 Thank you. Well, thank you to the organizers for the invitation and Exciting meeting and something that definitely Needs to go forward because of the practicalities and you know It's it's it's wonderful to be in a situation where we need to solve this problem as a point as opposed to Maybe what we should have done a few years ago, and that was try to solve the problem But you know sometimes we need that we need that pressure to to really go forward In the in the area of pharmacogenetics that the same issue was there and there's a number of us who were in a situation where We were going forward at our own institution with with genetic tests to predict drug effect But there weren't national guidelines or international guidelines or even discipline-based guidelines to go forward and so Three people in particular Mary Rowling at St. Jude's Dan Roden at Vanderbilt and myself Bemoan that fact and then we each set up our own separate way of doing it We had one called smart drug that we thought was well-named at least and then the the others I had their own versions and then the pharmacogenetic research network and we're sure long as here where it was able to really coalesce into a a much more formal and and a Concise a way of trying to really tackle this issue of something called the clinical pharmacogenetics implementation consortium and and so it really the the the issue that each of us in the room look at Pharmacogenetics is quite different There's a lot of the early discussion was really in the how do we take a genetic variance as they've been discovered Can we're under where the pointer is along here somewhere? How do we take genetic variance as they're discovered to use that one or is there a lightsaber version? All right. All right. The one that says eject Okay So, you know a lot of the discussions was a how do we take new variants that have been discovered and try to make sense of them That certainly is important There's work in terms of try to find those rare individuals that have some kind of either genetic predisposition or some sort of phenotype And do something about them. There's a lot of other phenotype base work But really on the on the clinical practice side There has been very little in terms of guidelines and recommendations in the pharmacogenetics area We're at least one from from eGap, but in terms of the volume of work. There's there's been very little and So we put together some effort to try to try to tackle this Part of the problem is been the way that we in academia have have tried to solve this issue And that is that we've been great at discovering things We've been okay at validating and we've been completely crap at anything after that and I know a hrq has tried to help us be better But we we have resisted their help and you'll tell us what we should be doing next in the next talk but really the idea of Stopping at New England Journal and rather going forward is is something that you know We we have to take some responsibility for And and has left us in a position like we are now trying to figure out a pathway and so in the in the Ways that these have been evaluated A number of different questions have been asked in a lot of times the question is is You know is pharmacogenetics useful or when should a test be ordered or what does enough data look like and then there's my personal Favorite is anything ever ready for primetime and you know those of us the right grants to the least in the US side I know there's a UK equivalent of this But if you ever don't like a grant, but you don't know why just say it's over ambitious And and it's the same. It's this is the over ambitious equivalent It's you know, well, it's not ready for primetime, which means I don't know how to do it and therefore It's not ready for primetime and so we we've really approached it in in that sort of way And so we try to change it around take you know those of you that speak French Please pardon me, but the Voltaire English translation version of a perfect being the enemy of good You know can we do something with these tests? And so yes, I stuck the word in there for you David You're welcome. If a patient arrives with pharmacogenetic, is it Action of all and yes, we have t-shirts and and screen savers, etc for you But the idea that not should we order the test or that's but if they come in Can we act on it or or should we act on it? It's been that the basis for for the the approach now the pharmacogenetic research network and the pharmacogenetics knowledge base, which is they the online affiliate of that have a detail a number of different consortium One of them being this consortium that I'm briefly talking to you about today This consortium has individuals from 60 different sites 33 different institutions Sorry six different members from 33 institutions Including some international representation those of you from the UK. It's Manchester and Liverpool I know the dots are so big it covers the entire UK, but there you are It would be great to have more representation from there, but that's a it's a start. Also. There's a funny color there in Leiden It's supposed to be Leiden because the the Dutch group brings a whole network of Dutch investigators in there Then we have Spain and Italy also a Taiwanese group and a Brazilian group Just to bring some extra flair Observers from the NIH institutes from the FDA are our participants in this list And it's really the approach for those of you that are under 30. This is crowd sourcing We have to have some translation because for those of us who are over 30 But we've just basically took a bunch of people and said all right Let's build some consensus around these in a expedited fashion now. We've we've Really prioritized based on community input. I'll come back to this in a in the next slide In terms of how we've we've developed this the list we've No, I'll prove that the the other part is we've really looked at recommendations around the the action that can be taken And so I put this on here that if you know, if you've ever had a paper that said more research is needed at the end of it What that means is we didn't do the right experiment and and it's the same thing You know, there's so many guidelines where more data is needed Well, duh, I mean of course more data more data is always needed But the the when the patient comes in they're not saying I'm sure I come in now or is more data needed You know, they're they're coming in for some help now And so you give them the best help you can give them now realizing if they'd come in a month later You might have been smarter and and that's just reality And so we've tried to take that approach where yes more data is needed, but what can we say today? Now let's see the other things I want to as a disclosure down here This is a group of people who think pharmacogenetics matters Many of the people on this group it doesn't matter what the question is the answer is pharmacogenetics So as you realize that you know, we're looking at it saying we believe but how should we apply it? So it's trying to figure out which version of religion not should we not is there a God? And so there is a bias there in terms of how do we implement this stuff? Not should we or even consider it There's an assumption that the data that we're talking about will go into electronic medical record And you'll see that as we get into some of the ways we evaluate this data that that is an important part of this We think that it'll be clear and the US Whatever the European or the UK version of that is for in terms of the quality of analysis We have also started with with what I consider baby steps. So we've gone and taken lists from professional organizations lists from FDA labeling Taken sources from center Medicare Medicaid services or other third-party payers Any place where there's lawsuits that have penalized the clinicians we haven't left that out So that's mainly been the Steve's Johnson syndrome type of areas where there's available standalone clinical tests where there's clinical trials just Suggesting the sort of functional variation Functional impact narrow therapeutic index, you know, I jumped the very last one Examples where there's clear evidence for for one drug and There's other drugs use the exact same pathway and have similar in vitro or in vivo Data suggesting that if it's true for a it will also be true for B And I couldn't think of a better way of saying that but hopefully you get what I mean In terms of trying to look at if we make a clear statement one way what other data what other examples should also then be be be true So this is an example of a survey that we did Mary Rowling leading this effort Looked at a number of members of the American Society of Clinical Pharmacology and Therapeutics They came up with a list of different drug gene examples they the most The the one that was quoted the most often was Ciptoce 9 and Warfarin and list goes down Three of the top 11 were for a thorough pure and methyl transphase And and because Mary Rowling was one of the pioneers in that area and she was the head of CPIC That's where we started. So this was a good excuse to do it But it was a key key one And so we've taken those kind of survey type data as a place to start We have a large number of examples that are either already published and I'll show you a little bit of those or are either impressed or have been initiated Again coming from either surveys or requests that have been made From a variety of different people from regulators from third-party payers from from clinicians from members of the CPIC alliance We developed the guidelines in a don't worry. I'm not going to go through each of these But we have a structured format in terms of the evaluation We've tried to take best practices from from eGap from a number of the other guideline building organizations and and put them into place with with the practical endpoints being around Interpretation and action ability It's information on the gene information on the drug Information that it includes available test options including non-genetic test options So for example, there are some tests where there's a genetic test. There's a red blood cell phenotype test There's a blood level test There's even a breath test in some cases that they give you the the exact same type of data And so we try to put all that in the same document. So one doesn't just think that the world is a double helix So this is an example of one for thought a period multiple transfer race that came out earlier this year was one of the first examples that that came out and From that really looking at what genotypes have severe functional effect that would change clinical action And then what drugs are so clearly affected that clinicians would be wrong not to act on the data So really looking at whatever David wants to call action ability in terms of our approach And we get these tables and this would be the kind of table that we would put on a t-shirt and give to every clinician No, not really this is sort of data that if you wanted to dig into it would tell you More information if we blow it up a little bit. We're actually giving Drug dosing recommendations and our version of the level of strength of the data So the it's not one should consider testing for it's you should test and here's what you should do Based on that Realizing that's an iterative process But the biggest complaint from for example the FDA label change has been they recommended that the test be used They identified risk, but didn't make any recommendations on what to do with it And so we went that final step now There are some examples where the answer is this test should not be used or that there is risk But we don't know what to do other than not give the drug and and so it's not exact It's not as if this select group has all the answers. We haven't been telling you It's it's as we look through the data can we act should we act what should we do has been how we've been driven In some cases, it's it's a an algorithm-based output that comes that comes forward But in skip through the interest of time As they they've come out We've been iterating in terms of the way we've done these in terms of the quality and also getting a lot more participants So the initially it was an insiders club in terms of people who were early adopters to the consortium Now there's people who have read these and say hey, I'm really interested in this topic I want to be involved with it and in some cases. I want to make sure you guys don't recommend something crazy Is has been the the motivation to be part of this Farm GKB itself has not only the papers and the recommendations, but it's also brought in other types of guidelines So for example, if you were to go to the site, I did this screen capture to show that it has for example The CPIC recommendations, but also what should an orange here are from the Dutch farm good genetics working group and and so any National or international recommendations that come out will be pulled into this site and so even within CPIC We don't think we're the answer to all questions But rather trying to pull things forward and in the case of the Dutch group They are now part of CPIC and so their their input is part of the recommendations that are that are coming forward this is the last slide and First of all was that there's a lot to do and so anybody that that wants to be actively involved with this or know someone who does Please go to the farm GKB website. You can see the rules. There's a memorandum of understanding. There's publication Recommendations except or not recommendations, but rules you can go on there and you can sign up and be be part of this Secondly, we we really want to do this, right? We're not doing this for for academic career development We're doing this to try to help the field go forward And so any comments that people have either now or or via the website Would be very well received even if they're hurtful and malicious because they they we do want this to be a better process As we go forward and then lastly in the clinic a no guideline isn't helpful We need to be trying to look at a lot of the drip What's been driven here is is not should we do it or not? But if the data is there whether it's from 23 and me from a whole genome scan from some quack that they saw before us If the data is already there, what should we do with it? And so rather than saying no, we need to say why it's no or how and when it's no In terms of those and so I'll stop at that point and do whatever we do next Questions or comments net I'm glad you clarified because I didn't know guidelines very helpful if you know why you're saying no right Yes, it's totally unhelpful, and I will own this is I don't know right and that's I think we're a lot of where we're at So you're right. We need to do a better job when we don't know So I'll pick on the TPMT just because it's it's one of my favorites and In the recommendations it it sort of separates out Or it doesn't address to my knowledge the clinical context in other words. Are you using is a fire print for treatment of? Inflammatory bowel disease as opposed to cute little phoblastic leukemia The you know the risks related to the efficacy effects, which you know some people are dismissive of I happen not to be Are different in those scenarios and so can you tell me a little bit about? how you're trying to balance the Efficacy versus adverse events because I'm cognizant of the fact that we're three times more willing to kill somebody by not doing something Then we are by doing something and that's well documented that we're much more Sensitive to adverse events then by killing somebody from not giving a proper dose So you've identified an important element in some cases the test and the drug are associated with one area And that's it, but in that period with the transferase the uses are dramatically different Not so much dramatically different terms of the the effect of the drug But in the terms of the type of monitoring that a patient receives with In this case we developed this initial one and it's mainly focused around childhood leukemia Partly because we wanted to get a first one through the process and out and then we can iterate on that Partly because we didn't have at the time a lot of rheumatology gastroenterology dermatology folks involved and that has changed And and and partly because of the focus of those who were involved It's very true that most of the time TPMT testing is not done in childhood leukemia even though that's where the package insert recommendation is mainly because most hematologists are very comfortable with neutropenia and the idea that that What in fact neutropenia is an endpoint in in some cases they they treat to in to neutropenia in rheumatic disease in gastroenterology And certainly in dermatology Often they don't see patients more frequently than once every month or every three months in in a case where where Someone might have toxicity on day 10. You don't want to wait a month And so there've been that's where the big uptake has been in the in the US and at least based on the literature surveys Also in the UK although I think that's changing but That's that's why we did it that way We're trying to get better at that and now that this is out there. There's some publications It's easier to go and get people involved. So we had an HIV example. It's coming through the pipeline It was very easy to go get HIV Physicians and and clinicians from different parts of the world involved with this because they could see what's been done in the past I didn't have to imagine it and they they knew it was an issue and then they they got in Does anybody doing health economics analysis over each of these variants to work out, you know prevalence in the population what the sort of dally affects So we have not included it yet in this for some of the same reasons and lack of expertise is an important part of that The the health the health economists so in for the TPMT example There have been a few health economic analyses that have been done both in the UK and the US the The good news is whatever you want the answer to be. There's a paper for you And and so I think what that's focusing on is that the right study hasn't been done or or or such And and but I do agree that this is a really important part of it I mean even in the US we're waking up to the fact that drugs cost money and we need to be aware of that They may have they're not the public domain that I'm aware of Actually that's being done again for reasons that within integrated systems. There are very few people that are actually have the expertise to do it We've we've done it In a couple of these examples Lynch syndrome Which we published in the American Journal Managed Care in August of this year The problem in the US is what perspective do you take? Because we don't have a national health care perspective as much We'd like to pretend that we do and so the issue that really comes down to is is that There may be a something that's cost-effective from a societal perspective But as a hospital it's going to cost me a ton of money And it may in fact make it'll the effect my margin to the point that I can't be viable and there's no way for me to recoup So we're in a very Challenged position to be able to do this from a US perspective since we really don't have one since we're disintegrated Yeah, I would afford the HMOs, you know From that point of view prevention is good at that too because well But but it isn't it isn't because how long are you going to keep that member? So if your member turns over in two years and you prevented something that's five years So it's not a it's not a simple question And that's one of the reasons why I think nationally there's talked about accountable care organizations So the idea is is that wait a second. We're all providing health care We all have a stake in the health of the nation Therefore, we all have to chip in to the pot now how that's actually going to play out in terms of implementation is not clear There's another dimension of that that should get inserted here And that is that any one person really doesn't give a crap about the effect on the national economy One health organization if I if I've got a condition or I'm being suggested to take or not take a drug All I really care about is is it going to work for me? I'm sorry, okay. Thank you