Event 4 – Translation into practice


  • Eric Low
  • Prof Carole Longson
  • Dr. Wija Oortwijn


Guest Experts: Dr Peter Clark


Leeza Osipenko: Today we will be talking about translating into practice, how HTA actually impacts clinical practice today. This is probably the most important we can discuss in terms of HTA, because if it’s making a difference the only way we can see if it’s making any changes at the level of consumption for patients, providers, and for society. In an ideal world, we may wish for a healthcare system to improve patient outcomes, save resources, improve system’s efficiency, improve access to healthcare/treatments, and to promote innovations and bring them to patients. This is a great list, very logical, whether it’s a universal health coverage system or a privatised system. In a reality these are very difficult to reach goals. The different tools that have been implemented across the world to try to achieve them, one of them being health technology assessment, which has been practiced more thoroughly in Europe that in many other countries. However, Canada and Australia have been very proactive with HTA. The developing world is looking into this and realising this might be a very useful tool to try to improve on all these points listed. The idea is that we can look at the innovation, at new products that come in, with the help of HTA, and see if they impact clinical practice and, hopefully, in the process we discontinue the use of outdated and inefficient technologies. For today’s session, we have a number of questions, but these ones will set the scene. Has the translation of HTA decisions into practice been successful? What have been the implications for patients, clinicians, payers, and policymakers? The next set of questions looks at the role of HTA in universal health coverage systems, and how HTA improves effectiveness and efficiency of healthcare in settings with universal health coverage, and what can be done better. A very interesting topic for discussion is whether HTA is helping with priority setting in different healthcare systems, and whether it should be helping in priority settings. Maybe, the situation should be the other way around, maybe it’s the politics and the priorities of the system that define what HTA activities need to take place in a particular country. So, where the balance between these 2 perspectives lies is what we’ll try to discover from our experts. 


Peter Clark: I’m an oncologist by trade, and I shuttle between NICE, NHS England, clinicians, patient groups, and pharmaceutical companies. My job for NHS England is to get as many clinically cost-effective drugs into clinical practice in England and make the most of the three-million-pound sterling that we spend on cancer drugs. There aren’t many reasons these days to be proud of being an Englishman, but there are some things that make me happier in life in regard to healthcare. Firstly, the NHS, a universal healthcare system that caters to 92% of the population. We have the NHS, we have NICE. NICE assesses the clinical and cost effectiveness for new drug indications, and it tries to do this as close to the date of marketing authorisation, so it tries to be maximally relevant to the evidence. There’s a legally protected mandate that the NHS has to fund all NICE recommendations. This is very powerful because whether the NHS can afford it or not, it has to pay for all new NICE recommendations. So the regulator looks after the first three hurdles of efficacy, safety, and quality. NICE looks after the fourth hurdle of cost effectiveness. But, it’s the fifth hurdle that really matters to patients and to clinical practice – that’s all about access to treatment. I speak from a cancer point of view, so I’m bias for a start. One would hope that clinicians involved in patients care would know everything about the disease and everything about new treatments. They would get this from their journals, from going to conferences, discussions with colleagues, and even talking to pharmaceutical companies. We live in a very busy world of day-to-day clinical practice, and it’s difficult for clinicians to keep up with things. In the last five years, there have been almost 220 NICE positive recommendations for cancer drugs. So, how does the payer try to ensure clinicians know of the new availability of newly NICE recommended options. We could talk about that in more detail, but in essence it tries to land the information onto their desk and into their multi-disciplinary teams for them to debate. NICE has said yes to drug x, and disease y, in place z in the treatment pathway, and the NHS is fortunate in the way it’s structured, because all cancer drugs have to essentially be commissioned by the center of the NHS, they have to be electronically prescribed, but the big way of keeping an eye on what’s happening in clinical practice is that for the last five years, every new cancer drug indication requires a clinician to fill out a very quick form to signal to NHS England that they want drug x, for disease y, in place z in the treatment pathway, and their use is going to be in line with that NICE recommendation. So, by filling out that form we know exactly what is happening about treatment uptake in the NHS in cancer. This is very powerful information as you can imagine. For most cancer drugs, we see the same pattern. If the drug is regarded by clinicians and patients as making a clinically meaningful change to clinical outcomes in whatever disease, we see steady state use within three months of NICE saying yes. On the day NICE says yes, NHS England has to provide the funding, but within three months of that date we see steady state use. The key thing is that we see them at levels that other ones we predicted from our knowledge of patient numbers. I suspect we’ll take about this later on, but there are examples where uptake is slower. Whether that is new technology, new diagnostic, new support system, other impacts on healthcare etc… There are certain technologies, such as CAR-T therapies, where NHS England takes a very active role in managing the implementation given the resource requirements that extend well beyond the chemotherapy clinic. In some ways, in England, we are fortunate because we have one connected access – the license regulator, the HTA body of NICE, and a healthcare system which, in terms of access to new drug indications, is completely aligned with NICE. So, HTA has made a huge and vital impact to what the healthcare system delivers because it’s only delivering those drug indications that NICE thinks are clinically cost effective. One thing that I am sure of, given the funding pressures that the NHS is under, I am absolutely sure as an oncologist, that without NICE present in practice, particularly within the last five years where there has been this explosion of new cancer drugs coming through, the NHS would never have the access to cancer drugs that it currently enjoys. And of course, it would never be achieving the value for money that we get from those drug indications within the amount that we spend in England. 


Wija Oortwijn: I can’t speak on behalf of all Europe, but yes, I think of course cancer drugs are a particular type of drug, type of intervention that are highly regulated and carefully monitored in practice. We also have technologies that are not so well monitored in practice. So, actually we do not know the uptake of some of these technologies, and we also do not know the impacts of some of these uptakes, and also whether or not if there is a new technology that flows into the system whether or not the old technologies are still being used. I think HTA can play a role in that respect as well, so it’s not only about entry, it’s also about trying to see where practice variation exists and where potentially this investment could take place. I can give you an example of the Netherlands, we do not like to talk about this investment anymore, I think that’s highly debated nowadays. We talk about appropriate care, so what our HTA agency does, in close collaboration with our NIHR which is a healthcare funding organisation of health research, is they work also with the medical societies to identify the areas where there is potentially practice variation. Then they review the current benefit package, what is offered, and to identify areas that potentially could be disinvested in. I think that’s a very important aspect which has not yet been fully explored within the HTA community. We see more and more attention for this but still I think HTA in all the years we have been involved was mainly focusing on the entry, especially of new innovative highly priced drugs, and not so much the efficiency of the healthcare system as such. Also, for example in the Netherlands, HTA is only focusing on a tiny part of the healthcare budget because it’s only focusing mainly on drugs and some medical devices. The inefficiency in the system, which is mainly in long-term care for example, there has not been as much attention for those areas compared to drugs, and that is because of the regulation. The HTA system in the Netherlands, it is set in law, that every new drug has to be assessed through the HTA agency. I do not think that is the way to go. If you look at the question about priorities, I think we can have a huge debate where we should focus on our HTA system.


Carole Longson: There are so many aspects to this topic, every one of our sessions the topic has been multifaceted, this is definitely one of them. We already have two aspects to explore, the first taken from Peter’s commentary is how do you build an end-to-end system if I can put it that way, that works together to enable the introduction of useful and financially sustainable healthcare technologies into the system. That’s the first, I’ll touch on a couple comments on that. The second is, ‘is that the only thing that HTA should be looking at in healthcare systems overall?’ My view is the obvious answer to that second question is no, the problem is we have so much flooding in that it's almost impossible to not keep your eye on that. So, I think the policy challenge, or the dilemma, that both HTA agencies and healthcare systems have, is they have to keep a handle on those new things coming in, but how do you then balance that with both identifying and then building systems that focus on other important priorities within the healthcare system. I don’t think the HTA machine has really cracked that yet. It would be really good to explore how we do that. I’m going to come back to some of Peter’s points because he made so many rich comments and insights it would be quite good to unpick them. The first is in the way that he described in the sense the interaction between NICE as a HTA organisation and the machine that is the healthcare system overall, NHS England and then clinicians. My insight from that is just how important building that link is. For example, when NICE was first established, that realisation was just not there. Everyone thought, ‘NICE is here now, it’s going to issue some recommendations, they’re going to pop out at the end, and suddenly the healthcare system is going to change’. We were eighteen months, two years, three years into NICE pushing out evaluations and nothing was happening at all. It was at that time, again as Peter introduced this link between having the financial flows available to actually be able to implement recommendations. It was at that point that the government and the health minister said we’ve got to give NICE recommendations some weight, and this concept of the funding direction came into force, which is basically an obligation on healthcare systems to find the financial resources in order to be able to implement that HTA recommendation. There aren’t many jurisdictions that have that lever in place in such a fundamental way. I would suggest again, as Peter has indicated, that it’s one of the most pivotal points of the translation of HTA into practice. There is no point having a HTA machine that is spending a lot of resources, both time and money, if you haven’t got some docking station inside the healthcare system to be able to take them up. The docking station is not just about clinicians and patient pool, but it is about financial flow, so that is the first thing. The second, again something that Peter has highlighted, there is an information and the intelligence system inside NHS England which has the data available to be able to understand whether or not implementation is taking place. Again, that is something that wasn’t there at the beginning, and absolute credit to Peter and others, who realised that in order to be able to effectively implement, you have got to have the information flows coming back, and possibly you have to have a few sticks in the system, so Peter’s mentioned that clinicians have to fill out a form in order to be able to prescribe, which then sets out the information flow, and until you do that you cannot get access to the drug that NICE has recommended. All of that, works now as a seamless and rather intelligent machine that is going from the HTA, into the system, into clinicians’ hands, and then back into analytics and into NHS England that demonstrates what is going on. So, you can see how much effort it takes to translate HTA into practice, and we’re only talking about cancer and of course cancer does have special and sometimes rather unique attention. Those learnings that Peter has highlighted and that we’re now talking about in cancer, don’t need to apply just to cancer, but you do need to have those types of infrastructures in place. I would suggest provocative there is no point in a HTA system unless a healthcare system is committed to doing something with its outputs. Otherwise, you literally have a wasted and inefficient process. We’ll come onto disinvestment I’m sure, but it’ll be really interesting to hear what Eric has got to say about that connected system, and other things. 


Eric Low: I’m all for connected systems, so I think like you Carole there are so many things and so many angles to come at this, it’s almost impossible to do everything justice so I’ll try to be succinct and just make a few points. First point is that in a very chaotic world, HTA does generally a spectacular job, NICE specifically and HTA generally do a very good job in a very chaotic and imperfect system. Second thing is that we definitely need to move to a systems approach. We have to stop working in silos and we’ve got to figure out how to get the drivers, incentives and rewards across the multiple stakeholders in the system much more aligned. We have got to create a demand side, so we’ve got to get better at signalling to suppliers what the health system needs and what patient needs, what research questions need to be addressed? So, we get more of the things that we need. I know HTA talks about life cycle management, it’s something we’ve been talking about for 15, even 20 years, this notion that HTA sits equidistant from demand and supply and is better placed than any other stakeholder to look upstream to supply, to look downstream to demand, and to connect the two up – much more than we are doing at the moment. I think what concerns me a little bit is if we talk about cancer, and I know the world doesn’t revolve around cancer, is that we rely on regulatory data sets. So regulatory trials are designed to answer regulatory questions. Most often, questions that the FDA are interested in and the US market are respective too. They are not designed to answer questions that patients, clinicians, health systems are interested in. Almost no proper pragmatic clinically relevant and plausible research questions are answered in regulatory trials, and yet the three billion pounds that Peter is talking about is spent commissioning what essentially flawed data from a health systems perspective is, with some exceptions. So the challenge that HTA has in that translation into practice, is how do we move beyond consequential pathways. There is just a torrent of stuff that comes at us, and somehow we have to figure out how to get it to patients. What that means is that we often have consequential pathways, which means that Peter and others must find shoehorn things in the system, rather than state of the art. The risk of this is that the health system, while it is managing its budget, it still buys costs more than it buys outcomes because we are not optimising the potential of the innovation because it is not coming through in future proof, clinically relevant ways. So I think what the next part of this translation into practice, we’ve got to figure out what the next step is beyond NICE, so we can start to shape intelligent, agile, thoughtful, responsive, and more personalised clinical pathways that save money but delivers more outcome, and puts a little bit more agility in the system to reflect the heterogeneity of real world patients versus those that were entered into clinical trials 10 years prior to satisfy the needs of the FDA. 


Leeza Osipenko: From my personal opinion this dynamic does not work very well, because very little has been generated in clinical practice, or has been generated too late, because no one is doing those relevant trials. With Cancer Drugs Fund, we pushed for it, so another push for this dynamic to get this system breathing rather than being static decision implementation. 


Wija Oortwijn: I was thinking along the same lines what you just said about dynamics, and I have a question for Peter because I agree with Eric that we are focusing very much on a linear process, and we are not thinking very well about what do we want to achieve with whom, and how, and why. So, I think this more agile, more dynamic process of what we want for a system, what do we want to achieve with a healthcare system? That brings me back to the question to Eric because I agree that HTA can be a kind of broker between the demand and the supply side, but we don’t have the mandate to do this. So, who is giving us the mandate to be the broker because we are pushed around? So, it is the systems approach, but if the system does not give the mandate or the responsibilities to those that could potentially act as a kind of broker, I think nothing will change. 

Peter Clark: It’s very difficult because the politics of new drugs means that there is this whopping demand for the latest cancer drug, the latest multiple sclerosis drug, cystic fibrosis drug. So, the point made about pathways, of course with cancer is the most fantastic example of that, because of course drugs are now being licensed nearly always, not quite always but on progression-free survival so you don’t know the effect on overall survival. The problem with treatment pathways is that they’re now getting so complex that you’ve got potentially third, fourth, and sometimes even fifth line treatments. If you want to do a really good job, of course you want to look at the whole pathway. All that’s undermined by the fact that things are changing so quickly. Myeloma is an example, there would be two new classes of myeloma drugs coming out, both look very exciting this year, and of course by the time you have evaluated their position at one place in the treatment pathway, they’ve jumped to the next, you know their license brackets, political imperative has now moved that drug earlier on. So, I think doing all this properly is incredibly difficult, particularly in a disease like cancer where things are changing so quickly, what makes it even more difficult, and I understand why NICE and I’m sure most people are familiar with the fact that NICE these days what’s called the single technology appraisal process. So it is literally drug x, in disease y, in place z in the treatment pathway is coming up for its license, we will appraise in that spot in the treatment pathway and model like hell what happens afterwards. That, of course, doesn’t lend itself to the more holistic approach to say we’ve got several drugs now coming in the third line space in myeloma, whatever it is, let’s appraise them all together. But of course, drugs aren’t like buses where they come along in threes, they come along in their own time scale. As soon as anyone, imagine NICE, says we’re going to put all three drugs together and delay appraisal for a year, there’s this outcry from patient groups saying we want access. So, it is very difficult when drug discovery is happening so quickly, when the politics of healthcare is paramount, for this systems approach to work. I’ll finish by saying, for the last five years NICE has had the option when it has key clinical uncertainties to the effectiveness of cancer drugs, to temporarily say yes while two things happen. A) the clinical trial data matures, B) there is real world use. So, there’s now some really fascinating examples of real-world use, where, as expected, the outcomes are far less good in the real world than they are in the clinical trial. But there are some examples where the outcomes are matched in the real world, in the clinical trial, generally because of reasons for selection. What makes NICE’s job even more difficult, when they’ve got more matured data available and there is real world evidence, is that the treatment pathways have changed in the time it's been in the Cancer Drugs Fund because two or three new drugs have come into the treatment pathways. I’m afraid I cannot offer a solution because NICE is barely able to cope with all these new indications coming in, I don’t think it has got the time to do the difficult whole pathway approach. Even if it does that, it is likely to be out of date by the time it has finished it, that’s the problem.


Eric Low: I think that’s why for me, we need to be thinking about this conceptually. Hypothetically, what would this whole disease model pathway look like, and what elements of it could be implemented. I guess I’m too optimistic about it but my dream would be that over time these pathways become the norm, and the system would change and supply would change in response to the demand these pathways created. Again, let’s not keep talking about myeloma, but I think it’s a good example of the craziness, one of the things when you think of a whole pathway model, is it tells you what you need, it tells you where your evidence gap is, it tells you what mechanism, what triplet, what you need, and it helps the system better make a value judgement in what’s coming through the system and we can signal, albeit just from one market, to supply to say, ‘look guys, don’t bring us another imid, another pi, another whatever, bring us this and if you bring this and we slot it in here, you’ll get paid sort of handsomely.’ So, all of that is hypothetical, but these principles if we could somehow start to put some of these principles into the real world, I think it would make a massive, massive difference. 

Carole Longson: Just going to pickup on a couple of things, one from Eric and one from Peter. They’re both sort of on the theme of can you bundle everything together and does it help when we do it. My bottom line is no it doesn’t. From many, many years of experience of multiple technology appraisals, you’d think that would be a really good way, you’ve got five or six new drugs in a similar class, let’s take a look at them all together, then let’s try to do one of two things – see if we can rank them in terms of clinical effectiveness, and see if we can as a consequence of that, sequence them in terms of giving some steer to the clinical community about how to use them. The problem is it comes back to the evidence, there’s never and there really is never, the evidence to be able to do that thoroughly. So what NICE ends up doing is saying, ‘well they all look pretty similar in effectiveness’, what it’s all about is the money, so if you’re thinking about it choose the one with the lowest acquisition cost, or NHS England go and do a deal perhaps. Dare I say it heretically, even therapeutic tendering under those circumstances may be quite a useful budgetary mechanism. So, you can see the issues on how does a HTA organisation actually give an effective and useful steer to a healthcare system? As soon as you start to layer on the complexity of the system itself, you start to make it pretty obvious that a purist HTA approach probably isn’t going to help particularly. Then it comes back to we’re all grounded in a HTA approach, and we’re probably not spending too much time, as Eric keeps pushing us, to think completely differently about how to solve this problem. I’ll give you one example, it’s not an example from the HTA world, it’s actually an example from the regulatory world. Some of you that in this discussion have been around when the EMA back a few years ago introduced this concept of adaptive pathways and adaptive licensing. The lovely Hans-Georg Eichler had to, what I thought was a really creative idea from a regulator, which is not that we’re going to lower our bar of evidence requirement, but we’re going to build a regulatory system such that the evidence collection for what the real-life therapeutic effect of a new drug is established post-initial regulatory approval, but still being monitored by the regulator. So, it’s a little bit like what we’ve developed in terms of managed access, managed entry, and HTA – but in a regulatory environment. And then as that data is collected, you refine the label according to the data that’s being gathered. That concept went down like a lead balloon, both in the regulatory environment, and I have to say the industrial environment. But, it wasn’t seen as sufficiently either robust or meaningful in terms of the magic moment of regulation. For the community to be able to take it and start thinking about how you could do that, and it was I think a moment lost because we had a significant regulator thinking very differently about the way they regulate things. Now, that has actually translated post Brexit into the MHRA way of thinking, so we’re still on and I’m sure the EMEA is also thinking about that and we have the FDA, but nobody is thinking about it in a systems perspective as Eric has said. Everybody is thinking about it, still certainly from a regulatory perspective, they’re back in their regulatory box. I wonder, whether or not, there is either an ability or a willingness to actually tear up the entire sheet of paper that we’ve currently got and think about how you would design a system, now with all of the knowledge we have in HTA, in regulation, in clinical practice, in patient perspectives, being able to frame all of that evidence that we collect, and design something very different from the way we’ve got it now, that still allows HTA people to do their job, still allows regulators to do their job, still has the healthcare system having to be engaged with implementation, but does it from a completely different place. Maybe that’s what we need. 


Eric Low: Maybe I’m too negative about a lot of this stuff, but when I think about adaptive pathways, IDAP, ILAB, CDF, IFM – all that stuff, some people herald this as innovation and the great things since sliced bread and electricity, I see it as evidence of failure, because we need this stuff because we’re not doing the right research and we’re not generating the right evidence so we create all these fandangled acronyms to try and deal with it and address it and to me the message that gives suppliers is keep bringing this stuff and we’ll come up with another acronym at some point, we’ll abandon and we’ll find a way to get your inappropriate data to patients. Why don’t we focus on, ‘let’s figure out what is the research question or questions that need to be addressed, how much of that can be achieved in a regulatory study versus a hybrid complementary or de-risking study that’s run in parallel,’ so we start to generate the evidence at the right time, for the right decision gate, for the right decision maker, rather than trying to say, ‘keep bringing sub-optimal stuff and we’ll find a way at some point to get it to patients by buying off or addressing the uncertainty and the risk.’ It doesn’t make any sense. For those of you who listen to me, the Myeloma UK clinical trial network back in the day, 2007 it was setup and was designed to address and de-risk the system by generating an NHS facing trial to de-risk the regulatory study. And I think just something as simple as that, even just within the UK perspective, MHRA and NCRI and all these clinical clinician-led study groups got their act together, did horizon scanning, engaged with the system and designed academic studies to de-risk pharmaceutical research – that in itself would make a massive difference. 


Carole Longson: I’m going to come in here because I want to join the topic of today’s talk with what Eric has just said. In order for that to happen, healthcare systems absolutely have to be engaged in this in a really meaningful way. When I say healthcare systems, I mean the everyday process of delivering healthcare, because unless you have the practice element engaged, you won’t be able to achieve the type of thinking that Eric is putting forward, and I think that’s another disconnect that we don’t talk about very often. We do have in the UK NIHR, we have massive amount of research going on, but is it really joined up with what we’re talking about? 


Eric Low: Not at all, there is no commissioning pathway. And Peter, sorry but there is no commissioning pathway for academic research. It is completely disconnected to commissioning. There’s some exceptions and some stuff around the edges, but the vast majority of cancer trials that are funded in the UK make no contribution whatsoever to solving the problem we’re discussing. 


Peter Clark: So yes, I agree with Eric, it is disappointing that the NHS, with all its expenditure, has all its budgets in the cliché of silos and that it can’t say, ‘well look, let’s spend a little bit of our drug budget to see if we can make outcomes better, and then perhaps of course save some money at the same time.’ I’m the first to say that. The biggest thing for me though is are there questions that are that big enough that can be addressed using the NHS, that clinicians, patients, whoever else, can agree on to say that is such an important issue for us to address now without the danger of putting all that effort in and the results, not being made redundant, but being made less relevant in the years to come. So, I need examples if you like, from Eric, to shake the scales off my eyes because I spend my whole life dealing with clinicians – they will agree on some things, certainly they’ll agree more on standard clinical practice, rather than what is the burning issue in this disease or that disease, in terms of a pragmatic trial of the kind that Eric has described. So, yes I agree the challenge is there to get the money to do it, because it should be there and as Eric knowns, in England the NHS has been talking to the NHIR for a long time about doing this, about having that separate funding stream, but I think that funding stream is there but it’s very modest. Clearly Eric’s scale is a much bigger one. So, does Eric think there is sufficient clinical agreement in a wide variety of important diseases, for such trials, to actually be used and the NHS harnessed in that way? 


Eric Low: It’s a good point Peter, short answer is yes, I think there is. I aged dramatically trying to do it in myeloma, but just one simple thing, because I know Wija has been very patient. If you want to herd cats, move the food. I think that clinicians will ultimately follow the incentive of where they get their research funding. They will do what they need to do to get the research funding. Right now they get funded to do crazy things. If we change the incentive, and we reward them and incentivise them to do proper, pragmatic trials that could be commissioned or contribute to de-risking a pharmaceutical dataset for NICE, then I have no doubt that we would get them there. But it would be a challenge, but we could do it. 


Wija Oortwijn: Well, I just wanted to react with an example because we are of course focusing on the NHS, but like I said at the beginning, in the Netherlands we try to work. The ministry of health has a kind of coalition or agreement with our medical society so with their association. So, all the medical societies are in one association, and they have an agreement, because we have a zero-growth budget line, a fixed budget in that sense. They have an agreement between the department of health, ministry of health, the association of medical societies, our HTA agency who is also the payer, our NIHR, for research patient organisations are involved as well, not industry. They have agreed to come up with the agenda for health research, HTA related research, to optimise our healthcare system. They, together, set the agenda, and that is what I tried to bring across – you have to think about what you want to achieve jointly with all the stakeholders together, and then you can decide or define the priorities, and of course this is not perfect but at least it’s a kind of way of system thinking with all the important players around the table and they link it also to the benefit package because if, for example, something is not a priority, then you can also see whether or not you would like to invest in these investment studies as well to see, for example, appropriate care practice variation, how can we optimise this? So, it’s all linked, and HTA is just a tiny part of that because a lot of health services research is related to that as well. So, I think this system approach is not only about HTA, but also about health systems research, health services research as well. Just to give you some inspiration that something is going on outside of the UK. 


Leeza Osipenko: Excellent that sounds very promising and I very much agree with Carole that we have 20 years of experience now, that we learned from. We saw the mistakes, we saw what works, going back to the drawing board, not just in the UK but many other countries that use HTA. How we can now make things better would be great. The question is, who should be doing this? Would that be the department of health whose responsibility it is. My other question for all panellists, the example Wija gave us is very important, I think every country should have this priority setting in the UK has it to an extent, but if we look at the concept of HTA, what Eric is saying is that we’re missing these trials. For example, we’re missing many comparative trials, in many fields, a lot of times the pharmaceutical rules will purposefully not run these trials and we can run them in the healthcare system to really setup league tables of what we can use or how we can price these drugs. We’re still talking within the concept of a specific country making a decision and when it comes to the trials that Eric proposes, or when it comes to the system for example that Wija is describing. If it concerns very specific issues within that healthcare that’s one view. But most of these questions are all of interest to many countries, at least across the European continent and it might be useful to the US, it might be useful to Australia, it might be useful to developed world. How can we join efforts? How can we ensure we don’t make Italian healthcare system run one trial, the NHS run another trial? These are huge resources, plus running such a trial might have problems with recruitment. Can we make them intercontinental, academic, and purposeful research? Or, that you see risks in this, or you think it won’t work. How can this be funded? Maybe talking about the EU is easier, but not the UK. So, from an efficiency point of view, if we joint efforts, we could have addressed many more questions and used more results. I think, especially with a managed access agreement, data might be generated that Eric refers to through some of these managed access agreements, but A) it is kept secret, it is not being shared, and it’s used only for the decision maker in that particular setting. However, the data that is generated, unless it is extremely specific for that population, in that country, which in cancer I highly doubt, we don’t benefit from this research. So, what can we do from being a bit more collaborative? 


Eric Low: I think these are all important points, and I’ll make two quick points. One being that patient advocacy needs to get its act together, because research doesn’t happen without patients. Right now, patients are going into research studies that aren’t even ethical, because it’s not about how future patients benefit from the results of research. Half of academic research isn’t even published. Most academic research doesn’t change clinical practice. So, patient advocacy needs to stop banging on the door of NICE and HTA bodies saying you’re the bad guy, and focus in on academic and commercial research, and start to get these guys to up their game. Being more collaborative, being more efficient, being more pragmatic, and answer the questions that are important to downstream decision makers, because trials are happening all of the time, we spend gazillions in investigating studies. In the UK, the association of medical research charity members spend about £1.5 billion a year on research, very little of that shows up in a NICE submission. So, it's being done anyway, and I would argue we need less research, less money spent, and actually let’s focus on quality and the right research to get done. I think patients need to figure out how they can start to advocate within government, within industry, within academia, to ask for this change. 


QUESTION (Lydie): My understanding from outside is that NICE is fully focused on cost effectiveness, while I think it’s very important that we de-couple the question about putting value from the cost effectiveness. That is exactly what now is happening in Europe with eunethta 21 where the clinical benefit will be evaluated at the European level, but the cost effectiveness will remain at the national level. I think this is really two different questions, and I think it’s a good thing that it’s de-coupled, because that brings me to Eric’s comment that I fully agree with, is that today what NICE is also doing is only looking at the regulatory dataset, means regulatory endpoints. This is not what patients want to see, what HTA wants to see. I think we can all agree, and we’ve learned from Ian Tannock also in cancer, of course this is difficult for cancer, we want to see data on overall survival and on quality of life. As a patient representative with EMEA, I can tell you that quality of life is even not discussed with the regulator. They only talk about safety, which for me is different from quality of life. This is a side remark, so let’s stick to the whole idea that now at least EMEA also has the intention that, as was said, the clinical trials should also answer the research question for the downstream stakeholders being HTA and patients. So, what is the possible solution. It’s a dream maybe, but people are starting to think along these lines, is that scientific advice should have input from HTA so that the clinical trials that are designed for regulatory questions should also answer at the same time and not in a later stage, the questions from the HTA. That is one way of thinking, but then of course scientific advice has to become mandatory, and most importantly the big difference with the system in the US, that today EMEA cannot approve the registration trials. This is not in the legal system today, and that’s a really major difference with the FDA system I think, so there we need to change. Maybe that can happen with the pharmaceutical legislation that can be revised, so let’s hope we get some changes there, and I also want to make a comment on what has been said about lifecycle management, and the endpoints that today in cancer it’s even not progression-free survival. I’ve looked at approvals from last year and almost half of them are even on response rate, which is not really a very solid endpoint. So, why don’t we think about more conditional approvals, and then follow up and see if the real endpoints are met later on and then have a reassessment once there are more data available. I know it’s all theoretical, and it’s difficult to implement, but at least I think this could be a way of going forward and really bringing those products with added therapeutic value for patients in the system. 


Carole Longson: So Lydie you make some really important points, and a few observations about NICE’s processes and methods. Just for clarity, there is absolutely no cost effectiveness assessment without having first established relative incremental benefits. So, whilst NICE does it all in one, it has to go through the sequence of knowing how much better this new drug works compared to what’s in established practice. It’s just the way that NICE processes work, you don’t see that distinction between relative incremental benefit and value for money as two separate steps, it’s all combined in one thing, but they absolutely have to do it. That’s one of the problems it gets into, because as you said what everyone sees at the moment is the registration study, that’s all that is available when many HTA organisations have to do their job, particularly when NICE has to do its job alongside that regulatory review because it wants to provide an access signal as close to a drug being on the market as possible. So, that’s all there is and that’s what the issue is, how do we do design a process that either allows us to collect data robustly and quickly and efficiently on the final endpoints: overall survival, health related quality of life, earlier than we do now. I think that moment has passed because the regulators aren’t going to go back to their previous way of thinking of not allowing these surrogates to come through and being used for the actual registration approval. So, how do we design a system that allows drugs to be used once a regulator has made a judgement, we can’t deny that that’s their job and that’s what they’re there to do. But allows us to both monitor the performance of the new drug, in real life, and do that in a way that feeds back efficiently and effectively into a HTA process in real time. That’s what we’ve attempted to do in the cancer drugs fund, that’s the point of it. Is it working sufficiently well enough? I’m going to ask Peter to give his view on are we actually achieving what we set out to do? And how do we engineer a whole system that allows us to work with the regulators and with patients and with clinicians, so that we do what Eric said, which is collect the data we know we need, and not the data we don’t need in order to inform two things – better decisions, downstream and definitely better discussions about value for money downstream.


Peter Clark: So, in the last five years, there have been about fifty odd drug indications go into the cancer drug fund. Just to emphasise that a drug goes in when the NICE committee has a) a plausible ISO on the table at the time that it appraises the drug but has key clinical uncertainties that would hopefully be addressed with the passage of time. Frequently, that is waiting for the relevant registration phase three trial to mature, generally because there is uncertainty about the overall survival estimates. As Lydie has mentioned, there are significant numbers of drugs that are showing great promise, certainly in terms of response rates, and being licensed on small single arm studies. The great majority of those drugs that have come to NICE over the last five years have ended up in the cancer drug fund. More than fifty have gone in, just over twenty have come out, all but one has gone into what we call routine commissioning, meaning NICE has delivered a final yes. I’m not sure that many of the clinical uncertainties were indeed answered by the time in the cancer drug fund. To a certain extent they may have been when you had three- or four-year overall survival data. But I think those indications that had been licensed on small single arm studies, those have been greatly helped by real world evidence, because the might of a single healthcare system with 55 million people in it, means that you can get a lot of data quite quickly, and the data that we collect is relatively crude. So, is this a clinical trial data set? Absolutely not. But we’re getting data retrieval of 98%, 99% of treatment duration and overall survival. Certainly those indications that have left or come back to NICE reappraisal that have been licensed on small phase 2 datasets, the great numbers that the NHS has been able to deliver has allowed two things, a) one thing is the company the confidence to model clinical benefit on the real world datasets, and that’s a real triumph because we all know that the real world is often a very different world to the clinical trial population, but also has allowed those drugs to be considered to be cost effective. What I’m not allowed to tell you is what price they came at originally, what price they went into the cancer drug fund, and what price they went into routine commissioning. But, all I will say is, was I alarmed at the final decision for every single one of those in terms of the price consequences, the answer is no I wasn’t. I think what has been learnt is that you can get good data, you can resolve certain uncertainties, it’s often the comparator uncertainties that aren’t resolved of course by the cancer drug fund use. Of course patients have had temporary access but, and this is where I pay tribute to the pharmaceutical companies, they have recognised the power of the single market, and of getting their drug into routine commissioning so it’s there for as long as it isn’t supplanted by someone else. And of course, they have priced their drugs accordingly. It’s been a success for patients, it’s been a success for NICE, it’s been a success for NHS England, and whilst pharma will moan and groan, most of them will regard it as being a success and that’s measured by the fact that of the first twenty that have come out, only one of them has actually failed to make it from the cancer drug fund into a permanent place. So, is this a model that we think works? The answer is yes, I’m the first to say I’m biased because I’ve had a lot to do with how it works, but in a healthcare system and in a country that isn’t awash with cash, the NHS has of course gone beyond cancer drugs to produce a fund now that is going to be for non-cancer drugs because it sees the model as having worked. As I said, just coming back to real world outcomes, NICE committees have been struck by what they see. In some situations, a very big difference between clinical trials and real world outcomes which I don’t think is a surprise, but have they taken that into consideration of clinical and cost-effectiveness, and the answer is of course they have, because they want to make the best decisions possible on the best set of data, but primarily they want to remain relevant to clinical practice. They have been struck too by those indications where, for a number of reasons, clinical trial outcomes have certainly been matched by those achieved by those in the NHS, so is it a model that NHS England is happy with? Yes. Is it a model that NICE is happy with? Yes. Is it a model that pharma is happy with? And I think this is the interesting question. Because on one hand they get their drug into clinical practice, and we know that getting your drug into play is so important when there are so many drugs from the same class or potentially getting licensed. But I think, I would imagine there would be some caution with some pharmaceutical companies in disease pathways that are changing very quickly. Because if it’s changing very quickly, it’s possible that by the time you’ve got some data mature or new data from real world evidence, the clinical pathway may have changed, and the drug may be rather less relevant than you thought 2 or 3 years before. So, in short Carole I think it works for most people and most stakeholders at present. 


Leeza Osipenko: A challenging question in the chat, ‘do you think real world evidence data collection can resolve the disinvestment issues?’ 


Peter Clark: I would hope so because as I think you mentioned Leeza, there is a built in NICE review timetable so that it is so routinely for every indication that NICE says yes to, correct me if I’m wrong Carole, but every three years NICE ask the question should we have a look at this again? Particularly for that, if adaptive licensing does ever see the light of day in any meaningful way, of course that would be the perfect time to look at it, both from the regulatory point of view, let alone from the HTA assessment point of view. My worry about all this is that the investment in molecular research, cancer or non-cancer, is now paying huge dividends in an ever bewildering variety of new mechanisms of action for drugs and new drugs, new combinations of drugs, so my worry is whether NICE actually would ever be able to have the capacity to cope with all those new drugs, because they can’t ignore them for a variety of reasons, the pathway issues let alone reviews of the basic question, did the drug actually deliver what it said on the packet?


Leeza Osipenko: In the chat Francois raised an interesting point, in terms of incentives, what kinds of incentives a pharmaceutical company has, what kind of incentives a healthcare system may have. For example, the healthcare system may say we are very interested in disinvesting just to make sure we don’t use obsolete technologies and to save money, but even if they have that incentive, do they have resources, do they have capacity. So, how do you see incentives playing in here on that?


Carole Longson: I’ll answer Francois’ point in a minute, but just on this investment first. We probably need an entire seminar on disinvestment because we’ve hogged the show with the introduction of new technologies into clinical practice. But a couple of things on disinvestment, and again just from my perspective of NICE over the years. We’ve spent quite a bit of attention on disinvestment, never quite cracked it, never quite achieved the goals perhaps and the aspirations of other. But that wasn’t because necessarily it didn’t explore things very thoroughly, but two things kept coming back in almost sort of a loop. It’s actually very difficult to identify a technology where wholesale it’s of no use. It’s usually about finding the best place to use a technology, which is also usually far less perhaps than is currently being done. So, over the years, NICE turned the phrase disinvestment into optimisation, and I think you’ve also had the similar experience in the Netherlands, it’s about finding the best place for the use of a technology in the main. There are some over the years, NICE had two or three goals programmes, disinvestment programmes, and all of it came back to clinicians not really being able to either agree on what topics would be useful to look at for disinvestment, because they all had their views on which particular patient might be useful to apply this technology to, and to then when you start to look at the evidence, you usually do find some effect somewhere. So, it’s a really interesting topic, and I think again, as HTA organisations, there’s probably a lot that we can explore from the perspective of different HTA organisations on the disinvestment topic. To Francois point, about there’s no incentive for companies, that probably is the case now because we have a regulatory system that is, I wouldn’t say embracing, but certainly accepting the use of intermediate and surrogate endpoints, as proxy for benefits. We are where we are with that. What we’ve done, and I think with something like a conditional approval in the HTA sense, and especially in a jurisdiction that looks at both clinical and cost-effectiveness, is that you can use the uncertainty that’s generated through the use of non-final endpoints and use that in a discussion about price. I think that’s quite a useful mechanism for turning what is sometimes a very negative thing, which is not having the real endpoints of interest, into something that’s useful for a healthcare system that always struggles with financial sustainability. So, I see it as a little bit more half full than you might do Francois. 


Leeza Osipenko: The comment that Peter made in the beginning, praising the fact that we have HTA and that it actually, at least within the NHS, enables access to very important drugs for the patients in England and Wales. I very much agree with the point that if we imagine the world without HTA there would be a lot of questions about lobbying, corruption, pricing, how and who made these decisions, at least we can show the paper and say that’s why, that’s how we did it. And then of course all the issues can come up whether the data was what we wanted it to be, but at least we have a very transparent process and justified decisions, and I think the value of that for translation into practice has been tremendous. But then, we spent an hour and a half discussing how HTA has so much to go, whether its HTA in order to actually have in the practice the goals that the society would like to resolve, that the system would like to achieve. We seem to be somewhat far away from HTA actually fulfilling all of these needs. I invite the four of you to give a one-minute summary on where you think we are now, do you think we’ve done a good job to date? Just a brief sentence, one wish you would like to make to improve things.  


Eric Low: Short answer is that I think HTA generally has done a great job in a very difficult, chaotic world. My hope is that, Peter made a very compelling case for CDF, I would contest though that we need to move that concept earlier into running that de-risking, that real world evidence generation, in parallel to the regulatory study. It is not that difficult to predict what the uncertainties are going to be based on a regulatory trial design. So, the things that come up at appraisal that lead to the need for this CDF, you can pick them up much earlier on and that’s where the opportunity is, to actually generate that real world evidence as Lydie and others have said, in parallel, in hybrids, in a complementary way to the regulatory study, and from that point onwards, everything becomes hopefully slightly easier, and the incentive for pharma is that the price they’re going to get from NHS England, in that process is going to be a whole lot higher than the price they’re going to get in a CDF when they’re trying to get this real world evidence that’s quite crude to change and address the uncertainties. That’s their incentive. That’s my hope.


Wija Oortwijn: I also think that HTA is great, where would we be without HTA? But, I rather like to focus not only on the influx of new technologies, I rather would like HTA to focus more on the sustainability of healthcare systems and I think there is a lot to gain there as well and of course it all depends on the resources that will become available for HTA but I think maybe we could even have more efficient systems if we focus less on the influx and more on what we already have and how to optimise the current systems. Involving of course all stakeholders. 


Carole Longson: We owe a lot to HTA, I personally owe a tremendous amount to HTA, it’s been most of my working life and it’s been both fascinating and rewarding but I do feel that in order to achieve what Eric has described, we probably do need to tear up a few current regulatory and HTA processes and clinical development processes and start with a slightly cleaner sheet of paper than we were anticipating now. 


Peter Clark: The bonus of having the payer act as part of directly involved in the HTA process cannot be underestimated, for all sorts of reasons because it allows the HTA process and the payers views to meet around the same table. It is incredibly important, and I think that’s been one of the great bonuses of what’s happened, particularly in cancer drugs in the last few years in England. The second thing is, this whole topic was about translation into practice. If you don’t collect the data as to what’s happening, you don’t know. So, we’re fortunate in cancer in England, whereby we do have systems where we do know how many people start treatment, and we do have information systems that allow us to collect albeit crude but important data as to actually what happens in the real world and those two things I think are terribly important if you’re ever going to know the answer to what happens to HTA guidance once it leaves NICE and leaves whatever body in an email attachment. What matters is what happens on the ground.