 Well, I would like to welcome you all. So as I was saying, we're going to start with this session on NPE Diaglose. And as I was explaining here, there has been a lot of changes, great things happening in the space of myeloma. But as you know, there are still a lot of challenges out there. We haven't focused yet on access issues across different countries in order to access to treatment. Also, there are issues related with some studies that are still showing that between 10% and 20% of the patients who are diagnosed with dialloma dies within 60 days from the diagnosis. Basically, there is still a certain lack of knowledge and awareness between the general practitioners community and some other issues in accessing to diagnosis in the myeloma. And well, to discuss of all these opportunities that we have now in order to win the battle against myeloma and also about the challenges that we are facing, we have five people who are accompanying us and they're going to introduce you to yourselves. So here on my left, we have Dr. Alberto Rial from the Maltogi Department of the Institute Catalana de Oncologia in Barcelona. Welcome. Also a very familiar face to you, which is Sofia Sacardoso, former director of the Portuguese Association against leukemia and could be a very active patient advocate at the European level. I said former because, yeah, right now she's basically doing advocacy at the European level. Also a very familiar face to you from many of you, which is Susana Leto, is a former head of patient advocacy in Novartis Oncology Europe, which is going to represent the industry point of view. Then Beatriz Flores, which is the expert medical assessor from the Medicis and Healthcare Product Regulatory Agency in the UK and also involved, of course, in the European Medicis Agency, which is going to give you the view from the regulatory side. And finally, Dr. Jaime Espin, PhD professor in the Andalusian School of Public Health, also a collaborator with the European Commission in Sandestad is about pricing and reimbursement and also a collaborator of the World Health Organization in the Global Pricing Initiative, which is going to give us a little bit more about the payer perspective. So before starting and opening the discussion to you, I would like to make an introductory question to each of you, and then please feel free to participate, to discuss, and debate, and give us your view. So I would like to start with you, Dr. Oriol. So as we were discussing here, it has been great with us happening in myeloma over the last years. You have witnessing new drugs coming, better understanding of the biology of myeloma and so on. And right now, from your perspective as a clinician and also involved in some clinical trials as a primary investigator, what is your view about how are we now in myeloma, and what are the challenges for the future? And also, I would like to know your opinion about this topic which seems to be arising. Are we right now heading accused to myeloma? Are we still trying to chronify the disease? What is your view about this? Well, from my point of view, we've been leaving a couple of important changes in the treatment of myeloma. The first one is, of course, we have new drugs. But maybe the big change now is another one, which is how to better use these drugs. In a sense, we have had Thalidomide, Helinodomide, Portesomib, Carthiusomib coming on. And we have introduced them given the concept that myeloma was not curable. So we've been sequencing the drugs. We've been using one after the other one just to treat relapse because we assume that relapse was inevitable. So we always try to kept drugs for a later stage. We always try to take the maximum of each drug before changing to another one. And that's been more or less what's been happening in the last 10 years with all the new drugs and all the new chances to treat relapse, mainly. The big change now is that we are coming to realize that we can use these drugs better, combining them all together from the beginning. And that means that instead of having an improvement of survival that we had, consisting of doing several treatments for several relapses and going, which is not particularly good for the quality of life in the end, because when you've relapsed several times, the quality of life starts to deteriorate very rapidly. Maybe if we just used all the good drugs at the same time, we could probably cure some patients. That's clearly possible. But even if we are not curing, instead of having several responses to treatment, we can have a long one, which in terms of quality of life is much better. This poses several challenges, of course. That means that we have, from the point of view of the patients, we have to see if that represents really an improvement in quality of life, because all these drugs may be toxic. Maybe toxic in the long run is difficult to tell a patient that's been well for 10 years to continue with treatment, because we are not only doing more intensive treatments, but we are doing more prolonged treatments. So that's an important challenge. It's a challenge for us also, because that means that we have to do clinical trials to prove that this is a real improvement. And these trials are lasting several years, because you don't see the benefit in only two or three years. And it poses challenges also to the systems, because it means that you are using lots of drugs for a long time, which are very expensive. So it's not the problem only for, I'd say, Pakistan. Or Angola, it's a problem for Germany or United States or Japan, how to just reinforce these drugs. That's more or less a summary of it. OK, thank you very much, Dr. Oriol. So now I would like to ask Sophia, because you have been involved for about a decade. Now in advocacy, you have had the opportunity to work both at National, but also at the European meeting many patients and having a lot of experiences. And as you all know, myeloma is a disease which not only impacts on, let's say, the physical side, but also has another impact on patients from what is called the psychosocial sphere. So from your perspective, right now that we are having patients that are living longer, but at the same time are starting to have more needs, what are the main points or the main things that you think are impacting more the well-being and the quality of life of patients and caregivers? That's an excellent question, Alfonso. I thought you were going to ask me about access, because that's always the main challenge that's great to ask. What about the challenge? Yeah, we still have a lot of time. That's very good. Well, I would divide between the younger patients and the older patients. Although in terms of follow-up and the follow-up phase, the cares are the same. There are different impacts and what concerns the younger patients. And I'm talking not only about the patients, but also the caregivers. And I want to point out, now that you're talking about this, about the younger patients, an issue that really concerns me a lot, which is the reintegration in the marketplace. Because after being cured or after being able to return to work, they need to go to work but slowly. And in many countries, including Portugal, there's not a special legislation or protection for these patients that allow them to return to work. So what happens is that this patient, which is capable and it's an economical value for the country, can't reenter the marketplace gradually. And it will happen that we will have to return home after a month or two. Or sometimes it has an employer, which is understandable and kind enough to understand the situation and let him manage that. But most of the times, he'll just lose his job. And this is so stupid because there are other diseases, chronic diseases, like in fact, like diabetes or others, that allowed people to have homeworking for twice a week. But like cancer is not considered a chronic disease. They do not have such kinds of benefits. So this is a challenge that I think we should be very concerned about how to deal with this legislation in different countries and try to reintegrate these patients when they are active in the marketplace so that they can regain as many control of as many aspects as they can in their lives and became independent as much as they and productive as much as possible. This is the main issue that I really want to say here. And of course, the other challenge is the surveillance of post-treatment phase. And that affects, of course, not only the patients, but also the caregiver and the stress which is to leave in the survival phase, let's say, like this, and the surveillance phase. And the caregiver really needs to know that the patient is caring and is taking notes and has his diary. And it goes to the checkup controls and does the best for his health because it is such a psychological burden. Of course, there are lots of things that we can do to support them. But I think there's more that we advocates can do about that. OK. Thank you very much for your answer. And I would like to go with Beatriz, especially I would like to know your opinion. I was working for Regulatory Body. When we were discussing during the briefing, we were talking that, as I said, myeloma is a winner. I think what has happened with myeloma is something with no many presidents in oncology and probably in other disease services, like having five new agents approved in the space of two, three years by the EMA and so on. And when I was serving the myeloma pipeline, it really seems that this is going to be even bigger. In the coming year, we have around 20 or 25 new molecules with phase two, three trials. So I would like to know your opinion in how does the regulatory deals really with this storm, let's say of new drugs during the proper process and also if something that has been discussed in the communities, how having drugs that are adding more value and how the regulatory can incorporate certain surrogate employees, like my minimal residual disease, which is kind of important, also patient preferences that are included in the drug development process beyond the hard employees such as overall survival or progression for survival. So I think you wanted to have some backup slides so if you want to go through the podium, that's OK. Thank you. Thank you very much. Thank you for inviting me today. I'm a regulator, but my background, I'm a hematologist. So I worked in the UK, in the hospital, in the hematology department. And then for over 10 years, and then I moved to the regulatory side. So I'm in the UK agency in the MHRA for over 10 years now. And I'm also a member of the oncology working party. So I work also at European level. So this slide is that from the regulatory side, the increasing trend we have in myeloma, which is unique. I mean, it all started in 2004. We had Velcade. And it was the first new drug that made a difference. Up to there, we were with the Melphaland and Pregnusolone and so on. But it didn't stop there. It just followed with the Revlimit and Thalidomide. Thalidomide, the drug with the bad history. It became a drug that was necessary and it was useful. And so on. But it's not only this slide up to last year. It's just if you look at the bottom, in 2015, we had two new drugs with different mechanisms of actions. And last year, it was three drugs. So I think this is quite unique. I don't see this for AML. I don't see it for CLL, for the chronic leukemias, and so on. So it's interesting and it's very encouraging. And the good thing, I don't think this is going to stop. So we have more drugs and we have different mechanisms of action. So in each column, different mechanisms of action. And in each column, we have choices. So patients, you have choices. If you don't respond well to a drug or you don't tolerate one very well, you can have another one and so on. So this again is quite unique. And it also shows that we are now learning more about the biology of the disease. Because to attack a disease, you know to understand the disease. And I think that's how a reflection of how we now know about myeloma. And of course, as Dr. Oriol has mentioned, with new drugs, we have new combinations. Initially, we had Velcade. Steroids were always there in combination. And then we have the immune modulators, Lenanidomite, and so they were the doublet combinations, two drugs. Then now we have triplets. And I think we are going to have more. I don't know if a patient will tolerate six drugs at the same time on combination. I don't know, but there is a big choice now. So this slide is just to put you a bit in the picture. So last year, we had 27 new active, basically, 27 new drugs authorized in Europe. And of course, eight were for cancer. Cancer is the leading therapeutic area. And of those eight drugs, three were for myeloma. If there was an Oscar ceremony, there's always a film that gets everything best director, best actress. If there was an Oscar for regulatory approval, myeloma would be the winner by far, by far. And in this slide, you have all the other diseases. For example, cardiovascular disease, just one drug. But there are areas that didn't get one, like psychiatry. No drug, no new drug for depression, for schizophrenia, for anything. So this is a bit of the context that I wanted to bring here. And of course, there's more to come at the American Society of Hematology last year. They had a slide with all these new drugs in the pipeline and probably soon will come. I put this once here, but we will have more. So there is a no stop. This is a lot of work for regulators, I have to say. Myeloma is in my unit, I work in the oncology unit as a regulator in the UK and my boss says, oh, another new drug on myeloma. And the myeloma tends to come to me. And I said, oof, another one. So we are keeping up the, and for patients, this is the best news you could have. I don't think it gets much better. But now, we regulators, we realized years ago we needed to change, okay? One of the changes is not only to approve a drug in a faster way, in a quicker way, it's for clinical development, has to be a bit quicker. So minimal residual disease, as Alfonso has mentioned before, is how much disease do you have after treatment? That is not detectable by conventional ways, by microscope, by blood tests and so on. So this is an end point in clinical trials that will lead to faster approval. But so we worked on a guideline on MRD for chronic lymphocytic leukemia and it was published last year, I think, or two years ago. So at that time, when we were working on it, we realized that it was not ready for myeloma. Because sometimes you know the concept, you know it's nearly there, but you need maybe the technology to detect it in a sort of valid way, not random way, to do a clinical study that you can see the results are true. So we left it for a little while and then the International Myeloma Group published a guideline last August and that's when we realized we were ready. So we published a concept paper in January, but we have already started on the guideline. So this is ongoing work, it's by the oncology working party and we hope to finish it by 2018. So what happens is we've got a draft nearly finished and then because when we do the draft, there's always questions. For example, when is the best time to measure minimal residual disease in a patient? So at the time of complete response, or a month later, depends on the, if it's taking a monoclonal antibody, it's having transplant, it's not having transplant and so on. So we have a number of questions and we will do a workshop with experts, scientists on that field particularly. And I hope that the draft will be published at the end of this year or early next year and then when we publish, normally we leave around six months so we are open for comments and you will have an opportunity then to comment. So this is a changing because we need to be faster in getting drugs to you. That was one of the things I wanted to talk about you and this is ongoing and we will get there. And the other changing in regulation is because patients are participating more and more. And it's not about where you are or which meetings you attend, it's the mentality. We as regulators, we are now changed. I mean, I've been working in regulation since 2002 and the mentality has changed. You are now part of it and the CHMP did a pilot project over several years and it was published two months ago in May and the feedback of that participation was very positive. And patients now attend scientific discussions. I was last month in a scientific advisory group at the European Medicines Agency and basically when the CHMP is deciding whether to approve a drug or not and many times the 28 member states are split and it's very difficult. So the CHMP invites this advisory group which gets external experts to discuss. So I was invited, it was for another disease in acute myeloid leukemia, but it has happened in myeloma and there were two patients representative there. So the patients are asked by the experts to vote their opinion. And that's taken on board for the final decision. Okay, we had a myeloma elicitation patient preference study. It was done last year and it was done at the European Medicines Agency, the UK Myeloma Group and also the University of Groningen. And it was very interesting, they invited patients to give us their views whether how would they trade, for example, extending their survival time against very bad side effects like very bad diarrhea and so on. And we the regulators thought, well, they are going to answer this and the answers were different. So, and that helped us that we will need to ask you more when we decide and define clinical studies. And this is about the patient participation is before and after approval is a complete ongoing process. And I think that will continue. Thank you very much. Thank you. Thank you, Beatriz. Well, thank you. Thank you, Beatriz, for that. So I'm going to, with Jaime, so Beatriz has talked us about these first steps, well, it's not first step, but from basically assessing how safe and how what kind of efficacy is so in a drug which goes through the proper process and giving the market visualization. And then when this happens, is when sometimes we're struggling with pricing issues and with having access to this treatment that has on this efficacy and has proved to be good for the patients. So, one of the main problems that we from the patient community have observed is sometimes when we go to pricing, especially within the EU member states, when you are talking about HTA processes, when you are talking about pricing and reimbursement processes, it seems that you are talking to a very different thing depending on the country you are. So I have the chance to go through the publication, you co-authored for the European Commission about commonalities and differences in pricing and reimbursements across the different member states. And I have a couple of questions for you. First of all, do you think it might be that there is some kind of a space for having some common processes, real common processes, so in order to grant better access to treatment in the different health systems. And also another question which has to be, I think, with pricing and affordability. What's from... Sometimes you are pointed out like the bad guys because you are not the one who are giving access to the treatment, but what is your perception? Because we have been seeing how we are having certain treatments in patients who are living longer. And sometimes you are talking about drugs which are costing thousands of euros per cycle, which sometimes systems are not able to deal with that. So I would like to have your opinion on these two questions. And also I think you have a few slides there, so feel free to use the podium. Okay. Thank you all for the invitation to be here. Thank you for these two very easy questions to understand about, you know, harmonization process in Europe for pricing and reimbursement. I need to clarify that I'm not a payer, but it's okay, I have been working like a place of a payer for a long time ago. I'm right now a professor teaching Pharmaconomics and Economic Evaluation, I've been working a lot with the European Commission dealing with pricing and reimbursement and WTO. So I'm not a payer, but I know how payers are thinking about that. So I don't think that payers are the bad guys in this movie. The reason because I want to give you some background is because I think sometimes the message is not very clear. So let me clarify. The first one question is about harmonization. So we are going to have like one single price in Europe, one single process for pricing and reimbursement. The answer is very clear. No, okay. So we have European Medical Agency that it was a very good for a long time ago, but there is no deposit right now to have a single process for pricing and reimbursement. The reason is very clear. Pricing and reimbursement is a national competence. And pricing of the medicine is paid by the government. So the government want to decide which medicine they are going to cover. If we go, there's many publications about that. This is one of the published a few years ago. If we go country by country, we can see that there are different agencies that are proving for pricing and reimbursement. This is not the main issue. The main issue is this one. In every country, they're using different criteria for pricing and reimbursement. In some countries, they are thinking about the budget impact. In some other countries, they are not dealing with affordability. They are dealing just cost-effectiveness analysis. So when someone say, okay, this medicine is efficiency in UK, it's okay, just in UK. It's not in Spain, probably it's not in Germany. So the issue is not that we don't have one single process. The issue is different process with different criteria. This is the most important issue. This is one of the reasons because there are some delay in introducing medicine in some country, person and other. But there is no, the only problem is not that there is many different criteria. The problem is that even when we are making economic model, not all the country are using the same modeling system. In some countries, they're using cost-effectiveness analysis. In some other, they're using cost-utility. That you know with cost-utility, we have to account at the preference of the patient. So different criteria and different model system. So I can say almost impossible to have one single price and reimbursement. But we have one model that many countries are trying to copy as the UK model. I mean, probably you're very familiar with NICE. Well, there are many, many things every year that decide not to cover because they are not providing good efficiency. And there are some other products that are reimbursed. That's okay, this is the issue. When some product is not reimbursed, the reason is because there is another product that is more efficiency than this one. So we are not, I mean, the payer in this case, this is not only the key UK case. This is the case in many countries. The reason because they are not covering this one is because they are not that it's more efficiency. This is very important to clarify. Because for orphaned medicine, we are working in a different way. Here, we are dealing with what is called opportunity cost. We are covering this one because it's better than this one in terms of efficiency. In some cases, in the last few years, we found this kind of message in the journal about the high cost medicine. What telecom is trying to explain every time is what we call opportunity cost. This is a very old picture published in British Medical Journal a long time ago. Try to clarify that if we spend a lot of money in cancer, in cancer, we don't have money for hepatitis C. If we spend a lot of money in cardiovascular disease, we don't have money for nothing. So it's opportunity cost. This is the way to explain how we have to select it anytime the most efficiency treatment. Of course, we have a very strong consequence for patients. This is a very old publication, 2007, published in Anaf oncology. They don't publish anymore. This very ugly picture. We can say that there are many countries in Europe. We are not speaking about Tanzania or Wanda. We are speaking about Cyprus, where they have only six medicine for oncology. This is the case of Cyprus. Again, it's not a developing country. We will go, for example, to Poland. The issue is no... Let me look for Poland. This could be here. Poland is not the issues about the access to medicine. It's the delay in introducing the medicine in the market. 2,190 days. Almost seven years. And here, we are discussing about Europe. So different process, different result. For Tua, we need to do something. But the most important driver of having this delay is the price of the medicine. So the question that we have been discussing all the time is why price of medicine are so high in some cases. I must say, I don't have the right answer. Many articles say that there is no rational behind pricing of medicine. There is no rational behind that. Let me make very clear. But I have some ideas. I have some clues about that. The first one is this one. This is an official WTO document to some form, explaining how pricing is setting around the world. Do you understand? Probably not, probably not. So the price of the medicine is setting what is called international reference pricing. So we set the price here very high. Let's go to this way, let's go to the way, let's take the average of this one. So this is, so how is setting the price? So we go to the journal, we make some marketing and say that the patates is called 94,000 euros. And then we go around the world with this price. I must say that this is very stupid, but this is how in many countries around the world, the price of the medicine is setting. We're using international reference pricing. But then if we go in practice and we are looking, I got this publication for Miloma, in many cases, for the new medicine that in the market, we got discount about 75%. So we are comparing price that artificial price that are no real price. Of course, they have a very strong consequence. In many countries they decide not to reimburse the product because it's very expensive unless you give a very, very strong discount. We have also very, very interesting sample that you know better than me. A long time ago, 2007, in the UK, now they decide not to reimburse Belkate. They say that Belkate is no efficiency product. I decided to introduce what is called outcome based agreement. They decided to cover for all the pricing and the manufacturer give the money back for all the pricing that did not get responded to the treatment. It was easier to just to give a discount, but if you give a discount, international reference pricing or if you make a price cap, international reference pricing have a very strong effect in all the countries of the world. So in this case, you prefer just to give some money back because this kind of money back is confidential. So still you have a very high price in the UK but in practice, UK is paying half of the price of the medicine. The issue is, what is relationship between pricing and outcome? Because sometimes we are missing this very close relationship. Let me go, I didn't find anything about myeloma, but I found this sample about colorectal cancer. Colorectal cancer, during the last few years, we got in efficacy or effectiveness, we got the double. A long time ago, it was 54 weeks, we got the double, 140 weeks. It's very good. Overal survival, we double. Overal survival is perfect. How much did we pay for that? We went from $100 to $180,000 a year. So we are paying around 80,000 times more for getting double outcome. This is what they are really worried about that. They are not worried about this. They are worried about the future. And the future is like this. I don't want to show more data but they are coming to the market that costs 500,000. Even more, there are some new coming to the market that costs one million euros per person per year for the rest of the life. So pay are really worried about that. Because sometimes I think that we are a little bit confused. We are a little bit confused because we are thinking that high cost means high value. I want to highlight this statement by Warren Buffett about price of what we pay and value what you get. In this case, and this will be my last slide, I'm sorry because it's Spanish but probably you can understand very well this is what German is doing right now. The medicine is in the market. After two years, you came with the new data and going to reduce the price according to the theoretical value that you are providing. So if the product don't provide a theoretical value you have to reduce the price. If you don't reduce the price you are no longer in the market. So I'm going to give you the opportunity to train the market. I'm going to believe your efficacy data after two years you have to come back with effectiveness data and we are going to review the price according to your value. So what we are going to do is what is called value by its pricing. We are going to pay according to the value. I think that we missed that during the last few years. In many cases we are paying so much. Thank you. Also thank you very much Jaime. And last but not least, Susana I would like to ask you for, I mean you have worked in the industry for many years. I know now that you are happily retired for a year and so on. And you have been working in different sides of the industry. Not only with patient advocates also in some other areas for a long time but you really have been both sides sometimes advocating for patients within the industry. And you have been witnessing how patient preferences and so on are more and more taken into account. Even sometimes we think it is not enough but we are reaching that point. So from your experience, we are always demanding to be early involved in the drug development process helping to set the research priorities to include the special preferences. So from your side, how do you think industries are adapting to this new, I wouldn't call it patient centricity because I had that term but to really involve the patient view into these whole processes. And also another question that I would like to ask you now that the pricing issue has arrived into the panel is we're not trying to point anyone here but do you think that in the particular space of myeloma every time we see a new drug coming to the market it certainly happens without me has explained. The outcomes are good but the price is increasing exponentially. So do you think from your perspective from the industry there is some kind of possibility from your point of view to really improve this and basically what are the solutions that the industry may be proposing to improve access to these new drugs across the different countries. Thank you Alfonso and thank you MP to invite me. I will disclose that my point of view will be personal based on years of experience in the industry. So I feel free to be a little bit provocative sometimes also versus the industry. Patient involvement, I started to be involved on that. So for the one who do not know me I was working in the industry for 40 years but in the last 12 years I was working in no artisancology in a relation with patient groups in cancer and in the last years in hematology. So I know MP very well and I even Anita can recall so all the development of the myeloma advocacy in Europe. Okay so patient involvement and importance to have the patient view and the patient voice in the industry is becoming important, is becoming well known, is becoming something that companies are now looking actively. Personally I started almost four years ago at the time the head of no artisancology in Europe was really advocating to have protocols that represent also the view of patient. Is utopia was to have a protocol saying okay this protocol was approved or developed with patients. So we started a lot of different, different try to have these voice and also I remember we involved the MPE and I think Alfonso you were one together with a colleague from myeloma UK to comment on a phase two protocol that we submitted to you and I was very happy because they were very fast in replying because again companies are elephants and to convince them of the value and the second thing they are always thinking about money so you have to show the value also of involving patient in clinical trial as early as possible. So and now what is happening there are really a force also thanks to your party that I hope you know that this is a very, very helpful project of the European Commission and IMI to educate patient but there was a lot of work parallel work on how to involve a patient and there are documents that I hope you know about patient involvement with regulatory, patient involvement with industry, patient involvement with ethics committees. But being back to industry we have to show value and my advocacy point was what if not and I have a case from Novartis it's not on myeloma but I have a clear case we had a drug approved in Europe two years later in the forecast because nobody, nobody listened to one comment that I collected from patient advocates about one, one exclusion criteria. They said listen if you maintain that and it was about number of drugs taken in. If you take that it will be a long, long time because we have few patient taking it. So and I was saying okay my dear colleagues in Novartis how much it costed these two years of delay because you didn't listen. So and I think it's starting but we have again to show to the community the value and I hope you know that I was a happy co-author of a paper that was done by two patient advocates, young guys there and the two industry representative, myself and at that time I'm representing Mary Houlonop who you know and we, we produced a roadmap of how to involve a patient in the industry and I remember when we proposed the first the comment to this roadmap was but what was the methodology? It was not a methodology, it was collecting opinion in different advisory board, like new party meetings and so on or how to do and how to do is from the beginning at the end and after as also she showed before and after. Access, pricing, I'm not an expert but I can tell you what I saw in Novartis. I saw an evolution of a department that is called Market Access that from one person become really a department of five or six person trying to understand that the complex situation of Europe. I was working in Novartis oncology Europe and he showed the complexity and also we know the complexity of economics in these countries of affordability. Again, we are there to make money. We, they were there to make money because if you don't have enough to invest innovation will not come. It's clear that public research is not able to bring such innovation that private companies are worth but on the other hand the conscious companies are really trying to find a way and they are adapting as again he showed their models to what is possible. And for example these payback if the drug is not working clearly there is a negotiation about how to define this drug is working in myeloma or in breast cancer is becoming also for example in my country I'm coming from Italy is becoming one of the way but I can say again there are a lot of efforts in companies I see what I saw in Novartis to see how to and in myeloma we had a drug to add on and I remember the discussion we had okay but I think it was heading to Velcade but I think Velcade is now out of patent or no or there was a drug that was in association with the Novartis drug that was becoming out of patent in any case is speaking about also the future understanding if a generic will be available so the cost will be more affordable also I remember we were speaking about okay but this is not a chronic these are cycles and show the value for the patient but on the other hand there were a lot of side effects and we had an advisory board to understand how to to explain to the patient how to manage these side effects because again diarrhea I remember the comments from doctors of patient and doctors diarrhea for patient can be much much more worth than what is described by doctors so I think that the conscious companies are working a lot to they understand they have a business but they understand they have to cope with the situation and therefore the ability. Okay, thank you Susanna. So now I mean I would like to open the discussion for you so if any one of you would like to make a question or to add something to the debate right now it's okay, so Viorica. Thank you very much to all of you. I have two questions. One is for Professor, Professor I'm sorry Espin. Thank you for your very inspiring presentation sir. You were talking about criteria for assessment are different for each individual country. Who sets these criteria? Are they set at the national level? Is the pharmaceutical company setting the criteria and the most important thing? Why criteria's cannot be the same for at least all EU countries because theoretically they should not be differences unless of course they depend entirely on the economic status of each individual country and then if that's the case then it should be it should come under the purview of the economic commission of the EU which unlike the health commission you know as far as I know sometimes controls from the EU headquarters this issue. The second question is addressed to Dr. Oriol. I take pride in saying that Miloma Euronet Romania an organization which I represent after 10 years of lobbying could finally succeed in including the Thalidomide in the oncological program yet very few people can benefit from this therapeutical you know because of the restriction imposed by the protocol of EMEA whereby treatment with Thalidomide is indicated only for the first phase patients. In other words the patients with refractory relapsed my husband had the refractory you know for example they cannot be administered this medication and now is the question for you what do you think and what is your opinion regarding the inconsistencies between the protocol of EMEA? The ESMO guidelines which are not quite very clear when it comes to the therapeutical use of Thalidomide and not in the least important, not in the least the fact that in both Australia and in the United States there is not such prohibition. I found out recently in a meeting with IMF that in both these big countries, big continents almost Thalidomide is used for refractory and for the people with relapsed. Sometimes it's a question of life and death for some of them considering particularly that in Romania and many other countries Thalidomide and Velcade are the only medication you can use because we don't have access to Nile, Ixa, Darude, Dutumabib and many others novel treatment. Thank you very much. You are the first. Thank you. I think that you made two questions and one comments. The question is why, who decide the criteria? The criteria is setting for every country. Remember that every country is the budget holder so every country decide the criteria according to introduced. I don't want to show you more data but if we see how many medicine are reinvesting in Spain I can say around 10,000 products in Spain are reinvested. If you go to Belgium I see around 5,000 products. So with the budget that every country have decides which are the criteria in order to reinvest the products. So different budget, different criteria for reinvestment. It's a national country, yes. Why are different? If we go back to the criteria you can see that some of the countries decide that one of the criteria is R&D, for example, of public or budget analysis. If you are a country like UK or Germany you have a lot of companies in the country probably you want to give one criteria for having R&D in the country. So you decide that one of the criteria is R&D. So you decide the criteria that could be not possible to have the same criteria because every country in Europe is totally different. So probably even when the same criteria probably the result could be totally different because if we set the same criteria R&D there are countries that have R&D probably the product will be reinvested but the country that have no R&D the product will be not reinvested. So even with the same criteria the result will be different. Your final statement was related to European Commission. I told you before, price and reinvestment of the medicine there's a very old 1989 directive of pricing of medicine is a national competence. So what they are doing right now European Commission is just checking that the countries are put in place the European legislation, that's all. They cannot do anything more. Of course, in the last European Union presidency there was Malta. European Commission was requesting to the countries more collaboration. So right now for example, we published a few weeks ago a paper about John Precureme. So what about small countries go together in order, let's go to see Malta, Cyprus, Latvia, to go together and make a tender together in order to take advantage of economy scale as economy call. Could be some product could be but not for all the product. But when we are speaking about R&D policies in countries there are two or three patients probably you go together, sit down with the pharma company to say okay we are not only Malta, we are Malta, Cyprus, Latvia and so on. Probably the final result will be better if you go alone. There are several problems here together. Let me see how I can answer to you adequately. When you register a product based on a pivotal trial in terms of safety is a good idea to approve it in the same conditions that you made the trial. That has advantages and disadvantages. The main advantage is safety for the patients mainly. And if you have a trial in second line with a certain product for myeloma you get the approval of the IMA or the FDA for the second line. Not for the third, not for the fifth, not for the first. That gives you the knowledge that you are approving that product in the situation in which it was proved effective and not in other situations in which you don't know about effectiveness. That's good on principle. Then there are some problems that come up. The main problems are that sometimes the trial was restrictive. So you are restricting that to a group of patients and you probably assume that it could be effective also in other groups of patients. But you are assuming that. So I think it's a good idea to approve a drug in the conditions it was tried. At least for a certain time. Afterwards it happens that you are using the drug in several other situations and then it's very important to collect all this information because you could stand the drug. For example, I agree with you that nowadays it is not logical to have Thalidomite approved only in one line of therapy. As in each day it was not normal to have for example Belkate approved in the older patient first line, in the younger patient second line, but not in the younger patient first line. But there was not a trial proving that it was effective in that situation. So I think that the balance could be you have to approve the drug in the situation in which it was tried. But after 10 years, 12 years experience if you gather enough experience that you can combine you can give Bortesomite with Dexamethasone or with Doxoribicin or with Lenalidomite or Thalidomite you could have a more general approval like Belkate is approved in myeloma and give it however your knowledge of the drug allows you to do. That would be a good idea. And then there's another problem also with that sort of approval that companies are not always interested in all the drugs they have. So if you have a very good drug but you are not particularly interested in having it approved for a certain indication you will never have it. For example, Rituximab for Linfoma has been used it could be used in all B cell Linfomas. But of course trials were made in the more prevalent Linfomas. The first large B cell Linfoma, follicular Linfoma. Who cares to make a trial to prove that Rituximab is also important for example in Burkitt Linfoma. Nobody will make that trial. Why? You have the drug in the market. You have the drug in the market for 80% of the potential patients who cares of doing a trial for the other 20. And that's another problem of all the regular Rotary marketing. So there's several points where all the safety that you have in terms of a may approval on this is failing. Mainly small populations. When the drug has several years and your doctors are very experienced with it could you expand the indication and make it more broad? That would make sense. But in any case for example talking about the case of Romania. Of course, even if Thalidomite is only approved first line, if you don't have an alternative for the second line it should be authorized also in the second line and the third line because you don't have an alternative. Another thing would be okay you have Thalidomite for the first line but you have Lenalidomite approved for the second line. But if you don't have the second choice but that happens now in Spain for example with Carfilzomite. You have Lenalidomite, Carfilzomite, Dexamethasone approved the second line but patients that were before that approval are having Lenalidomite and Dexamethasone second line but they cannot have Carfilzomite, Dexamethasone, the third line because Carfilzomite, Dexamethasone is not approved yet. So there's always inconsistencies in all these approvals because of course if a new patient can have Len, Carfilzomite, Dex and an old patient relapses after Len, Dex why is not he able to have Carfilzomite then? Because there's not an approval. So there are some inconsistencies that should be treated apart and have special conditions for situations like this of course. Yeah, of course. I understood that, yeah. I have another question more. So to Dr. Oriel. At the AR we had a discussion with one of the doctors was Dr. Mateos about, she pleads that already in the stage of smoldering byeloma you should treat patients. That's a bit of a taboo I think for some clinicians because why should you treat patients who have at that moment no complaints? But we look at the high risk of course. But you treat then the results although they don't have complaints. How do you look at that development? Would it be the future for me alone? That it wouldn't be a taboo to treat patients who have no complaints but we see it in the results to get them at that stage at the minimal risk. Well sometimes you have to break with tradition. That's progress. I mean initial trials with smoldering myeloma were very negative but it was logical. You were treating patients with smoldering myeloma in general. That means that you were treating patients that at least a third of them would never have required treatment and that's wrong. And you were treating patients with very ineffective drugs. So I'm very toxic drugs. So it obviously was, that was the main reason why a patient with smoldering multi-myeloma should not be treated for 50 years. But now you have two situations which are clearly different. The first is how you identify high risk patients. Those patients that in three, four months time will have symptoms. So this is an asymptomatic patient but it's an asymptomatic patient that is asymptomatic by chance because in four months he will have symptoms. And you can't identify this patient. That's one thing. And the other thing is that you have more effective drugs. If I think that at the point, let's imagine some years from now, at the point where you have effective drugs able to cure myeloma and not so toxic or even if they are a little bit toxic but they can cure myeloma, the point of not treating asymptomatic patients will lose its sense completely because if you can have a treatment that can cure you, you don't have to wait for symptoms. You don't do that in breast cancer, you don't do that in colon cancer. Even if you have a small polyp, they take it out. And if there's something left, you have chemotherapy. So the future is going towards treating more patients but to do that, you have to go slowly because you need effective drugs and safe drugs and that's important. And we are starting to have that. That's why the question of small myeloma arises now and has not arisen 10 years before. Yeah, thank you for the dialogue. It's very good to have a dialogue to be more provocative and to have all the stakeholders. My question is kind of a general one which goes to each dialogue participant. It's a little bit provocative but as I'm very happy by the way to hear that Oscar goes to myeloma because three out of I think eight regulatory is for myeloma. But when you look at the overall future of myeloma treatment, Oscar is a sort of festival of hundreds of films and the budget, the pay to payers and the patients only have money to buy two tickets, meaning that the budget is limited. So how would you see, I mean it's good that we have excellent drugs yet the efficacy, safety and the value of the drug needs long years to evaluate but still how would you see in terms of budgeting and the new drugs? Thanks. I can make some comment. I mean from the point of view of payers, they are very happy because more pros in the market in many cases mean that you increase the competition in the market and you know that the competition in the market is better because the price goes down. That this is okay. The issue is that you know that when the product came to the market, came with a patent, during this patent period of time, there is not really a competition. So the product can be set in a higher price. In many countries we can see that even the product is not launched because due to the international reference pricing and due to parallel trade, if you launch the product with a very low price in Poland, many countries are going to make parallel trade and the product will be no any longer in the market. So from one side, it's very happy because many products will be in the market. You see also that pay one to people get cured but at the same time they are very worried because there is no rational behind the price. So you know, from one side good news and from the other side bad news. In other cases what is important is to give very clear message to pharma company. Say, okay, if you are providing new therapeutic value, I'm going to approve high price but the new high price will be related to a therapeutic value. If you are providing, let me say, 20% extra outcome like an overall survival or whatever that you're using, I'm not going to give you 100% extra price. And right now my spending with Pella, they are not giving this clear message. And this could be more clear according with the criteria. And for Chua, we are dealing here with content with high income, another content with lower income compared with the first one. And some issues should be related to what happened in practice. I don't know what's going to happen in the future but probably one of the issues to resolve that is to avoid parallel trade. So if we avoid using parallel trade, the content that's setting the price will be the price only for that content. So it have no sense to set on our content. So one other solution is the price for Malta, it will be the price for Malta and the price for Poland will be priceful. It will be some kind of differential pricing. So higher price for content with higher GDP per capita and lower price for content with lower GDP per capita. If you avoid parallel trade, the price will be only for that content. Could be one of the solution. Isimba could be one of them. I think the faster access will come with faster development. And I think one of the things we hope regulators will help for that and eventually will help to drop the prices will be to have different end points for clinical trials. And we had a conference in London this week in fact on Monday and it was on oncology, not just myeloma. And there were scientists, the HTA bodies were invited, people from NICE, academia, industry and so on. And now the challenge is which end points to use. So industry takes less time in getting an approval for a drug in development. We approve it quicker. So instead of waiting for example, for median overall survival, for three years follow up in a patient you may have in seven months the end point or in a year. So it's just, I mean it's a big reduction of the clinical development. So that will be a faster access I think. And hopefully, because the investment should be less, it should be in theory reflected in the price. The other thing is that for a long time the European Medicines Agency has been looking into that as well. And when they designed the adaptive pathways, one of the things they brought also in the dialogue early on was the HTA bodies. And in the UK we had a similar scheme is called the Early Access Medicine Scheme. So for drugs that have very promising results and early on, we put them in the market in the UK only but the company, the industry have to provide it free until it gets the full development and the full approval. So we regulators have been already going on how to get all these faster access. But I think it will be the quicker development with new end points that will make a difference. But we will have to wait a bit. But I think that's the next change. From my point of view, I agree that we have all to agree on the value of what is available. And I remember at the U-PATI course there was a discussion about a drug on pancreatic cancer that was evaluated by the HTA French body. And it was significant, but I think it was one month more, something like that. And I remember we discussed it with a patient advocate and say, okay, but so the value, so from you patient also you have to advocate. And this is what I also told in Novartis, if we have a good drug, the patient groups will work with us to show that there is a need. But we have to show the value. If you have a drug that is not really giving value to the society, to the patient, don't waste money. The value is what we need all to agree where it is. And the value is also to find the good end point to use. And this overall survivor for some cancer drug is killing the process because it's too long to show overall survival. So we have to find, to agree all together, patient, regulators, any industry, what are the good end point to use to... I'm not an economist, I'm a clinician and I'm very bad at an economy. So I've always thought that if prices were lower, access would be more granted and there wouldn't be so much restrictions and probably companies would make more money. But when I say that, economists don't really believe me. So I may be wrong. So I live in a country where you have restrictions for all expensive drugs, you don't have restrictions for cheap drugs. So I think probably they should make the drug cheap and make more money, but they make their sums and probably they've done some up. I think too, what she said about value, I think that the situation now in myeloma is very transitional because in the long run, you see that drugs that are really expensive for the payer are drugs that you are having in the long run, drugs that you're having forever. For example, if we go towards a curative treatment, that curative will be value for sure and it won't be expensive, whatever the prices of the drugs are. And many companies are working in that line also because they are thinking about combinations of four or five drugs, but when they think about that, they don't think about four or five drugs forever, which is unsustainable by all means. It means that four or five drugs may allow you to cure a new cure. You don't have to have long-term treatment and then there's value there because you need a big budget for a very short course of time, which is very different than have a lower budget for forever. So curation of myeloma is really the value that we have to look for right now. Are there any questions? Oh yeah, please. The question is for Dr. Oriol. I'm representing the Azalea Miloidosis Group, but the question is the same. You talked about mixing drugs for treatment of myeloma. It's the same for Miloidosis. I understand very good the procedure of developing a new drug, which has clinical phase one, two, three, and so on. And then it goes to the FDA or whatever to get the improvement. I would like you to explain how you start to use different mixes of drugs. I mean, since it's not done by a pharma company, it's done by doctors. So it's a trial and error way of deciding or what is the procedure to prove this mix of drugs also? Well, Miloidosis is one of the typical cases where approvals are just going backward because there's less patients. Normally to prove that one combination of drugs is superior to another, you need a big number, or either a big difference, or either a big number of patients. And you don't have a big number of patients who have Miloidosis. Tell me about the myeloma. Sorry about that. No, sir, I would like to say, and perhaps you can support me, that especially if the disease is rare, there are ways even for a company to propose a drug based on very few court of patients even in an open phase. If there is a rare disease where even there are no drugs and then you use adapted pathway to go on and you work with Emma to have trials. Again, in Novartis, we had a drug that was approved in a very rare disease with 26 patients from a center in the US. So let's say an investigator initiated trial who showed the value and then you work with the regulators to continue to show. Then we had a first approval asking Novartis to do first trial. So there is a way, especially for rare disease. You can do it. For the combinations, there are trials done over the years that show that combination works better than a monotherapy or if you have three drugs, better than two drugs and that the safety, the risk and the safety is manageable. So normally this is based on data evidence that is produced by industry, really. That's how they are approved. Yeah, it does. I mean, yeah, that's how it's done. There is data provided to us regulators that that combination works. That's why they are approved as combinations. But whoever decides the combination of the drugs, it's not the doctors. I mean, every one of the drugs is done by another pharma company. So actually they're sitting together and decided to try three drugs together? Yeah, I mean, normally when you get the combinations in clinical trials, you have had previously other data like non-clinical data in animal models. That is very often when industry gets approval in one drug, they will study also the same drug with other combinations and they try first in non-clinical models and then if they see a synergy, they move on the development. So there is a previous evidence, but it's industry. It's happening that companies are working in some cancer. They are now studying together combination. It's happening. It's long process again. And the more drugs with different mechanisms of factions that are there, there are more combinations coming because then people study if together are better. What you said, you need a preliminary data that gives you the confidence that that combination will be better than the two drugs by their own. So that's normally animal models or cellular cultures or whatever. Would you have time for one more question, Sue? I would come back again to drugs and prices, but at that time, not for high prices, but for low prices. We have the problem. For example, for myeloma patients that from time to time, we can't get malphalan. It's a very cheap drug and there's only in the meanwhile, one company which is producing it. And in Germany, for example, we had twice the problem that malphalan was not available and patients couldn't be transplanted. So what can be done on this problem too? Is there someone from Spain in the room? I think that I'm not very clear because I wore on that a long time ago. There is a very clear legislation that if you have market authorization in the country, you have the obligation to supply. If you don't supply, I mean because I know that when there are some problems to supply, it should be in the Spanish medicine industry. There is one session that says, okay, these problems have problems to supply. So you need to justify why not. I know that in some countries where the prices have been set very low, the manufacturer can go to the minister of health and say, okay, look at here, the price is so low that even we don't cover the marginal cost. So please increase the price. And we have several examples in Spain with the price where the product was lower than two euros and the government decided to increase the price. But, assumedly, there is a mandatory obligation for former companies, and probably you can complete the information, if you had the market authorization. If you don't have the market authorization in the country, you don't have the obligation to supply. So in many countries, the manufacturer did not apply for pricing and reimbursement, so you don't have any obligation. As soon as you have marketing authorization and you apply for pricing and reimbursement, you have the obligation to supply. If you have stopped out, you have to make notification about that. So in the case of Germany, please read the legislation about how it's working. And the best is the minister of health contact with the former companies in order to know what happened. Because in some cases, it's just stopped out for a shorter period of time. It's another case, it could be different issues. So, it's right that there's been problems with the melphalan supply in several European countries this year. And I recall three years ago, the same happening with dexamethasone. So these things, I suppose that in the long run, it's important to have at least a couple of suppliers in each country, so you can do for shortages. That's important. That's what's been happening with melphalan since the last shortages. Every country has at least two or three suppliers. Because I know that I mean, it's to leave. I don't know if you need to leave and also, but you're not very attentive to. Can we, so... How much time do you have? When do you need to leave? That's why. Okay, so... I'll come in afterwards if you want to. I mean, it's important, I think, because the melphalan issue, we've tackled that, Lisa, and the problem was not low prices or anything, it was a bit related to something similar to blackmail that Aspen was doing to certain governments because they wanted to increase the price. So we had no proof of that, but the commission is already investigating this, and probably they will... There are several cases in the US. Remember, Hillary Clinton made a very famous tweet because one price goes from 20 euros to 300 euros, and she said it's not going to happen anymore if I win the election. We know that happened also in Europe, one company winning, one company increased the price without any rationale behind that. So in this case, European commission can play a role in order to look up for the competition. Yeah, always related to money. It really seems that we have run out of time. I'm pretty sure that we could be talking here because I think it has been a very interesting panel, and I would like to thank again Albert, Sofia, Susanna, Beatriz, and Jaime, because this is the historic day, this is the first time that we are organizing a multi-stakeholder panel, so hopefully it's not the last one. And so thank you very much for being here today, and we're looking forward to meet you again. And for all of you, we're going to have a 15-minute break, so we will be coming back at quarter past five, okay? So thank you, thank you very much. Thank you. Thank you.