MolDX Open Public Meeting - June 04, 2020 - JE Part A

JOCELYN FERNANDEZ:
Good afternoon and welcome members of the public, Noridian’s Open Meeting for two proposed LCDs.

The proposed LCDs for this meeting include Liquid Biopsies for Solid Organ Transplantation add Prognostic and Predictive Molecular Classifier for Bladder Cancer.

The meeting will be recorded. The audio recording and written transcript will be posted on our website following today's meeting.

All lines are currently being muted by our system and will remain muted throughout the meeting.

Only registered commenters will be allowed to comment during today's meeting.

For the commenters, each of you are being allotted 10 minutes to make comments.

Your line will be opened when it is your turn to speak.

Make sure you are not on mute within your system, or we will not be able to hear your comments.

You should be prepared to begin your comment immediately when called upon and will hear the moderators voice when one-minute remains.

By signing in today, you are giving consent to the use of your recorded voice and your comment.

Please be mindful of sharing any personal health information.

We asked that any comments made today also be submitted in writing.

While only registered speakers will be commenting today, anyone in attendance may submit written comments.

I will now turn the meeting over to Dr. Lawrence Clark or an overview of the proposed LCDs.

DR. LARRY CLARK:
Hi, and thank you, Jocelyn. I want to thank everybody, in attendance, and particularly those of you who are with us yesterday. I hope you're back, not just because it's a job requirement, or something like that. But did you actually got something, as I did add of yesterday's academic discourse, I did get some positive feedback on the discussion of why we're here and the implications of the 21st Century Cures Act on our current process. So, what I'm going to do is repeat, because people actually like it, I'm going to repeat, a brief reading that I opened yesterday with which is section 13.2.3 of the Program Integrity Manual.

“Prior to drafting and during the development of an LCD, if available, the MACs shall supplement their research with clinical guidelines, consensus documents, or consultation by experts. Recognize authorities in the field, medical associations, or other healthcare professionals for an advisory opinion when applicable, when a MAC consults with an expert, they shall inform and obtain consent from the expert, that their opinion may be used disclose publicly and clearly identified as such within the proposed or final LCD.”

And I just want to thank, again, as yesterday, all of the associations are state, regional, and national associations who are offering to review critically these policies and to help us form an evidentiary basis. So, with that, our two policies today are DL38629 and DL38647, the first agenda item is going to be the Liquid biopsies. Jocelyn, I'm going to turn it back to you at this point. Thank you.

JOCELYN FERNANDEZ:
Thank you, Dr. Clark. Our first LCD today is Liquid Biopsies for Solid Organ Transplantation.

Our first commenter is Matthew Mega.

DR. LARRY CLARK:
Mr. Mega, your line is open.

MR. MATT MEGA:
Great, Thank you. Doctor Clark, Thank You for giving us this opportunity. Just a brief introduction. My name is Matt Mega.

I'm the Vice President and market access at Natera, and specifically interested in the development of this, Liquid Biopsies for Solid Organ Transplant LCD, my questions revolve around the MolDX component of this LCD. I note that on the CMS website, it is listed at the MolDX LCD and I'm curious and I set these questions ahead of time.

If there's any circumstances where Noridian would, uh, I guess, finalize this LCD in a different form than the LCD that will be finalized by MolDX just trying to understand the process and how the MACs work together in the development of these LCDs.

DR. LARRY CLARK:
Honestly, I can understand that question.

That is not something, that per the process we are supposed to discuss in advance of the meeting here, or actually in advance of the finalization of the policy. That is something that industry put in through Congress to protect the value and the proprietary nature of their products. So, I really can’t say, particularly, I read the Program Integrity Manual and what Noridian will be doing by the process to review the policies presented today. At that point, then, we will let you know what our decision is.

MR. MATT MEGA:
OK, I appreciate that response for my follow up question. Is in the same context, as we submit comments regarding this Noridian Draft LCD 38629 will submit comments to Noridan, and I understand that you'll be responding to those comments and publishing an article Response to Comments specific to the Noridian LCD and separate from the Response to Comments that MolDX, and Palmetto or the other MACs might publish. I'm just trying to understand if we should be working with both entities or should we be working through the MolDX Program.

DR. LARRY CLARK:
That, I can touch on that, again, within the constraints of what I legally can discuss with you, you are, I believe, a California – based corporation, is that correct?

MR. MATT MEGA:
That's correct. Yeah. Natera is based in California.

DR. LARRY CLARK:
We are your MAC, now, CMS is fully supportive and directive for us to collaborate whenever and wherever possible, so that there is consistency and coverage of the Medicare program.

However, we are ultimately responsible for processing your claims and ultimately, also held up to the metric that I just read, and I read yesterday, which is that we are supposed to have full and open, transparent discourse about the clinical services, and particularly the clinical effectiveness of the services that we are approving.

So, while you are dealing with a collaborative entity, the final decision for a California based Petitioner, we are your MAC. So, I hope you'll like our process, we're adhering to Congress's mandate the best, we can Sir, OK,

MR. MATT MEGA:
Yeah, I've got one follow up question, and what is the process for us to facilitate dialog with you, specifically, regarding these LCDs, rather than through the MolDX program? How do we how do we schedule pre-submission or discussions about the clinical validation or clinical utility of our services? With you, or with Noridian specifically?

DR. LARRY CLARK:
Well, you're here today, and we have our experts on the phone, and we have people ready to review your policy as we do all of our Noridian policies. So, you've started your process, and you have an opportunity, obviously, to submit in written commentary, and then we will proceed according to the 21st century process.

MR. MATT MEGA:
Great, Thank you.

DR. LARRY CLARK:
Any interest in education, I do not think this discourse here was germane to your presentation so it's 2:10 p.m. Jocelyn, reset the clock so Mr. Mega’s 10 minutes begin now. Go ahead, Sir.

MR. MATT MEGA:
Well, that's all. I didn't have a presentation. I just wanted to get some clarity on the process for addressing LCDs moving forward. You've done that for me.

DR. LARRY CLARK:
Hopefully, I have satisfied your questions, and it definitely, I recommend, we recommend as Noridian that all of our stakeholders are practitioners or institutions review Chapter 13, and the Program Integrity Manual. Jocelyn, back to you.

JOCELYN FERNANDEZ:
Thank you.

Our second comment, is Danielle Scelfo, Ms.Scelfo, can you hear me?

Ms. Scelfo? Are you able to send us a message in Chat?

OK, let's move on to our next LCD. While we try to get Ms. Scelfo connected, we can add her back in at the end.

Our next LCD for today is Prognostic and Predictive Molecular Classifiers for Bladder Cancer.

Our first commenter is Dr. Ewan Gibbs. Doctor Gibbs, can you hear me? Doctor Gibbs Are you able to enter your audio pin?

Give us a moment while we try to connect him, Hold on.

We will try to get Dr. Gibb connected. In the meantime, we will move on to our Next commenter, Elai Davicioni Mr. Davicioni, can you hear me? can you unmute yourself?

Give us a moment while we try to connect with Mr. Davicioni.

DR. LARRY CLARK:
Jocelyn, may I make a suggestion that if they're having problems, particularly Dr. Davicioini and Ms. Scelfo, give them just the audio dial in and don't worry, they don't have presentations any way, since I'm working on the direct audio dial in. So, let's get them in one way or another. Thank you.

DR. EWAN GIBB:
Hello. This is Ewan Gibbs. Sorry, I couldn't get this audio connection to work.

JOCELYN FERNANDEZ:
OK.

DR. EWAN GIBB:
Can we go? Can we go back a few slides to start, please?

JOCELYN FERNANDEZ:
Sure.

DR. EWAN GIBB:
Thank you.

JOCELYN FERNANDEZ:
You may begin.

DR. EWAN GIBB:
All right, thanks very much. So, yes. Thank you for the opportunity to present our classifier to YOU today. My name is you and give I'm a senior scientist in the Bladder Cancer Program Lead Decipher Biosciences. Next slide, please.

So, to give you a little bit of background about what bladder cancer is, so this is a tumor types that arises in the bladder linings surrounding the bladder lumen in the US and Canada. It's the fourth most common cancer in men and the 12th in women and it has a higher prevalence in men, which is three times more common than in women. It's a disease of the elderly, its median age is about 73, that diagnosis, it tends to be a very aggressive disease associated with a high risk of both morbidity and mortality.

So, in muscle invasive bladder cancer, we're looking at about a 50% five-year survival rate without treatment.

It tends to be very expensive cancer, and this is in part due to the high costs of monitoring due to high rates of recurrence more and the non-muscle invasive side than the muscle invasive side but also some of the treatments can be quite costly as well.

Next slide, please.

So, bladder cancer really clinically comes in two different types so that the highest-level split is into non muscle and muscle invasive bladder cancer. So, in the non-muscle invasive side, which represents about 75% of the incident cases, the tumor actually has invaded the into the muscle layer surrounding the bladder.

Whereas muscle invasive bladder cancer, the tumor actually has progressed and either penetrated into or through the muscle tissue and even beyond that into the fat layer and this can reflect the stage of the tumor with higher stage being more invasive.

Next slide, please.

So, bladder cancer management is actually incredibly complex with many decisions to be made. On the left top box, we have non muscle invasive bladder cancer, so even after being positive or diagnosed with bladder cancer and non-muscle base of bladder cancer, patient and physician have to make a series of decisions in order to treat the patient.

However, typically, or, often, the cancer can recur, which requires frequent monitoring, which introduces another set of decisions after that point as well.

Conversely, muscle invasive bladder cancer, this is really the worst of the tumor types has a lot of other decisions that need to be made primarily oriented around decision to therapy. So, with different therapies having increasing intensities. So radical Cystectomy maybe among the least intense, but still highly morbid treatments with chemotherapy or radiation becoming much more intense, much more aggressive.

There's also a small cell, bladder cancer, which is again, just reflecting how complex this disease is, but this tumor type is matters similarly to muscle invasive bladder cancer, but it has a different chemotherapy regimen, and this will become important downstream.

Next slide, please.

Thank you.

So, our model and our test are based around a long history of literature based on molecular subtyping. So, this concept was originally developed in breast cancer but has been recently, over the past eight years, ported over and developed in bladder cancer as well.

So, over the past eight years or so, there's been a lot of diagnosis - sorry, models developed around molecular subtyping. So, our assay is actually the Decipher TURBT assay, it is a molecular subtyping assay built on this longstanding history based around a high-level split of basal luminal biology axis in cancer.

The test is indicated for patients diagnosed TURBT with bladder cancer, and were indicated for high grade, non-muscle invasive clinical stage T1 all the way up to clinical T4 specimens, and none of the patients for our test yet received a radical cystectomy.

Next slide, please.

So, the test is an array-based assay uses a clinical grade, uses a whole transcriptome assay to measure the tumor biology.

So, we actually have a very small amount of tissue requirements. So, you use FFP, TURBT tissues, extract the RNA, run the arrays and then we have a cloud analytics platform to ultimately present a standardized clinical test report.

Um, test itself actually uses 209 genes to classify patients into 1 of 5 molecular subtypes. So, this is a categorical model, so your patient always reported out as being 1 of 5 different classes.

The test has been extensively, analytically validated as a sole source laboratory develop, test, and we are clear certified.

Next slide, please.

So, this is an example of part of our test report.

So, again, as I was saying prior, test classifies a patient to one for molecular subtypes are worst or varieties of bladder cancer.

So, the report itself, actually, in the case of probability of being each subtype, so every patient will receive a probability score for each of the subtypes with the highest probability indicating the subtype of that patient. So, in this example here, you can see the basal has a high percentage score, and so this is the class that patient would be considered in this case at basal subtype.

And we also report out a clinical recommendation for this classification.

Next slide, please.

So, where this starts to become important in the clinic is how you would interpret these subtypes clinically, and how you would use this information, and so the Decipher Bladder test actually unpacks multiple therapeutic options based around ordered intensity.

So, for example, we have the luminal subtype at the top, so these patients really have a higher probability of being organ confined, meaning their tumors are restrained to the bladder hasn't quite penetrated through the bladder wall and there's no evidence of nodal disease, and these patients have been found to really have limited benefits the adjuvant chemotherapy. Whereas the basal subtype is quite different, these patients are much more likely to be non-organ confined, having T three plus and or node positivity, and observed just received significant benefit from cisplatin-based chemotherapy based on their studies so far.

The claudin-low, these are a basal-like class, have high immune infiltration. These patients actually have been found to receive great benefit from immune therapy particular pembrolizumab, but do not respond favorably cisplatin as we found in this particular study.

As indicated, the neuroendocrine light subtype, which is actually a very interesting group of patients. These patients have tumors that neuroendocrine-like clinical behavior or a small cell like clinical behavior and biology. But the tumor itself does not present with small-cell histology. So, these tests really are required to identify these patients at diagnosis. They have extremely aggressive tumor, behavior requiring top of sudden cisplatin, and this is based on the NCCN guidelines for management of small cell bladder cancer, because they have neuroendocrine like features.

Next slide, please.

So, based on the criteria indicated in DL38576, we believe that, we've actually met all the coverage criteria, as indicated by the checks on this particular slide.

So, next slide, please.

This is a set of references for those who are interested, which is all the supporting references used in this presentation, for those who are interested in following up on this particular talk.

Next slide, please.

That said, I can take any questions for those interested.

DR. LARRY CLARK:
Yes, sir. Are you a clinician? I know doctor Milkowsky was joining us, but are you a clinician as well?

DR. EWAN GIBB:
I'm a I'm a scientist.

DR. LARRY CLARK:
OK, great, then what I'm interested in is a couple of things. One of them is you referenced 209 genes, but the policy only references I think the two well-known ones, the fibroblast growth factor receptors 2 and 3. Where did the other 207 come in? and are these a part of the NCCN or an AUA approved guidelines or anything?

DR. EWAN GIBB:
So, I'm a bit confused at which of the fibroblasts genes where that reference was?

DR. LARRY CLARK:
The policy was representing FGFR3 and FGFR2, which I thought were the two big ones in muscle-invasive bladder cancer, and so there's 207 genes that we don't know about where, where did they come in the policy and in the treatment- decision making?

DR. EWAN GIBB:
So, the 209 genes are used to molecularly classify the patient into one of the five subtypes. So, we don't look exclusively at one gene, we found this is really not a very tractable way of bidding patients. So, FGR3 and FGR2, I believe that FGR3 is part of the model, which would be helping classify patients into the luminal axis.

But otherwise, the rest of the genes are basically, again, used to classify the patients into one of the other four subtypes.

So, we really need this high-level granularity in order to identify correctly which biology the patient both best fits, and thus, which treatment the patient might be most likely to respond to.

DR. LARRY CLARK:
Do you think it would be appropriate if we had a representation of at least those genes that were NCCN 2A or higher accepted in the text of the policy?

DR. EWAN GIBB:
That's an excellent question.

I think it would be appropriate to include some of the genes, I mean, obviously, because it's proprietary modeling, we can't reveal all the features of the classifier. But for all

DR. LARRY CLARK:
I'm not asking for all the features; I am just asking for the genes that I think would make this a standardized treatment through the cancer community.

DR. EWAN GIBB:
Yeah, that's a great question.

DR. LARRY CLARK:
I'm sorry Dr. Milkowsky didn't come for a couple of reasons, I think, because there are some clinical questions here and those questions lead to the appropriateness of the coding representation of this test as well, I notice that 81445 and 81479 are included in the policy. Do you know why they would be included?

DR. EWAN GIBB:
No, sir. I don't.

DR. LARRY CLARK:
OK, yeah. I can expect that. OK, well, anyway, the other reason was the Lineberger Cancer Center.

DR. EWAN GIBB:
One of my colleagues actually has indicated, if he could comment, if you could unmute Scott Nelson

DR. LARRY CLARK:
Please do.

DR. EWAN GIBB:
Yes, thank you.

SCOTT NELSON
Good afternoon. Thanks for giving me a moment to comment and I'm the Director of Advance (unrecognizable) here at Biosciences, and I'm actually working through the coding exercises (unrecognizable).

Just to clarify what’s going on here, what we are representing here from us is multianalyte assays with algorithmic, and we're actually going through the process with the AMA right now, and what that does, is that represents one code that will be determined in the future, right, for our technology that would replace either 81479 which is unlisted molecular pathology procedure or 81599 which is unlisted multianalyte assays with algorithmic analyses and that is what reference of what the other codes are.

What Ewan is describing is a 209 gene panel that uses an algorithm to produce a score that moves it to one of the subtypes and that output would be (unrecognizable) to the genes themselves for the MolDX program.

DR. LARRY CLARK:
OK. Are you a Clinician?

SCOTT NELSON
I am not, no Sir.

DR. LARRY CLARK:
OK. Thank you.

I was just going to say, that Dr. Milkowsky, the facility that he practices. It was named after somebody I practiced with here. So, anyway, just pass that on.

OK, do we have any other speakers to this policy Jocelyn?

Yes, doctor Clark.

JOCELYN FERNANDEZ:
Doctor Matthew Milkowsky will not be presenting today due to scheduling conflicts.

DR. LARRY CLARK:
OK.

JOCELYN FERNANDEZ:
we are trying to connect with Elai Davicioni

OK, so in the next slide, so in the meantime, we'll move back to our first LCD Liquid Biopsies for solid organ transplantation. And we'll get Ms. Scelfo on.

DR. LARRY CLARK:
Thank you.

JOCELYN FERNANDEZ:
Ms. Scelfo, can you hear me?

DANIELLE SCELFO:
Yes. I can hear you, Jocelyn, can you hear me?

JOCELYN FERNANDEZ:
Yes, and I apologize. I apologize for the connectivity problems. Sorry.

DANIELLE SCELFO:
No worries, is the connectivity working well now?

JOCELYN FERNANDEZ:
Yes, it is loud and clear.

DANIELLE SCELFO:
Fantastic. Thank you all so much, and I really appreciate everyone's patience with technology.

We're all in a virtual world these days, and certainly appreciate just the commitment to get all the speakers on, And I want to also to thank the others that spoke on the solid Organ transplant policy in the questions that mister Mega had, they were very helpful to CareDX as well, too, So thank you.

CareDX is the leader in the application of gene expression and cell free DNA to high transplant, high impact transplant diagnostics. We're very glad that Palmetto was able to extend the comment period due to COVID, many of the key opinion leaders and experts in this area were at their annual society meetings this week, and I know, Doctor Clark, you had mentioned how important it is to hear from experts in your community. We believe that this now more aligns to comment period with the original Noridan schedule, and we look forward to getting insights for you from KOLs and Academic Centers of Excellence to this policy.

Since 2017, donor derived cell free DNA surveillance has been in use across the country to manage patients with kidney graft health at leading transplant centers in every state, donor derived cell free DNA testing has added a new and valuable way to survey the health of the transplanted kidney and other organs impact and identify rejection or graft injury to avoid downstream, transplant failure or other adverse events. It's important to note, I think, unlike oncology and that certainly was, was my background previously.

Unlike oncology where diagnostic tests are performed to drive a chemotherapy or endocrine treatment decision. In this circumstance, transplant patients are on immune suppression medications for life due to ongoing risk of rejection. So, using donor derived cell free DNA testing, to monitor those patients continuously over that timeline, has added new, critical information for guiding patient management and critical treatment decisions. As my Medical Director, who's an Oxford transplant surgeon once told me, that donor derived cell free DNA is kind of like the smoke alarm in your house. That tells you that there's a fire somewhere even before, potentially, you might see it.

So, you know, we applaud Noridian and MolDX for really leading in this space with this L D this draft LCD. We look forward to submitting detailed clinical comments by that July timeframe, and we will certainly copy you, Dr. Clark and Dr. Oakes if appropriate in that submission that we have to MolDX. Thank you so much for your time.

DR. LARRY CLARK:
There are some questions from me or take them on to your Medical Director?

DANIELLE SCELFO:
I can. Indeed. Yes, please.

DR. LARRY CLARK:
Do I understand? I mean, we didn't have someone else. There is a significant conflict with national meetings, and we're aware of that, that came up yesterday and one of our speakers had to cancel. One of the things that I think is common clinical knowledge is that T-cell mediated graph rejection versus B-cell mediated rejection have different process is and actually have different clinical significance in the patient population, and yet they seem to be melded together in in these clinical trials. Wouldn't there be a better way of doing the trials? I mean, I mean, I'm a little disappointed. I think we should have taken the time to establish a stronger evidentiary basis. Because I believe we're seeing more applications and more of this technology coming down, I mean, I don't think you are the unique product in this space Are you?

DANIELLE SCELFO:
There are other products for donor derived cell free DNA. I believe the CareDX was the first on market and probably has the greatest history. I do know, Dr. Clark, to your point, the COVID impact to clinical trials has been significant, I think, for everyone this year. So, you do bring up a good point. I did jot down a T-cell mediated responses versus B-cell mediated and the differentiation in clinical trials and we will highlight that with our submission for the LCD to help give you more information there.

DR. LARRY CLARK:
And there's another question again about the cell free DNA, people get to the end-stage of needing to be transplanted different ways and the processes that they get there, the deposition like in diabetes and amyloid, or immune processes, like in proliferative nephritis, lupus, stuff like that.

Don't they impact the baseline of release and cell free DNA? I mean, you're applying this particular technology to multiple different disease processes and treating them the same.

DANIELLE SCELFO:
Yeah. You know, that's a very good question, and I do appreciate just the various different disease etiologies, and to your point, you know, you do have each patient, a diabetic patient is certainly very different from a management perspective, from a lupus patient, I think to be able to give you that in-depth clinical information you're looking for, though, I would defer to our Medical Director. He's a transplant surgeon as well, to what I will do is I have him specifically speak to that or reach out to you one-on-one. Just to be able to provide that insight as it is.

DR. LARRY CLARK:
I would prefer writing because I also have some transplant experts from our jurisdictions listening in today and we'll be providing comments. So good written, evidentiary basis is what we're looking for.

DANIELLE SCELFO:
You got it. Thank you, Dr. Clark.

DR. LARRY CLARK:
Thank you.

JOCELYN FERNANDEZ:
Thank you, Ms. Scelfo for your comments. Now, we will move back to the LCD Prognostic and Predictive Molecular Classifiers for Bladder Cancer. Hopefully we can get Mr. Elai Davicioni

ELAI DAVICIONI:
Oh, great, I just can you hear me?

JOCELYN FERNANDEZ:
I can hear you.

ELAI DAVICIONI:
OK, Thanks everybody. Thank you, Dr. Clark.

Uh I just wanted to further comment on perhaps I can provide some clarity to some of your questions. For Dr. Gibb.

So, my name is Elai Davicioni, I'm the Founder and Chief Scientific Officer at Decipher Biosciences.

We're mainly known for our work in prostate cancer, but we have been working in bladder cancer for quite a number of years and really, I think it's important first to acknowledge and support what CMS is doing for bladder cancer patients and they really are almost an orphan disease on many levels, just in terms of funding and progress, Um, for, for therapy. It's very much a lethal disease for many patients.

There's a major issue in the United States, specifically, with under treatment, and primarily, because of lack of physician awareness. Physician certainly know this is aggressive disease.

But typically, in the United States, it's handled first by a Urologist, after the diagnosis, and they tried to manage the patient surgically for as long as possible and then subsequently involve Medical Oncology, or Radiation Oncology, or both.

What we're trying to do big picture with genomics, specifically, for our test, the type of bladder with transcripts only, is to bring bringing information into routine clinical practice that that's actually going to help them to, to personalize treatment for each patient.

And I think doctor Gibb gave some examples from the published literature. Some of these are actually also mentions, specifically in the LCD, the last couple of paragraphs. So, the, uh, many times, because under treatment is a big problem.

I think the main use of the Decipher bladder test is to indicate to the Urologist. Hey, you know, this is not a patient that you can just manage surgically. You need to follow guidelines and bring in medical oncology much sooner.

But also many times there are, the Urologists are following the guidelines, there just are too many options to decide from, and that's actually we're looking at the biology of the tumor, can be super helpful in figuring out, um, which, which of the many options to select from and help the patient.

Dr. Clark, I think you mentioned because in the In the LCD in the Summary of Evidence Section, I believe it's in the first paragraph, it does reference FGR2 and 3 mutations, Um, which again, is part of the actual label for the Fitnib Drug.

What we've been working on, is complimentary to that, It's a little bit earlier. These are, the drug is used on people that have already failed chemotherapy. We're actually testing people before they had chemotherapy.

So, the decision is they've had a definitive diagnosis. They have either high grade disease, non-muscle invasive disease or muscle invasive disease and the next step is to decide between getting radical cystectomy alone, a radical cystectomy with chemotherapy, either neoadjuvant chemotherapy, adjuvant chemotherapy, neoadjuvant platinum-based chemotherapy is preferred Um, method for most of the muscle invasive patients currently in the guidelines,

Um, then there are other therapies, including immunotherapy now. We expect other drugs in the near future that are being invested in trials and the consistent theme and why this is important that Medicare has actually been very proactive in that space and it'd be great if they could do these sorts of umbrella LCDs, policies for, for every indication, is because, you know, these drugs are becoming more and more specific to the tumor biology, and there's no way for, for ...

Radiation Oncologists, Medical Oncologist to know what that tumor biology is without some kind of molecular diagnostic approach. You cannot see it by still pathology. You can’t just see it under the microscope.

Um, so as more and more therapies come that, our molecular, we've targeted, these types of policies and the tests that they, hopefully cover, are our important to help our physicians better manage these patients.

Um, what's different about FGFR2 mutations, is that's looking at tumor biology on the DNA level. So, DNA mutation, and the molecular subtypes that have been described in the literature that read into for tumor biology are based on gene expression levels, or transcriptome level data.

So really, the 209 genes, just listening to the comments, the 209 genes are used to classify with the algorithm of subtyping algorithm classify patients based on these gene expression patterns of the tumor into one of the subtypes and it's those subtypes that show differential response to therapy and Dr. Gibb gave several examples from the publication.

So, that was all the remarks I had. But I'm happy, and we will be doctor Clark, we have a comment letter to more specific remarks, so we'll be sending that in shortly, but I'm happy to take any questions.

DR. LARRY CLARK:
Yeah, I guess we are looking on the coding article here, and you do list. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15. I think those are just examples. In this policy, there are two genes, The FGR2 and 3 are listed as actionable and we still have 207 to go.

So, if you would explain how those other 207 apply to the decision making of the muscle invasive bladder cancer, I think that would be a real start.

ELAI DAVICIONI:
Sure. So, the 209 genes form a panel, really, a signature, or it's actually signatures, that when measured using a machine learning algorithm, provide a classification results, the subtype of the cancer.

DR. LARRY CLARK:
So, and what is machine related to

ELAI DAVICIONI:
The specific type is the it's called the GLM map. Quite commonly used in, in uptake in classifiers in the scientific and medical literature. Developed at Stanford.

DR. LARRY CLARK:
OK, can you send something on about that, because that is referenced, and again, I don't. I looked at the reference articles, and I didn't get a clear explanation of what that was.

ELAI DAVICIONI:
Sure. So, would you like when we send in the comment letter, to send you the publications?

DR. LARRY CLARK:
Yeah, that'd be great.

ELAI DAVICIONI:
OK, thank you. We can do that. You're welcome. I don't have any further remarks.

DR. LARRY CLARK
Thank you very much, Jocelyn.

JOCELYN FERNANDEZ:
Thank you, Mr. Davicioni. Dr. Clark, do you have any final comments?

DR. LARRY CLARK
No, just to thank everybody that attended today and to particularly thank our speakers and to invite you to join us next week on June 10th for a discussion of urine drug testing and I'll turn it back to you, Jocelyn.

JOCELYN FERNANDEZ:
Thank you. In closing, we would like to communicate the next steps in the policy development process.

The comment period for the Proposed LCD will remain open until June, July 12, 2020. As noted earlier, all comments to be considered by our Medical Directors for the proposed LCD must be submitted in writing. Written comments can be emailed to policydraft@noridian.com or mailed to the address on your screen.

Comment information for our proposed LCDs are located on our website at noridianmedicare.com. Upon review of the comments, our medical directors will finalize or retire at the proposed LCD.

Please monitor our website or register for our listserv notifications to be informed when actions are taken to implement or retire, our proposed LCD.

Thank you, doctor Clark, and thank you all for joining our open meeting today.

This concludes our meeting.

Have a wonderful day.