 So, yes. So one of the issues that keeps coming up every time I talk to anyone about the medical device determination for these kinds of pipelines that we're talking about is that this data can always be revisited for, you know, in the future to find other useful information. How is that being dealt with as far as, like, how do you include that in the definition of this medical device? Because it seems to be really unclear how that's being dealt with from the FDA's perspective. And I think that's difficult because when these regulations were written back, you know, in the late 70s, this was not done. And so obviously it's not there because, as we said, you even said, you know, things have changed in the last 10 years. We used to not have a lot of IDE studies. And now we have more. And now we're talking about people doing that. And I also think that it's been interesting with the revisions of the common rule and some of the issues have come up there with, for example, going back and how are we going to address that in consent, which I still think is a big question that people are struggling with. So I think that's hard because I think the question really is how are you going to be able to inform somebody that this could happen and that you're not going to be able to actually provide a concrete description of what may happen in the future. So I think when we are doing IDs and risk assessments, we can only really deal with what you're proposing to do at the time and that obviously when you're talking about going back and potentially recontacting, that's a whole. Unfortunately, that's almost a whole different assessment of risk because it's going to be different than what your original study is for. And I also think, as I said, I mean, I think it's an interesting conversation that we're having because even the common rule is touching on that and how we're going to do that. But I mean, you're not going to be able to consent or tell people how that's going to happen at the time of the original study. So I think you're going to have to almost then go back and do a new decision matrix when you're talking about recontacting and doing new research with the same data because it's different in my role. Hi, I'm Marcia V. Tall from NHGRI. You talk about the level of risk above and beyond the standard of care. And you've talked about common diseases such as cancer and infectious diseases. At NIH, we deal with a lot of rare diseases and some of them are extremely rare. And for some of these diseases, there really isn't a standard of care other than what RPI recommends because he or she is the expert in the field and he or she is the person who sees this cohort of patients. So how do you, with the FDA, judge standard of care for these extremely rare diseases? Well, we recognize that there are rare diseases for which there is no accepted standard of care. So in doing a risk determination, for example, we would not likely feel that a patient in a current trial would be with a particular disease where there is no standard of care would be, we would not typically feel that they would be likely to be denied standard of care or denied alternative effective therapy. So that probably would not enter into our risk determination equation for that particular trial. So as someone who has been handed a significant risk assessment by the FDA, I have to say I went through all the stages of grief, every one of them, including anger, but I'm firmly in acceptance now because it actually was very helpful to think through, for example, in our cohort where we will be giving parents a choice to learn about things like a BRCA1 mutation in a newborn, right? What are the possible deleterious downstream effects of that? I think what is challenging is that because you're not taking into account benefit, essentially any research now that returns results, I think, will essentially have to be determined as being a significant risk because there will be impacts on that person's medical decision making on a result that they wouldn't have been aware of. And so I worry that there's not a good indicator of when something is not significant risk in my type of research. I don't think that it has to do with confirmation, actually. I think that wasn't a decision at all. It was, these are healthy babies, they're getting some results and there's potential downstream harms. The same thing can be true of healthy adults receiving potential results, even if they're recommended by the ACMG, there could still be downstream harms. But the reason that they're considerable is that the benefits are thought to outweigh the harms, right? But if all we're looking at here is harms, then I worry that it's, you know, we're looking at IDE submissions for just about any genomic medicine study that's returning results. Prove me wrong. I just wanted to acknowledge that I realized what I said was at odds with what Dr. Cappacino said earlier today that, I mean, it says in the talking points, the points to consider that my colleagues at NHGRI have helped to generate, which it clearly has all the appropriate disclaimers. This is our document, not an FDA document. But it suggests that in cases where there is Sanger confirmation of results that are being returned that the IDE may not be needed. And now I'm not so sure and that may really open a huge influx of studies and questions about whether there's really going to be cases where an IRB like mine is going to be able to have an NSR determination in hindsight. So I didn't say that when I was up at the podium, but I wanted, and that had meant to acknowledge that I realized that was happening and unfolding during the course of this conversation. Yeah, I mean, the regulation says confirmation by medically established diagnostic procedure. And that actually has two pieces, it's the analytical, but it's also the clinical validity piece of, I mean, it doesn't just say analytically valid, you know, confirmatory procedure. And I think that when we took into account, so that just makes you move into either NSR or SR. And so then that's, you know, takes you out of the exempt bucket, if you will. But then I think, you know, we have a lot more information about what this information means if somebody has signs and symptoms, has a phenotype. I think the problematic place is giving this information to people who are not symptomatic. I mean, we're still learning about the prevalence of these things in healthy people, we're finding them actually a lot more often than we thought. What does that mean, you know, how can we actually once again relay that information to those people that is, that they can actually rely on knowing what that means for them because they don't have a phenotype and we're surprised by the frequency of these things. And I think that's where, you know, the information about giving it to people that you're also not going to be able to find out 40, 50 years from now what they did with that information is, I mean, there was actually a lot of factors in some of these studies as we think about what the risk is for a healthy person receiving that information when they normally would not. Hi. So at the NCI we are more and more frequently conducting or overseeing large clinical trials where we're sequencing tumor but in the lab report there are suspected germline findings that are produced. And so the question becomes what to do about those results in some situations they are returned as research findings to the submitting investigators who then are faced with options of whether or not with counseling to advise patients to get confirmatory germline testing. How would you all assess the risks of that? I guess it's how I want to ask the question. How would your IRB or how would you at the FDA consider that in the context of risk determination? I'm not sure I can answer that question. Maybe somebody else from my office can chime in. No? I mean, I think we have difficulties where people are proposing to return research findings and leave it up to the patient to decide whether or not to confirm them or not. You know, especially depending on how well your platform really is set up to, I mean that's sort of the question. Have you analytically validated? You know, are you ready to return those results? You know, how confident? Can you be, you know, because it's also not fair to give the patient and say we found this, we don't know, go confirm it, where you know, that's not often inexpensive to do so. So there's a secondary consent process with genetic counseling where they're offered the opportunity for confirmatory germline testing. And this is information that's returned to the investigator. So the investigator may look at that and then make the decision not to discuss it with the patient. But it's, there's a second level of review. So it's not going directly to the patient in the report. So I just wanted to say, so you're talking about the oncology setting, right? So this is a trial for cancer where you're getting the secondary results. So I don't know to the degree to which we faced it, but I think our assumption has been just in, you know, at the current time is that a patient with cancer, the secondary findings are really secondary in that, you know, they're faced with a life-threatening illness. So their risk for something that might occur 10, 20, 30 years down the road is not going to be really of primary concern to them or, you know, pose a major immediate risk if they have a prognosis. Having said that, I think it really depends on the setting, what population you're talking about. Is it a cancer that could be cured? I mean, would you expect with treatment a long lifespan or the other thing is, and that is an assumption on our part, there may be patients who have cancer even with relatively poor prognosis who may still want those results, but that has been, I would say, our assumption up to now. It would be interesting to hear to what degree patients' requests from those types of trials, those secondary results. I think that would be very informative in guiding future analysis of risk in those settings. I don't know if you have anything else to add. This is a question from online. What happens when IRB decides that the device is NSR and later the FDA finds that the device is SR? As she said, the FDA decision is the final decision, and so if you would like to move forward to the study, you should submit an IDE. So I've got a similar kind of question. So if Sarah and the IRB and an investigator are somewhat confused or questioning whether somebody is exempt or not in a significant risk and they contact the FDA, so that you say they reach out to the FDA through the pre-submission process, does that imply that there is actually going to be a submission process that they're going to actually have to submit an IDE? Well, a pre-submission is what we would want, a risk determination pre-submission. And generally, the main thing we need is a full clinical trial protocol. There's no fee with that submission. And although the regulatory requirement is something like 75 or 90 days, we generally get those out in 30 days, for the most part. So we turn them around pretty quickly. And you'll get an official letter from us telling you, informing you what the risk determination of the study was. So I guess the question is, if an IRB has questions, is the way that they ask those questions, does it require a pre-submission process in order to get. So is the FDA in that scenario trying to empower the IRB and the investigator to come to their own determination as to whether it's non-significant risk or exempt? Or at that point, is the FDA taking upon itself to come to its own determination and then tell the investigator in the IRB whether it's exempt, non-significant risk or significant risk or whatever? Does that make sense? Well, if the question is an IDE needed, or is this an SR or NSR study or exempt, then yes, you should send the pre-submission. But as far as FDA submissions go, it's very simple. I mean, it's basically a clinical trial protocol and some generally minimal information about whatever device is being used. But it's really, and there's no fee with that. So, and we turn them around pretty fast. So I think, yeah. I just want to ask a quick question following up on Kelly's answer to the other online question, which I've heard many times from folks in our community about what if the IRB goes through the process, makes a determination, documents it, has done a diligent job, and then the FDA comes across the protocol and believes that it may have a different decision. I guess I just want to address the fear that might come out of what you said, which I understand is true, that the FDA determination is the ultimate determination. But what are the repercussions for that if the process has been followed appropriately? I don't know if David could speak to that, but I mean, obviously the best example that we unfortunately have is the Duke case. You know, it's hard. We obviously don't have the ability to know everything that's going on. And oftentimes we sometimes only hear about it when bad things happen. And we find out that we had informed somebody to come into the 90 and they didn't. But we do have also, I mean, we do have an arm of the FDA that, for example, goes out and actually inspects clinical sites and IRBs. And so obviously, although that might not happen at the time of the study, oftentimes things will be detected at a date down the road. But I don't know, Dave, do you want to speak to anything more? I think the only other thing I'd say is that, yeah, I mean, if there's a non-significant risk determination, we really wouldn't know, on the IRB level, we're not going to know about it, right? Unless something really extreme happened or by some, you know, it came to our attention by some, you know, chance. But if that were to happen, and let's say there weren't harms per se, but just, you know, IRB made a determination and then FDA made a different determination, we would request an IDE, you know, and there'd be a question of does the study need to stop while that's done or not. And this is something we've encountered more in, again, oncology trials where, you know, sometimes because you have, you know, phase one, phase two, phase three, sometimes the IVD might enter in phase two and then, you know, they're ready to get started and what do you do? But we're, you know, in generally, the first step is to ask for information and then the second step is to say, okay, well, you need an IDE here, then work with them to submit it. So there's no, you know, I think, like if IRBs and investigators are making honest assessments of risk and documenting that, that's, you know, that's what we would want to have happen. And I think people will naturally disagree because there's an element of value judgment in assessing risk. You know, I mean, even internally, we have some very interesting arguments about some of the things we see. So I would say, you know, 10 years ago, I don't think people were documenting these decisions and that's what, you know, are thinking about it. But we do want IRBs and sponsors to be empowered to make those decisions and that's sort of what we're trying to get at. Thank you. Can I ask a question of my fellow panelists? I'm very familiar with how IRB processes work in terms of a back and forth with investigators to often adjust and make revisions to a study to help manage risks. I didn't, I think my ability to sort of figure out from the presentation today is limited to understand that in the course of an IDE submission process, are there examples you can point to of things that came out differently from what an investigator's original plan was that you would require to help manage the risk in order to be able to get an IDE approval? So you're saying like a lessons learned or? Well, in the course of the process and I see that subsequent questions are asked of investigators to get closer to a very clear understanding of exactly what the validity is, for example, of the tests that are being done. Has that ever actually resulted in a different research plan for an investigator from beginning to end over the course of the FDA's review of an IDE that you can think of? I don't know of any specific examples of that. Looks like David has one. I don't know. You might want to say it on Mike. My experience has been that, you know, sometimes our medical officers will ask for certain patients, vulnerable patients, to be specifically excluded. That's one of the things I could think about. But yes, I think we sometimes start with a protocol and end up with a different one with some changes that we feel address some risks that maybe the investigators didn't identify. You know, and I can think sometimes there's actually things missing in the consent process. So including statements that, for example, this is an investigational device. We've had ones where people are trying to do IDEs with dosing algorithms. I mean, those are not standard of care when using genetics to do dosing algorithms, telling people that those algorithms are investigational. So that they understand, I mean, that's part of just informing patients of the risk that often people don't necessarily think about including a consent. So sometimes we're just, a lot of the back and forth I find is just making sure the information in the consent process is relevant as well as obviously sometimes we're worried about the populations, especially if we've had somewhere our medical officer worried about, somebody might be naive to treatment and you're gonna start them on the highest and that's not typical. And so sometimes we just wanna make sure that there's safety monitoring and things like that that might not have been there or as explicitly stated so that we know the protocol includes it. There can be issues with changes in clinical protocols. For example, in oncology trials, we know that they're constantly making changes. I mean, you know, the dozens of changes occur over the course of months or perhaps years, most of which do not affect risk determinations but if a change is made that the principal investigator feels might change the risk of the trial, it's up to them to resubmit or submit no risk determination to the FDA because our risk determination really applies to one specific clinical trial protocol. Once you start making changes to that, the risk could change. So I don't know if this will help but I will give an example that we had at Duke and I'm Yelena Berglund, that we submitted a protocol to the FDA that was deemed to be significant risk. It was a genomic predictor that the samples will be taken from biopsies and since tumors could be anywhere in the body because it was the biliforma, the study was deemed to be significant risk. An investigator really didn't want to have an IND so we literally had a conversation. How can we mitigate the risk to go down one bar to be non-significant risk? And the FDA requested that we modify the protocol to include only samples that are collected as a part of clinical treatment, so no research samples. And the other one that we're gonna do biopsies samples only from the tumors that are in the periphery like inguinal lymph nodes and axillary lymph nodes but if I think it was lymphoma, if that would be deeper in a body position that those samples would simply not be taken. So FDA thought that that is enough to deem this study non-significant risk and PI was happy with that approach so we modified the protocol. So to your point, basically changes in the protocols. We also had examples out of the way around. I just wanna share. So I wanna go back to the question again, Sarah, in terms of, actually both Sarah and Jeffrey, in terms of, for example, CCGO, you haven't got an IDE exemption for that sequencing. And in the CCR we're doing germline and tumor and we are, because they're not necessarily on a clinical trial but the actual sequence, we are assuming, as far as I know, basically I'm asking you, are you saying that if we sequence the germline and there's a potential for secondary findings, would that be considered a high risk or a minimal risk? That's the question. Have you decided on that yet? That sounds like the same question that we heard about 10 minutes ago. And I say, you're saying it's not. Is that what you're saying? Well, I didn't answer that question. We haven't made a determination quite as explicitly as you're describing but we've, our IRB has only analyzed the part of that research that entails the analysis of secondary results from the exome sequencing that's occurring under that protocol and felt it was a non-significant risk. Determination was appropriate but we weren't, we weren't looking at it in as nuanced a way as you just described. We weren't, that wasn't our, our slice of that particular, it's a very complex and multi-site protocol with multiple IRBs. So we're assuming it's not gonna be high risk currently unless the FDA tells us otherwise. I mean, I think it depends on what, what information are you returning? I think that, that's the question, you know, of how clinically valid that is for that, you know, the people in that trial that you're doing or whether or not you're really deciding to use colorectal cancer patients to now evaluate an Alzheimer's variant where, you know, that's the question I guess. I'm talking about, I'm talking about, for example, ACMG gene is one category and the other category is, so there's a 10% risk concerning pediatric cancers that the patient that you're sequencing will have a germline mutation that's actionable maybe significant to the patient and to the family. And so that's, that's coming our way and I think we have to make a decision whether, and those will be, currently at the CCR there will be, go into the electronic medical record and we genetic counseling be, patients will be informed with that. I mean, I think it's getting to be more typical for especially certain cancers that, if someone has one that as part of their assessment you wind up doing, you know, if you know that there's a germline variant that winds up, people want it susceptible it was Lynch syndrome or something like that and that's sort of become typical for certain patient population to assess that in order to tell them as well as their families. I mean, I think that's the question about whether or not that's still research or whether or not that's become more standard of care in that group. And I think that's the questions that we would have for you, you know, the people that are coming and talking to us and asking questions about that because we know that that, you know, might have become really sort of more standard, you know, for certain populations. So that's the question I think that we would have, you know, who are you talking about and is that, you know, becoming more typical? And I think in many cases we know that is, you know, we have a lot of drug, new drug applications where it turns out that, you know, there's a lot of genetic information for the people in the trial and it's done standard of care for that site, for that group. So I had a quick question going back to Dr. Seidman's comment that it's not the device or not the trial that determines risk but how that output is issued is the determinant of risk. So I was thinking about this in the context of Dr. Kingsmore and Dr. Berg's studies. So if an IRB saw them and they saw Steven's study and they would say, all right, these results are going back to critically ill children who may die. And so that would be the first layer that the IRB would look at and they would just say, all right, so the risk of returning to a child who would die versus not returning is not insignificant. And so that would be the gateway for the IRB and whereas Jonathan's study, they would say, well, there are healthy newborns involved. Now we need to look at all of the steps along the whole spectrum. So the sequencer and the analytical and the clinical validity and forward. So that would be just kind of, I thought that would have a higher overview of how to think of things. Yeah, I think the critically ill infant could be somewhat similar to the terminally ill cancer patient where the risk of harm is relatively mitigated. Thanks. All right, I think that was an interesting discussion and on that note, we'll break for lunch and come back at 1.15 for a case study session.