 Okay, why don't we go ahead and get started with the discussion. I realize we're all still sort of munching on our lunches, but at least I'm glad that we're munching and that you got fed one way or another. So my apologies for Dan Rodin, who is unable to make it to the meeting today. He had a family emergency and then a travel problem. So I'm going to play Dan for the session today, which are tough shoes to fill, but I will do my best. So I realize we've had a little bit of a break since we heard about the initial discussions on international experience, but I wondered if there are questions to start or if we can kind of stimulate some. So you'll recall we heard about Europe from Dr. Muchenhaupt, about Taiwan from Dr. Hung, the ISAC from Dr. Paramahamed, and Thailand from Dr. Chan Tritita. So are there questions or comments to start off with? This isn't pertain to the differences in the talks that we're given today, but I mean right before this break, but one thing that struck me is that some of the alleles that are associated with these hypersensitivities, and I know Elizabeth has thought about this before, are actually ligands for killer cell immunoglobulin-like receptors. And they're expressed on natural killer cells, and natural killer cells are one of the cell types that make granulicin. So I was wondering whether some of the, for example, with the back of the ear, some of the individuals who are B57 positive but do not develop hypersensitivity, whether it may be modulated by cure interaction. So if you didn't have an appropriate, if you had strongly inhibitory cure, might that reduce the granulicin production and confer some protection against that subset of B57 people who don't develop disease? And that could be applied to any of these, not so much the 1502, B1502, because that's a BW6, and that's not a ligand for any cure. So I wouldn't expect cure involvement in that. But I'm just wondering if there, because some of you were talking about modifiers of specific HLA effects, that it's not just the HLA allele, but there may be genetic modifiers. And whether anyone's looked at in those, because I can tell you on GWAS, the cure locus, because it's expanded and contracted so much, that locus is very poorly covered on GWAS chips. And even for full genome sequencing, it's a messy region, because sometimes there are 15 genes, and sometimes there are only four. So we actually did genotyping, cure genotyping, and this is sort of, we're hopefully just about finished, and once we're finished the last part of it, it doesn't involve cure, but in the abacavir predict, well, predict plus cohort. So it was basically 95 patch test positives versus 43, 5701 tolerance. And there was no difference in sort of, and we did the complete cure genotyping, so there was no difference between those populations. But I think there is some interesting data with nivarapine, and I'd sort of welcome sharing that with you later, so thanks. Great, and I should note that we were added by Dr. Mary Carrington from the National Cancer Institute in Frederick. No, that's quite right, and also by Dr. Howard McLeod from Moffitt, Florida. So where it's sunny and nice, and why in the world would you have trouble flying in? You're playing the game. Oh, really? OK. Great, further comments? I was wondering if we might talk a bit about international collaborations. Obviously, we heard from two large and effective ones in the Regisgar and the ISAC, but there are a number of other groups that could conceivably be collaborating with your two groups. And so I wonder, Dr. Mukenhaupt, if you could talk a little bit about, sorry, if you're in mid-Chu, but how you might be able to expand your network or take on potentially affiliate members or ancillary members? Well, I have not really shown how many teams are right now in the Regisgar group, but I think our Taiwanese colleagues have, so there's several European teams. There's Taiwan, there's South Africa. And we're open for other teams to join. It's only that, for the moment, every team has to provide some own funding. We have a hard time struggling to be funded and survive. And we had some European funding from the European Commission for a few years, but they usually like to initiate things and not to do a continuous funding, which is a problem, because for some people, research starts when you have all the samples, you have all done the data management. Everything is set, and then they start with their samples. But all this other thing has to be financed by research money. So the point is, it needs a lot of interest and also frustration tolerance to start that and some initial funding. But we have always helped people if they wanted to join to come to our meetings and things like that. The basic requirement is that a network is set up, that the cases are interviewed according to the Registrar rules and questionnaires, and then people get access to the database, which is remote database entry. And the cases are reviewed together in one setting. But we are open for that. But each team has to do the legal issues, because they are still different. France has different rules for ethical committees than Germany or the Netherlands. So there's a few things that we can help with, and it can be set up. And then a start is possible from one place, not the entire country. For example, we now have a team from Spain. They started with two hospitals, and now they are covering the entire area of larger Madrid. And it works very well. Great. Thank you. Yes, Mark. I wanted to follow up on that, because the question arose, and this is actually going to come back at you, Terry, which is what would be the role of an emerge or one of the other NHGRI-funded networks that is in the space of looking at phenotypes and genotypes? And one of the questions, the reason I asked Dr. Perlman the question about the electronic data access is how amenable that would be. And this also anticipates Josh's talk to a bit. But it seems to me that there would be an opportunity within some of the funded consortia from NHGRI and others to contribute data to some of these international efforts. So I guess I'd appreciate your comments on that. Sure. And for those who aren't familiar with the electronic medical records and genomics network as a program initiated by our institute about eight years ago or so that really was set up to do genome-wide association studies within biorepositories that had electronic medical records, that at the time we set that up, GWAS was just sort of getting started. And there were a lot of questions as to whether EMR-defined phenotypes would be nearly good enough to do genome-wide studies. And we proved happily that they were more than adequate and, in fact, led to some very interesting extensions where you kind of turned GWAS on its head. And Josh Denny may probably won't have a chance to talk about some of the very nice work that he did in doing phenom-wide association studies where you take a variant and then say, well, what else is this variant related to on the phenotypic side? So that would be one group that could participate. The numbers of patients need to be large in order to pick up cases of this if you're dealing with groups that are not at risk. But you noticed at the beginning of my talk, I identified a number of other institutes that are in the room here and that are working with you that have large cohorts of people who are on carbamazepine, or on navirapine, or abacavir, or other things. There are huge, huge collaborations related to HIV-AIDS and that that are funded by our sister institutes and all. So might there be some way to consider participating in some way? And presumably, many of these groups are collecting information on a lot of things. So it might not be a huge marginal cost to add in a questionnaire for the rare case that develops this condition, which is something that you're probably going to try to document anyway. Wouldn't it be nice to have a standard form to do that? Munir. So just with regard to the SAC, it was funded to do the H consortium in terms of numbers. And we've reached that target. And what we're trying to do at the moment is to identify potential hits using the GWAS studies and other functional studies sometimes. But one of the aspects that we're finding is that we do need to collaborate with other people. So some of the signals I showed you do need to be replicated. So if there are people who have the relevant samples here who want to follow on and collaborate with us in terms of replicating the samples, that would be much appreciated. I think in terms of follow on to the SAC, obviously, and Maya's quite right that often from funding agencies you get funding to start off something, but you don't often get recurrent funding to continue it over 10 years, 15 years, and so on. And that is what is needed. And the way we're trying to do that in the UK is two ways. One is to have the infrastructure funding to the kind of structures I showed you before, but also actually working with patients. So we've set up a patient group, which is called SJS Awareness UK, and through their contacts and through Facebook, would you believe they were able to find me more patients with SJS TEN within a year than I was able to find it for five previous years. And by going back to the case notes, we were able to look at those and validate those and utilize them for some of our studies. The problem obviously always is that retrospectively the case notes may not have enough information in there, so you may not be able to completely recruit all of the cases. Perspective design obviously is very good to have, but it's expensive, and because of the rarity, you may not be able to collect enough and you may need to go for many years to be able to collect enough. And so retrospective cases may still be valid to be able to recruit, especially if you can identify what the case criteria are and if there's enough information, particularly some of the things that Neil talked about in terms of histology, et cetera, is available for you to be able to validate those cases. So I think that is very important. Coming back to electronic medical records. Actually, maybe I'll just stop you for just a moment because when you mentioned having patients to actually contact you, we have Andrea from a patient group and Andrea maybe you introduced yourself and say. Alton from the Stevens-Johnson Syndrome Foundation. We have a database of over 3,500 patients from all around the world. We put out questionnaires as well and we would offer collaboration for studies which we tried to put together for people, mainly with regards to the sequelae that come out of SJS as well. We could help that, it would be very, very good, but the database is very important. We take calls night and day and usually our website is the go-to for people who have never heard of Stevens-Johnson Syndrome before and they're wondering what's going on with them and they're usually missed one, two, three times before someone finally gets it. By that time, there is full slough of the skin. They are very well-spoken and it would be happy to come forward and advocate and talk about what happened to them, especially around the world if we can help, we will. Great and you commented that you do refer them to clinical trials or to other studies as well? Yes, absolutely and we tried to put together clinical trials stem cell research, mainly for the ocular involvement which everybody seems to suffer from whether it is full blindness, severe photophobia or dry eye syndrome. It always seems to be the biggest issue as well as which we can't figure out is the joint pain and that is something I have not found any articles on that so if anybody knows why this happens, I would please come and talk to me because when people call, they ask me where should I go and naturally I say rheumatology and they don't know how to figure it out so it's just a big mystery sometimes and I often say when patients with SJS get out of the hospital, they're usually at their best because the sequelae seem to come later on as it develops, especially with the ocular involvement and then other things seem to happen with the finger nails, the toenails, the teeth and all the mucosal surfaces. Thank you. So Andrea Dalton and she's here and I think I'm very eager to develop collaborations. Sorry to interrupt you, Muneer. No, that was very useful actually. I'll talk to Andrea later, but that's very important. So I think the SJS Awareness UK group have been in contact with the group here and in order to increase awareness of SJS, I act as a patron of the charities and it's now a charity in the UK and we were able to get some funding for them to be able to develop their own website and things like that. In order to increase awareness, we were able to persuade a member of parliament to actually launch the charity in the House of Parliament in the UK and we're trying to persuade them to have an SJS Awareness Week in July this year so it increases the awareness of SJS and I think that's very important as part of this of education of doctors, other people to be able to recognize it because one of the biggest issues that comes from them when they talk to me is that people are late in recognizing the potential danger signs and carry on with the drug don't ask, take a good drug history, et cetera, and the drug is carried on. I think stopping the drug is crucially important in the early stages. So I think that's important. I was very useful now. I would like to talk to Andrea later on, is that okay? In terms of the electronic medical records, so when I did do the analysis on the electronic medical records, it wasn't UK-based database, but there were issues in terms of how the cases were. There was ICD coding, saying that there was Steven Johnson's Romantoxic Epidemiocrosis but when you actually looked at them, there was clearly they weren't in terms of the kind of data that was provided, so it's very difficult for me to be able to even recruit one case from that electronic healthcare record. So, but we have been trying in the UK to start doing that, so we've undertaken, there's something called the Clinical Practice Research Data Link, which links 10 million people in the UK at the moment. And we've started off with a different phenotype, which was statin myopathy, and able to identify those cases and have been able to validate the case definition and then validate some of the associations which have already been found. And we've now started to develop the diagnostic algorithm to be able to identify patients with drug induced liver injury, let's say to flu-cloxicillin, but now we're starting to think about, within the electronic health record, how we can develop the diagnostic algorithm for SJST and because it's so rare, so therefore you do need to go into electronic health records to be able to really identify those cases. And in terms of, I think we'll hear a lot about the electronic phenotyping from Josh and others later this afternoon. In terms of collaboration with you, I know the SAAC was set up to be a global consortium in collaboration, but how would people, you go to your website and you find out what the criteria are and how to join? For what I've shown you today, it's all on the SAAC website in terms of what we're doing. We've also published in terms of the criteria we were using in clinical pharmacology therapeutics, so they can either contact me in terms of they want to replicate or Arthur Holden and we work together to be able to help work with them collaboratively to be able to replicate some of the signals we've already identified. Wonderful, great. Matt Nelson, I'm Blacksmith Smith Climb. I'm also the chair of the Serious Adverse Event Consortium Scientific Management Committee. So part of our bylaws is the SAAC, a year after the data are generated, those data become publicly available. So right now those are being hosted on the SAAC website. So almost everything that we've published to date, the clinical as well as the genetic data, genome-wide genotype data, are available for download. It's a fairly simple process to essentially acknowledge the conditions for use of the data and then to download it. The data that Munir talked about today will be up there in the coming months as well. So all of that is expected to be ready. The SAAC itself is in its sunset period. So we're not continuing any new project at this point, although the individual component studies like itch may continue on in their own ways. Great, thank you. So in terms of other forms of kind of global lessons that we can learn, we again heard from two large consortia into much smaller sort of local or individualized settings in which we heard very promising things about implementation of screening and use of genetic testing to prevent this, terrible condition. And so one wonders what is it that's unique or unusual about those settings that enables that to happen? And I think we heard a couple of things, one of them being there has to be an appreciable prevalence or incidence much higher probably than what we see in the US and perhaps in other countries. But at least it needs to be recognized as a significant health problem where enough people can relate to it that you can get some attention. Also you need to have a relatively higher frequency of the risk alleles. But it seems also that there needs to be sort of a receptive governmental interest in this. And so I wonder if when Hung perhaps you could comment on what was it in Taiwan that made this work was there an individual champion? I mean is there somebody in your government who said this is a terrible thing or I had a son who had it or whatever, or was it much more of a kind of an understanding in general that this was something that needed to be addressed? In Taiwan the situation is for Kawasaki is the story is more straightforward because the government puts the information and we have a post base study then the tests are covered by insurances. But for after the Kawasaki story then the government can change to be more conservative now such like our appeal now and we did have levels of our appeal but there comes in now to be they need to be considered not just the training test because they are now have a new job and they also know that the test cannot cover 100% to protest the patients. So more and more political thought should be put together. And also the price, the training test or so-called the pharmacoeconomic analysis. So we need to think about how to put the clinical implantation of the genetic test. And so apparently it's a good example but now we are struggling to make our opinion or could be one of the another successful pharmacogenetic test in Taiwan. So I think we, but I think Taiwan is a small area so our expert can put government to do something. It's easier, I think it's easier for us compared to the state, I think it's more complicated. And in Taiwan because our population is more homogenous so we don't, the one thing is what we want to do or not. So for us, I think it's more easier. And then some of the researchers come from Taiwan so I think we have chance. But I'm thinking we always, in previous we do the research by ourself and also the post-patient genetic test of also doing my time. So I'm thinking it's someday, if the NIH can not did, but participate our ongoing post-patient screening I will be appreciate it because then such like in Thailand if you can participate our to monitor and to improve our quality of post-patient screening or also the kind of implantation I think we will be our appreciate. None of my research but also our government should be very appreciate. Okay. Thank you. I might ask Dr. Wasan also to comment on what made it feasible within Thailand to be able to implement this screening? Was it, was there government interest in doing this? Was it something that was identified by the government necessarily as being something important or did you bring it forward as clinicians and say, you know, this is a terrible thing and it's something we can now do something about? For the university hospital, you can do it immediately. And the one who pays is the patient, not the government, but a little bit hard for us to push for the government in case of the government. The first one I already told you, this is a government sipping. We do the cost effectiveness and it works, that's why the government does support it. It will start with the 2014 and now one year, now they under evaluate that the government should be implement nationwide and the information perhaps this recommended can apply more for me because you're working with the government. Great, thank you. So I think for Thailand, we have several fortunate factors. It was begin, it began 10 years ago. I think it's 2004 that we started the Firmaco Genetics Project. This was not the, I mean, based on our policy, it was actually began because of McKinsey went to Thailand because of our prime minister asked McKinsey to evaluate over by a technology center and McKinsey suggested that we should do Firmaco Genetics, which we don't know why in 2004 we should do Firmaco Genetics. Anyway, and then the politician become interested in Firmaco Genetics because of McKinsey recommendation and then later on, there was a fighting from Taiwanese that there was a genetics factor that we can use to prevent Steven Teng from coming to Spain. And we know we have a senior epileptologist and he is very influential in the Epilepsy Society and he was very interested to having this test available for the Thai people. So he is the one who like the champion of this test and he has a very large network of connections. So he influenced many sector in the government and the university-based researchers. And then from his influential and the supporting policy, we receive, I mean, our technology people or capability was already mature, I think. We can develop the test that cost us only 30 US dollar is a little specific PCR for the 1502. So it's a simple PCR test, really similar to what the private company in Taiwan is developed, but it's the primary pair was different. And then based on that cheap, low-cost typing technology, the economic equation became feasible. So then that equation when it become feasible is and this problem is really a big problem in our country. We have 100 cases per year, every year for many decades. So it's a real problem. And even we don't have any Facebook of the patients, they usually went up in the newspaper, in the lawsuit or something. So that's a very, many fortunate and unfortunately when it's combining together, this makes it feasible in our country, I think. No, that's an excellent point. And as my impression from looking in the US at various health systems that have done this kind of work is that there's a champion. There's somebody who recognizes the importance of it and pushes it forward. And so it sounds like you have the same experience. Good. Yeah, I think I'll just also share that in Singapore was also a fortunate convergence of events. So the chairman of the Board of Health Sciences Authority, which is like the FDA was also chairman or head of the executive director of the Genome Institute. And so he said to HSA staff, genomics is the next wave of knowledge. You guys should figure out some way to apply the knowledge. And there was at that time, a small amount of money that was set aside for innovative research in regulatory science. And so that's how we got our start. Also, there are about 80 to 100 cases of SJSTN per year in Singapore for a population of five million. So that's much higher than in the other parts of the world. So, and then another signal that was troubling to us is that about a quarter of the cases of carbamazepine SJSTN were people of Malay ancestry and they're only 13% of the population. So that was a signal to some kind of maybe genetic component there. And of course, the work from Taiwan showing us that there is a high likelihood of a genetic association. Great, thank you. Oh, those excellent comments. Mike, did I see your hand up? Okay, so last brief comment and then we'll move on. So I was going to follow up because I have been very fortunate to work in Japan and Taiwan. So I did observe some commonality. So the first key factor for the successful implementation is you have to have very, very important key component supporter of the testing. So in Japan, I was used to getting the Gamora in Taiwan was YT Chen, obviously. And I think the clinical trial that's conducting the country played an important part. Early on, I think many physicians, they had reservations about genetic testing but the clinical conducted in Japan have not published yet. And in Taiwan, I think they identify a key person in medicine and get them to be involved in a trial. And that's the best way to make them see the benefit. I think after that, the question really diminished. So the Japan is using the same strategy. They are conducting a clinical trial testing A3101 and they look at the recruitment sites all over the country. So I think that's the only way, well, one of the important method to get a message across if you have a trial in the country and I think that basically will answer most of the criticisms that people have for genetic testing. Excellent point, thank you. All right, so we'll move on then to, sorry, very briefly. It's sort of around the same topic of the countries that sort of have the mandatory genetic testing. I guess the question that I have is more of an epidemiologist. Is do you have any evidence that the patients with seizure disorder are better off now that they're using a different drug after they've been tested for Tegretol and not using it? And do you have any evidence that there's fewer cases overall of Stevens-Johnson TN in your country now that you're screening 4502? Since we issued a dear doctor letter saying that it's now considered standard of care, we haven't had a single case of carbamazepine, SJSTN. That's not my question. Oh, sorry. There are fewer cases. Oh, yes, because they used to come, yes. So they're mostly, I think they're mostly being described KEPRA, Leveracetam, and our letter said to avoid phenitone as well in 1502, so I think, but yes. The last two years, the total number of SJSTN cases has gone down. Is that, Tegretol? Great, we do need to move on. Maybe you could have this conversation afterwards, sorry, but I don't want to cut time off for our speakers. So great, so our next session is on case finding and surveillance. The speakers have 20 minutes and I will be ruthless in cutting you off at that time so that we can allow time for questions. So Dr. Lois Labrenade from the Food and Drug Administration will be speaking on pharmacosurveillance in the U.S.