Hello, everyone, and welcome to ASAP's virtual town hall, titled An Overview of the FDA's Final Rule on Laboratory Tests. We thank you all for joining us today. We have a very large group here. Over 2,000 folks have registered, and we have a great expert panel. I want to introduce you to our expert panel. First, I'll introduce myself. I'm today's moderator. I'm Chris Tormey from the Department of Lab Medicine at Yale, where I hope to oversee the transfusion services here. Our faculty, as I mentioned earlier, are truly expert in this area, and hopefully will give us a great afternoon of understanding about this new regulation. One of our first speakers will be Dr. Jonathan Genzin. Dr. Genzin is a Chief Medical Officer and Senior Director of Government Affairs at ARUP Laboratories. He's also a professor at the University of Utah Department of Pathology. We'll also be hearing today from Dr. William G. Finn. Dr. Finn is the Medical Director of Joint Venture Laboratories in Allen Park, Michigan, and is also a past president of ASCP. We'll also be hearing from Ms. Michelle Campbell. Michelle is a Senior Developer in the Department of Laboratory Medicine and Pathology at the Mayo Clinic, and an Adjunct Assistant Professor at the Division of Clinical Laboratory Science at the University of North Carolina at Chapel Hill. We do have some housekeeping slides before we get into the meat of today's presentation. We have some disclosures that the views expressed by faculty and panelists are their own and do not represent the views or opinions of their employees or employers. Faculty and panelists are not authorized to speak on behalf of the FDA. Discussions and interpretations do not amount to medical advice nor specific compliance advice. And lastly, the faculty and planners have no relevant financial relationships for knowledgeable companies to disclose. Some other additional housekeeping reminders. Do keep in mind that this is a recording. This will be actually posted after this session completes. By participating in this recorded video conference, you're agreeing that ASCP may use the recording of your image and or statements on the ASCP website. We ask that if you are sharing information in the Q&A section of the Zoom link, please do not share PHI or PII. And then lastly, CME and CMLE will be available from today's session. Instructions for claiming credit will be shared at the completion of today's presentation. In terms of what we hope to address today, from a broadly overview perspective, we really hope to walk away having a better understanding of what are the requirements in this final rule? What are the deadlines of upcoming requirements? What requirements apply to different types of tests? What are the FDA quality system requirements? And what could this mean for laboratories moving forward as we really try to grapple with this rule across the United States? We again mentioned earlier, we have well over 2000 registrants. We've received a number of great questions and comments, well over 200 questions and comments from audience members. I also did want to be clear that there were a lot of questions about specific tests and test platforms. That's really beyond the scope of today's presentation. Today's presentation is largely going to focus on the items listed on this slide, but it's important to note that please stay tuned to ACP. As we get additional information and additional knowledge, we'll be developing tailored education to really meet the needs of the community with regard to specific tests and assets. Before we also start, we did want to get a general poll out to the group, just to get a sense of the level of comfort or discomfort, as it were, with the potential impact of the new regulation. So poll question number one is how concerned are you about the potential impact of the LBT regulation or rule on patient access to certain laboratory tests? Are you very concerned, somewhat concerned, or not concerned? And you should have an opportunity to vote in this poll right now. And I think not surprisingly, this one has a good pretest probability. Most are either very or somewhat concerned about this. I think the panelists share your very or somewhat concerned nature. And again, the hope will be today we'll try and calm some of these fears that we all have and the concerns we all have about this new regulation. Well, without further ado, I'd like to hand off to Dr. Finn at this point, who's going to walk us through a brief history of the framework that we're going to learn more about today. Thanks, Chris. Those very familiar with the LDT saga will know this is a very abbreviated history, but I thought it would be good to provide some historical background for those who might be a little less familiar with the evolution of these issues in the FDA. In 1976, Congress passed the Medical Devices Amendments to the Food, Drug, and Cosmetics Act. This defined medical devices to include products intended for use in the diagnosis of disease or other conditions, which included clinical laboratory tests, also known as in vitro diagnostic devices, or IVDs. Since that time, FDA's enforcement efforts have centered mainly around manufactured IVDs, and FDA has chosen generally to practice enforcement discretion for laboratory developed tests or LDTs, which are defined as IVDs designed, manufactured and performed in a single laboratory. In 1988, we're all very familiar, the Clinical Laboratory Improvement Amendments or CLIA 88, redefined federal oversight of clinical laboratories. We're all very familiar with CLIA, and it closely regulates how we all practice laboratory medicine and how clinical laboratories assure quality in the performing of clinical laboratory tests. CLIA closely regulates the analytical validation of laboratory testing, but as FDA has contended then and now, it does not formally oversee clinical validation or claims regarding intended use of individual tests. In 1992, FDA published a draft compliance policy guide in which it did focus attention on what it called at the time, quote, homebrew tests, unquote, and noted that these products were subject to the same regulatory requirements as any unapproved medical device. In 2010, FDA convened a public meeting to discuss its oversight of LDTs. It reiterated its authority to regulate LDTs, and subsequently went to work on drafting guidelines regarding LDT oversight. In 2014, these guidelines were released by the FDA in the form of a framework guideline that outlined a multi-year phase in of a more active LDT regulation by FDA. Plans to move forward with this guideline were later suspended in late 2016. In 2018, initial drafts were circulated of what became known as the VALID Act, which would have codified in law a risk-based regulatory framework for LDTs. VALID was eventually introduced in Congress, but it never passed. Because there was no passage of legislative relief or definition, FDA in the fall of 2023 released its proposed rule on the regulation of LDTs and opened the rule to public comment, and that brings us to where we are today. The final rule on FDA regulation of LDTs was released on April 29th, with an official publication date in the Federal Register of May 6th, 2024. In 2009-2010, ASCP was active in representing its members, representing our patients in the discussions that were evolving around LDTs. ASCP convened workgroups that discussed FDA regulation with respect to LDT oversight. In 2010, ASCP published a policy statement entitled Regulation of Laboratory-Developed Tests. From about 2011 until this year, really, ASCP leaders, both volunteers and staff leaders, have attended multiple meetings with FDA officials, both public and private. In 2015, we took part in a public meeting held on the campus of the National Institutes of Health in Bethesda and submitted formal comments on the FDA framework guidelines. I had the privilege of taking part with some of my colleagues and ASCP staff. We served on expert panels and discussion panels at that time. From 2017 to 2023, ASCP did review and consider the legislative alternatives that were coming forward during that time. And in the fall of 2023, ASCP commented on the proposed rule. We issued extensive comments that were drafted by our talented staff in the Center for Science, Technology, and Policy in Washington, as well as by our president, Dr. Bob Goulart. And that takes us to where we are today. And now I'll turn it over to Dr. Ginzin for an overview of the current proposed rule. Thank you very much, Dr. Finn. It is my honor to be here today. My goal in the next few minutes is to summarize 528 pages of the final rule into about 15 slides. But we're going to walk through kind of a concise summary of what's in the final rule and what we think that might mean in different laboratory settings. The rule itself is actually very brief. It's only a 10-word addition to the definition of an in vitro diagnostic product or an IVD that specifies that IVDs are devices under this Federal Food, Drug, and Cosmetic Act, including when the manufacturer is a laboratory. So the FDA is actually not formalizing or codifying a definition for laboratory-developed tests. They're just saying it's an IVD, even if you're building it in a laboratory. Along with that rule, there's a new set of two policies, general policies that they're rolling out. The first is that they're phasing out general enforcement discretion for LDTs, and that term enforcement discretion is really important. That term means that an agency believes it has the power to do something. They are just choosing to not regulate it. That's actually legal in the US. You can do that in a federal agency. They're phasing that out. So now they are proposing they are going to regulate LDTs instead of having this policy of enforcement discretion. However, they're adding additional targeted enforcement discretion policies for specific categories of LDTs. And so they're going to defer that oversight for a few subcategories, and we'll mention what those are over the next few slides. So they propose a timeline. Now, all of these stages are not going to apply in all settings, so we're going to talk about when they do and don't apply later in these slides. But I thought it would be helpful to go over the timeline first, and I'm going to go over this rather deliberately. Notice in each bullet point, there's this little link, 21 CFR Part 803, for example, in the upper left corner of the first bullet point. That's a direct link to where you can find that information in the Code of Federal Regulations. So when we distribute the PowerPoint or PDF after the talk, all of this is directly available to you. We wanted to make sure you had access to that. So in Stage 1, which is in effect one year after the final rule was published, so on May 6, 2025, clinical laboratories that this applies to will have to follow medical device reporting requirements, correction and removal requirements, and then complaint file requirements. That last one is actually a quality system requirement. We'll talk about that later. But since it's so close to medical device reporting, they included that in Stage 1. In Stage 2, which is in effect in two years, so on May 6, 2026, laboratories will have to comply with registration, listing of all of their LDTs with the FDA, labeling requirements, that's essentially the package insert that you think about with an IVD kit or a drug, compiling all of that formal information into labeling, and then also complying with investigational device requirements as well. Stage 3 is in three years from now, May 6, 2027, and this is the phase in of the quality system requirements. These are FDA-centric quality system requirements. They're different than what you're following under CLIA, perhaps. Specific to laboratories that develop LDTs, they will apply design control requirements, purchasing and supplier controls, acceptance activity requirements, corrective and preventative actions, and then records requirements as well. We'll dive in a little bit into what some of these things mean, but these are going to be their own educational products or activities going forward. You can take way more than an hour talking about any of these individually. Three and a half years from now in Stage 4, so November 6, 2027, clinical laboratories that this apply to would have to submit their high-risk LDTs for pre-market approval and review. As long as you meet this deadline, you can keep your test on the market, but you would have to meet this deadline. And then Stage 5, which is four years from now, so May 6, 2028, clinical laboratories would have to submit their moderate and low-risk LDTs if applicable. This is the 510k pathway, and you may also hear this term de novo. The de novo is kind of an intermediate pathway. It's something that you think isn't high risk, but there's actually not a predicate device out there, so you can't do a 510k lower moderate risk submission. You choose this intermediate category and hope that it ultimately gets categorized as 510k at the end. So here's the timeline. I'm going to show you a schematic diagram at the end that also illustrates this again, so don't worry about memorizing this, obviously. This will just keep coming up throughout the talk. So I mentioned all of these regulations are online. For those of you that are interested, here is a link to go to the Code of Federal Regulations for Food and Drug Administration Requirements. You don't have to read anything on the right here, but you'll get this big list of all these different requirements, and then you can click on the ones that are applicable and read them in more detail. Okay, so I mentioned earlier, the FDA intends to continue targeted enforcement discretion in a few specific areas. So just to remind everybody, this means that the new rules won't apply to these particular categories. There's three groups on the left, and I'll explain some of these in a little bit more detail in subsequent slides. The first is 1976 LBTs. In general, think about these as very manual tests that were around before that law that authorized the FDA to regulate IVDs was passed, so manual tests for the most part. The second of these is HLA or human leukocyte antigen testing for transplant purposes only. They're going to continue enforcement discretion there. And in the third category are tests solely for law enforcement or forensic purposes, not for clinical use, but for law enforcement forensic use. They're also extending enforcement discretion in two different settings, one of which are LDTs performed in Veterans Health Administration facilities, so VA hospitals, or LDTs used by Department of Defense. So if your testing is in any of these categories, the new rules that the FDA is proposing in general won't apply, but certainly look to make sure of that in the final rule. So there are three categories that are getting a lot of attention right now. And these are categories where some of the new regulations apply, but not all of the stages apply. So these three categories, and we're going to talk about these first two in a little bit more detail. LDTs that are currently on the market, unless there is a significant modification to that test. So we'll talk about test modification separately. So if you have an LDT currently on the market, as of May 6, or today, you can keep it on the market. But there are some other requirements you'll have to comply with going forward. The second group of tests are testing for unmet needs. But this is a very specific definition. So we'll go into this in detail in just a bit. The third of this these categories is rare red blood cell antigen testing, because they know it's hard to get these reagents. And if they overregulate it, it would be hard to work up a patient in a transfusion setting appropriately. So for these three categories on this slide, the stage one and the stage two requirements apply. The only stage three requirement, however, that applies are records requirements, making sure you store your documentation and store documentation for future manufacturing activities. But stage four and five, the actual submission to the FDA, those requirements don't apply as long as you're not significantly modifying your currently marketed LDTs. So we'll show this again in a diagram toward the end. So it all kind of makes sense in a comparative sense. But everybody's focusing on these categories in particular. So let's dive in a little bit more detail to what the FDA said about LDTs currently on the market. So their explanation are tests that are first marketed prior to the date of issuance of this rule, officially, that was May 6, 2024, and that are not modified or that are modified in only certain limited ways. They are worried that if you significantly modify a test that may increase risk and there are circumstances where they would want you to submit that test for pre market review with a modification. So what are those significant modifications that would trigger these other requirements? And those other requirements are compliance with stage three quality system requirements, and then pre market review stage four, or five, depending on whether it's a moderate or high risk test. So here's their explanation of examples. Changes in indications for use, I would I would familiarize yourself with that definition of indications for use, because it's something that's going to come up a lot as you focus on labeling, what are you using the test for? Changes in the operating principle or certain critical reaction components, use of significantly different technologies, and they describe four specific examples to help you think through this. Addition of artificial intelligence or machine learning, change from targeted sequencing to whole genome sequencing, change from immunoassay to mass spectrometry, or change from manual to automated. This last one concerns me quite a bit because many labs automate things on liquid handlers just to improve efficiency or quality. That depending on how you read the final rule, I believe the FDA is saying would require you to potentially submit something to the FDA in the future. We'll need clarification from the FDA on each of these points. The last one I think is obvious adverse changes to the performance or safety of a test. These are not exclusive, but this is what the FDA pointed out in the final rule as examples. The other modification that they described, and I think this is going to be really helpful for many hospital labs to think about in particular, are what happens if you modify somebody else's FDA cleared or approved IVD? You purchase an FDA cleared kit, you modify it in some way, what are the rules there? This is how they describe it. Going forward in high complexity CLIA lab settings, if the test you're modifying is a low or moderate risk, so 510K or de novo test, and if you're following design controls, those quality system requirements in stage three, design controls is one of the quality system requirements, and you have to follow the rest. Then if it is not a major change or change in intended use, like we described on that last slide, the FDA does not intend on requiring clinical labs to submit those tests for pre-market review to the FDA. There's another bucket of tests though. So if you are modifying something that is a high-risk test that has a pre-market authorization, a PMA, you still have to follow design controls and the quality system requirements, but they would expect you to submit those to the FDA for review. This is one reason why the FDA is saying that they will be working hard to down classify many high-risk tests to moderate-risk tests, class 3 to class 2, to decrease the burden. That is going to take some time, however, and there are many important tests that are high-risk on FDA classification that are common modifications currently done in clinical laboratories, particularly for infectious disease. So the next bucket of testing that we talked about are LDTs for unmet needs, and this one gets pretty detailed, so I'm going to walk through this slowly. These are LDTs, this is the FDA's terminology, LDTs manufactured and performed by a laboratory integrated within a healthcare system to meet an unmet need of patients receiving care within that same healthcare facility. So only for the patients in your facility, if that makes sense. They include a definition of what an unmet need means. This is the the left-hand sub-bullet here. Unmet need definition includes there is no FDA-authorized IVD for that disease or condition, or there is an FDA-authorized IVD, but it is not indicated for use on your patient or their unique attributes that need to be added, or there is an IVD authorized, FDA-authorized IVD, but it is not available to the patient for some reason. That last one sounds like there could be some flexibility there, but they also include some limitations here. This does not include patients being treated at an affiliated hospital with a different corporate ownership, right? This precludes, in my interpretation, the ability to meet this unmet need principle for outreach testing, for example. There's a huge negative impact in that setting. Another limitation is limited to LDTs ordered by a healthcare practitioner on the staff or with credentials and privileges at a facility owned and operated by the same healthcare system employing the laboratory director and performing the LDT. I can see this one being particularly problematic in settings, many settings as well, because the lab director may be an employee of the School of Medicine and not the hospital, for example. So this corporate ownership idea is going to need clarification because I do anticipate some significant conundrums there. They include two other caveats at the end I'll mention very briefly. They do not consider performance improvements or lower cost to qualify your test for unmet needs. So just because you can run something cheaper doesn't meet your meeting an unmet need or running it better than a send-out lab, for example, that doesn't qualify as an unmet need. And then once the FDA authorizes a test that meets the needs of that patient, your LDT would no longer meet that unmet need enforcement discretion definition. So I went over a lot of detail here. Take a little while to absorb it. We'll share the slides at the end because I think this is a really important one in most hospital settings, and it is probably overly restrictive. So they give some additional examples of what unmet needs could be, and they've said they will consider providing more examples if it's helpful. Cytogenetic analysis for rare diseases, certain metals testing, viral load monitoring for some transplant-associated viruses, or diagnosis of certain mosquito and tick-borne diseases are examples, as long as there is no other FDA-authorized test for those needs. They include four other examples or clarifications that may be helpful to think about. An LDT for an alternative specimen type. In my mind, I read this as body fluids, but only when the specimen type required for the FDA-authorized IVD is not and cannot be made available. So it's probably going to be hard to apply this one to body fluids. LDTs for pediatric patients, when the FDA-authorized IVDs are indicated for use in adults only. I think many of us are going to need to check our package inserts very carefully to see whether the vendor has or has not said anything about pediatrics or adults. LDTs for the same indication as an FDA-authorized assay that is offered only in another healthcare system that is not accessible to the patient, and the developing laboratory will not make the IVD available outside its system. So I think what the FDA is saying here is send the patient to another healthcare facility, or send the specimen to another healthcare facility. And if you can't do either of those, then you could meet the unmet need definition. Again, oddly restrictive. The last one of these is LDTs for an emerging pathogen for which there is no FDA-authorized IVD, and for which the FDA has not identified an emergent situation. So there's not an emergency use authorization in effect yet, an EUA declaration. Again, but this only applies to patients in your healthcare facility. Another big category that they talk about, and I would encourage labs that are New York accredited to read this in close detail, within the final rule, are tests approved by the New York Clinical Laboratory Evaluation Program, or CLEP. So these tests would not be subject, if they are approved by New York CLEP, would not be subject to stage 4 and 5 submission to the FDA, but they still expect laboratories to comply with stage 1, stage 2, and stage 3 for these tests. But if you get approval by New York, they're saying you don't have to submit to the FDA. We are obviously going to have to hear New York's perspective on this and their plans for the program going forward, but this is a big part of their discussion within the final rule and the preamble. So I mentioned this 1976 type LDTs, essentially manual tests. These are also subject to that enforcement discretion, where none of the rules that we've been talking about would apply, at least currently. They describe these as use of manual techniques without automation and without the use of software, so that's key. Use of components that are legally marketed for clinical use, so you could not use RUO reagents, research use only reagents, for this category of tests, and that are performed in a single high-complexity laboratory setting. And they provide some examples of what these 1976 type LDTs are. Immunohistochemistry tests that involve no automation or preparation or interpretation. Again, very limiting. Tests that use staining antibodies and general-purpose reagents for cytology, hematology, and bacterial infections, as long as there's no automation. Cystic fibrosis sweat tests, certain colorimetric newborn screening tests, karyotypic tests, and fluorescent in situ hybridization. Again, as long as there's no automation or use of software. Again, you can see if you work in a clinical lab how this is challenging to apply. So one thing that I do want to mention before I forget is, if you think back to the beginning of these slides, that final rule was only ten words. Everything else is an explanation or a policy that's described within that document. The way that they've crafted this is, technically, the FDA can change their mind on all of these enforcement discretion policies. It would be up to their discretion. A very few of the details that I've talked about are actually codified. So I do want people to keep that in mind as well, and the approach that the FDA has taken with this. This slide I put together to just summarize everything I've talked about in one view, so you can sort of compare across categories how your test may fit. So on the leftmost column is the requirement, either stage one, two, three, or four, with those links to the Code of Federal Regulations. You can see in the middle, there are those 1976 type, HLA for transplant, forensic testing, or Veterans Administration or Department of Defense testing. None of the regulations that I talked about today apply in those categories, but then you've got that group to the right where some or all regulations do apply. So in New York State, you have to comply with stage one, two, and three. The next three columns, unmet need, currently marketed LDTs, or rare red blood cell antigen testing, you have to comply with stage one and two, not three, except for records requirements. And then for any new LDTs or currently marketed LDTs that are significantly modified, you're expected to comply with all of the requirements as shown in the table. I'm happy to update this table going forward. If you identify any edits or corrections, I included my email address on the slide. Please reach out to me directly, happy to do so. I believe that is it for my summary. Great, thank you so much Dr. Sfinn and Genzin for that comprehensive overview of the current regulation and where we've come and where we are likely headed. Before we move into the Q&A portion where we'll have Dr. Sfinn, Genzin, as well as Michelle Campbell answering questions that have been submitted, we did have two additional poll questions before we move into that. Take a deep breath everyone, there was a lot to digest there. So poll question number two, how confident are you that your lab will be able to comply with the FDA's LDT rule over the next four years? Are you very confident, somewhat confident, or not confident? And we see a bit of a spread here that about a quarter of the audience feels that they are not confident to be able to meet or comply with the rule, whereas about a little over half feel somewhat confident and a small percentage feel very confident. I think likely reflecting the field in general. And poll number three, on a scale of one being least to five most, how prepared is your lab to currently meet the pre-market review requirements for LDTs outlined in the final rule? Again, one being not at all prepared and five being very, very prepared. And we see here that seems to be the majority of folks look like they're not at all prepared to slightly unprepared and it's a little over 50%. And our goal with this town hall and with other future educational endeavors is hopefully to get you into the slightly to very well prepared stage going forward. All right, so we really spent the last 30-35 minutes going through background information and really a wonderful comprehensive deep dive into the issues and the regulations themselves. We did also, in preparing for today's town hall, sift through the more than 200 questions and comments that were submitted by registrants and attendees in today's section to really try and come up with some broad categorizations for questions. It's very challenging, of course, to do Q&A on the fly, but we really did want to put these together to represent and reflect to the best of our ability what registrants and attendees for today were looking to have answered. So the first category that myself, Dr. Finn-Genzen and Michelle Campbell looked at was what we kind of defined as an overview of defining terms and making sense of the new regulations as they broadly apply to tests in the laboratory. And some of this was covered in the slides, but obviously it's a lot of information. Some of this may be a little bit of a reiteration of what we talked about, but Dr. Genzen and John, I'd like to ask you the first question if you're ready. What is considered a lab-developed test or an LDT, and how does analyte-specific reagent or ASR designation apply to LDTs in light of the regulations you just covered? And then as a sub-question to that, are FDA-approved tests that are modified considered LDTs? That's a really, really good question, and it brings up a couple of important terms that are worth going over very briefly. Again, like I mentioned earlier, there's actually not a definition for an LDT. It's just an IVD that is manufactured within the clinical laboratory. The ASR and RUO rules and prior guidances don't change under this final rule, at least to my understanding at all, and that's worth pointing out. But let me describe what those two terms mean in a little bit more detail because it may be helpful. ASR stands for analyte-specific reagents. These are the building blocks, things like antibodies or primers that are used in molecular tests that an IVD manufacturer may use to build their own in vitro diagnostic. These reagents are created using FDA required good manufacturing practices. These are standards that they have to follow, and because of that, there's a few rules that go along with with them, and one of them is that for an ASR, they actually can't market them with clinical claims, right? It's just a building block. It is not a test unto itself. RUOs are research use only reagents, are intended for research only as the name kind of implies. They don't have to be built following FDA good manufacturing practices. Because of that, they're exempt from most regulatory controls because they're supposed to be used for research. Why am I going into those two definitions with this question about LDTs? It relates a little bit to that 1976 type question and what the expectations as well of using RUOs would be by the FDA going forward. And again, this is just my opinion, but this is having read the final rule. My understanding is under the final rule, labs that use RUO reagents would be responsible for determining whether that RUO reagent meets the acceptable performance through the purchasing controls that are part of the quality system requirements. So long explanation short, the lab would have to do what the manufacturer is doing for an ASR, for example. So there's additional requirements that go along with that. So there are clear advantages to using ASRs versus RUOs under the final rule as well. Yeah, I think that hopefully answers the question, at least initially. I think that's great, John. Thanks so much. Question two, Michelle Campbell, you're ready and available. The question number two from, again, representing a compositive question submitted by the audience. What is the likelihood that there will be a quote-unquote grandfathering process for LDTs that already exist in our labs? And as a subset or follow-up to that question, do you think there's any sense of leeway on grandfathered tests that may undergo additional modifications, and will those be subject to regulation? Absolutely. So I can dive into this one, and I want to start by mentioning that although we hear it a lot, and I'm seeing it in the Q&A with the live questions on today's webinar, the term grandfathering is a colloquial term, and you'll notice in the final rule that the FDA only uses this term in quotation marks when they're responding to comments that were submitted to the proposed rule. So while I know that's a fine detail, I think it's really important to point out as we're having these discussions. In fact, in their webinar last week on May 14th, it was explicitly stated that there is no quote-unquote grandfathering as it relates to enforcement discretion for LDTs. Again, a fine point, but it's crucial to underscore when we're talking about this. Now, what I believe this question is referring to are LDTs that were available and marketed before the issuance of the final rule on May 6th, 2024. And the final rule does state that the FDA generally intends to exercise enforcement discretion for these currently marketed IBDs, again, that were offered as LDTs and marketed prior to the issuance of that final rule. Specifically, with respect to pre-market review and most quality system requirements that Dr. Genzin shared on his slide in the presentation earlier, with a caveat, of course, that this is as long as they are not modified after that date or modified in a certain number of limited ways and are not significant modifications, which again were shared today. For these LDTs that were marketed prior to May 6th, the FDA does, again, expect compliance with Stages 1 and Stage 2 of the phase-out policy, as well as the records requirement under Stage 3. Specifically addressing modifications to these tests, the final rule includes quite a lengthy section responding to questions about modifications to IBDs, so I encourage everyone to dive in and read some of those comments and their responses. They call out when manufacturers, including now laboratories that manufacture LDTs, must submit a pre-market submission for a modification to their own device, which generally speaking are modifications that could change the safety or effectiveness of said device. When we're speaking about changes that trigger the rest of Stage 3, as well as pre-market review, like was already mentioned, it's things like changes to the operating principle, intended use, or other changes that could impact the test performance. I'll wrap up by saying that the FDA did state in the final rule that they intend to develop targeted enforcement discretion policies for certain really common changes, such as extending specimen stability and certain alternative specimen types. Great, thank you so much, Michelle, for that detailed answer. Our last question in this category, John, I'm going to, Dr. Gansin, I'm going to take it back over to you. In your opinion, how might these regulations impact something like the quote-unquote send-out process for smaller laboratories and assays not currently performed in-house at a given facility, and do you believe that reference lab servicing health care systems are likely to be considered part of that health care system under these new regulations? It's another really good question, and I suspect a lot of people are asking the same question with concerns about small laboratory settings in particular. I am worried about the impact on small laboratory settings and those that are resource limited as well. The FDA does get into that discussion a little bit in the final rule, and they believe that some of the enforcement discretion policies, the targeted enforcement discretion, could ease some of the impact on a small setting. I'm perhaps a little bit more skeptical of that, just given my experience in working in smaller settings over time as well. I would say the final rule clearly will result in less LDTs being performed in some local settings and more send-out testing, and this is getting to that second portion of the question related to reference labs in particular. That will place an increased burden on send-out labs, and that's not just processing the specimens to sending them out, but also identifying appropriate labs in having contractual relationships to do testing at lower negotiated costs. I think as many of us have worked in lab know, if you don't have that contractual relationship, list prices for patients can actually be unbearable at times, and so I'm worried about financial impact there as well. I just suspect in general this will be a logistical nightmare in some settings and will likely increase cost of testing, and that was something we've pointed out in our concerns to the FDA in the proposed role stage. The last part of that question was, would a reference lab be considered as part of the same health care facility? I would say in my read of the final rule, not if it's under different corporate ownership. It certainly wouldn't qualify for the unmet needs provisions, but again, kind of what I mentioned at the end, none of this is actually codified. It's just policy, so the FDA could certainly address some areas of significant concern. I would hope they would think about that, having received more information, but they certainly had time to do that before the final rule as well. Well, again, thanks so much, John, for that very detailed and thoughtful response. We're gonna move now to this next cut of questions, the next category, which we as the panelists and organizers thought were the next cut of questions, which are digging a bit deeper, really trying to work through practical implications of these new regulations on the workflow of a laboratory. And Dr. Gensin, John, I'm going to stick with you for this next question that came up again, this composite that came from the group. The question was, can the presenters, and specifically Dr. Gensin in this case, as feasible and with the information we currently have, provide an overview of how the submission process to the FDA might go? So for instance, how one might submit to the FDA, how long might a submission take, and what information or data might be required at the various stages of submission? Again, John, to the best of your ability, with the information we currently have. Sure. I went to an FDA workshop several weeks ago, and I've just been learning about this myself in anticipation of what the final rule might be. So there is a system that laboratories and all IVD manufacturers use called the eSTAR system, the Electronic Submission Template and Resource System, and that's how IVDs are submitted to the FDA for review. It's essentially a really big PDF file that can expand or contract based on your answers to questions within that PDF template. That streamlines the process for FDA review. I think you asked about timelines as well. These are posted on the FDA website, and they are different for 510K submissions versus pre-market authorizations, which take a lot longer. I think the 510K, you get preliminary comments back within 60 days, and their goal is for a final review in 90 days. But if they have subsequent questions or if they need more information, that whole process can take longer. The goal for PMAs, the high-risk tests, I believe is 180 days, so six months. But again, if they have questions or need more information, that typically I think can take a lot longer. These timelines are all specified as part of the medical device user fee negotiations, I believe, and so there is some opportunity for those to be updated over time. There is a question, I just learned about this too, there's a question process for submitting your questions about your submissions to the FDA. People call it the pre-sub if it's before you submit, or the Q-sub process if it's along the way, and it's the formal mechanism by which the FDA provides answers. They will set a meeting to discuss their answers. The target is within 70 days of the time that you ask that question, so they've got a process to do it. That 70-day number may be striking for those of you who work with patients and recognize the extreme time pressures that come with things like emergency validations, but that's what the process currently is. If you want more details on either of these, they're easy to find on the FDA website. If you just Google something like timeline for 510K submission or timeline for FDA PMA, you can find all of the logistical details there. And the information, the amount of what you have to submit differs based on whether it's a 510K versus a PMA submission, that moderate risk versus high risk submission. It's something to keep in mind, the standards for what they're reviewing are different between those two groups as well. So if it's a 510K submission, the standard is substantial equivalence to another test currently on the market that's FDA cleared or approved. So they are not looking to see if your test is better, they are looking to see if your test is substantially equivalent. And they actually bring this up in the preamble to the final rule. Claims of superior performance will likely garner additional attention by the FDA when they're looking at your labeling because that's something that potentially could set off a red flag for the FDA. So there's a strategy that labs will likely have to follow here too on optimal submissions. The standards for premarket authorizations, the high risk tests are very different though. Those are standards that are demonstrating safety and effectiveness of the test and those usually require clinical trials or studies that provide clinical supportive data because you're demonstrating that as opposed to just saying you're substantially equivalent to something else on the market. So this is, again, probably a topic for whole nother webinars or educational products in the future. There's a lot for us to learn here. Certainly those of us that have not worked directly with the FDA intensely in the past. Thanks, Sean. It's a daunting process, but yes, as you said, our hope is that ACIP will be there to help guide us through the way as we learn more about this ourselves. The next question is for Dr. Finn. Dr. Finn, lots of questions actually submitted by registrants and attendees today about costs. And can you maybe give us an overview of how might the process be looked at from a fees perspective and how might hospitals look to pay for some of these submissions to the FDA for rules and review? Yeah, I think John alluded to some of the complications within the process in his answer and his presentation. There certainly are user fees associated with things like registering with the FDA as a medical device manufacturer, submissions for pre-market review, and so on. I have mixed feelings about citing actual dollar amounts for each of these since we don't necessarily know what the structure is going to look like with respect to LDTs by the end of the phase-out period several years from now. But these are publicly available dollar numbers. They're generally determined by a congressional act that gets reauthorized every several years known as MDUFA in the business, the medical device user fee amendments, I think. But for example, registration with FDA, there's an annual establishment registration fee of just over $7,600, $7,600. Pre-market notification fees are a little higher, a 510K I think is currently listed for submission of something over $21,000, $22,000. De Novo pathway submissions are in the range of $145,000 and so on. True pre-market authorization reviews, as John Gensin was pointing out, are much more involved and they are much more expensive. But as Dr. Gensin alluded to in his presentation, there's also FDA published in January its intention to undertake a reclassification project within IVDs and LDTs, IVDs marketed as LDTs, to essentially downgrade the risk category of most. It says most, not all. Class three, that is high-risk IVDs to class two. That would have many effects. One of them would be eligibility for the less costly pathways for submitting for pre-market review, which would put less of a burden on labs who are going to have to do that. But it is much more complicated than that. There are discounts for organizations deemed small businesses and so on. There are other exemptions. There's the entirely separate issue that I haven't seen a lot of people bring up of whether FDA will engage third-party reviewers as it does now with certain IVDs, and this could also have an impact on user fees. I think part of the question was, are the fees linked to complexity of the testing? And I found that to be a very interesting part of the question because to me, this is a little sort of reflection of how we in the lab business or in the lab practice are going to have to start switching our lexicon from CLIA to FDA. CLIA tends to speak in the language of complexity, whereas FDA tends to speak in the language of risk, and they are different. I think risk often goes hand-in-hand with complexity, but FDA meters its fee schedules and things based on the level of risk that your IVD is assigned in the application process. So, class 1 is the lowest risk of medical device. Class 2 is moderate risk. Class 1 and 2 are eligible for either these 510K or de novo pathways that are less involved, less expensive than the class 3 high-risk true premarket authorization or premarket approval process and so on. It tends to be true. It gets more complicated because FDA actually does assign CLIA complexity at the outset of inventing a lab test, but from there, it is a different process. So, while more higher-risk tests tend to be high-complexity, there are, for example, tests that are highly complex under CLIA that are considered class 2 by FDA, so it isn't exactly a kind of one-to-one translation. There are public databases, though, that list both complexity under CLIA and risk under FDA that are searchable, but part of this will be whether your submission includes assessment by FDA that your test is either low or moderate risk, class 1 or class 2. It would be interesting to see how that unfolds because I think there's a lot of change that's going to come with that. The sort of first deadline with a price tag, if I'm not mistaken, would be 2026 on the phase-out, which is when labs will actually have to undertake the registration process. As John sort of alluded to, I think, there are likely to be changes and adjustments to the fee schedules between now and the final submission deadlines. I'd be interested in hearing what other panelists think about that, too, but those are my thoughts on that. Thanks so much, Dr. Finn. I think in the interest of time, while we'd love to also hear from the panelists on this, we're probably going to move to our last category as we wrap up today. And for those of you who are Jeopardy fans, this is a bit of a potpourri category, but there were lots of questions about test platform specifics. As we mentioned earlier, we probably don't have the ability to get into test-specific platforms, but Dr. Gensin, I did want to pick your brain just a bit on what are additional approaches that could be considered for LDTs that involve multiple analytes or markers. There were lots of questions about flow cytometry, immunostochemistry, special stains, and multiplex toxicology assays that our members and our registrants had. Can you give us maybe a brief overview of your thoughts of those questions in those domains? Yeah, incredibly important question, and I know a lot of people are asking this. I didn't see definitive guidance in the final rule on this category specifically. This is the idea of a multiplex assay, whether you would have one submission per orderable versus multiple submissions per analyte. I suspect some of this may be up to the discretion of the submitter, but I'm not sure, and so we're going to need guidance and clarification from the FDA on this because there's many assays that fit this type of category. One thing I do want to point out is that the FDA has been talking a lot about this concept of predetermined change control plans, or PCCPs. Remember that, PCCP, predetermined change control plans. This is the idea of before you submit something to the FDA, you put a plan together on how you might have to change it in the future, and then if you follow that plan, then you wouldn't have to submit it back to the FDA if you made those changes in the future. You can very easily see how this could be helpful for multiplex assays, for flow, for molecular testing, NGS testing in particular as well. Unfortunately, I don't believe this concept of PCCPs can be used for existing tests. It can only be used for new submissions going forward, but I would definitely read up on that. My understanding is that the FDA is going to release a new guidance on PCCPs later in 2024. At least that's what they've said publicly. PCCPs also are quite relevant to the ongoing issues of artificial intelligence, machine learning, that kind of stuff, software as a medical device, and that sort of thing. Yeah, great point. Great. Yeah. Thanks so much, Dr. Spinnin-Gensler, for that. Michelle, Michelle Campbell, I'm going to ask you the next question that came under this general category, which is how does or how might this ruling affect different sample matrices or matrix types for testing that's not FDA-approved by intranet manufacturer? And there were a lot of questions about how, for instance, as I think Dr. Gensin alluded to, this might impact things like body fluid analysis. Yeah, absolutely. So like you just touched on, I know Dr. Gensin spoke about this a little bit on his slides where he was talking about the whole unmet needs category that we're describing. The implications for changes to specimen types for assays can really vary greatly case by case. None of us can really responsibly provide a straightforward answer to this question. Changes to specimen type have potential ties to many portions of the final rule. For example, the final rule addresses changes to third-party tests, such as adding new specimen types. And they do point to a few resources that are already available, two of which are published by the FDA and are already available. You can find the full names of these or full titles of these documents in the final rule. One touches on deciding when to submit a 510K for a change to an existing device, as well as another about modifications to devices subject to premarket approval. They also call out a standard that they recognize, CLSI EP35, which is on assessment of equivalence or suitability of specimen types for medical laboratory measurement procedures. This is related to bridging to new specimen types. Again, like I mentioned at the beginning of my answer to this, there's another tie-in to the conversation on unmet need. And one of the examples that was mentioned in that slide are LDTs for unmet needs that are mentioned in the final rule, including LDTs to accommodate an alternative specimen type that is infrequently tested and the specimen type that's included or required in the package insert is not and cannot be made available. So that's where it's a little tricky with body fluids. So if the package insert calls out serum or plasma, there's this requirement for the specimen type to not to be available, and of course, those are usually much more readily accessible than body fluids in many cases, but they do call this out as an example of a variation from the indication for use of an FDA-authorized IBD. Again, as I mentioned in my response to the first question that was posed to me, the FDA did state in the final rule that they intend to develop more targeted enforcement discretion policies for certain really common changes. And they were pretty vague in what that meant, but they gave examples of extending specimen stability and alternative specimen types. So there's a lot more that's yet to be seen there. But I think it's important, as I close out my answer to this question, to reiterate and underscore that while we on this call and many others cannot provide specific guidance as it relates to the final rule, including how to handle alternative specimen types, just recognizing that this can be very nuanced and situation dependent. So remember that it is appropriate to direct any specific questions related to this topic as well as many others directly to the agency. Thanks so much, Michelle. We have just a few minutes left, and I think time for just one or two more questions. John, I'm going to ask you as our resident legal scholar, lots of questions came up from the audience. Is there likely going to be litigation against the FDA resulting from this regulation? And can you give us maybe a quick synopsis of what your opinion is on that and how that might affect things going forward? No, thanks for asking that one. And to reiterate, I am not a lawyer, so this is just my perception of what may happen on a litigation front. I want to be very careful about talking about this too. That term litigation basically means a lawsuit. In the case of a new federal rule, the litigation relates to something called the Administrative Procedure Act. That is the law that a new agency has to use to introduce a new rule, and that's what the FDA has done here. There's basically two buckets of things that this litigation or lawsuit can look at. Does the agency have the statutory authority to do what it did? Did Congress actually give them the right to do this? That's a big question. And then the second bucket is, did they follow the appropriate requirements as part of that APA Act? And so those are two things that litigation might look at. The other term that I think you mentioned was injunction or the concept of a preliminary injunction. So when there is a lawsuit, sometimes the plaintiff or the group that's filing the lawsuit can ask the judge for something called a preliminary injunction. That could potentially pause the rule until the judge has a final ruling in that litigation or court case. There are some tradeoffs to that approach, though. It might slow things down, and some judges may believe that the phase-out stage over the five steps could perhaps mitigate the initial impact on labs. I think if you're in a lab, you're already recognizing the need to start planning and starting to allocate resources. So watch closely whether there is any litigation and whether there is a preliminary injunction, and we'll try and keep people updated on that. Thanks so much, John. And our last question is a very important one. I'm going to ask Michelle Campbell to answer that. And it's a question lots of folks from the audience had. And what is the ACP doing to help support labs through this process? Thank you, Dr. Tormey. So as a fellow laboratory professional, to many of you who are on this call, I certainly agree with the many comments that we received that there are significant educational needs as it relates to the issuance of this final rule. We're very lucky that the FDA has announced or stated that they do intend to provide additional resources, including webinars, templates, additional guidance documents, and participating in conferences. But as far as ASCP's plans, I'm confident that they will continue to be an educational resource for pathologists and laboratory professionals. They closely, very closely, monitor this topic as well as others that are of importance to all of us and related to this arena. And so you can continue to expect virtual content like we've had today in the future, as well as live learnings. And I do want to close my response to this question, as I know we're reaching the top of the hour, just emphasizing how essential it is to bear in mind that we're all navigating this new landscape and learning together. And so I think that provides some comfort to many of us when we remember that. And also remembering that we need to ensure to kind of keep this unwavering focus on why we're all here and why we all show up to our jobs every day. And that's to address the needs of the patients that we all serve. So I'm very grateful to be here today talking to you all. And it's evident through the questions that we received how important this topic and access to testing is to all of us. Well, great. Thanks so much, Michelle. And really, that's the end of the hour and the end of today's program. I, again, like to sincerely thank our expert panel, Dr. Skenzin, Dr. Finn, Michelle Campbell, for their insightful comments, their ability to answer these challenging questions. I think we're all learning. And we are very grateful to have experts like yourselves guide us through this process. I'd like to thank the ASB for giving us this venue for this town hall. And I can't go out saying enough, thank you for all the wonderful questions and comments that were submitted. I really encourage folks to take the survey and follow up. You'll see it's not just the standard survey. It actually does ask questions about what additional education, what additional needs do you have specifically in this domain of LBT regulations and rules. So I please encourage you to take that survey that will kick off as soon as this webinar and town hall ends. You will also be receiving instructions on how to claim CME and CLE shortly in the next few days after this town hall is ended. Again, thank you all for joining us today. And again, thank you so much to our panel for all your insightful comments.

FDA final rule

laboratory-developed tests

Chris Tormey

regulations

compliance

medical device reporting

logistical impacts

ASCP

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