PODCAST: After the Court Vacated FDA’s LDT Rule, What IVD Developers Still Need to Get Right

Emily Friedland: I'm Emily Friedland, VP of Clinical Research at DCN Dx and this is Expert Insights. Today I've got two people who look at lab develop tests from very different perspectives. Dan. Jesse. Tell everyone who you are and what you do.

Jesse Young: Hello, everybody. I'm Jesse Young. I'm the medical director of clinical device trials and research at TriCore Reference Laboratories. We've been working with LDTs in a variety of different spaces, either helping vendors and sponsors who are marketing LDTs get their FDA approval or even employing some of them in the clinical lab here at TriCore Research and TriCore Reference Laboratories.

Dan Simpson: Hi, I'm Dan Simpson. I'm the director of regulatory affairs at DCN Diagnostics, and I approach LDTs from the other side, from where Jesse is. I work with IVD developers and manufacturers to help them get IVDs through FDA cleared or approved, and also developing LDTs, either as a stepping stone to go to FDA or to operate the LDTs long term.

Emily: Well, thanks to both of you for being here. A federal court threw out FDA's LDT rule last year, and a lot of people interpreted that as the LDT path being wide open. Again, I want to use this episode to ask whether that interpretation rings true to you and what it takes to run one of these tests well. Jesse, let's start at the very beginning. A very good place to start. What is a laboratory develop test? And at a high level, what function do they serve?

Jesse: So LDT starting from the very beginning stands for laboratory developed test. Right. So these are often tests that are employed at a singular institution and are often in response to a specific unmet need for that community. And Dan will I'm sure fill us in on that throughout the episode. But there's really good function and use case for these for many diagnostic institutions. I, being on the research side. Don't employ any of these necessarily in my lab, but from our clinical side we do a lot of LDTs to answer a variety of different etiology needs for our patients in this particular area. What it also indicates is that this is not something that has been reviewed by the FDA. It can be developed and even manufactured in some cases by that particular lab. At least that's the interpretation of what an LDT should be. But it's often not a widely marketed. It's not something that's maybe purchasable through your standard vendor sponsor relationship. You may even be buying singular components that make up a larger assay, and then developing your own pipeline on the back end to support whatever that diagnostic is for your community.

Emily: In March 2025, the federal court vacated FDA's final rule on LDTs. Could you give us an overview of how we got to where we are today? For someone who hasn't followed the case, what did the court decide? And just as important, what did it not decide?

Dan: And so yeah, great question. And kind of again why we are talking today. So FDA for 20 to 30 years probably has been attempting to regulate LDTs. And by regulate I mean specifically that when medical devices were incorporated into the food, drug, and Cosmetic Act, FDA decided that this certain test. And I think Jesse described lots very well of how FDA saw LDTs. Those type of assays would be under enforcement discretion due to the nature of their specific patient populations, their very local patient populations. And really what Jesse was saying, it was of public health to that particular area. So FDA instituted this general enforcement discretion for tests that were developed, manufactured, and run within a single lab. Over the years, there has been some changes to the way certain companies have marketed these devices. And Jesse will say there's some bad players too, but they've induced what what FDA considers more public health risks. So that caused them to want to regulate all LDTs. What we see here is pendulum swinging right, going from nothing to all of this, which happens in the regulatory world a lot. So FDA then instituted this final rule, which of course caused backlash from the clinical lab community. There was a lawsuit. And in 2025, a judge concluded that FDA didn't regulate what they called laboratory services. So this actually even went further than what FDA originally had with the enforcement discretion, because the court got into the FDA regulated physical devices rather than laboratory services. This kind of opens the door to nobody really knows how to interpret this, right? There are no laws, guidances, anything from that board decision to go off. So that has led me, when I deal with clients to kind of interpret where FDA has been, what, you know, the definitions in CLIA and FDA of LDTs, what enforcement actions has FDA taken before and after this? And then also knowing that and I think Jesse agrees with me that FDA is never going to go away. They might come back again. So how do you protect yourself in the long term too. It theoretically changes a lot, because the court ruling tends to leaves it open to any type of lab. Service is not regulated, but in reality, you have to consider where we've been as well.

Emily: So at a baseline then would you say that now we're back to FDA's original enforcement discretion around LDTs or are we in? It sounds like from what I heard you say, that we are still in this kind of unknown zone or now in a new world where we're not necessarily in the old enforcement discretion space, but we don't really know what's enforced and what's not.

Dan: Exactly. And so the way that I kind of interpret it, there are some things that used to be from a regulatory perspective, selling RUO reagents to a lab to turn into an LDT. I mean, everybody did it. Everybody still does it. But FDA always said that that wasn't an option that they didn't think that was, but CLIA allowed it. And so it was one of those things. As a regulatory professional, you have one agency saying one thing and one agency saying another. Now that the court has said that FDA doesn't regulate lab services, I think that is wide open. And it already kind of was. So that's one way where I think that's been cleared up. But there's not many other things that really have changed all that much, I think.

Emily: Jesse, from your perspective, did the ruling change anything about how TriCore operates day to day, or is this more of a manufacturer's problem than the lab's problem?

Jesse: This is a lab's problem for sure. From where we we see it. And I'm going to step back to when we initially heard about the LDT ruling. I know that there's lots of arguments and opinions out there, but this was so disruptive and could have been so detrimental to our community. It changed everything that we did at TriCore in some way, shape or another. We had to look back and completely reevaluate our test menu because yes, we do run LDTs here. Many of the assays from even whole departments may have been affected by that LDT ruling. So with the reversion in this block, I think what it does is it opens us up to make sure that we're continuing to. Serve patients with incumbent LDTs that the FDA was going to force us to regulate. And I think that's a point that shouldn't go lost here, right? It's not just new things. It was things that you were already doing and that would have been horrific. We have 2900 test codes at TriCore, and I think one estimate plugged 1200 LDTs that are specific to our community, not maybe specific everywhere. Yes, people have some generalized flow cytometry assays, for example. But, you know, a perfect example of this is a lot of our flow cytometry would have had to been reevaluated and then meet FDA standard of a 510(k) submission to be considered a legitimate assay. I think one of the things that was the biggest sort of eye opener, and really would have shut us down, is that it's billions of dollars. We're not talking hundreds of thousands, we're not talking millions. We're talking billions of dollars for us to get up to speed on all of our different assays that immediately looked at a huge cut to our directory of services that would have made us untenable to our community. And that's not great to begin with. And yes, we all know the LDT rule was bad, so I don't want to spend too much time there. But with this change, I don't know that it changes anything day to day other than we will operate going forward with a little bit more caution around the LDTs that we do bring in. It has created a shift in the executive leadership and the med directors to look more towards approved assays or things that are on the verge of being approved and adopting more from that space. Because I think as an institution, it's not just me and I can't speak for TriCore. I'm here as Jesse Young, but. I do notice a shift in us daily that we are much more motivated to work with assays that do hold approvals already, because of the continuing and ongoing risk. Dan has mentioned some of the history here. There's a lot. This is from the 1970s to now. It's 50 years of historical attempts to regulate. It's not going away. Please don't let your guard down. Please stay thinking about this and how you and your lab will deal with what the FDA has to say next. I think it's important.

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Emily: I always thought that the LDT rule was in place for technique driven assays. Right? Like microbiology tests where there's not like necessarily like you're growing things and there's not necessarily specifically a kit. Right. You're doing this by technique. And so you're validating in your laboratory. And I would guess that there are still tests, lots of tests out there that you do have to kind of develop and validate in the laboratory simply by the nature of the test and the technique, and not necessarily because you're choosing to do that instead of using a manufactured product, but because there is either no manufactured product or the nature of the testing is that it is technique driven.

Jesse: To add to that, a test that the FDA hasn't created enough understanding around to even regulate, right? So you're totally right. Micro very subjective technique. I mean, yeah, we have hundreds of textbooks that give that information. But, you know, how do you FDA approve? Culture from school. Like we know it's not happening. But yeah, I think the other interesting side of that coin is if we think about like next generation sequencing and all of the the wonderful technology emerging there, frankly, the FDA, I don't think, has the tools right now to be able to figure out what a good standard is for being able to adjudicate that.

Dan: Yeah, I would jump into mass spec has been a challenge as well. And that one is, you know, they have cleared some single site assays of those. But really the standardization and all that, it is difficult. So those are some of the LDTs that maybe should remain LDTs.

Jesse: Yeah, totally. And adopting those right is is important for communities. You know we can't we can't go without some of this stuff. And that was what really felt so bad about the LDT ruling. And now it makes it feel like was mentioned. It's a little bit more open. Doesn't mean we're not proceeding without caution though.

Dan: I will say too, you know, I can see things from both perspectives. Right. And and FDA does have a case when it comes to some of these monstrous laboratories that multiple sites, you know, running LDTs in ten different sites across the country, you're basically distributing an IVD at that point. So there have been some abuses, and there are some high risk devices that probably need to go through FDA like companion diagnostics and cancer diagnostics, potentially. So there is a middle ground here. And like I said, it's the pendulum swinging that kind of causes the problems, right?

Jesse: Yeah. It's not bad. Through and through. It's not the worst thing ever. Regulation is important.

Emily: We talked a lot about FDA, but really Dan, there are two agencies that are governing this space. It's FDA and CMS. Now through CLIA. Where does one stop and the other start?

Dan: FDA regulates medical devices. And included in medical devices are in vitro diagnostics. And so in vitro diagnostics you usually think of as manufactured kits or tests of any kind that gets sold to clinical laboratories to be run in the clinical laboratories. So LDTs are technically IVDs also, but they were carved out in that enforcement discretion if they were manufactured, developed and run within a lab. So FDA regulates the manufacturers of those products. And so you need to go through your normal 510(k) or de novo or PMA clearances. You had to have a quality management system. It's all the things that Jesse was freaking out about, right? Because the labs have probably systems that are based on CLIA. Not always, I guess sometimes have called these systems, but they're CLIA-based, so would have been a big change for them to have to go through that. So FDA regulates the manufacturer part. Where they stop is when those products, reagents, whatever, go to the CLIA lab, and the CLIA lab tests them. And then they have to do some sort of validation, which Jesse can talk about. I believe that they're FDA cleared or approved. It's a little bit less of a validation. And then if it's a research use only or an LDT, they do more. And then that's where CLIA takes over, and that's where I'll hand it off to Jesse.

Jesse: Absolutely right. I think that passed to CLIA in that regulation. CLIA/CAP is what it feels like, you know, in the lab space and what we deal with more. I'm a bit of an oddball in the clinical trials space where, yes, I do also deal with the FDA from a different audit standpoint. But sticking to LDTs, I do think that CLIA/CAP is who is going to come in, and they're going to look through their checklists and make sure that you're compliant to what your menu is, that you have the right quality documentation and compliance documentation from. See to procedure to proficiency and competency testing for the staff running that test. So I think if there's a line in the sand, it's really when it goes from the manufacturer and comes to a lab. But Dan also alluded that those lines get blurred sometimes when you all of a sudden become a manufacturer. And I think what is really interesting is in thinking about that. There's a lot of certifications that these manufacturers hold that are not tenable for a clinical lab without significant overhauls. It's not really financially tenable to create a whole line. And if you've ever been in a specific vendor's manufacturing area, the technology in those places is outstanding. The regulation, the quality control that goes into manufacturing by good manufacturing practices is, frankly, to me, incredible because on the lab side, we have ours. And then if we don't really you don't think about it, right? We buy the kit, it comes in a box and we do the test, and then all of a sudden, you know, seeing what it takes to actually create that reagent really goes a long way. So I think that line in the sand is a pretty good definer for normal in like normal spaces. Right? CLIA steps in when it's in my house in the lab. Otherwise FDA is is really making sure that that manufacturer is living up to the claims that they make and getting those claims appropriately.

Dan: Yeah. I think just to summarize, then, you know, the easy way to think FDA regulates the products that are manufactured. CMS and CLIA regulate the performance of the lab running those tests. Generally speaking. But then it gets blurry, as Jesse says.

Emily: So when a lab develops a test in-house, it is technically manufacturing potentially a product and using it. Does this combination draw these attention and and why would FDA be concerned about this?

Dan: That's kind of the crux of why FDA initially said we regulate these products because you're manufacturing products. But we're going to turn the other way for now because these are all, you know, like you were saying, I think your micro example was great. That was what the original 1976 LDT was, more than anything, I think. And then it's evolved over time. That's what caused FDA to always be in here is your manufacturing product, even if it's within the lab, regardless of all the other issues and feelings that this issue brings up in everybody. That's why FDA has always said that they had the right to regulate.

Emily: We've got three microbiologists on this call, so I think we're always going to go back to that as our example. Dan, one distinction that trips people up is geography. A test can be a local LDT in one lab, but once a lab runs it across multiple sites nationwide, is it still an LDT or has it now become a distributed IVD? And where do we draw that line? Where does FDA draw that line?

Dan: FDA has always contended that an LDT was a single lab in manufacturing, with, and developing and running within a single lab. Industry has always, of course, as industry will do, has always pushed the boundaries on this. So they would do contracts and licensure and things like that to say, well, this lab is really a part of us or we're a part of the lab. And then, you know, if you had multiple labs, then they would have agreements that covered everything and they would say, well, you know, legally we're one site. But really, when it comes down to it, the FDA definition is a single site. And I think this is where I still urge, and, you know, I try not to be the regulatory person that says you can't do this, but what I tell is that to be nicely compliant, it's a single lab. The more labs you add on. The less compliance and more risk you take on.

Emily: Jesse, does that split match how it feels for you on the ground at the lab? Who's inspecting you and how often?

Jesse: It's clear. CLIA and CAP, I mean, the FDA isn't coming here and regulating us unless it's for a different purpose, right? But in the phase of what we're offering on our clinical menu, it's CLIA/CAP, and it's all the regular intervals for those agencies. TriCore is even more complicated because we are quite large. So we do have two core facilities. So going back to your geography question. We're still centralized in a singular core lab that serves New Mexico. We do about 85% of the business for the state. So I think that still helps us to be more compliant with those limits. We do have a second core location, but it's very limited, and it's all FDA approved assay that we just needed better turnaround times because of the actual physical geography of New Mexico. It feels that way on the ground that there's a split, like if the FDA is coming here, you know, there's something else happening. Or, you know, maybe we have started to sell a test. But, you know, I think. This is where where Dan mentioned earlier. You know there's there's bad players, right? You know people who just think, oh well, oh wait, I can monetize this assay. That works really great for us. Well sure. I'll send you my, my fridge antibody for whatever that assay is. I mean, that's that's pretty risky, right? You know, I think there's a lot of things that you have to be careful about in sharing that. But I think we certainly do not see a lot of FDA coming through here. Again, I'm a weirdo. I see the FDA every once in a great while when there's an issue on a trial, but different speed than the lab. So that doesn't mean, though, as a as a sidebar, that if the FDA is here and they saw something that they didn't like, they couldn't turn around and create that. So another regulatory recommendation is that if you're doing this and you have a reason why the FDA could come, you might want to be careful with what they end up seeing.

Dan: I think what you're speaking to specifically is labs. A lot of labs run clinical studies for manufacturers. And so you're having what they call the BIMO section coming in and out of need for clinicals. It's always and I'm sure you're all over it, is that keeping those functions siloed is is important to keep FDA in their spot and don't let them because they should not be inspecting you for LDTs because the court said they do not regulate that.

Jesse: So the reason I bring that up to those that for many folks, you know, I'm fortunate in that we're first and foremost, we're not an academically associated diagnostic lab or a standalone diagnostic lab. We are not for profit. And we have a siloed research institute. That's not a typical case for practicing or educating hospital units that also have to employ LDTs and are engaging in clinical trials. For example, if you get into one of these micro studies, let's not use that. Let's use a flow study, maybe, and you have some flow assays. And they just happen to see that, you know, while you're explaining what's going on for the trial, you know, there's always possibility to blur those lines. And this is not something we've learned the hard way. But we're always warned about like, do not. Do not let that trickle across. Because if there's, you know, congruence of those sections, it could trickle across and you could end up with a whole different level of inspection for an LDT. Before you know it.

Dan: Yeah, FDA loves it. If there's a thread to pull, they will pull it and it may open up a big hole in the wall.

Jesse: Yeah. They're gonna.

Emily: Dan, the common route is a manufacturer supplying research-use-only reagents to a CLIA lab that validates them and offers the test as an LDT. Why is that route attractive and could it get a manufacturer in trouble?

Dan: First of all, research use only product, RUO. Are you kind of throwing it around? It didn't really define it is product that's intended for for research use only. You can't make any clinical claims about it. There's two reasons for that. It's for development of maybe product that's going to be going to FDA. And it's also there's also obviously, as Jesse will speak to, there are plenty of research essays that are only really there for research. And so it's just to detect a biomarker or a molecule. And there's no disease implications. Any type of disease management recommendations, anything like that. As you mentioned and I mentioned before, this has been a general practice that. IVD manufacturers will sell our RUO reagents to CLIA labs, and the clinical lab may run it as an RUO, but they may also run it as an LDT. And the difference being that lets you report a clinical result. So now what we're seeing, and this goes to be the FDA really hasn't gone away on the LDT issue. And where we're seeing that is on the reagents side. So they now know that. And they've always known that even when they said they couldn't that IVD manufacturers selling reagents to clinical labs for LDTs. So now they've stepped up enforcement of RUO products. So there's been several warning letters against IVD manufacturers where they've gotten them on everything that you know. And this isn't unfair. This is just the FDA's focusing because FDA has clearly said what requirements of our product are. It's just now they are heightening their response. Well, if we can't regulate LDTs. We are going to be right outside the door. Grabbing the RUO product and taking a look at it. Right. Or just inspecting those companies. And so they've gotten IVD manufacturers on anytime they have mentioned any type of clinical use. And this could be in the labeling. It could be they've gone through customer service records to see if their complaint handlers have been telling labs that they can use it for, or implied at all, that they can use it for clinical use. So that's where FDA now is really focusing in on enforcement close to the LDT space.

Emily: I would say also, I've seen this challenge with manufacturers who offer analyte specific reagents, which are clearly not just analyte specific regions, but like full kits right outside of the definition. And then it goes beyond that to almost making claims. Right?

Jesse: ASRs is for sure.

Emily: Yeah. ASRs and RUOs together. I actually worked for a manufacturer where we had an ASR that we acquired that was truly a full product, and we were under enforcement discretion because it was literally the most commonly used product or for that test. And we were working with the agency to figure out how to get it cleared, because it was similarly like one of these genetic tests where we could identify a new mutation constantly. And so then what does that look like as a product, right, that FDA approves. Like how frequently do we need to say like, oh, also this mutation we're going to claim, you know, for this. So and so we never got anywhere. They just kept us under enforcement discretion forever, pretty much because there was a medical need for that product. Jesse, one thing you've raised is how low the barrier can be to create an LDT. Now, someone with basic tools, a bit of Python in a command line can put together a clinical pathway. What worries you about that? And where's the line between useful innovation and a test that isn't ready for patients?

Jesse: First things first, I think clinical data is really important to make sure that we're delivering a right diagnostic to a patient, and I really want to frame that. It's not that easy to make a diagnostic test. There's a lot that goes into it. And a lot of our innovation comes from research. So I'm not Pooh pooing those folks and discouraging that. It's just that the line from, hey, I found something during my PhD to, hey, this is a game changer in the oncology space, or this is a brand new biomarker, can actually be quite long and and oftentimes fraught with a variety of different regulatory issues and performance endpoints that we need to manifest through those validations and putting it through the rigorous endpoints of regulation so that we're not just putting bad tests on the market. In the same breath, you have to say the Covid word. I think it's really embodied by the pandemic. There was so many different tests that came on so fast. Emily, you and I worked on a lot of these together. It's not to be a name caller, but there was things getting approved that would boggle our minds now for performance. I think we saw the slide of, you know, this isn't specifically an LDT, but it relates to them because a lot of those start this way. We're talking about that pathway, how it begins here. And then this institution realized, hey, we may have something on our hands here. How do we commercialize it? I think we have to be cautious and make sure that we're hitting those regulatory marks. If we're going to begin distributing it, key here is distributing it and saying, oh, buy my test or this test solves this. That is really when that switch gets flipped again. As Dan as elegantly described. But you know, there can be a lot of use case for those. And the ease of that I think I undersold a little bit. But if you think about it, we have so many wonderful experts. It's easy because we have smart people and wonderful technology. But realistically, gone are the days of us base by base, putting together a primer and it costs hundreds of dollars. You go to any one of these websites and you buy 50 different primer sets for 20 bucks. You know, I remember writing grants for specific primers that I wanted for my end point and it was declined. I'm like, now what do I do? So I think the bar has come down also in our ability to leverage the technology with that technology. So just rushing something out and putting it in a lab space to answer a clinical question doesn't mean that it's not a good test. It means that as an LDT and not a distributed product, it can be localized and important for that group. So when again, we cross that line and we begin to go to a space where, well, everybody should use this. And I have a bunch of it. You guys can have it too. And you over there as well. That's really the line.

Emily: When a manufacturer brings you RUO-labeled materials. What do you need to see as a lab before you validate them?

Jesse: You better have your certificates of analysis ready to go for me. It just tells me that you have good manufacturing processes in mind, that you know what your product is, and you've done the right assessment of that product for me to know that, hey, when I start challenging this particular product through my verification validation process, I'm not going to be having to have to worry about, hey, my polymerase changed. Oh, our antibody manufacturer is no longer in business. There's so many different angles from which this can change. I think it's really important that we're tracking that, and we're pressuring those vendors or sponsors to produce documentation to show us that it's a clean and reliable reagent. And then the next piece that I will ask is, do they have control of their supply chain? This is going to sound crazy, but we go from LDT to a commercialized kit in this RUO phase that we were talking about things that sometimes ruin assays for all the scientists that listen to this, you know, we've we've had the simple thing like, oh, well, my centrifuge wasn't calibrated right. And now I don't get the answer. I expected things like, oh, I have a different plastic in the well plate that I provided in my kit. They make a difference when those supply changes change, you can get massive performance changes and then before you know it. So what if I did a validation. The whole assay is different now. So I really pressure them for those certificates and to understand their supply chain and to make sure that it's reliable so that we're not going to be dealing with major endpoint changes that are going to cause me to have to revalidate. It becomes a whole new product. If that plate is completely different. Wild example of a, you know, conical versus flat well. We can only get the same plastic and its in a different well type. That's a complete revalidation of something like an RUO. And people forget that sometimes there's ways around that in regulation. You can do some comparisons as long as they're thorough, but you got to be really careful. Those things can bite you in the end.

Dan: That's a great point, Jesse. For labs, it's that because I've worked for IVD manufacturers and when you sell an RUO kit, you are not under the quality system regulation. You are not. And so you're right that that's that's maybe part of the concern with FDA too, is that research use only product does not have the enforce quality standards that you have when you as a lab by an FDA cleared or approved kit. So you have to take the burden suddenly of and that can be hard for the labs. So that is a good warning, is that you can do this route, but it puts a lot of pressure on the lab from a quality perspective.

Jesse: A lot of people can't afford that. They can't afford to maintain that too. Right. It could be a really good assay that changes the diagnostic landscape for my institutions, but we may not be able to support it if you can't stabilize your supply chain or if the antibody is going to change every three weeks.

Emily: So we've talked a little bit about GMP and even better than this, having an ISO certification, right, for manufacturing. How that gives you assurance around product quality. What separates a manufacturer who's easy to work with from one who creates problems for your labs down the line outside of maybe this, you know, certification process.

Jesse: One that's forward thinking and has a regulatory mindset already. I'm not going to say that all people are nefarious, and they just want to make money from their RUO reagent. A lot of people have really good intentions and they're trying to get it to market. But the bottom line is, is that we have to remember who it goes to. And I know we're sticklers in the lab science community for we really got to know if we're delivering the right answer for the right etiology. We can't just be testing everything all the time. It's why FWAs exist. It's why other compliance and ICH guidelines and, you know, even some of the things like our Hippocratic oaths go into effect, where working with a manufacturer who just wants to sell something really quick versus somebody who's put the effort into, look, we want to get this to market. We think this is the right pathway. Here's all the information from our kit that really is going to separate those who want to play in the space and are intending to make a great assay. And more importantly, support it long term. That really is what separates them. Oftentimes flash in the pan. Are you manufacturers that maybe have one assay? I squirm a little bit because I never know what the longevity of that is. Let's say I go through the pain of a full COSI CLIA CAP validation on a product, and six months later, they've discontinued it. The burden financially on my lab is maybe hundreds of thousands of dollars, depending on what the test is, and now I can't support it because they're defunct and I can't even buy that reagent anymore. So now it's a cycle of, okay, well, we just dumped a bunch of money. We did the validation. It was useful to our communities, but I can't support it because there's no long term plan to continually support that product. So you want to talk about down the line? I think that's important. And that doesn't mean that a company with a single assay cannot be successful. Certainly in no means doesn't mean that. But have those hard conversations when you're looking to adopt that kit, you know, hey, what is your 18 month? What is your 36 month plan to be able to consider offering this or continuously offer this test really will help you in the end. Fight off the oh well, we started it, we sold it and then we sold it to somebody else who couldn't maintain our manufacturing chain. We made our money and we're out. That's not what we need as lab scientists.

Emily: On the other side of this, Dan, can you advise companies who manufacture these types of products in just these types of scenarios? What do you tell them about working with a lab without stepping over the line to looking like a test manufacturer?

Dan: My preference always is that LDTs, I mean, there are exceptions that Jesse has mentioned, which I almost consider almost like public health assays where there is a disease and a particular area that there really isn't anything else out there. That's kind of a different TMI opinion. A lot of times manufacturers think of LDT as a way to get on the market quickly, either before FDA clearance or even just keep that LDT running as long as possible without FDA clearance. And so that's where you can kind of have the well, let's just get it out there and then we'll think about design and development later. And then that puts people like Jesse in a bad spot. Right. Because this is supposed to be a clinical assay. I tried to have manufacturers work that into their design control process that they need to do for FDA. And really you can have different levels. You can have the FDA endpoint further down the line and have the LDT. But you you're designing requirements that you know the lab needs. Right. And so that'll make Jesse sleep better at night. Right. Knowing that you have these endpoints, these quality requirements for the lab you're already designing, you know what the labs need because they're your customers anyway, even if it's FDA cleared. And that's what the FDA makes you do in design controls. Consider your user needs. Well, the lab is your user. You should be considering those user needs even for the LDT space. Bring it over to the lab. You know, is is like throwing it over to your manufacturing or throwing it. You're going to have problems. You don't want problems either. As a manufacturer. You don't want Jesse calling you on the phone saying, this is crap. You know? It's in the manufacturer's best interest to design LDTs with the lab in mind. And they are your customer. So you should be trying to make life easy for them.

Emily: And, Jesse, a CLIA lab has to validate every LDT. We've talked about this a bit. TriCore is a large regional lab, but for smaller regional labs that can be hard. What would be the constraints there for those smaller labs?

Jesse: Funding. Secondary to that is accessibility to the analyte. Sometimes these are really rare analytes that we're looking for. You may only have 1 or 2 pathogens or biomarkers or whatever it is that you're looking at. It can be hard to fulfill a full recommended validation or verification schema to complete that testing. I'm not saying that we don't need to do it, but we need to be creative about what that is if there is available contrived stock. But again, we come back to funding and supporting these assays. So generating that clinical data is not as easy as I've also mentioned sometimes, right? Some of these really niche assays can pose significant challenges. And frankly, if you're doing a qualitative assay versus quantitative assay, that can change a lot as well. Hopefully those biomarkers or that pathogen, depending on what it is, it may be important to do that. And the bar just continues to rise as you add complexity that test to qualitative. Yes. No on a bug or biomarker is significantly easier than a hey, here's your clinical decision points in this quantitative assay. That can really make a big difference. So I think the constraints there from the the validation space are really driven by CLIA/CAP. And while I think they're appropriate because we need to make sure that we are delivering good tests, I'm not going to say there should be, oh, a special path because I'm not always the biggest fan of that. I think some of that end user case that Dan was mentioning should be considered by CLIA a little bit more in these rare disease endpoints, and it is I'm not saying that they come in and they throw the hammer down or the gauntlets at you or whatever. But I do think that, you know, sometimes there's a lot of pressure there. But the onus does need to come back to the lab to generate a data set that really supports that. If it is a really valuable endpoint, then it's likely that you have the data that you need, or you can leverage the community if you're patient, to generate a good validation verification argument, to say that it is a important and valid diagnostic for your group.

Emily: Some of these tests exist just because a region specifically needs them and no one makes them. You actually engage with some unusual tests due to where TriCore is located, right? Due to New Mexico and disease states that only kind of occur in the desert landscape. What would heavier regulation cost patients who need these tests?

Jesse: Fatal? It could be fatal. I mean, we may not have the answers that we need diagnostically. Now, I'm not going to sell our clinicians short. Like there are empiric ways to do this. Although diagnostics plays the long game with them to help manage symptoms, if maybe the first guess isn't right. It's really important that heavier regulation avoid completely stomping out these different LDT unmet needs I think. You know, Emily, you were sort of referring to the fact that hantavirus is really important for us here in the Four Corners region. New Mexico is one of the hot spots of the world for hantavirus. Although yes, it's been in the news and there's other areas. That is a nice point of something that, hey, is really important. It's not so niche that nobody else on the planet has it. But how do we get a good diagnostic here? How do we develop that? How do we go through the ASR RUO pathways to get an assay on board that we can turn into an LDT? We actually did both. We went from the ASR side. We went from the in-house development side, trying to find the right way that we got a test that we really believed in. That's still ongoing work because hantavirus is also troublesome. So this is the other thing is that these things evolve, right? There's change. The fact that they are very mutable viruses, and that there's degenerative primers needed to even begin to detect. Some of this calls kind of the spirit into what LDTs originally were to card in that, hey, we need to be able to constantly develop so that we can keep up with this disease state, not because we don't want to be regulated, but because by the time we get through a regulation, it may have changed or it's too hard to say, without a doubt, that we're going to have that particular pathogen in this region. So then what? We're going to go back and do a whole nother FDA approval for an assay that is no longer beneficial to the community. I'm going to go out on a limb here and say that it would be really nice if we could work as a, you know, scientific collaborative and come up with some really nice guidelines or some minimums. There's plenty of publish things out there, but there's not any released regulatory document that says, hey, in these sorts of cases, we attempt to do X if that minimum cannot be met, do Y, and if it really can't be met, please submit use case or whatever that example is. I've outlined something dangerous there, but I do think that we as a community could potentially really collaborate to hammer this out. It doesn't have to be a single voice. It doesn't just have to be the government. It doesn't have to be the regulators, but as scientists, I hope that someday we get to that point where we're using regulation for positive, and we're still not hampering the scientific and RUO side, that that can really meet some of these needs.

Dan: 100%. Jesse, I have a question for you on that. So in the final rule, FDA did carve out public health assays as being exempt. And so I'm curious if that hantavirus assay would fall within that or if there was issues with you falling within that.

Jesse: I think it does. Right. I think as a public health response, of course. But, you know, it gets gets deeper and deeper. There's other things, you know, I think about we mentioned, you know, Mass Spec and some of these other things prior in the call. You know, being out here in the desert with a lot of the mining and everybody seeing, you know, certain movies about certain major nuclear events lately. That's endemic to New Mexico. That's where it all happened. So there's you know, I'm not saying that we employ those assays per se, but those public health response things are important to to heavy metals and whatnot in, in our patients. So bringing that on and being responsive can be public health. But as soon as we cross that line and we begin buying something, then we're playing this other game back into the okay gray area.

Dan: Yeah. Where does public health ending clinical diagnosis begin? That that's where it would get tricky, I would think.

Jesse: Well, and frankly an interesting thing. So public health there's Department of Health and state lab divisions. So DOH, SLDs, whatever it is in your area that it's referred to as your public health lab. There's that lab. But if it goes into your lab, are we crossing the line? They have assays. But if I'm offering it diagnostically at my reference laboratory as part of a menu, does that change that regulation? Because what I can tell you is that CLIA and CAP are going to look at that validation in my facility. So then we're back to we're all the way back. Right. So I don't want to create strife on the call, but this is exactly the type.

Dan: No, no. And this is exactly it. Yeah. It's there's so many gray areas.

Emily: This is maybe a kind of off the wall question for Dan, but for in those cases, like with hantavirus, for example, or any other disease state that's not endemic to the US, but maybe is in another region, but in this very specific part of the US, suddenly there's a vector borne outbreak, right, of something that we don't see commonly in the US, but that there are tests that have been approved or cleared in other regions outside of the US, and a lab wants to acquire those and bring them in and validate them. That should fall under the same rule. Is that correct or is that a grey area?

Dan: Yeah. I mean, so I think for all the reasons that Jesse just mentioned and that's why I dived into it, is he's absolutely right. What is exactly a public health assay? And I don't think FDA really defined it all that well. Is it something that's run at CDC or at these state health labs? Or if somebody like TriCore takes it and is using it for that purpose, can they say it's a public health assay? And then you bring up a great point in another region and bringing it in under the current system, a lab like TriCore would have to bring it in as an LDT if it's cleared and approved in another country. That kind of my head almost takes it out of the public health space. And so it would be an LDT again. This is what I think is a great point. So FDA went from the general enforcement discussion to what they call targeted enforcement discretion validities. So public health assays. They even had the thing that I think some of these micro tests we were talking about, if it fit the definition of a 1976, there was also a little carved out enforcement discretion for some of those assays. But how do you justify that to and really what's the boundary for that? So these targeted enforcement discussions were in place. So we can give FDA credit that they saw that some of these assays, you know, still would need to be LDTs, but then the problem was, is is really what the definitions of those were. So yeah, I think in the case you're saying, I think it would still have to be an LDT. And then it would have fallen under that FDA final rule that. They probably wouldn't have been allowed and you would have had to get them through FDA.

Emily: Moving on to the future, FDA enforcement has run cycles. We've talked about this a few times and how it comes and goes, and it's not necessarily administration administration, but it definitely is cyclical. Right. We see waves of enforcement or wanting to enforce more. And then, you know, decades where people want to pull those roles back then. Right. Do you expect it to come back the enforcement or and if so, what do you think that would look like?

Jesse: It's coming back. I just I think it would be unwise for us to think that the FDA is not going to do this. Dan's pinned it to the wall with a 50 year exposé of what they've been doing and how they the FDA, exists. Food and Drug Administration, they exist to regulate. That's why they were created. They will try to do this again. You know, I don't know what it will look like or what little envelopes or, you know, edges they'll try to find on the ruling as it is. But there's really important intelligent people looking at all the bylines, trying to find loopholes. It will come back. And I think that, you know, for all the discontent we've spewed at regulation, it is really important. I don't think anyone would say that. Oh, we don't need any regulation whatsoever. We think about crux high, high, high stakes examples that have been global news about companies that come up with wild claims that are now defunct. I'm not going to name, but I think everybody can think of some major examples. We need the regulation to be there to ensure that we're doing the right things in our communities. It's just how it's leveraged. It feels like an attack. And my previous statements where it's like, hey, how can we make this more collaborative? How can we come to an understanding that scientists, by and large, I'd like to believe, are trying to deliver good diagnostics for the patients to create a better life for everyone? The FDA. We just paint as a bad guy who's trying to take all of that away from us, but I don't think that's the central message of it. I think we're just trying to keep those bad players and those sometimes companies that maybe are too naive to know their assay doesn't work that well, can't support it like we've talked about, or even just want to make money and are not in it for the patient. I think if we can watch those and create the right pathways when it comes back, it's not going to be a world ender. It's not going to shut down reference labs. I think as long as we're attuned to it and we're we're patient and we can act as a community. I know I'm asking for the sun, the moon and the stars, I think at the same time. But I think if we as a community on the lab side, at least protect ourselves and realize that it's coming back, it may not feel like the absolute earth shattering that it was.

Dan: From the manufacturing side, I think, from the FDA's side, I think, you know, Jesse mentioned for all of my friends that are watching this from the FDA, I will say that, you know, they are often painted as a bad guy, but you have to also remember, they're kind of in a thankless position. Whenever they lose some regulation, something bad happens and then they get blamed because they allow this horrible safety event to happen. You know, like I said, regulation can be a pendulum. They swing the other way and then they get, oh, you're stifling innovation and you're you're causing other public health crises by not allowing certain tests to be available. And that's what you know in this case could be the. So so you're either causing a public health emergency because there's this safety issue, a bad player in the LDT space that is marketing, let's say a companion diagnostic across the globe, and people are being subjected to drugs or not being subjected to drugs that are lifesaving, are causing horrible side effects. Something like that. Right. Some LDT that that that is high risk that is being abused or you're causing some of these community assays that Jesse's talking about to not be available to a really critical population that needs it. So FDA is trying to walk the line. We mentioned before that what allows them to be in this space that they're manufactured assays. So that is what they regulate. I think Jesse's absolutely right. There's got to be a happy medium where you're minimizing public health risks on both sides. Right. Because that's what it's all about. So how do you get the fringe ends. But keep the middle where a lot of those LDTs lie. There's got to be an enhancer in there somewhere.

Emily: I totally agree with both of you and direct to camera. I will say we do like the FDA. And the other thing that I would want to say to manufacturers and for us to realize is these original rules were written in 1906, right. They were again Bicentennial baby. We as an industry have to understand that FDA aren't oracles, that technology has leapt forward decade over decade. And I think, you know, this relaxation of this rule is also in response to the fact that we have technologies and we're not really sure what their applications are yet, but we still need to let labs, you know, kind of develop these because there may there is life saving technology that we don't know how to regulate yet. And I think FDA knows that. And their enforcement discretion reflects that. That's always what I've said. You know, I've worked for a lot of innovative companies, and I think the hardest part of being at the FDA is keeping up with the technology, right. Keeping up with the science and figuring out how to regulate it. Because when you truly have a new product that can save lives, what do you do right? How do you make sure that it is safe and it will save lives? So just my my little soapbox here. Just two last questions for each of you. Dan, we talked to a lot of manufacturers. Clients who are interested, let's say, in developing their product as an LDT, and they're trying to figure out if that's the correct pathway, if that makes sense. What is the first thing you tell them to get right if they are considering going down the path?

Dan: Not to do a shameless promotion, but for the Regulatory Affairs Professional Society, I wrote an article on this subject and you know, we talked about the geography aspect, right? But really, there's a lot of risk factors that have to be analyzed altogether about what the assay you're developing is and whether it should. It could be an LDT, should be an LDT for maybe for a limited time and then get FDA clearance. Or if it could just operate as an LDT. And there's a lot of different factors. You know, risk to patient always comes to mind. And like this, you know, we're saying what FDA is concerned about is public health risk, right. The severity of risk to patients. How many patients are being exposed to this, whether it's the local community assay is obviously less public health risk than something that is a multicenter LDT across the country. So there's a lot to consider. So it's really having an assessment of the compliance risk. And you know how FDA views your assay. You know and I never really say no because I think you can always do an LDT. But it's really looking at how sustainable it's going to be and what kind of risk you're going to put your company into down the line.

Emily: And then Jesse, from the lab side, what's the one thing that you wish manufacturers understood before they reached out to you?

Jesse: I hope that they've really considered that if we're going to bring it on, we're going to be using it to change a patient's life. I think there's a lot on the line with that sometimes. And oftentimes the lead in is like, oh, we have the new one and only greatest assay. Come forward with data, come forward with intention, the clarity of what the product is and a clear way to execute that product because it will, in our space, change people's lives. I don't think that's always lost on people, but sometimes it gets lost in the years of endless boardroom meetings around redesign and change and what the performance is, or melt curves or whatever that data looks like for them. We can forget where the endpoint is, particularly on that, and then when it all comes together, there's sometimes this rush. It can show up as a really unpolished, but it's the greatest thing. It's so good. We've all heard that a lot. Like, I want to know what the data is. Can you show me that it performs? Where did you do the work to to suggest that it's going to work? And do you know that your product is reliable and stable and the other thing is reproducible in someone else's hands? Lots of times I get an insert. It's the greatest assay. We know it works. Sometimes these folks live, breathe, eat, die this assay. And it gets to my lab and it doesn't work for anything because they've forgotten a critical control metric of altitude, humidity. Different operator who's not just a molecular technologist, but a molecular technologist who hasn't lived every day the past X number of years working on their product. So I think they got to understand that, that coming out of their space, it's going to make a huge impact. It's going to be used in people, and they better be ready for Jane Doe and my lab, John Smith, to be able to run it and to understand it, too. So I think that's what I would I would ask.

Emily: Great. Well, Dan and Jesse, thank you both for joining me today. Dan recently authored an article called Diagnostics in Limbo for the RAPS Journal of Regulatory Affairs, and it goes through the history and the compliance options in more detail than we can do. Here, you can read it in the upcoming September issue. If you're weighing the LDT path for your own program, you can reach out to our regulatory team at DCNDx.com/contact. You can reach Jesse's team at tricore.org/contact. Thanks for listening to Expert Insights.