 Okay. Thank you. Thank you, Shanita. Okay. Ebony, you want to come on up? Before NHGRI can publish a funding opportunity with a set-aside of funds, we need the approval of an external advisory group. Now we always use our counsel for concept clearance so that you know the full range of things that come forward from NHGRI. So Ebony Madden, Program Director in the Division of Genomic Medicine, is going to present the concept for Ignite 2, and then there'll be a discussion by the counsel and a vote following that. Hi. Good afternoon. I'm actually presenting on behalf of the Ignite team that you see here, actually implementing genomics in practice. So a few of them are here with me and they're forward. They'll come when it's time for questions, the entire team will come forward. So Shanita just described what's going on currently in Ignite, which is one of NHGRI's networks that was developed since 2011 to explore genomic medicine and clinical care. In these programs, we've learned information about EHR-driven phenotyping and follow-up, return of genomic results, newborn and clinical genome sequencing, variant curation, actually implementing genomic medicine in diverse clinical settings and populations, pharmacogenomics and complex disease risk. From the first genomic medicine meeting in 2011, we heard about the need for the evidence of clinical utility. We also heard these reports from the National Academy of Medicine Genetics Roundtable, professional societies and consistence groups, as well as insurers. Eric talked about this report and his director's report. They actually, a quote from that report is, the gold standard of clinical utility is the evaluation of results from prospective trials that have randomized subjects genetic testing or no genetic testing in an effort to compare differently genetically informed treatments with usual care. And over 10 years ago, Evans and Relling said that their enthusiasm for advancing molecular technology and defining the human genome has not yet been matched by the willingness to incorporate this technology and knowledge into well-controlled and monitored clinical trials. So this illustration from that committee shows that the level of confidence and the evidence of clinical utility for the different study designs, the arrow on the left denotes increasing confidence and evidence. It goes from case series is having the least confidence to case control studies, observational studies, controlled trials without randomization, single randomized controlled trials, and then independently replicated randomized controlled trials. Randomized trials assess the impact on patient outcomes and they're widely viewed as the most solid form of evidence supporting clinical adoption. But they do have biases as well. They have selection biases as well as adherence bias and sometimes they may contradict observational evidence such as what happened with the women's health initiative. Randomized trials are also expensive, lengthy and cannot be conducted for every intervention or every gene. Although the classic randomized controlled trials provide the evidence of clinical utility, the interventions are not always quickly implemented into clinical practice. In fact, a review by Ford and Norrie stated that pre-magnet trials developed out of the concern that traditional trials did not translate into practice. Traditional randomized controlled trials study the treatment impact and carefully selected persons under ideal conditions and thus they just focus on efficacy. And traditional trials often see reduced effectiveness when implemented into routine clinical practice. But pragmatic trials are designed to test real-world effectiveness in broad groups. They use flexible protocols to assess effectiveness in real-life clinical settings and results can be generalized to routine practice settings outside of tertiary care. It's important to point out that the classic standard trials are high costs and need a controlled environment but pragmatic clinical trials have high external validity. Large sample size, a simpler design can be done in diverse clinical settings. They can be customized to the local setting. They have greater generalizability and usually are lower cost. So back in 2012 when we were contemplating at night, we had major questions about the feasibility of genomic medicine implementation outside of highly specialized centers. So at night was initiated to assess and disseminate methods for effective implementation in diverse care settings and Shanita did a nice description of Ignite. It was a series of network groups with lead site and partner or doctor sites in diverse population settings. And we've learned that the genomic medicine implementation strategies have translated well into underserved populations such as those in the Harlem and the Bronx as well as to rural populations such as those in rural Iowa. So, Shanita gave an overview of a discussion that happened at the Ignite and Beyond meeting and there was recommendations and what we're proposing for Ignite II is based on the recommendations from that meeting. So the goals for Ignite II is to conduct pragmatic clinical trials and what we mean by pragmatic is in the real world setting in genomic medicine to measure clinical utility and cost effectiveness of genomic medicine interventions through large pragmatic trials, assess approaches for real world application of genomic medicine in diverse clinical settings and produce, oh, I'm sorry, and to produce generalizable knowledge on types of genomic medicine interventions requiring clinical trials and effective methods for conducting these trials. So to go over the design, so Ignite II will support four to six multi-site clinical groups involving diverse settings and populations and the clinical groups would conduct two to four pragmatic clinical trials of established genomic medicine intervention. So as you see, it goes from four to six clinical groups to two to four trials, which means that every trial that's proposed by the clinical groups will not go forward. Each clinical group application will propose one trial to test the intervention that has the evidence of feasibility in prior studies, addresses clinically important outcomes achievable within a year of randomization, and is adaptable to a wide range of clinical settings. Ignite II will also have one embedded LC study on the impact of genomic medicine implementation in diverse settings and populations. So the scope of objectives is to expand and test interventions proven feasible and successful on a smaller scale, includes stakeholders such as payers and policymakers and study design and protocol prioritization, ensure at least 50% of patients recruited from diverse clinical settings, ensure at least 35% of racial and ethnic minority populations. And the diverse clinical settings are community hospitals, family medicine, clinics, primary care practices, those kind of things. So ensure at least 35% from racial and ethnic minority populations. And similar to what Lucia and her team did in CSER II, we would like to release a separate RFA for enhanced diversity with at least 75% of racial and ethnic minority populations. So I am going to walk you through the protocol selection and monitoring process. So applicants will, we'll encourage applicants to talk with staff about the pragmatic trial that they plan to propose, responsive applications. We'll go through peer review. And we will make funding decisions with the help of council. Awarded clinical groups, the pragmatic trials proposed from the awarded clinical groups will then grow through a review process by external committee, the protocol review committee. Those protocols will be prioritized. And NHGRI will select those protocols based on feasibility and importance. The selected protocols will then be adapted and implemented by the steering committee. And NHGRI will monitor performance with the help of a data safety and monitoring board. Okay, and just to walk you through the protocol prioritization process of how that's going to happen. We envision clinical groups proposing a pragmatic clinical trial in an LC research study, such as the example in clinical group once one may propose a CVD risk identification in a LC research study, the differences in implementation. Example in clinical group two, it may be a neurodevelopmental disease or disorder pragmatic trial. And they're looking at the differences in acceptability in populations for the LC research study. So envision the number of trials in LC research studies being proposed. Then a protocol review committee will review both the pragmatic trial in the LC research studies and prioritize those trials. For instance, they may consider the CVD risk identification trial to be a priority, but not the LC research study of clinical group one. Another example is they may not feel that either the trial or the LC research study from one group is a priority such as that in clinical group two. NHGRI will select the protocols to go forward based on the feasibility and impact. And so to adapt the protocols, the steering committee that includes NHGRI in the coordinating center will adapt and implement the protocols. There may be instances such as shown under clinical group one where each clinical site implements a single trial or in clinical group two, the example clinical sites may implement more than one trial. There also may be an instance where a clinical group may not be able to implement every trial that's chosen to go forward, although we'll aim for all the clinical groups to participate in all of the selected trials of the network. This may not always be feasible and we do realize that. So proposed pragmatic trials should be adaptable to a wide range of settings, including resource limited sites. Proposed an intervention with preliminary evidence of improved health outcomes and cost effectiveness, be able to be expanded network wide, be relevant to racial and ethnic minority participants and resource limited sites, and address conditions of high public health significance. Expectations of the clinical groups, they should have demonstrated ability to implement agreed upon genomic medicine and LC research protocols. They have evidence of institutional support and success in participant recruitment and retention. The genomic testing should be done in a clear certified environment. The clinical group should have a plan for integrating the genomic results and harmonizing the clinical decision support into the patient's electronic health records. They have the ability to recruit at least 3000 patients per clinical group, so that's all the clinical sites within the clinical group. In a high proportion of diverse clinical settings and racial and ethnic minority populations. Possible research topics could be pharmacogenomic space drug selection and dosing, risk reduction in genetically defined high risk individuals, or early diagnosis and critically ill newborns. And as I said before, applicants will be strongly encouraged to discuss proposed trials with staff before submission. So the embedded LC research study will be one network wide study of genomic medicine implementation in diverse populations in clinical settings. Possible projects could be an assessment of near mid or long term outcomes of importance of patients, clinicians, and communities. Or comparison of implementation strategies across the network to identify potential barriers and solutions in different communities and settings. The Coordinating Center for Ignite II will participate in the planning and development of the network infrastructure and committee structure. Participate in the adaptation of the protocols. Develop the manual of operations and reporting forms. Receive and disseminate recruitment in other monitoring reports. And receive data from the clinical sites for statistical analysis. They'll also help in the preparation and writing of reports in the manuscripts. So we propose that Ignite occur in three stages. Stage one includes protocol prioritization and adaptation and IRB submission and approval. In stage two, we expect to start recruitment in six to 12 months and expect recruitment and follow-up to take about three to three and a half years. As you see in the light gray, we expect at least one or two of the trials to go forward at the end of the first year of the network. Stage three includes analysis and disseminations, which will be done in the final year of the program. Protocols should have the power to detect clinically meaningful differences within two to three years of recruitment and intervention period. So, why the complicated design? It permits multiple investigative initiated trials rather than a single NHGRI selected trial. It allows the adaptation for network-wide implementation after review, which ensures currency and timeliness. It permits trials, it splits large trials across a broad spectrum of clinical settings, and it utilizes a mechanism that's been proven effective and nimble in other programs. Although this model is new to NHGRI, it has been tested in other programs, as I mentioned before, and these are just a few of those programs where it's been tested and it's been very successful. So, the funding model is a little complicated because it's a complex program. We expect to provide a base level funding of about 250,000 direct costs per year. The clinical groups would then agree to milestones and timelines for each protocol implemented. Each clinical group would receive a multi-year supplement to carry out the selected trials, in addition to the base level of funding. And supplements for each of the selected trials will be reviewed for approval by council. The budget estimate for Ignite II is about $32 million over five years, and it's total costs. We expect the first year of funding to be lower for the clinical groups is only the base level of funding will be provided for the steering committee to work together to adapt the protocols. And also, I would like to point out that the LC program is contributing about $400,000 a year to support the network-wide LC research study. So, unique aspects of Ignite II will be conducting network-wide genomic medicine implementation trials in multiple disease areas. We're providing generalizable knowledge about the use of pragmatic trials in genomic medicine, comparing trial results to non-interventional studies to identify biases in observational data, and providing clinical as well as cost-effectiveness outcomes. We're assessing genomic medicine implementation across the first settings in populations. And thank you. I would like to particularly thank the extramural research program that really worked together to improve the initial concept. I'm happy to answer any questions or entertain any comments you have. The 19th, the 4th. Eric? I have a couple of comments and a question. The first comment is, I'm enthusiastic about the design. Although, when you presented it, it did sound complicated. You had a slide with four or five. There are many examples of this, and it is sort of a way of moving forward with pragmatic trials on a national basis. It's not, somehow I get the feeling the group thinks that this is a big experiment, that this works very well in other settings. It does take a lot of management. I'm involved in one of them, so there's a lot of management that's required to make it work. My other comment is, and I apologize, this is probably my fault. I missed that there's going to be another RFA with a minority supplement. I guess I don't understand that at all, because it seems to me, I thought Ignite was about moving the programs into diverse communities, and it sounds like you're, I just don't understand it at all, and I'm not sure I'm in favor of it. And then my question is, why is this not just a new program? I'm laughing because that is what staff has moved around. I mean, maybe this is semantics in silver. You can call it, you know, whatever. I don't know. The mother fire analogy. It doesn't sound like Ignite II. I think that's a trivial point. So I would not let, I won't, don't get bogged down on that. But I, the thing I worry about is it could influence the review. Continuations have a subtle difference in review than new programs. Just keep that in mind. But I think this, the question of a minority component, you know, I'm wildly enthusiastic about the need to include, to increase the role of minorities. But again, I thought that was the entire purpose of Ignite. And now there's going to be a separate RFA. I just, I think it emerged the Institute did a very good job, and the investigators followed on course, doing a very good job of using that mechanism to increase minority and underserved involvement. But I find it, I just think it's, it's a dangerous precedent. It's every program going to have a minority supplement. And particularly when we have a program whose entire purpose was to expand the role of genomics into diverse communities. And now to have a minority supplement seems to undermine the very program we tried to promote. It's a bit circular. Yeah, that's a great point. And when we initially thought of the concept, we started out as just one and really pushing for the diversity. But we stepped back and we're afraid that the early adopters would not be able to have the percent diversity that we would like. And that's the reason for the separate RFA. But I do understand your reasoning. And I think we should maybe take that back to staff. Yeah, if I could just comment. The reason we did this in CSER is that we were concerned that there would be good groups that were, you know, really very effective at implementation of genomic medicine that just couldn't meet the diversity goals. Right. And in Ignite, the goals there are not only racial ethnic diversity. There are also sort of clinical setting diversity. So getting outside of specialized care and out into, you know, real care. So the minority RFA part of this is only for racial ethnic minorities. It's not, all of them are expected to have 50 percent diverse settings. So it's really, and the 75 percent actually takes it up a notch from what we did in CSER. So in CSER 2, it was 25 percent and 65 percent. And we did really well in getting those. And so we felt we needed to provide additional resources to sites that were going to recruit a large proportion of minority sites and not provide those additional minority participants and not provide those resources to sites that weren't going to recruit those. So that's why, but if Council feels that we should go with one overall number somewhere in between, that would be something we could do. But to be clear, Council, I'm not speaking for Council, I am sure there's going to be wild enthusiastic support for increasing minority economic and just non-traditional sites. You're going to get enthusiastic support. But I think Council probably would continue to balk if each RFA had an attack on, an add-on. It seems like we should look at the entire program and think about the entire program, both from a financial planning point of view. And second, in this case, I think the logistics will become very difficult. I would just comment, it's not an add-on, right? If you're going to do it like CSER, it's two RFAs. And I would agree, I think you're going to get it's already a very complicated plan. I would say it is a complicated plan. I agree there are cooperative groups, but they're complicated. And now you're going to also have two different groups with two different minority. And then the question is, are you counting ethnic diversity in that? And I think it might be better to just pick a number and then have more sites, given all the different aspects of diversity you're addressing. I guess I would just comment. I think it is a little different than the examples that you quickly went by. I think almost every existing example is based around a type of disease or a group of disorders. And I think the big challenge here is the design doesn't specify even, I don't know, my understanding from the concept, which I read in advance, does not like specify projects that would be appropriate for family medicine or doesn't categorize it at all. And the examples you gave with where there's this one newborn one, right, critically ill newborns, and then the others are all much more general medicine. I think you're going to have a very hard time if people view those options, you'll have people applying who then really cannot participate in several of the studies. So I would consider in the language of the RFA trying to not be quite so broad and at least come up with some general medicine description or something, or general pediatric description, so the groups are likely to be able to participate in the projects that are selected. Okay, thank you. So I want to go back to Eric's point. And I do think that there are two different things here. There's the diversity of the sites and the types of sites, and then there's the diversity of the populations that you're looking with. And I think it's actually probably a good idea, so I'm going to disagree a little bit. I think it's actually a good idea to be very explicit that you're actually looking at those two different things and having two RFA's, one of which is specifically asking for a high level of diversity of the populations, I think will actually get that idea across. So I would be more inclined to say that that's okay. Ideally, you get that across all the sites, right, but I think this will help to get that idea across. Okay, thank you, John. Oh, thanks, Eric. So I had a question about the structure, the process where the projects that are going to be targeted are chosen, and that's going to happen after the teams are chosen. And I wondered whether it could actually make sense to flip the process around where maybe even the whole the entire community could help to suggest concepts for, you know, these are projects that should be done and then the teams could apply specifically on the basis of their abilities to tackle those particular projects. And I'm wondering if that would actually produce a more coherent team and teams that are better suited to be able to cover the array of projects that are selected by a larger set of people. You may also get better ideas if you've got more people from the community weighing in. Yeah, that's a good point. We considered doing that of NHGRI proposing, but not actually the broader community, and the reason that we wanted the trials proposed was to get those novel trials from the community proposed and persons that could actually do it in the variety of disciplines and clinical settings. I guess based on experience in Ignite One, I think it, others, they're already piloting, implementing other projects among the sites and just dropping it in. And so it hasn't been a problem, but I don't know how you're saying like maybe a RFI or something or maybe I could comment on one of the things that Ebony tried to point out early on was that we have a considerable experience now in terms of what can be implemented feasibly in genomic medicine from our existing programs. And we want to build on that experience to be able to say, okay, you know, we've seen that this works in pharmacogenomics. It works in critically ill newborns. It works in risk of complex diseases. Trying to get a group together to propose things, unfortunately, often come up with stuff that just isn't feasible when you get down to doing it and when you have the applicants propose it, they, you know, they actually have to do the stuff. And so they tend to be much more practical about it. So it seemed, it felt to us that having a protocol selection committee that would have outside voices that would then say, you know, this really doesn't make a lot of sense or, gee, you know, the field has moved on now since the applications came in, might be a better approach than trying to, you know, set out a set of things that could be done and then, you know, a year later trying to implement them. Right, okay, but that's going to occur in part after the projects are chosen and funded. That's true and, you know, any clinical trial that gets designed when you first start out with it by the time you actually get to doing it, it sometimes changes dramatically and we would expect the same thing that would happen, would happen with this kind of a program. Can I ask one follow-up? So to what extent would the grant review be focused on the proposed project as opposed to the ability to create the trials in general? Excellent point and Rudy has asked us exactly that question. So what we would anticipate is that there will be much more emphasis placed in an RFA like this on the ability of the group to implement a broad range of things than their specific protocol. I can't imagine that a group would get through if they had an absolutely horrible protocol and a great infrastructure. But, you know, probably there will be a lot more weight placed on their ability to do a broad range of things than you would see in, you know, a program where they were being judged on their ability to do that particular study. Doesn't the core network this way? Yeah, I have a comment and two questions. So the comment is that I think it's wonderful that you are going to have sites that are essentially doing similar things. Using similar kinds of protocols, using similar measures, harmonized already because I think the CSER program, which was my experience, and of course that was five years ago, exciting, but harmonization was always a really big issue. I mean, it just has been, it was, et cetera. Now, and it was a baby starting out, learned a huge amount and a lot can be built upon. But that, I think, made it tougher because nobody was telling us exactly what we ought to go out and do. So I think that's a good, that's just my comment. I think that's a good thing. I have a specific question with the pragmatic clinical trial because usually there's a comparison, right? And so I, it's not a randomized control trial, but what would, I didn't hear what the compare, what the- It is randomized. And so it would be the people who have the genomic intervention compared to the people who are being treated with standard of care. So it's standard care is the control. Yes. I mean, it would depend on what the, what the applicant is proposing. So it, so it could be, you know, current clinical care. It could be testing, you know, a panel test versus something else. It could be a variety of things. So, so the, the randomized trial and the pragmatic trial are both randomized. The issue is that the pragmatic doesn't have a very strict protocol with very carefully selected individuals and, and it's, it tends to be built upon clinical care, you know, using electronic records, et cetera, at a much lower cost. So I was looking up quickly definitions and certainly there's a lot of them out there, not, not all of them exactly that. However, that's a great answer to my question. So, but then, then my other, not surprisingly, you'll be to hear that my question is about the LC part of the study. And there I have two issues. And I've seen Nicole is sitting in the wing. Yes. Nicole probably anticipated all my questions, but those, those did not seem, those two possible, here's what they might be, really did not seem to encompass LC. In fact, it actually seemed like any kind of pragmatic trial auto include measures of, you know, perception of what's going on, impact, impact could be economic, could be other kinds of impact. So, so, and equally important though is the idea that you've got a group with an LC study in it, and you may take some, but you won't take the other, you might take, not take, you know, groups propose LC projects not in a vacuum. Like, hey, there's somebody on the street. I think I'll bring them into my LC study. Oftentimes these are people who've worked together a long time. They, they, and so I, I'm really a little concerned about the idea that you would delink them. So, I'd like yeah, comments on both those. What would the LC study be and why would you delink? So, so Gail, the selection of the LC study we would envision would be somewhat similar to what Eboni described for the pragmatic trials. It would go through that protocol review committee and part of what they'd be looking for there is what would make sense based on what pragmatic trials were selected. So it would be chosen in the context of the pragmatic trials and based on things like feasibility, expertise that's available at the different sites. So if one site has a beautiful legal analysis but the other sites really couldn't implement it that might be a lower priority. So it is kind of interwoven which would make, I agree would make it challenging because the LC study will be related to the pragmatics clinical trials. But I think you raised in your comment one of the reasons why we're motivated to do this that we think would be very powerful to have an LC study done across all of the different sites where they're doing the same thing and using the same measures. And it might make sense you know kind of depending on what's selected maybe the LC study is really only related to one of the genomic medicine interventions and not the other one or two. But all of that will have to kind of be worked out. Okay so there'll be one LC study across the entire network. Yes. Oh, uh-huh. I gotta think on that. Okay, thank you. Jeff. Two two sort of quick questions I think. Is there an economic analysis that's anticipated to be part of the outcome measures for each of the studies and a sub question there is are you anticipating that the genomic intervention, the genetic testing will be covered by the trial itself or are you looking at in the pragmatic nature of the intervention whether in fact insurance covers it whether people are willing to pay for it the economic impact of the intervention. Well the for the first question will it be an economic analysis across yes we're wanting them to incorporate cost-effectiveness measures for the trial or your second question will it be part of the trial it depends it will depend on is in the current ignite we have some of the interventions that are covered by insurers but it depends on the insurer it depends on the setting I envision that a lot of the interventions may be paid by the trial because it's going to be once we implement it network wide it's going to be a diversity of what happens across those settings. Yes, yes, definitely we're actually budgeting budgeted for the testing the average cost of the genomic testing. Okay so quick second question that I think is there been any discussion of using the trial innovation network that NCATS is developing multi-center trial support central IRB central contracting data coordinating centers those sorts of infrastructure support are being developed by NCATS and this might be a wonderful opportunity to collaborate with them. Thank you I appreciate that we are thinking it will be a central IRB but I appreciate that we'll look into that as we if it does go forward. So just follow up on that for a second I mean the the trial innovation networks are pretty much run through the CTSC's which may or may not be able to reach out to some of those community in more diverse diverse locations that you're we I think all probably want to see happening. I just want to make a comment and then I have one more question. The comment is I think this is great. Okay I think it's it's really nice and I really appreciate the detail that you gave in the presentation because the three pages limits an awful lot of details. I had a bunch of questions that you all answered in the in the thing. One of the things that I think was in there that I'm not sure that I that I heard was the comparison of the pragmatic trial the clinical trial to the observational to potentially comparing that to the observational data that you might also have to see where the biases might be and the observational versus the trial which I think would be a really cool thing to be able to do because if you could identify where some of those biases are it might help you actually be able to get more information out of observational trials and than the clinical trials which might be a more efficient way of doing things going forward. So is that something that's that is built into this or elaborate a little bit on that. It is built in. We're asking that each applicant have a plan to compare the trial data to the non-interventional or observational previous studies or the data from current studies. And so that will then as the trials go forward we hope to take that plan and compare that across the network. Terry you had did you have more to add? No, I think you've summarized it well and recognizing that in order to prove that the trial that they're proposing is feasible they're going to have to have a base of observational data and then to be able to go back and compare to that when they have the results of the trial. I think we'll be really informative as to what kinds of studies we actually need to do trials in the future. Just a practical point your timeline is quite aggressive. I mean for the that last kind of Gantt chart and particularly if it's going to involve having to get supplements out and everything you know it just seems the reality of getting the IRB approved protocols and yes have used the central IRB and if all the sites are willing to do that I would just caution that it seemed a very rapid ramp up and so you may just want to build some window around that you know for your own planning. This is a great point we agree it's very ambitious and we'll try to take that into consideration thank you. So my question kind of builds on that which is you're going to get applications to be members and they might have the infrastructure and expertise to do the trial they are proposing but their trial might not be selected and but they're going to be asked to do these other trials which because of you're pushing this out into perhaps into smaller specialized settings they might not be equipped to do the trial that selected. So is there going to be an opportunity for those groups to come back and ask for additional support so they can in fact be ready to do the trial that selected if it's somehow not optimal for their situation. So we will supplement the groups based on the implementation. So the clinical groups and the clinical sites within those clinical groups that will participate in each trial will be supplemented accordingly. So we would provide the resources for the implementation needed such as if they need to enhance their clinical decisions for their electronic health record will that's part of the multi-year supplement that we will give and we're hoping that yes they will have the resources and environment to implement the trial they're proposed but we're hoping to write the RFA to ask for a broader environment with different disciplines to implement other trials that may be implemented in the future as well. And just keeping in mind their their base funding will be really base right. So so they just get 250 direct costs per year and that's that's basically to maintain the you know the investigative group and then one of the reasons we didn't want to have them come in and get funded for an entire trial was that they could propose a three million dollar trial and end up doing a 12 million dollar trial and and then how would we handle that and those supplements will come back to you so so you will see what we're proposing in terms of of the trials. So the other quick thing is that you you showed a slide of other pragmatic trials underway and and people have said that there are other ones that they know about I'm assuming none of those have like a genomic medicine implementation component to them that that's one of the unique things that this whole yes yes. Just one more quick thing I've just been mulling over it feels to me like the LC component of this while I could see it being a logical thing to have LC applied for with these different applications. I think it makes more sense to simply send out a request for LC projects that could be applied to these kinds of trials. It doesn't make it almost makes it makes no sense it seems to me to hook yourself up to somebody that may or may not get chosen or funded or whatever you want to be able to be nimble as an LC project. So I'm wondering why you've that's just a comment it but it just feels to me like it really might you might get the best quality proposals if it's if it could be broadly applicable to whatever particular site and setting et cetera you that you have. So Gail, just to make sure I understand your comment are you proposing that perhaps the LC study could be awarded after separately once the pragmatic trials are chosen? Yeah. And then then the applicants could say I have an idea about the pharmacogenomics study that was selected and I proposed to implement it in this way. So it strikes me that there's a lot of LC I don't want to say that's generic but there are particular questions. Oh, please don't ever tell anyone I said that. It's being webcast Gail. Otherwise I'll have to you know, I don't know what but no but it just it to me it doesn't make a lot of sense to embed it I mean embedding only makes sense if those are your guys and gals and that's what you're going to do and that's who you'll work with and that's the best thing for the whole project the whole team but it doesn't sound like that at all from what you've just said. I mean like you just the example you said well suppose somebody's just awfully good at legal analysis but not at something else well I mean I would think it should be good at all you know legal et cetera I think it should be applicable to all the kinds of trials that you might be considering. I don't know why you wouldn't think that would be of kind of a better plan. Well that's a different definition of embedded. Yeah, so I think overall we were really enthusiastic about having some LC component in Ignite that would be implemented across all groups. I think in terms of how that is structured that's a really interesting point that if the LC component is going to be reflective of the pragmatic trials it might make sense to have a delay or have it awarded afterwards so that that can be taken into consideration because they'll both be adapting the LC trial that research has actually done in the LC research program and to the different pragmatic trials and the different populations because of course if there's a lot of pediatric trials selected you might want to ask different questions than if their adult trial selected. So I think that's a really good administrative suggestion Gail that we can think about what is the best way to still have that work done and tie it in terms of a phasing to the to the main project. Since you just mentioned the pediatric thing and I would give very careful thought when you're writing the RFA about whether you want each team to therefore be able to accomplish both the pediatric and adult trial I mean I would word that pretty carefully because yes there are definitely large networks to care for both children and adults but there are a lot of networks like the VA for example that only care for adults and might put in a great project and I would just think about because that way people will at least put the right kind of team together whether you want them even if they don't even if they propose to adult projects that they at least have to describe who in their team would do a pediatric project. I just think that would will make it easier to get groups that are going to be able to work in this model where the where the projects are decided afterwards. Great suggestion. Thank you. This will be criticism but I'm not sure that there's an answer to it and that is that as I as I think about this and look at it and I've read the proposal I am very concerned that this is way too tight a tight timeline and way too expansive a program. The you know we had a we had half a slide on an economic analysis. Now that could be the entire budget for this. We were uncertain whether we have pediatric or adult sites. We also have oh by the way this is going to be in a clear environment and embedded in your electronic record and that's not going to happen over the course of a week or 10 days either. That's a process that at many institutions will take long long times to get to get accomplished. Now that may be a parochial comment in the sense I think it takes a long time at our place and maybe every other center around this table can do it in a week and a half but I do think the timeline and the expectations the timeline is very tight and the expectations are excessively high. And I don't know I don't know how to I don't know what response I expect from that comment because at the end of the day I think this is probably the right idea going forward rather than sort of saying well you know we're going to do a clopidogrel trial or we're going to do a pediatric cancer trial the idea of going forward with a sort of a menu that then everybody agrees on and I'm not sure who the everybody who makes the final decision is but that's sort of to be determined. So I'm very concerned that this is an example of trying to cover all the bases with a budget that is clearly or that looks or feels to me inadequate and timeline that feels unduable so I don't want to set us up for failure so I'd be interested in your comments sorry. Yeah I think in terms of the timeline one of the advantages of building in the you know the supplement model is that we could postpone awarding the supplements until they're ready and that's probably a better way of doing it than building it into the grants from the from the outset so that would be the plan. Also don't you have the ability just to do I believe your number was the low end was two you know so you just reduce the number of trials if indeed you get squeezed which you may be. All right that's been very thorough discussion so can I get a motion to approve the concept? Second all in favor any opposed any abstentions and Aviv you can vote by email. All right thank you very much. I also see it by phone and I'm voting by email. Thank you dear. Thank you. No she doesn't get two votes. So I'm concerned about your caffeine levels why don't we take a 10 minute break be back at 320 to resume with the the sear concept. Okay.