 Can you use the pointer? Good morning, and thank you to Terry Carolyn and Jennifer and the rest of the group that organized this very interesting and stimulating workshop. So I will share with you the experience in Singapore from the Singapore Health Sciences Authority. OK, just to get oriented, Singapore is a tropical country located just one degree north of the equator. And our nearby neighbors are Malaysia and Indonesia. A little further afield is Thailand. And quite a bit to the north and east is Taiwan, and even further north and east is Japan. I'm sorry. OK, so it's a very small country, 26 miles wide and 17 miles north-south in this island. And just for some perspective, it's only slightly larger than the area encircled by the Washington Beltway. So we have some advantages of being a very compact country. So there are 5.5 million people in the country. About 70% are citizens and permanent residents. And the ethnic composition of that group is a three-quarters Chinese ancestry, 13.3% Malays, and 9.1% Indians, and then a small percentage of others. Oh, sorry. So one thing I did want to mention is that it does not have a national health insurance system. There's mandatory deduction from wages to medical savings plans that you can use for large hospital expenditures. There's a system of polyclinics, which are subsidized by the government. But most of the primary care is taken care of through private GP practices. So the population is very sensitive to costs of medical procedures. So the Health Sciences Authority is a relatively new governmental organization. It's only 14 years old. And it consists of three major groups, the Health Products Regulation Group, which has a function very similar to FDA CEDR, CBER, and CDRH. And it's mostly primarily organized by pre-market and post-market, not by clinical discipline. And there are about 300 people who work in that part of the organization. They also run the National Blood Bank. And then they have an Applied Sciences Group, which does all the forensics and some of the drug quality testing. OK, so I'm affiliated with the vigilance program. And so HSA, like most drug regulatory authorities, collects cases of adverse drug reactions. It's a voluntary system. And if we organize it by system organ class, skin and appendages disorders is the largest class with about 50% coming in under that category. And from about 2009 to 2012, about 80 to 100 cases of SJSTEN were received by HSA per year, about 100 per year. So in 2008, we launched a pharmacogenetics initiative. I think I mentioned yesterday that the chairman of the Health Sciences Authority was also director of the Genome Institute. And he urged us to move in that direction of trying to figure out how we could use the advances in knowledge and genomics toward regulatory science. And so really, we had some simple objectives to build some in-house expertise in pharmacogenetics, establish collaborative networks with health care professionals and research institutes, and build some infrastructure to collect and store DNA samples and the associated phenotype data or clinical data of patients experiencing ADRs, and also to collect drug-tolerant controls. And the ultimate goal was to be able to update drug package inserts and make recommendations to health care professionals based on local data. So we started out first setting up clinical sites at the two major hospitals, the National University Hospital and Singapore General Hospital in 2009. And we worked with the dermatology departments, because we were mostly interested in the high number of SJSTEN cases. And then we also were collaborating with neurology departments, because we needed to collect the drug-tolerant controls for the anti-epileptic drugs that seemed to comprise a large number of the SJSTEN cases. And more recently, we've added two other sites, Changi General Hospital and also the National Skin Center. So altogether, we have four sites. And recently, we also expanded and are now collecting dress cases. So we have now, after five years, 59 cases. Anti-eptoleptics is the largest category. Then we have antibiotics. We have seven allopurinal cases and then a smattering of other things. And in that other things, we include two cases of strontium raliate. So we collected 13 carbamazepine cases and 26 drug-match controls. These were patients who had been on carbamazepine for at least three months with no reaction. And all 13 of our cases were 1502-positive. And whereas only three of 26 were HLA-positive in our controls. So we were able to validate the finding from the Taiwan group that this was a very significant association in our local population. In the 13 cases were three people of Malay ancestry. OK, so while the collection was going on, we were also concerned about the cost of screening all patients who would be going on to anti-epileptics and trying to understand what would be the economic burden of requiring that. So we worked with Duke NUS, the Health Systems Services Group, and they helped us to develop a cost-effectiveness model. Our population was newly diagnosed adult epilepsy patients for whom carbamazepine or phenytoin were considered appropriate treatment. And we looked at three different strategies, just the status quo, which is give it when you need it, and deal with SJSTN as it occurs, genotype, and then prescribe carbamazepine, phenytoin, only to those who tested negative, and then give Valproate or some other alternative for those who test positive. And then the third one was just to start avoiding carbamazepine altogether. Actually, we've been hearing from a lot of neurologists that that's what they were doing because they'd heard about the association. And then in that case, just go to some other alternative drugs. So just to show you the prevalence of HLA-1502 in the different ethnic groups in Singapore, it's a precedent about one in eight to 10 Chinese. It's very common in Malays, one in five, much less common in Singapore Indians. And then from other global databases, we found that it's probably about 1 in 500 in Caucasians and less than 1 in 1,000 in Japanese. So it's certainly not an Asian marker. So we developed a decision tree analysis. And we use a common metric, which is the incremental cost-effectiveness ratio. And a commonly accepted cost-effectiveness threshold is if you have to spend $50,000 US or less to achieve one quality-adjusted life year, then that's considered cost-effective. So if we use an ethnicity-weighted approach to the Singapore population, it came out to $30,000. So overall, it was cost-effective. But if you drill down a little bit deeper into the different ethnic groups, you see that it is cost-effective for Chinese and Malays, not so much for Indians. OK, so with the cost-effectiveness findings and the strong odds ratio in the case control collection, we felt we needed to update the drug label. But before doing that, we held a consultation session with clinicians. And we told them that we wanted to go out with something very strong in the label. And we got a lot of resistance. And they said that, well, the test costs $300 US, and it takes a week to get it back. And that's just too much money. And we need to know the answer faster. So we had a lot of discussion about how to deal with this issue. And we came to the conclusion that we needed to have a centralized testing facility so that we could get economies of scale and the throughput so that we could turn around the samples faster. And the director of the National University Hospital Molecular Diagnostic Center offered to screen various formats for this test and validate one and become the centralized facility. So she was able to get the cost down to under, like, about $170 US and turn around time two to four days. We were happy with that, too, because at the time, the only place where you could get this test was at the blood bank, which they do for tissue typing. And so we felt a little uncomfortable saying, we're going to mandate a test, but you've got to come to us. OK, so anyway, just to quickly then go through. This was what we came up with our final recommendation. The Ministry of Health came in and said, this is now standard of care. HSA changed the package insert to highly recommend testing. We stayed away from the mandated. But we did have some caveats. It's not required in patients who've been taking carbamazepine for more than three months. We said it shouldn't be prescribed before knowing the results, that you should not use benetone, either, if you're positive. And then we had some other caveats that you should still maintain appropriate clinical vigilance. And we've had about 200 tests per quarter. The rate's been pretty constant over the last year and so. And since making testing standard of care, we haven't had any cases, whereas before we had, on average, 15 cases a year of carbamazepine, SJSTEN. So just as my last slide, we learned through this. It was really important to engage the clinicians, especially, and that we needed to really focus on lowering cost and turnaround time. And that we needed the cost-effective analysis to help the Ministry of Health come in with, actually, they came in with a 75% subsidy for low-income patients. And that really helped cushion the effect of our recommendation. So these are the people involved. Thank you. Thank you very much. We have a couple of minutes for questions and discussion. I was just wondering about B-1502 and screening. And the issue of if it's pretty clear in Southeast Asian populations that if SJSTEN does occur, it's going to occur in a B-75-0 type that's not 1502 in a screening type situation. So I was wondering, I guess, first question is if you've got any information about the B-75 serotypes other than B-1502 and whether it might be a cost-effective approach just to actually identify B-15, given that most of the B-15 in Southeast Asian populations will be the B-75 serotypes just to encapsulate all of the risk alleles, even though there's only a very small risk, I guess, of having B-15 B-75 serotypes outside of B-1502. There still is a risk. Well, so we know that there's in the Malay population, I think it's 1511 or 1513. I can't remember. That's actually quite high. And I don't think that that's associated with SJS. So we did need to go to 1502 to four-digit resolution. I'm not an immunologist, so I don't know if that answers the question. Yeah, I mean, I'm just wondering if there's a way of designing an assay, like even an SSOP or a molecular assay that defines the risk without actually as a screening test. I guess, similar to what we did for 5701, where we actually defined in the unlikely setting that there were rare alleles that came up that were very similar to 5701 that might be risk alleles that you'd still be defining that area at risk. And I'm not sure if that's being done for 1502 or B-75. I know in other populations, and Wenhang and Shwenyu, you've had certainly a number of patients that have had B-15-21, which is another risk allele. In Taiwan, most of the hospitals do the easier way. B-15 just took at B-15-02, because the time is quicker than to look at all the HIV phenotype. But some hospitals can provide all the HIV phenotype instead of HIV-0-15-02. So if we, some hospitals have more information about all the HIV phenotype, we will find some patients with B-75 earlier, such like 15-11 or 15-58. Then we will also recommend, should be careful, and recommend them to show another anti-evident drug. But it's not just, not available for most of the hospitals. About 10%. Could you use your microphone? With deep sequencing techniques now, some of the alleles that were previously called B-15-02, for instance, on Sanger sequencing, actually will be recalled B-15-21 anyway. So I just wonder if there's any data of how much of, I would assume we're encapsulating most of the risk population by screening for B-15-02. But it's not the entire risk population, I guess, is the issue. So you're not quite up to the 100% negative predictive value, not including all of the B-75 serotypes. But it may be very population-specific, I guess. So that's one consideration. Thank you, Dr. Philips. That's a very relevant comment. But we need to go on, please, to the next presentation on the Indonesia experience. And we have Dr. Rika Yuli Wulandari, who is the head of the YARSI Research Institute at YARSI University. I'll have your slide. Which one is it?