that had been outlined in the methodological guidance that has come out over the last couple of years that they wouldn't be accepting conference materials. But we were unclear how that would actually be implemented. So for this specific ⁓ appraisal, it's clear that they rejected that one trial because it was only available in conference format. And their ⁓ rationale for that was there wasn't enough information on the methodology of the trial and the patient characteristics and the sort of conduct of the trial in order to use the information. So that could set a precedent that we don't include any conference material in JCAs going forward. We do still wonder how they would accept the data if the conference materials were a secondary publication. So if we already had a full ⁓ published article with all the methodology and the patient characteristics and things, but we had a secondary article that maybe presented an additional outcome, whether JCA would consider that appropriate. For now, our assumption is that we shouldn't submit any conference material to the JCA. ⁓ And that's important to note because that does differ to what we usually do for national HDAs. And obviously all work for JCA is meant to be sort of reducing the work of the national HDAs. But here it means we might then need to submit additional work that's only been presented at conferences to national HDAs that we know the JCA won't consider. So that's still an area we're looking into, making sure our systematic reviews meet those requirements, but making sure we're being careful in terms of any conference. ⁓ information that we may not present it to JCA or if we present it we know it may not be considered. So that's really useful learnings for all our work that we've got ongoing on future submissions. Again, the current evidence is really just for an orphan indication. It'll be interesting to see the first full indication with multiple PICOs and and lots of evidence available.
speaker-0: Great. ⁓ and as we all know, those SLRs really start to feed into the ITC and other evidence generation work. What are some of the insights that we are seeing on the on the ITC side as it relates to Tovo?
speaker-1: Yeah, so as Vijay mentioned, only one PICO was actually considered by ⁓ the assessors for this specific ⁓ appraisal. And that was because they have a single-arm trial, they couldn't do any standard NMA approaches and they used ⁓ unanchored matching adjusted indirect comparison or MAIC. ⁓ and from the critique of it, we can see that the coordination group really don't favour unanchored ITCs. But in this case it was all that was possible based on the data available. And a lot of the criticism of the analysis does come down to that unanchored nature. So that's really very important for other ⁓ manufacturers that have got orphan drugs available or orphan diseases with drugs coming through JCA. And if they've got single arm trials, the more they can ensure that they're designed thinking of these comparisons that are going to be needed for JCA and to ensure that any comparisons are as robust as possible. Will be really helpful. Then, in terms of the match adjusting indirect comparison, one of the other key criticisms that the assessors had was the lack of clear reporting on the identification and selection of treatment effect modifiers and prognostic variables. So the methodological guidance does say they want to see a systematic literature review identifying TEMs and PVs, and Ibsen had done that. But they were criticized that although they'd done an SLR, it wasn't clearly reported how they'd gone from their long list of potential treatment effect modifiers identified down to the ones that they actually talked about within the submission and aimed to adjust for in their analysis. They did mention they'd done an advisory board, but again, there were no detailed notes in terms of what the advice given at that advisory board was. So a key learning here is make sure you do the systematic literature review of your treatment effect modifiers and prognostic variables. make sure you report it transparently, clearly. And if you do get external input from clinicians, again, you need to report that in a clear, unbiased way to demonstrate how you identified the TEMs that you've included in your analysis. And then a second criticism was that they were unable to adjust for all the treatment effect modifiers. And again, this is going to be a risk with orphan diseases or really any disease where if your comparators haven't published any data by those Characteristics, then you can't adjust for them. So again, things to consider for all companies that have got products coming through that are going to be based on single-arm trials or need any form of adjusted indirect comparison, to do make sure you're very robust in your assessment of the TEMs. So, and I guess a key thing from the indirect treatment comparison was that their main outcome, which was progression-free survival or PFS, The matching adjusted indirect comparison actually demonstrated that the comparator was more effective than TOVO with a hazard ratio of 4.88. So although in the report they don't draw any conclusions about that, they do mention that obviously it looks like TOVO is less effective in that outcome than the comparator. So this really shows that if you've got data, you know, you need to be prepared that the JCA will publish those findings, but equally they won't take into account any of your explanations or narratives around those outcomes. or why they might be less robust. So that's key that whatever you put into your report to the JCA may well end up in the published JCA report. Another criticism that they had was that although Ipson had had a SAP to identify the analyses they planned to conduct to support the JCA submission, they didn't include any primary analysis or any hypothesis testing. So all of the analyses were given equal footing and there was no clear primary analysis. And equally, although they did multiple analyses, they didn't ⁓ do any controls for that multiplicity. So obviously, if they were doing tens of of analyses, there's an assumption that some would appear to be significant just on the basis of the numbers done. So the assessors wanted to have seen some adjustment to allow for the fact that they were conducting multiple analyses, and the and Ibsen was criticized for not having done that.
speaker-0: Fix Caroline, these insights really provide some ⁓ key learnings that support the need for strategic planning, time, ⁓ expertise in the methods, et cetera, to help prepare for this JCA submission. So shifting gears a little bit on the overall implications for orphan drugs and evidence generation based on the first report. What are your thoughts there, VJ?
speaker-2: Well Peter, although orphan medicines don't formally fall under the joint clinical assessment mandate until twenty twenty eight, ⁓ approximately half of the JCS currently underway are actually for orphan medicines, the torofenib being the prime example here. So in practice, this is already very much an orphan rac conversation. So what particularly striking is that the HTA coordination group made no allowances whatsoever for the fact that this is a rare disease with a significant unmet need. That sends a pretty clear signal to other ⁓ health technology developers. You will be expected to follow the exact same methodology, and small single arm studies are unlikely to provide sufficient evidence for ⁓ robust conclusions. So that's a massive challenge. Now for ultra-rare diseases specifically, the reality is that you simply can't always run a large trial or a randomized controlled trial. There just aren't enough patients. And that problem isn't going to go away. So the practical takeaway here is that ⁓ manufacturers of orphan drugs need to design the most rigorous trials they possibly can and critically plan far ahead ⁓ for where the evidence gaps will be, because they will exist as we've seen in this case. So one thing that stood out in the assessment itself is the assessors didn't independently evaluate. The Firefly One single arm trial. As Firefly One is a non-comparative study, no no direct comparative data are available to inform any of the PICOS, and ⁓ no data are available to inform an analysis within a connected network of evidence, as Caroline has ⁓ already mentioned. Given how important single arm evidence often is in orphan evaluations, that's notable. It effectively leaves individual member states To interpret and assess those non-comparative endpoints on their own. And finally, that brings us to perhaps the most pressing question for this discussion. Evidence was only provided for a single PICO, covering something in the region of less than 20% of the indicated population. So, what does that mean for the majority of the population, the other 80%? How should member states approach decisions? For that vast majority of the patients, where there is no direct evidence. That feels like a massive open question that this report simply hasn't answered yet.
speaker-0: Thanks for those insights, VJ. So I noticed that they had not included any value statements in the JCA. So how use it and what is the possible impact for the national HTAs? Caroline, what are your thoughts?
speaker-1: Yeah, so although no value statements were made, the report conclusions were quite damning. ⁓ and as Vijay just mentioned, they didn't allow for any leeway due to the rare nature of LGG in the resulting evidence base. So throughout the report, there are statements such as major general uncertainties and bias of unknown magnitude and direction in the resulting treatment effect estimates. So As Vijay said, it's really unclear what the implications are now for the national HTAs and the reimbursement in the twenty seven EU member states. Because generally most countries do allow some leeway for rare diseases and will consider other factors than just the indirect comparisons with the available treatments. So it now will come to the in the separate national HTAs and how they then take the JCA report and implement it within their own framework. to allow for reimbursement of these products. So again, as well as waiting for for additional JCA reports, seeing what happens to this first product in terms of the national EHTAs is going to be key moving forward and for for companies to think about as they're preparing for JCA. Another key change that's happened this week has been that two more of the ongoing JCAs have actually been discontinued. And that's something else we're looking out for. that relates to this point because they've been rejected based on the companies not having submitted all the evidence that were requested by the assessors, co assessors. So here again, we're not clear what's going to happen for those in terms of national HGAs and that's going to be an important point as well.
speaker-0: Great. Thanks for that insight. so as we wrap this up, can each of you offer three quick tips for drug developers when it comes to generation analysis and communication for future JCA reports? Kind of the do's and don'ts. Carol?
speaker-1: Why? Yep. So the number one, and I think everyone's been hearing this now for the last couple of years, is plan early. So both in terms of your clinical trials, maybe getting JSC input before your phase three trial, but even if you don't get JSC input, then making sure you're designing your trial with JCA in mind, whether that's a single arm trial and making sure you've considered the possible treatment landscape, what indirect comparisons you're likely to need in the future, and how you're going to be able to provide evidence for those. ⁓ but then also your synthesis later on. So really early planning in terms of JCA and thinking about the PICOs if possible. I mean, we know often the work's already been done and people are having to pick up with with what they can when the phase three trials are already ongoing. But again, the earlier you plan, looking at your likely PICOs, working out your evidence synthesis, the better. Then as we mentioned earlier, the in terms of your evidence synthesis, making sure you're clearly and accurately reporting all of your gathering of evidence, so your systematic literature reviews and how you're synthesizing that evidence in your indirect treatment comparisons is really important. In the current report, the IPSI were criticized in a number of places because it was unclear what they'd done. And that's also going to be important as you go into your national HTA. So Making sure you're designing your systematic reviews to meet the needs of both JCA and the national HTAs, clearly reporting all steps that will really help with both the JCA and the national HTAs that follow. And then my final one is in terms of your statistical analysis plan for JCA, make sure that you design your SAP based on the anticipated PICOs, think about what analyses you're going to need and pre-specify them within your SAP. But also make sure you've got a primary analysis and hypothesis testing and that you account for the multiplicity of analyses that you're conducting.
speaker-0: Great, thanks Caroline. Vijay, what are your thoughts?
speaker-2: ⁓ I mean if anybody still has doubt, this process is intense. It doesn't stop at a dossier submission. HTDs need to make sure they are prepared for multiple additional information requests and very short timelines. ⁓ the second one is that JCA is very process driven and ⁓ manufacturers can't assume that factors such as rarity, unmet need, ⁓ lack of comparator evidence will be considered in the decision making. As they are by the national HDAs. And finally, we shouldn't forget that this is the first report and in a rare disease, as Caroline touched upon earlier. So we can only learn so much from one report in a rare disease. We cannot extrapolate too much or assume precedent. So it is important to keep monitoring as additional GCA reports are published, as they will continue to provide insights, particularly for non-rare products.
speaker-0: Great, to be continued, right? so thanks for listening to Pharma Unscripted from RTI Health Solutions, where knowledge leads to understanding and strategy drives impact. As we've discussed, the first EU Joint Clinical Assessment Report offers an important early look at how evidence may be evaluated under the new EU HDA framework. From PICOS and systematic reviews to indirect treatment comparisons and single arm studies. First report on Toborefinib for pediatric low-grade glioma highlights both the complexity and the evolving expectations for evidence generation. It also raises important questions for manufacturers, especially in rare diseases, around how evidence is generated, communicated, and ultimately used to inform future access and reimbursement decisions. And from this conversation, it is clear that manufacturers need technically strong agencies to With deep methodological expertise and capacity to support this process. A big thank you to Caroline Lang and VJ D'Souza for sharing their insights and practical guidance for future JCA submissions. Thanks for listening.
