So our next speaker is Paul Cooper. Paul is a clinical neurologist in Manchester, UK. Paul has a remarkable expertise in guideline development in the UK, has worked on various guideline panels. He's worked previously for the Cochrane Collaborative, or maybe currently, and also for NICE, which is a UK organization that evaluates drugs and products and provides recommendations for what is cost-effective and what should be used. Thank you, Paul. Thank you very much, Atif. And I'm feeling slightly intimidated coming in as a UK neurologist into an American group. Let's just see, how do we bring that up? That's great, thank you. Yes, so Atif has given a comprehensive review as to how the AAS produces guidelines. And I was asked to provide perhaps a personal reflection on differences between how we as an organization, the AAS, produce guidance, and how it's done elsewhere in the world, and particularly in the UK. And I would point out that this is a personal reflection and perhaps giving my views as to differences in emphasis as much as in differences in structure. I've got no financial disclosures of relevance. The number of other potential conflicts, I've chaired a number of neurological guideline development committees for NICE, which is one of the UK organizations that generates guidelines. I was previously a specialist advisor to NICE on their horizon scanning process, and in fact will probably take that role up again. But it is important to realize I'm not an employee of NICE. I don't speak for them. These views are my own, and they're my subjective interpretations, if you like. I have spoken to a couple of senior individuals in NICE about this talk, and I've had advice from them. I am currently a member of the Association of British Neurologists Quality Committee, and we have a role in reviewing UK guidance, and not of relevance to this talk, but I also chair the UK Driving Agencies Medical Panel, so we make guidance and recommendations for driving standards in the UK. So those are the learning objectives, just to give you a feel for how guidance is developed in countries other than the US, and how to look perhaps at the end as to whether some of those processes are appropriate or not. Now, Atif has talked a little bit about this already, but I think it is important, particularly when reflecting on how other organizations, other people in the world, produce guidance, and what they call guidelines, and I think we do need to be robust, and a clinical practice guideline is a systematically developed decision aid, and we've just heard how that is done, with a specific scope, a multidisciplinary panel of appropriate skills, defined PICOs, and graded recommendations, and this whole process is directed by a guideline manual. It's not a textbook, and we heard earlier that these are guidelines, they're not tramlines, they're not obligatory, and there's also been alluded to that they can be an issue in medical negligence litigation. If you're following a guidance, it does give you some protection, so they do need to be robust, and I have to say that from my experience of working with the AAS guideline panel, I think the process in the US does actually provide greater clarity between these aspects, between what is a true guideline, and what is a consensus statement, and many things that are quoted to be guidance produced by other organizations elsewhere, their distinction does tend to be blurred, and when you read international guidance, I would caution you, because sometimes there's a tendency for what are called guidelines in a publication, are in fact consensus statements, and not true guidelines developed according to a process. Now, we have heard about the history of guideline development, and neither of these are what we used to have, which are rather pejoratively called a gobsat, a good old boy sat around a table. I think many of you will be familiar with, that's how people used to produce recommendations, and Professor Petri was the father of guideline development. He founded the Scottish Intercollegiate Guidelines Network back, I think, in the 1980s or early 1990s, and he has been personally responsible for over 50 clinical guidelines, and the reference to his views on how to do it is there. So, there are various processes for producing what are called guidelines, and in the UK, which is where I'm from, there are two organizations. There's NICE, which is responsible for England and Wales. Northern Ireland acknowledges the NICE guidance, but doesn't actually formally use that, and SIGN is a separate organization in Scotland, and I won't talk very much more about SIGN. Now, in Europe, there's various processes of varying quality. Scandinavia, I will come back to. There may well be Scandinavians in the audience, and if I'm disparate in some way, I apologize in advance. I'm aware there may be many people in these countries present in the audience, and Australia and, to a lesser extent, New Zealand have a different network and a different process that, to a certain extent, reflects what we use in the UK. There is a Guidelines International Network, which you can join. It's relatively cheap if you join as an individual. It's quite costly as an organization, and that can give you... It has a database of what guidelines are present and what organizations are developing them worldwide. So, in the UK, which is where I've been involved, NICE is a public body funded by the UK government with a substantial budget. We've heard how much guidelines develop. You know, $68 million per annum is the budget, and it provides national guidance and advice to improve health and social care on a statutory basis. SIGN is a Scottish organization. It's a consortium of academic institutes. The funding is less. It's funded by the Scottish government. Both have similar processes, and one of the things I think I'm going to be highlighting is with the differences between what we do in the UK and how many guidelines are developed in the US and elsewhere. There's a substantial health economic analysis of the cost benefits of new interventions. Both NICE and SIGN have a substantial patient and public involvement in guideline development. Patients and carers are figures within the central core guideline committee, so when I chair a committee, there will be two or three patients on that committee providing a major input into the guidance, perhaps more so than within the US system. So NICE, which is the organization I've been most involved with, produces two products, essentially. There's the guidelines, which are mainly clinical, but we also address public health and social care and medicine practice, and then separately, a process involving technology appraisal, which addresses specific new products, usually a new drug and the cost-effectiveness of that new drug. Now, these processes, they use similar methods, but slightly different processes, and technology appraisals are the process by which new drugs are introduced into the NHS. For instance, there's been a recent one for sinobamate and for fenfluramine, and they are actually now funded by the pharmaceutical company that wishes to introduce that drug. Guidelines address the best way to care for a condition, so they are different, and TAs are quicker and a separate process. So we've heard from Atif about how, in the AAS, we develop guidance. Similar process within the UK. There's a considerable stakeholder consultation at a very early stage. The proposals go out to stakeholder consultation, and there's often a lot of feedback and modification at an early stage. There's a wide range of professionals. There's a technical team, professional technical team, and one of the things that you gain from working within a guideline committee is working with these experts in library and in literature searching, and, as I've mentioned, major patient and carer involvement. Now, Atif has alluded to the costs. I think the AAS gets this on the cheap. A big, nice guidance is costing over, you know, your figure, $630,000 per guidance. It's a major process lasting up to three years with further stakeholder consultation during that process, and the aim is to address and maximise not only effective but, more specifically, cost-effective care for the NHS, and this is perhaps one of the biggest differences between how the AAS and other American organisations and NICE address their guidance, and this is the concept of the opportunity cost of a new treatment, and the UK Health Service has a finite budget. That's a political decision, how much the UK government will spend on healthcare, and the inevitable consequences of that is if we spend more on one thing, we have to do less of something else, and so if we want to introduce something new, could we be doing more good by spending the extra money in other ways, and the opportunity cost is the value of the best alternative use of the resources so that new treatments should only replace old treatments if they produce more benefit for the same cost, and you can question whether you might be better spending the money on, for instance, chiroprathy for old people to prevent them falling and ending up in hospital compared to the latest interventions for neurostimulation for epilepsy, and that is the sort of discussion that we often have within our organizations as to whether this is actually a cost benefit. I'll come back to how that calculation is done, but central to that is a figure known as a QALY, and many of you will have heard of QALYs. It stands for Quality Adjusted Life Years, and that is central to our process, and it's the quality of life for one year of perfectly healthy life for one person, or for instance, two years of life with 50% of quality of life, or one year of life with 50% of quality of life for two people. It's almost always perceived as being a positive. There is an argument as to whether you could have negative quality of life. Some conditions, motor neurone disease, for instance, it might be perceived as having a negative quality of life, but what we would try and calculate and assess is whether the new treatment over the lifetime of that treatment provides an overall gain in QALYs compared to standard treatment, current treatment, acknowledging that, for instance, a new intervention might reduce quality of life during the initial process of doing the surgery. So the cost-effectiveness of a new treatment determines the recommendation that we would make. And so if the benefit is greater, you can accept a greater cost, and there's a gradient to that line, and it has been typically about $25,000 per QALY. So if you can get a greater benefit, then you can justify a greater cost. Now, that figure is a little bit flexible, and for certain conditions, in particular for cancer, we would have a greater cost per QALY threshold. So it's not an absolute figure. And then just to give you an example as to how this might work, this is a decision that we made in a guideline that I was involved with. Because this is a CME presentation, I've anonymized it, although it is in the public domain, and there's a reference there to the guidance. And essentially, this is a new treatment for a particular condition that was felt to improve the quality of life with individuals with that condition. And we analyzed the potential improvement in quality of life, comparing, and we're actually relatively generous to this product, in that we only analyzed those individuals within the studies who responded. The model was stratified for drug responders, and that obviously enhances the cost-effectiveness of the drug, because there's the assumption that only the responders will remain on it. But you can see there that despite this being a product that many neurologists will know of, and which is felt to be beneficial, it's not an epilepsy product. The actual benefit on quality of life was modest, but the cost was substantial, over $15 a day. And on the basis of that, $200,000 per QALY. So we didn't recommend this product. Now, within this analysis, and I know the use of health economics for deciding about treatment is a challenging one outside of the UK, but we then have a second phase to this, which is a probabilistic sensitivity analysis, looking at how sensitive that recommendation was dependent upon uncertainties in the various assumptions that you made in that health economic calculation. So you establish the various variables that are measured, and you run a sensitivity analysis. If that estimate was wrong, how much does that affect your conclusions? And so what is the uncertainty in the model? And it's a statistical process, looking at how changing each of the assumptions within your health economic analysis affects the outcome of the analysis. So you get this sort of scatter plot, looking on the incremental cost and the incremental effectiveness, depending upon different changes and different estimates of the various variables. And you can have a threshold there, where you can get a feel for whether you're actually in the right ballpark. But perhaps more helpful is that you can then generate a statistical plot, looking at what the probability is that your intervention is going to be cost-effective at different willingness to pay. So how much are you going to have to pay for this new intervention to make it likely to be cost-effective? And then this can produce this cost-effectiveness acceptability curve, which gives you an idea as to how, along the bottom there, what your willingness to pay for a particular product or new drug is, how likely that is going to make that new drug cost-effective on the basis of the analysis that we use with QALYs. And I can come back, if you like, maybe at the end, in discussion, to explain how we come to that figure for the QALY. So the initial figure is this incremental cost-effectiveness ratio, the ISA, which is the absolute cost per incremental use of effectiveness, which is what we would conventionally use. But the PSA is more granular and gives you an idea as to how probable it is that this new intervention is going to be cost-effective. So just to look at some other international processes. And again, I have to be slightly cautious here, because I don't know if there are any committee members from the ILEA itself present, but we are a chapter of the ILEA, and the ILE has a guideline development process, which some of the members of our organisation are part of. And the initial publication, you may recognise names on there, was in 2015. There was a recent update trying to sort of promote the development of guidelines within the ILEA, published seven years later. And I'm not sure they've done very much. I have to be careful here. So if you look on the website, they list 185 guidelines. Many of these are not actually guidelines. Many of them are advisory. Many of them are actually guidelines that have been developed by other organisations. Within that 185, many of them are guidelines in translation. So there will be half a dozen which are in the different languages, and they are listed as separate guidance. And in fact, in terms of guidance that I think the ILEA has actually developed, I found two. One was seizure detection devices, and the other was standards for VT units. Although I know that they have a list of proposed guidance, maybe he mentioned that the ILEA is also looking at a status guidance guideline. I couldn't find that on their website, but I believe they are developing one. Maybe their website is out of date. So the ILEA has a process, although they don't do very much, to be honest. And I think we've had our discussions within the status guidance that theirs is a bit like stirring a treacle. It's not moving very fast. Ours is the AES is getting on with it. So within Europe, there's a whole hodgepodge of lots of different processes, and none of them are as structured and as robust as either the AES or within NICE. The European Academy of Neurology has a limited register of professional body guidance. In many of the countries, the structure of the healthcare is such that the hospitals are very disease-specific specialist hospitals, and guidance is developed locally and reflect this process. But there's little to be gained. It's very disparate in Europe. In Scandinavia, I'm informed that there is a national process, but this tends to be rather politicised and there's an emphasis on social care topics. There is an economic component to this, but there's a rather directed process to identify social care topics that may improve and probably rightly so, healthcare within the community. The Australia has a state rather than a national process. It does rather mimic NICE, but lacks economic modelling, and New Zealand tends to follow Australian guidance. Many of those look, those states will actually look to NICE to inform them. And this is where NICE is actually selling itself internationally with a structure known as NICE International, where a little bit like the AES may assure guidance sent to the AES, NICE will either licence its own guidance to allow another country to adopt it, and as a cost effect dependent on the population size and the GDP, or will further contextualise it and adapt it to that country, provide NICE logo and branding, and adapt it to the local situation at greater cost. So just to look where these things are moving, NICE has 350 guidelines, all developed within this same sort of process, 20,000 recommendations. It's very difficult to keep these up to date, and there is a move to focussing on more specific updates and a continuous process rather than an episodic review, and an instruction to target identified products for the NHS. So we're slimming down the portfolio. We are integrating guidance, as we've heard, into EPR systems, use licensing third parties to incorporate that into commercial EPRs in the UK, and also adopting others' guidance, and are currently NICE are working with Australian guidelines. And also, and this is an important, and this is a difference, which I have only really relatively recently become aware of, is targeting specific perceived needs. So not only looking for the professional healthcare professions to put forward topics, but to target specific needs where there's felt to be some area that needs guidance to guide treatment, and then going out and making guidance, and then potentially getting people to develop drugs for that topic. And NICE has recently targeted drug development where there's a perceived need for a particular product, which then develop the development of guidance as to how that product might be used, and then going to the pharmaceutical companies with a subscription contract based on the calculated benefit of the drug within those health economic calculations, which then drives a contract with pharma, and that has incentivised pharma to develop a novel drug for a specific need, knowing that the NHS will then purchase that drug at a pre-agreed price prior to marketing. And indeed, two new superbug antibiotics have just been licenced and funded in the UK under this scheme, and there's a reference there which will give you the details of those drugs. So the pharmaceutical companies have developed and marketed a drug that they would not have done otherwise, knowing that the NHS would purchase that drug for this specific need with a health economic analysis that we did at NICE. So just briefly, both US and particularly AES and the leading non-US guidance use very defined structures. I do feel that NICE perhaps has greater parent and care engagement with quite widespread stakeholder comments, both prior to publication and after development, and NICE and some others use a health economic analysis in order to inform decisions to a much greater extent than is used in the US. And impacts on clinical care, well, we've heard a little bit of what makes a good guidance. It's a decision aid. It's not a textbook. It's not a tramline. It's a guideline. There needs to be a formal process of development based on a manual, a recognised system with a systematic review, and importantly is a consultation with relevant stakeholders and involvement of patient carers at an early stage, and then, as we have heard from Atif, implementation and ongoing review and updates. Thank you very much. Thank you.

guideline development

NICE

economic analysis

patient stakeholders

Quality Adjusted Life Years

international collaborations