Video 33 min

Panel Discussion Regarding Debated CMS National Coverage Decision on NGS Testing

September 28th, 2022


The below text is a transcript from the webinar. Because it is a transcript, there may be oddities that arise from the process of translating speech into text. We recommend accessing the recording, above, to gain full context. 

Shalini: Okay. Thank you. Hello, everyone. Thank you for joining this today. My name is Shalini Verma, I'm the medical and the laboratory director at PierianDx. It's my pleasure to welcome you all here for this discussion on CMS recent proposal regarding coverage of NGS-based testing for cancer patients. We believe this is an important topic that deserves our collective attention to ensure that unconditional access to high quality care remains available for cancer patients at all stages of their condition. It would be fair to say that this proposal has made us all anxious and has been instrumental in bringing us here today.

Shalini: Once again, thank you so much for your time. I would like to start by introducing our distinguished panel members who have very graciously agreed to lead this discussion. We have with us today Dr. Karen Kaul, Chair, Department of Pathology, NorthShore University Health System. Dr. Theresa Boyle, molecular genetic pathologist at Moffitt Cancer Center. Dr. ManiMahadevan, professor of pathology and medical director of molecular diagnostics laboratory at University of Virginia School of Medicine. Dr. Nicki Sidiropolous, Director of molecular pathology laboratory at University of Vermont Larner College of Medicine. Dr. Ravindra Kolhe, medical director of cytogenetics laboratory at Medical College of Georgia. Also joining us as our moderator is the CEO and founder of PierianDx, Dr. Rakesh Nagarajan. In addition to his role at PierianDx, Dr. Nagarajan, is a key member on several cap committees for molecular oncology, genomic medicine and NGS. He's also an adjunct associate professor at department of pathology and immunology, Washington University School of Medicine, and to all his roles, he continues to make a positive impact on the practice of Laboratory Medicine. With that, Dr. Nagarajan, I open the floor to you and our panelists. Thank you.

Rakesh: Right. Thank you Shalini. I'd also like to thank our panelists in advance for participating in this very important discussion.

Rakesh: I'd also like to thank the audience for attending and participating in and at this time, I'd like to remind the audience to post questions in the questions panel that's available on the go to webinar as we get started on this conversation.

Rakesh: To really begin the conversation in earnest. I'd like to kick it off by talking about this first question, namely, how does an FDA approved test compare with an LDT in terms of clinical utility? What is the process a laboratory has to go through to bring up an FDA approved test versus an LDT. I wonder if I can call on you, Karen to initiate and start the conversation on this question.

Karen: Thanks Rakesh. I'll take this one on. And I'll speak from the perspective of someone who spent a large number of years developing LDT and the clinical laboratory for molecular purposes, not all of which, of course, we're in [inaudible 00:04:26] is but a variety of analytes and targets and methods. And, you know, historically, I think if we look at LDT, or LDP procedures if you'd prefer that terminology, I think what we'd find is that most of the applications and clinical purposes for which we are now using these were done, the groundwork was laid using a lab developed procedure, not an FDA approved kit. And it wasn't until the necessity of doing these molecular studies was well established that companies invested in the clinical trial necessary to get the data to take this through the FDA. So we've got kind of a historical perspective there that has been in place for many, many years.

Karen: If you're speaking about clinical utility, my perspective is that there really is no difference. If the assays, the FDA approved assay and the LDT are equal in terms of their analytic and clinical capabilities, then, you know, they should be performing identically more or less identically in terms of the clinical utility. Now, I'll say that, with the caveat being that one of the points of contention that's been expressed to the last couple years is that unless you've used that exact lab developed procedure on the same validation panel of samples that the FDA kit might have use, you might see some differences. But I think those are generally going to be due to the spectrum of mutations or genes included in the panel, or also might be attributed to analytic differences in terms of sensitivity, specificity, and so forth. But if the two assays are really performing the same, I think the clinical utility should be the same.

Karen: It would be wonderful to have reference materials that allow us to demonstrate that and there are groups working on this. The tapestry group comes to mind in terms of getting better and more fully validated reference materials out there for us all to use. But, I think the literature would show that the performance of these tests and utility of these tests would be the same be the FDA or LDT.

Karen: Now, obviously, those of us that have been working in the lab know, there's a big difference in terms of the verification process that we go through for an FDA approved kit versus the validation process that we go through for a lab developed tests, which is obviously quite a bit more extensive, and generally starts out with, you know, nuts and bolts, identifying the appropriate, you know, primer sequences and genes to include, you're really starting at the point of test design, and that can take a good deal of time. Then taking through the various steps that we're all familiar with, in terms of analytic performance of the test, and so forth until we, you know, get to the clinical utility stage of this, where we're looking at, a series of clinical samples.

Karen: I think, for most of us, if there is a good performing kit available that is, a much easier process for us to bring these up into our laboratories. But often what's the case is that there are applications that we need to apply this kit to that are off label and that requires us as clinical laboratorians to take that to the next step and perform some extensive additional studies, essentially turning a kit into a LDP again, in order to perform the assay on a tumor that's not approved from sample type, that's not approved for so forth. So we're right back into the soup in terms of treating it like an LDT.

Karen: And I think at that point, I'll stop and let others chime in.

Rakesh: Any of the other panel members, would you like to add on to what Karen has already talked about to this question?

Theresa: One thing I wanted to add on is, that I don't think many of us have experience with the process that a lab has to go through to bring up an FDA approved test, because it's really too expensive and beyond the capabilities of a typical academic lab, or even most industry labs. So, and it also takes a long time. So, I think most labs across the country are using the lab developed tests and going through the extensive validation just described by Dr. Kaul and doing the proficiency testing and getting the inspections per the lab develop test.

Karen: And I would simply add that my comments there about bringing up an FDA approved test, there are some in molecular not in next gen at this point that we're all doing. So, you know, if you look at the cap guidelines, that would be a more straightforward verification of performance process in general, still pretty extensive in the next gen space to be sure.

Muni: It's not really clear to [inaudible 00:09:38] that necessarily using an FDA approved kit is that much better than the lab developed test. Because sometimes the tests that we developed in the labs may have capabilities that go beyond the restricted capabilities that are part of the FDA approved test.

Ravi: And the other problem with the FDA approved test is you get locked in with the content, especially when you're concerned about using evidence based medicine, evidence based pathology to treat patients. And it was a process takes somewhere between three to five years and you're working on a content, which was good five years ago. So that's another major drawback for an FDA approved locked content.

Karen: Most certainly, and I think we can't speak to this so much from NGS yet, although that's happening, but certainly our experience a few years back with, with RAS testing, and finally getting a K-Ras assay in the market but the one that got through, it was really an obsolete test. So, you know, I think one other important point I'll make is that we're finally seeing a lot of data or some data being published to show the performance of these two types of assays is really quite equivalent. There been a few peer reviewed articles recently, some of it starting to come out of the CAT proficiency data, which I think will be extremely useful for the lab communities to develop, or to illustrate the point that lab developed tests really perform equally well as do the FDA approved counterparts.

Karen: And I'll mention here although we'll put my disclaimer that I did author this but there was a article looking at 20 such analytes, not all of which are NGS that was published online last summer in academic pathology that kind of goes through proficiency testing and comparing FDA approved and LDT publications, and as, the beginning of getting some of this information out there to the broader community to show that the quality really is equally good.

Ravi: And, if you go back to the clear regulations and they're written mostly to allow these on FDA, LDP's, because even in at that time, there was a realization that the labs will need to adapt to the changing evidence rather than locked into one test. And especially, I mean, every year if you go to ask or [inaudible 00:12:21] the new mark has come up, new guidelines come out and having one test locked in, I think that's not beneficial for us.

Rakesh: Great, thank you all for participating on that question. And you know, I would say the consensus that I heard are the LDT's have an equivalent level of analytical and political validity with appropriate validation and verification that's performed, per either clear certifications or cap accreditation by NGS checklist. And further that LDT's performance when compared to FDA approved test with published manuscripts that Karen has referenced, and also as come out from the cap, show equivalent or superior performance. And finally, the concept that LDT's are actually more nimble in being able to add new biomarkers as they become clinically relevant. So all excellent points that the panelists have made.

Rakesh: I'd like to now move on to our next question, which is that, how will the NCD, (if it's approved in the current format) affect the monitoring of patient response to therapy, either during or after treatment and in early stage testing for initial diagnosis. And I wonder, Terry, if you wouldn't mind leading this conversation.

Theresa: [crosstalk 00:14:09] Sure, I'd be happy to.

Karen: Go ahead.

Theresa: Oh, so I want to start by just describing what the current format is for this question. And the current format is that the Medicare proposal is offering to cover next generation sequencing when performed, when a patient has not been previously tested using the same NGS test.

Theresa: So, they have to have advanced stage or metastatic or recurrent cancer and not been previously tested using the same NGS test and the patient must have decided to seek further cancer treatment.

Theresa: So, basically, what this is saying is that if a patient has been tested once within a particular NGS assay, they cannot be reimbursed for being tested a second time. And so that means that there won't be reimbursement at all for monitoring of patient response to therapy during and after treatment.

Theresa: And so, this includes the liquid biopsies. So, for blood testing, there are NGS blood tests that have been used for monitoring response to therapy, because it's easy to get serial blood tests. And, so if the initial NGS test is performed on tissue, there won't be reimbursement for blood monitoring during the treatment. So then the question is, well, maybe it's not really needed. But it really is because at least in lung cancer, I can provide an example if the patient is diagnosed with lung cancer and has an ALK translocation, they will receive ALK inhibitor therapy. And inevitably, the patient will develop resistance to the ALK inhibitor therapy, and oftentimes with different point mutations in different places in ALK gene. And so the only way to know what the resistance mutation is and what might be the next best therapy is within additional and usually NGS testing for coverage of the entire ALK gene. And there can actually be other genes that are mutated that are the cause of the resistance. So, if you only have a small amount of tissue, it really makes sense to test for resistance with the NGS test the second time, and that really does need to be reimbursed for best patient care. That is standard of care at most cancer centers. So, it really would harm patient care to not reimburse serial testing.

Theresa: And another example, in lung cancers, is EGFR, that's just the classic mutation, where in the past, it's been treated with first and second generation EGFR inhibitors. And then patient usually developed an EGFR T790M resistance mutation, which doesn't require NGS testing. But because of the flora clinical trial, this third generation EGFR inhibitors now being given in the first line. And we don't really understand all the resistance mutations that can occur with giving the third generation EGFR inhibitor in the first line. And so that will require NGS testing.

Theresa: And, so this will severely limit reimbursement for needed clinical testing with NGS after therapy, when resistance of all. So, and then the early stage, that's more and more the clinical trials are starting to do the comprehensive NGS testing for early stage cancer for enrollment into clinical trials, and can improve the long term survival of such patients. So, to basically not reimburse early stage lung cancer, when an oncologist thinks it's medically necessary is just another limitation. Now, not too many oncologists are ordering NGS testing on early stage cancers right now. But that could change based on the results of clinical trials. And I think I'll stop here and let other people chime in.

Karen: So it's not only going to and I agree 100%, I mean, it's not only going to limit reimbursement, for, you know, any test that would be required or necessary after that first test. But when reimbursement becomes a problem, my guess is most of us on this call. And a lot of listeners have also experienced, oncologists not performing the test saying this is not going to be reimbursed, let's then not order the test and pursue another course of action that's not informed by genomic testing. I can speak to a case that happened like that at our institution this past week. So when the reimbursement becomes an issue, certainly that in my experience has affected then the monitoring of patient response to therapies. So I just wanted to add how important it is the point that Terry made when reimbursement fails and doesn't go through, that does have a significant real world impact on clinical providers actually not ordering the testing.

Muni: [inaudible 00:20:53] Another clinical situation that we run into is where our clinicians are actually using the genomic testing in situations..

Muni: The genomic testing in situations where patients have say two different lung masses and they want to know if those are actually related cancers or not. And we've actually been able to sequence the tumors and identify that they represent two different primaries versus one that's metastasized and that has a huge clinical significance. And so with this kind of NCD, that would limit our ability to do those kinds of tests.

Nikki: I'd also like to bring up in terms of the early stage testing. Terry had brought that up a lot of times that's seen when clinical trials are potentially the route that maybe chosen or is top priority for a patient. We had quite an interesting scenario now that PDL1 and the immunotherapies have taken their place in courses of therapy for non small cell lung cancer, where we have payers in our region covering patients in our region who actually will not issue immunotherapy for a patient unless a PKI for a non small cell lung cancer has been excluded. So, you know, sometimes early stage it depends and there's practice variations in terms of when immunotherapies are potentially used and sometimes I just think that we ... in early stage disease and how you define that can vary a little bit. But certainly sometimes options ... they're requiring that this testing be done, which I think is the more unusual scenario to see a payer say you know what we really want you to rule out and exclude any PKI therapy in this particular case. But it did happen and did kind of catch me off guard and I said huh, I wonder if we're gonna be seeing more and more of this. So to exclude this testing either in early stage disease or as a follow up to a targeted therapy is certainly worrisome.

Theresa: Yeah, right.

Karen: I also wonder.

Theresa: Go ahead.

Karen: No I was just going to mention I'd be curious what the rest of the group is going to worry about if you think about CNS tumors, fibroid, maybe hematolymphoid where an NGS panel might actually be instrumental in making a diagnosis.

Theresa: That's what I was going to bring up. Yes.

Karen: Very very early stage.

Theresa: Yeah I forgot to mention that. And the diagnosis, sometimes the mutations can help with knowing what the primary is for tumors of unknown primary.

Karen: So I think that obviously would be impacted by the way this NCD's currently written also.

Nikki: I would agree.

Theresa: I agree.

Rakesh: As a follow up to this question, I'd like to go to the next question and have one additional comment on it if possible by Shalini which is what's the overall impact of this decision on early stage cancer patients versus late stage cancer patients? And then I think I'd like to make some summary comments on both of these questions put together. Alright, Shalini.

Shalini: Thank you Rakesh. The November 30 proposed decision memo that proposes to cover only patients with recren metastatic or advanced stage four cancer who wish to seek further cancer treatment, I think if this is finalized then this decision could limit the access for early stage cancer patients too, clinical management options that require knowledge of NGS based genetic results in patient tumors. For a patient this could also mean a missed opportunity for life saving therapy when the cancer was smaller, less advanced, and easier to treat. The late stage, early stage distinction aside I think it is important to note clinical NGS testing is not just indicated who seek further treatment or wish to seek further treatment as implied by the proposed NCD. These cancer genetic alterations when determined by NGS genetic testing can also actually help in determination of diagnosis and/or prognosis of certain cancers. And with that I would request others to chime in as well here.

Ravi: This is Ravi. The other area we've not been discussing is non oncology. I mean NGS in constitutional in other fields is also being used in genetic centers. Again we go back to the early stage versus late. In heme malignancies we do it at the time of diagnosis for stratification and prognosis. That pretty much will limit the use.

Theresa: One thing I learned from one oncologist and I'm not talking necessarily about NGS specifically, but genetic testing in general in early stage cancer patients, if an oncologist sees let's say an early stage patient has an EGFR mutation, they still treat to cure the patient at that early stage and patient goes home and hopefully does fine and we never see them again. But if there is a recurrence and the patient knows they have an EGFR mutation, they're going to be more likely to return to care knowing they have a good targeted therapy available to them.

Rakesh: Makes sense. I'd like to kind of summarize this part of the conversation by echoing what I believe I heard which is that cancer is a very highly dynamic disease, requires multiple rounds of testing in early stage. As a part of monitoring that patient with cancer, whether to look for existence of a recurrence, managing the efficacy of current therapy, things of that nature, as well as in more advanced stages as it's being done today. And that these tests are very important, not only to make therapeutic decisions, but also to potentially confirm or establish the diagnosis and importantly considering all cancers to assess the prognostic impact based on molecular findings.

Rakesh: I'd like to move to the next question now, which is what is the potential impact of the national coverage decision on local coverage decisions that may already be in place for specific NGS tests. And Nikki if you perhaps could kick off this conversation?

Nikki: Sure yeah. You know I think that the concern here is that a lot of local coverage decisions and what happens also with private payers can follow in the footsteps of what's put out at the national coverage decision level. So I can specifically speak to our region, we have been very proactive in reaching out to a variety of payers in our region and have educated them before going live with our testing. What is the test. What's the technology. What's the content of the test. What is the clinical utility of this test as we see, as a transdisciplinary team who created this test. Why are these targets on here. What are the resources, the references that support the particular targets on the panel. Why have we built it the way we did. Who were the parties involved in choosing the content of this panel. It was personally curated by a transdisciplinary team at our institution for this set of patients. Right?

Nikki: So that's not an insignificant amount of work. And I think that if you're doing it right, you're taking into account in that panel a variety of stakeholders that are gonna be impacted by the testing. And the payer being one of them. So doing that education, breaking ground with them, saying you know we'll do prior authorization with you, we'll set up our informatics infrastructure to support everybody who's going to be impacted by this test. And have that in place and putting into effect what we think is partly our responsibility, right? Coverage with evidence determination and doing the parallel work that goes along with the testing to say what is the value of this in our health network. Doing all of that and then having the threat of an NCD then come down and undo all of that work.

Nikki: And also all of that work that I described, it's our personal philosophy in this region and I'm sure it's shared by anyone that's doing this at a local, underlying all of the testing that we do is the genomic medicine education. And that goes across a variety of stakeholders and there needs to be local support right for when is this test or this series of tests or this portfolio of tests, when is the test necessary? When is it not necessary? Test utilization. And then once the information is generated, having that local expertise there to help translate a lot of the information that hasn't necessarily been included in everybody's medical education. Right? So undercutting all of that with the threat of an NCD that will then under do, undercut, these local relationships.

Nikki: You know our practice region is a little bit different than you know perhaps the practice that Northshore has or Moffitt has. We all are a little bit different. And I think the practice of genomics, the way it stands currently, there is an element of why your location is important. It does color how the testing is done and how the community is educated. Right? So to undercut that, the threat of undercutting that, is really gonna have a negative impact on taking this type of testing, this technology that promotes genomics informing cancer care, and undercutting that and slowing it down. So that's a significant concern. And with that I-

Theresa: I agree I think it already has impacted it. Because I think a lot of labs are putting their development of NGS on hold right now. I'm thinking about the 170 gene assay that Illumina put out recently. It takes a lot of resources and time to validate these assays and if you're not sure that it's going to be reimbursed or covered, can you really move forward to validate these assays? So I mean fortunately we moved ahead and we validated it but for labs that are in that decision making process I think they've already had a negative impact.

Karen: I would agree and I've heard of institutions that are actually debating additional instrumentation and just investing in this entire area in general until this is sorted out. And I think this is a decision that's going to have huge ramifications for patient access in a very negative way.

Nikki: And I think a lot of labs have started in the cancer space and we personally did that and we're moving towards some other areas where next generation sequencing as a technology could be useful for different clinical care pathways. We certainly have learned so much in getting started with NGS in the cancer space that it's hard, it's definitely difficult to validate and bring up NGS and implement it as a clinical genomic service if you will.

Nikki: And so, so many of us have expertise where if another one of our colleagues is starting in this space we reach out to each other. We help the other one to get going and the whole field has been growing in that way. So if you start taking the people out of the field who have this experience to get this up and going in other labs, it really ends up having a snowball effect. Collegiality goes a long way and if you take your colleagues out of the game, you start to have a significant impact on bringing this to a clinical lab and in the end it is the patients that we serve that are going to be negatively impacted and so to say that it is ... I cannot, I cannot, I think that this particular NCD in my opinion is one of the most harmful things that has come across this particular field. It's not moving things ahead. It's slowing things down and I think it has the potential to do so in an exponential fashion if it actually goes through.

Karen: I think we'd all agree.

Rakesh: Right, thank you guys for the comments on this particular question and I really believe the overwhelming and singular response in this direction from multiple medical directors and organizations that believe in the value of NGS based testing in a very flexible form, both from a reimbursement point of view. LCDs versus NCDs. And having a steady state there as new advances are made are critical as well as the concept that we talked about earlier in that LBTs are a more nimble approach to the practice of medicine and in treating real patients with cancer. I'd like to move on to the next question now and this question is, how does a test qualify for coverage with evidence determination under the proposed NCD and will laboratories performing NGS testing be able to take advantage of this option? And Ravi I wondered if you could start the conversation on this question?

Ravi: Sure thanks Rakesh. For this particular question I ended up reading the 28 page document and it is a very small portion especially in part two, where if you're not able to get into an FDA approval or FDA clearance the proposal put together some guidance under the umbrella of coverage and evidence determination, or CED. I'll go through exactly is in the CED and then probably comment on what it means.

Ravi: Based on the CED guidelines the only mechanism by most of the labs, especially under the part 2b, they can qualify for reimbursement if they participate in an NCI clinical trials networks trial. The problem is these trials are very few in number and mostly unavailable to participate in even the academic labs. Again these are ... you need to have the NCI match file open in your place, match like trials open in your place, and this will again be limited to a very small number of academic labs which will have some access to these trials as part of the NCTN trials. The CED also notes that you need to have at least 13 different trial requirements and the trials have to show benefit of sequencing in an intervention and again also not be non duplicative. So that's one way the section 2b where the CED claims the labs can get into is why the NCI trial network.

Ravi: Another way is the process of FDA approval. Something what MSK impact from Memorial Sloan happened is you submit your test through New York State Department of Health and get approval through via [inaudible 00:39:22]. Unfortunately it takes about 3.5-4 years for that process so ideally these are the two options. One under the CED and one via New York State Department of Health. The problem is with these proposals under the CED are extremely rigid and the mechanism under the 2b is ... the onus is on the lab to provide the evidence and clinical utility. And my fundamental problem in that is if you have the exact same content, let's say you have FDA approved test with 100 genes and you have and LDT with the exact same 100 genes in a CLIA lab, how is it different? The clinical utility is going to be the same because the content is same.

Ravi: But based on the CED, or coverage with evidence determination, it is up to the lab to provide that evidence to get the reimbursement. And that's again very critical space for smaller or mid sized lab even in the academic setting. Rakesh?

Rakesh: Thank you so much Ravi. Others on the panel if you'd like to comment on this question, please do so now.

Karen: Actually a question for Ravi for a laboratory that was going to pursue this and really validate the test in compliance with New York State requirements or others I'm not as familiar with, what reference materials would be needed to show equivalent clinical utility? Do you have a thought on that?

Ravi: So if you're going with the New York State Department of Health, the last month the New York State Department of Health came up with official guidelines on NGS, liquid biopsy, TMB, and MSI validation by NGS. And I'll be happy to share with you. I think this is the first guidelines where I saw there's a clear requirement on what reference material, how many samples, apart from CAP and AMP guidelines and the publication, Levi Jennings publication. So I think that's the starting material for the labs if you want to go through the New York State Department of Health route.

Karen: Well that's good to know that information. Thank you.

Ravi: You're welcome.

Karen: That's good to know, that there's information. Thank you.

Speaker 1: You're welcome. But the problem is that it takes somewhere between three to four years, maybe more than that, post validation in your lab to get the New York State officials to come and approve. Then again, it's a Class Two versus Class Three because it's not a true FDA trial approval. There's some other concern that whether you'll be really eligible for reimbursement by a New York State Department of Health approval.

Muni: Given the three to four years, it doesn't seem like a viable option for a small, medium, or any kind of academic lab to go through this process.

Speaker 1: I agree.

Rakesh: Right. Thank you guys. [crosstalk 00:42:59] Yeah, go ahead.

Speaker 1: I was just going to say that by the time you get through that kind of thing the test is antiquated.

Rakesh: That's right and I think again in summary what I've heard from the panelists are that while feasible that there's a mechanism provided in the proposal for laboratories to qualify for CED under this proposed NCD. The barriers are pretty high, the process is pretty onerous, time consuming and by which time the assay itself may be obsolete in that new biomarkers are available. Again, kind of highlighting the earlier statement that I made that LDTs tend to be more nimble because of the very nature by which they can be modified and appropriately then analytically and clinically validated by CLIA certified and CAP accredited laboratories.

Rakesh: I'd like to [inaudible 00:44:08] the conversation to the next question now. And this question is really in asking whether it's even appropriate to treat NGS itself as a diagnostic test or a laboratory technique and Karen if I can call on you again to lead the conversation here.

Karen: Okay. I can get us started on this. I think this is something that we've all been talking about and it takes us back a little bit to just LDTs in general. What is a test? What is a test kit? And what is a laboratory procedure or method? The end of the spectrum we have things that might take place in our chemistry lab or hematology lab where it's really an instrument that runs a fairly straightforward anolyte and that it doesn't require stepwise checking of quality parameters, there's really no tweaking of that process or procedure that the laboratory would get involved in to make sure the result is as it should be. It's just a black box and it runs and you validate and verify that it works properly. That, I think everyone is comfortable calling, a diagnostic test or a test kit.

Karen: At the other end of the spectrum are the lab developed procedures and I think everyone on the call would agree that many molecular tests and next gen sequencing in particular fit better into this category where there are a series of steps that the laboratory has to optimize to make sure that the entire process is working appropriately, there's quality steps at several steps along the way and then there's a lot of homework that goes into making sure that the results that come out at the back end are really appropriate.

Karen: Large reliance on proficiency testing and sharing of samples between laboratories and that sort of thing. When I was thinking about this in preparation for this call I found myself thinking about a clinical pathology AP trial I was involved in some years ago where a group of laboratories was trying to demonstrate that they could all get the same results within immunohistochemical stain, something that is clearly viewed as a laboratory procedure and were having trouble in doing so and the reasons were that everyone's histology operations are different, the length of time that we fix, the temperatures at which we're fixing, the length of time at every step through the histology processors, I mean all of these are different and unique to each laboratory and each AP laboratory is then responsible for optimizing IHC or special stains or even H&E stains to make sure that the outcome, the output, the slides and the tissues are maximally beautiful and able to be read by the pathologist.

Karen: So these are procedures that we're experienced with and that no one has ever proposed be regulated by the FDA and in my mind that kind of a parallel story to what we're seeing in many molecular tests or with NGS. We're working with tissues that have come to us in a variety of ways but we take that material, that DNA, do the appropriate quality checks and then take it through a complex process that has been outlined nicely with respect to the CAP checklists and a variety of consensus documents that have been published in peer reviewed literature to show us how to collectively get the correct answer out of those disparate materials. And I think, again, the laboratories are doing a remarkably good job at demonstrating their quality here so it's a technique, it's a multi step process, and it's certainly not a black box in my mind. I think we can make an appropriate case that NGS fits squarely in that latter category.

Theresa: I agree. It's a technique and historically the CPT coding system has been agnostic to the method used to get the results. So, the current reimbursement structure is based on what you're testing and what results you're producing as opposed to the methodology or the technique and so this is a big change from what has been the current reimbursement structure.

Nikki: And I couldn't agree more and I think even in our own department which, the genomic medicine section of our department is just a small part of our whole department of pathology and lab medicine. We have to constantly educate, even our pathologist colleagues not practicing as a molecular genetic pathologist that we're very careful about the language that's used and very proactive about correcting when it's called, when what the testing that's being ordered is being ordered, you know, let's perform next generation sequencing testing on it. It's like, well, we use next generation sequencing as a technology, it's a work flow and there's a variety of tests that we run using this technology, which test, you know, are you ordering? So I think there's also, we in this field have to be very proactive about the education piece. I spoke about that earlier. The education is pervasive. We're educating ourselves, our colleagues, the clients at the other end, patients, the payers. So it's a pervasive issue and you would think that even as pathologists that we would understand this and so we have to stand up and do our part to do this education piece. I couldn't agree more. I think that Karen described it very well and I've thought about that myself in terms of the immunohistochemistry, it's been discussed at our own institution.

Rakesh: Thank you guys so much. I think that, just to add a little bit to this conversation, next generation sequencing itself is a phrase and not necessarily a specific technology as we know other than sequences can be determined in a massively parallel way. The underlying technology there that [inaudible 00:50:58] vendors have taken themselves have been different whether that's semiconductor based or sequencing by synthesis so at the very core the technique itself is even different. The DNA or RNA capture or amplification approaches are different and the number of variable that are introduced in that process make it fall into a laboratory technique today. I think that fixing all of those variables in a package is what ultimately results in a diagnostic test which could then be associated with appropriate reimbursement. But I completely agree with the panel here.

Rakesh: I'd like to move to the next question at this time. And this question, I'd really like to have all of the panelists provide their input. Mainly, what are your proposed revisions to the NCD and if possible, Muni, it's be great to start with you.

Muni: Well I think the issue with the NCD is that it's very restrictive. It restricts what kind of tests you can do, when you can do it, how you can do it and it limits our ability to be flexible, to be responsive to the clinical needs of our doctors and our patients, and it results in tests that, by the time we keep up with the literature and the clinical trials and the drug developments that's going on in a field that's as hot and moving as cancer it's just way too slow. The other thing is I think it doesn't give due justice to the existing regulatory systems that we already have. So things like CLIA and CAP and the surveys that we have to do and the inspections that we undergo on a regular basis are legitimate ways that have been accepted for decades for monitoring the quality of testing that is done at institutions across the country and around the world. So I think having the NCD phrased the way it is basically takes away any legitimacy to things like CAP and CLIA and their role in the development of testing in this arena.

Theresa: So I agree and how I would change it, I'd eliminate all language that proposes non coverage of assays that are developed in CLIA labs. It's not the coverage of the foundation or the FDA approved NGS assays that's the problem. It's the non coverage of all other NGS assays and the other things too, not to limit the testing to one time only and not to limit the testing to advanced stage only. Leave the testing to the physician discretion if medically necessary.

Karen: I would agree with both of the two speakers, Muni and Terri. I think this really is a step back in terms of current state of the art standard of care that we can offer our patients because of the limitations on coverage here. I think we should have coverage both for CLIA lab as well as the commercial laboratory. And I would love to see whether it's in this NCD or elsewhere increased emphasis on development of consensus guidelines and attention paid to the quality of the assays be they done in any setting to show that the assays are being done equivalently with equivalent quality and we can prove that so we can provide data to support coverage of all of these tests.

Nikki: And for the sake of time, I know that we're coming up on the hour and we want to leave time for questions and additional discussion so I agree and don't have much more to add in terms of how I would, what revisions I would propose. I agree with the 3 speakers and I think we need to take the restrictive qualities out of this NCD. I am not exactly sure how this is going to benefit patients and I'm having a hard time seeing this NCD from that perspective. So I do agree with putting more emphasis on the quality across the board and including the LDT as a reasonable alternative should it meet the right criteria to be a reimbursable test based on using NGS technology.

Speaker 1: Alright. I have one other point I want to add is even there's an NCD but I think CMS should continue the LCDs also work on the local labs for other assay coverage. I think that will help the local regions in having better patient care.

Rakesh: Perfect, great. Thank you guys all for your comments on this question. I'd like to move to one final question perhaps before we have to wrap up. This question really kin of riffs on the idea of education and transdisciplinary teams mainly that we all understand that precision oncology is a medical practice that occurs at the interface of the patient and a multidisciplinary or a transdisciplinary team especially in precision oncology where we've seen successful execution of that approach through team members who together put together the cancer patient's management namely the radiation oncologist, medical oncologist, surgical oncologist, the [inaudible 00:57:56] or pathologist, genetic counselors where appropriate, nurse practitioners, nutritionists among others who ultimately come up with the appropriate way if you will to manage that patient. And second, the collaborative nature of developing and validating an LDT wherein young pathologists learn NGS space techniques and the impact of the NCD in limiting that to a single commercial lab send out so I wondered if folks could comment on the educational aspect of and the impact to that educational aspect as well as the patient management aspect as a transdisciplinary team where you send out versus run that test internally and participate in the management of the patient. Nikki, perhaps take that on since you've been driving the education flag.

Speaker 1: Yeah, I think this goes, I don't know if I'm going to be adding much more to what I said earlier but I certainly think that we in this practice in our health network, any of the molecular pathologists who have been on service and including a lab based genetic counselor, we are constantly engaged with I'll call them clients but really it's the end users who say okay what do we order, when should we order it, there's constant questions coming in a priori about the testing, so the test utilization piece, and then there's a lot of information. You're also educating your anatomic pathologists and sometimes your hematopathologists when you're actually looking at samples and triaging. I call it the art of triage, right, because its really a molecular pathologist when they're looking at all patient samples get to put together and look at something and with a little bit of a different endpoint and you get to educate your anatomic pathologists and say, you may have failed this but we actually go it to work, here's how. So there's been a lot of education at that level.

Speaker 1: Also, at the front lines when the biopsies are occurring, that trickles down so people know when do we stop, when do we get more. Certainly, the medical students and the residents and fellows on service they're learning how to interact with us. It's not just NGS and genomics and we don't know what that means and we don't even know how to begin to ask that group questions. So we're breaking down barriers. We're talking to our payers about why this is important and educating them around, yes, you have 50 targets in here and whether you're doing 50 or 30 or 10 it's gonna cost about the same overall and this is why we do it this way and we mitigate extra biopsies and delays in care and we're also talking to our clinicians in the back about the nuances, about, yes we call this a variant of unknown significance however this is what we mean in the fine print when we talk about look this is downstream of another activating mutation, if you're not getting the results you're expecting back well then it might be because of this so you may want to change course more quickly. I mean there's nuances to this and the educational piece cannot be underestimated and to cut that out would just be devastating.

Rakesh: Thank you so much. We have run into the 3 O'Clock hour and I'd like to be respectful of the time allotted to this webinar. I want to conclude the webinar by thanking our panel of experts on participating on this very important topic relevant for cancer patient management. I'd also like to thank our audience for attending and participating. We look forward to seeing you at a future webinar. Thank you very much.




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