Proposed LCD DL35396 - Biomarker for Oncology
Proposed LCD DL35428 - Thrombolytic Agents
Jyme Schafer, MD, MPH - Contractor Medical Director
Sidney Hayes, MD FCCP - Contractor Medical Director
Barry Whites, MD, FCCP, MSHA - Contractor Medical Director
Sunil V. Lalla, MD, FACS - Contractor Medical Director
RaeAnn Capehart, MD - Contractor Medical Director
Alidad Mireskandari, PhD
Thomas Nifong, MD
Good morning and thank you for joining us for today's Novitas Open Meeting. All participants will be in listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by zero. Throughout today's meeting, registered presenters will have the opportunity to speak with us about the proposed LCD's. Novitas Contractor Medical Directors will then have an opportunity to ask questions.
Please note, this meeting is being recorded. I would now like to turn the conference over to Dr. Jyme Schafer, Novitas Contractor Medical Director. Please go ahead.
Dr. Jyme Schafer
All right, good morning everyone. I'd like to welcome you today to the Novitas November Open Meeting. My name is Dr. Jyme Schafer, I'm a Contractor Medical Director here at Novitas and on the phone with me today are my Novitas colleagues which include Dr. Barry Whites, Dr. Sidney Hayes, Dr. Sunil Lalla and Dr. RaeAnn Capehart.
We're holding today's open meeting to discuss the review of the evidence and the rational for the LCD revisions with stakeholders and any other interested parties based on recent revisions to the program integrity manual that's Chapter 13 of the PIM, regarding LCD development. This new process is slightly different in that our medical director will provide a brief overview of the proposed LCD; all other requirements for the meeting remain unchanged.
For the two proposed LCD topics for today's meetings are, DL35428 which is thrombolytic agents and the second one, DL35396 which is biomarkers for oncology. Both revisions are the result of LCD reconsiderations of requests. During today's meeting, interested parties, generally those that would be affected by the LCD, will make presentations of information related to these proposed LCD's but please remember, all formal comments need to be submitted in writing. Also, as a reminder, today's call is being recorded.
At this time, I would like to turn the meeting over to Dr. Sidney Hayes for a brief overview of the proposed revisions for thrombolytic agents. Dr. Hayes?
Dr. Sidney Hayes
Thank you Jyme. Good morning. We should be on Slide 6 and then go to the next slide. We have a current policy, L35428 on thrombolytic agents. The original effective date was 10/1/2015. We have a reconsideration in process to open more coverage with these agents and at this time, that is what we are discussing.
In the past we have had infusions for venous, through venous structures but at this time we are opening it for arterial structures as well. The present policy says in patients with acute pulmonary embolism associated with hypotension who do not have a high risk of bleeding, it is suggested to provide systematically administered thrombolytic agents over no such treatment. At this time, we have added a caveat in selected patients with acute pulmonary embolism associated with hypotension and a high bleed risk patient and, in parenthesis, we've given some suggestions that are in sync with the American College of Chest Physicians such as acute post-op major surgery, recent trauma in surgery, recent ischemic stroke, recent GI bleed. And I'm sure there are other issues that would fit within that parenthesis that are not listed. Catheter directed treatment with thrombolytic agents may be used if the appropriate expertise and resources are available.
The third bullet talks about the draft article. We have expanded CPT codes to include 37211 which is an arterial infusion all the way to 37213 which is arterial or venous. Comments are limited to these specific revisions of the proposed policy. Next slide?
I see that we have no presenters for this reconsideration and change and draft policy. I want to remind you to please submit any comments in writing through the normal process. At this time, I'm going to turn this over, meeting over, to Dr. Barry Whites.
Dr. Barry Whites
Thank you Sidney, thank you Jyme. This is the discussion on three reconsiderations that we have received in Novitas on our biomarkers for oncology policy. This is the revision that has -- the comments (PH) from this in response to these requests; I'm on Slide 10. The comments are limited to the revisions that are made with this revision and not open to general discussion of the rest of the policy. Certainly, any reconsiderations to the rest of the policy are always welcome. We had three separate reconsiderations. The first one was with multiple leukemic (PH) bile markets and also lymphomas, the hematological malignancies and we rely very heavily on the NCCN guidelines of 2A or better. In addition to quality literature, there is not one that we use over the other but those two items are items that we considered in making our consideration.
As you can see, there were several genes that were added for the various; we've got leukemia's and we also have mild proliferative disorders. We have hairy cell leukemia, myeloid leukemia. We had some of the other Hodgkin's disease embedded (PH) but, again, none of these fit the criteria either of the literature or of the NCCN 2A guidelines. It's for that reason that not all, but these were the ones that were submitted for coverage and they were added to the policy.
The next request that we had was to add ThyGenX (PH) which is a thyroid panel that we have a ThyGenX and they changed it to the NEXT (PH) and they added more genes. All of those genes that they requested did have literature to support their utilization, in addition, all of those genes met the criteria for NCCN 2A (PH) guideline and that test is being used in place of the current GenX. The only change that's going in that; dropping one for the other.
The final request that we had was to add Cxbladder, which we've had several requests to do this in the past. We have, at this point in time, I think the major reason for the request was a designation by NCCN guidelines of molecular testing designated 2B, not a 2A, which is even less evidenced with the 2A being low evidence with strong support for it.
Coming in here on the first -- on the first line that it did not support clinical utility and clinical validity; I think validity was certainly less of problem with the utility. This is where we've had a problem. In addition, the information that was forwarded to us primarily was concerned with the NCCN guideline and when you look closely at the NCCN guidelines, they were for different genes and not those that were included in the Cxbladder test. For that reason, it is not being expanded to cover Cxbladder.
I'll be happy to now go to the presenters and hear their comments on this. Again, any comments that are made or any changes that would like to be or corrections that would like to be made to this proposed policy needs to be presented to us in writing with document of the references that you are using to support your position.
Jyme, can we go to the presenters now?
Dr. Jyme Schafer
All right, first up we've got Alidad Mireskandari and Greg Richards. I apologize in advance if I mispronounce your name. Thank you very much. And please state your conflict of interest before you present. Thank you.
Dr. Alidad Mireskandari
My name is Alidad Mireskandari, I'm in charge of endocrine business development for Interpace Diagnostics. I'm a paid employee of Interpace. Today I'm here to talk about biogenetics which is a second generation next gen sequencing panel for thyroid franchise (PH). My goal today is to talk you through -- what did I do? Sorry about that. To talk to you about, walk you through, some of the markers we added to the second generation product, discuss the reasoning behind choosing the markets that we did and then end the discussion with a review of the supporting literature that allowed us to add the markers that we did.
When I got tasked with create a second generation product, we wanted to make sure that that product hit a couple of needs for the business and for our clients. These included improving the clinical validity and the utility of the assay, increasing numbers of what I call actionable, clinically actionable markers in the panel. It had to impact patient management, of course and we wanted to make sure that the assay was useful to the end users. And equally important for me as a scientist was to avoid markers that didn’t have clinical utility. I'm not a big fan of adding markers for the sake of having a larger panel; that's not how we do things at Interpace.
We did do a thorough review of the literature before we embarked on finalizing the roster or the markers and we contacted a lot of KOL's in the thyroid space and got their input as well. We have strong physician support of what we've done. I think I -- there you go, sorry about that.
Our previous version of the test was commercially called ThyGenX, it had about 15 DNA and RNA markers in it and it was also run on an NGS platform and it was -- it used a CPT code of 81445. The current test has a commercial name of ThyGeNEXT and has a combination of 52 DNA and RNA markers in it. It is also run on an NGS platform and we're asking for a new CPT code over 81455.
This table shows you the markers included in the original panel which are in the white boxes and the markers that are in the green box are somewhat (inaudible) are the new markers that were added. On the DNA side, we've only added five new mutations. ALK, (inaudible), P10, RET and (inaudible) were the five new mutations.
I could have added 50 new mutations if I wanted to but when we did the literature search and we put the criteria that I mentioned in the previous slide into place, we realized that these are really a handful of mutations that have clinical relevance, clinical utility and have a high correlation with malignancy.
What happens if you add mutations that don’t have a high correlation with malignancy, you're going to get a lot of false positive results that drives your specificity of your assay down and it brings the PPD (PH) of the assay down. And we were very conscious of that fact. I didn’t want to sacrifice the specificity of the assay by just adding non-specific markers to it.
On the RNA side, we actually added over 30 fusions. The fusions are highly specific. If you have a non-cancerous cell you typically don’t see any fusions. The presence of fusions is highly predictive of a malignancy. We were very comfortable that adding these new 30 markers would not really impact our specificity of the assay in a negative way. When it was all said and done, we had 52 diagnostic markers that ended up in the panel; that's what you have on this screen right now.
As far as the reasoning behind some of the markers we picked, there were some that were associated with aggressiveness of cancer and thyroid. Thyroid cancer is typically a cancer you die with, not one you die from. In some cases, it becomes malignant and aggressive and when that happens it's a very fatal cancer. ALT and (inaudible) are highly indicative of thyroid aggressiveness; we thought that would be valuable to add to the panel. There are other markers that actually do the opposite. Gene assay (PH) P10, when present, seemed to indicate (inaudible) even if you have a rash or rash family of gene mutations.
We also put in RET because it is a marker associated with medullary thyroid cancer and some of the fusions that we put in there are really important in malignancy. We also, as I said, talked to physicians, KOL's, we took their feedback and this limited panel approach was really an area, way, for us to move forward. It's comfortable for us and eventually ATA, even I'll show you some data, the American Thyroid Association put out some communication that the limited panel is actually quite useful in detecting thyroid cancers.
As I said, we did a thorough literature search and I'll show you some evidence for the sake of brevity in this presentation. We only list 30 but there was a lot more papers supporting the role of every single marker that we added to this panel. As far as physician support, the product was launched last summer, I believe?
June of 2018.
Dr. Alidad Mireskandari
June of 2018 and we've gotten a lot of positive feedback from our end user customers. I'll show you just a few examples. This is from Dr. Cipriani (SP) and Dr. Angelos (SP) (inaudible) Chicago. I know you can't read the actual letter, it's too small, but they were very happy that the test has prevented numerous unnecessary surgeries. Another letter came from Dr. Malchoff (SP), the University of Connecticut; very happy with the kind of report that this test generates and allows them to see this patients based on the best evidence and science available.
This is the American Thyroid Association communication (PH) that came out late last year that a small panel of genetic mutations can be very effective. There are other panels out there that have 160 genes. I'm not a believer that all 160 genes, or mutations, really play a role in cancer so we kept ours sort of limited and we're fine with that. Talking about the evidence for this meeting, I went through every single marker that we have and I referenced each paper that supported the role of that marker in thyroid cancer. I think we have hard copy summaries of each paper sent out a couple of weeks ago to everybody and we have actually PDF's of every single paper electronically available as well if you're interested, but as far as I was concerned, I needed at least five references for each marker we added to the panel to prove its utility in malignancy and here's an example of -- sorry, I should do this, of the number of papers that support each and every one of our markers in the second generation.
And here are the actual titles of the papers that we used to create that reference list. I won't bore you with reading every single title of every single paper, but the evidence is there. They're all peer reviews, they're independent labs and we have listed copies of every one of them. With that, I'll stop and answer any questions you may have.
Dr. Jyme Schafer
Dr. Whites, do you have any questions?
Dr. Barry Whites
No, I do not. Thank you for the presentation; very good.
Dr. Jyme Schafer
Very nice. Thank you very much. All right, next presentations; Dr. Thomas Nifong and Jacqueline Walker. And if you'll announce your conflict please?
Dr. Thomas Nifong
Yes, I will, absolutely. Thank you, good morning everyone. Left and -- yeah. Okay, all right. Good morning everyone. Thank you for this opportunity to present this morning. I'm Tom Nifong, I'm the Medical Director for Pacific Edge Diagnostics and our CEO, Jackie Walker is in the audience. I am an employee and a shareholder of Pacific Edge.
We submitted the NCCN guidelines update for 2019 and two recent peer reviewed publications which we believe, along with the previously submitted evidence, support the coverage of Cxbladder. While we appreciate the careful review of our submission, we disagree with the non-coverage decision of Cxbladder. In the presentation, we will review the draft LCD summary of evidence and rationale for determination for Cxbladder and explain where we disagree and why we think Novitas should cover Cxbladder.
Format changes when you convert them over here. We're a New Zealand-based company with U.S. headquarters and commercial operations locally here in Hershey, Pennsylvania. We commercially launched Cxbladder in 2013 and since then have provided tens of thousands of patients, patient-tests, including over 25,000 patients in the Medicare-aged population. We offer Cxbladder in all states including New York.
We have two coded Cxbladder MAAA tests; both measuring concentrations of messenger RNA and voided urine of the five genes that are shown here with algorithms applied to provide a risk score for having either primary or recurrent urothelial carcinoma or UC. This is a snapshot of the literature on Cxbladder for both primary detection of UC in hematuria and in surveillance. The clinical validity was demonstrated consistently from 2012 through the present; although we only submitted recent peer reviewed publications for this consideration request, we have previously submitted all of these to Novitas and in Dr. Whites' introduction, he did indicate that the clinical validity did not seem to be an issue with our request.
Our strong clinical validity has been consistently demonstrated for our Cxbladder test in both primary detection and surveillance. For comparison, Cxbladder clearly outperforms FISH, NMP22 and cytology for detecting UC.
The relevant change to the NCCN guidelines is shown here, whereas the previous version on the left named FISH and NMP22 as biomarkers for consideration. The updated version eliminated that direct reference and, instead, references the biomarkers in the meta analysis in reference 89. Instead of recommending consideration for FISH and NMP22, the guidelines state that evaluation of urinary urothelial tumor markers may be considered during surveillance of high risk, non-muscle invasive bladder cancer.
These are the details from the NCCN reference 89 which show the urinary tumor biomarkers that are recommended by NCCN guidelines are NMP22, BTA (PH), FISH, ImmunoCyt and Cxbladder. Now, it appears that the reviewer considers NCCN consensus 2B recommendations as non-supportive. Now, keep in mind a 2B recommendation has a consensus with a panel vote of greater than 50%; a simple majority. You win elections with a simple majority. In fact, most of the laws that have been passed are passed with a simple majority. Obama Care became law with a one-vote majority. All right?
A 2A recommendation actually has the exact same underlying level of evidence but rather it requires a uniform or super majority consensus with a panel vote of greater than 85%. And we think this is just too stringent. I mean, really, what requires an 85% consensus? You can veto or remove the president with a two-thirds vote, all right? We also are not aware of any requirement for Level 2A recommendations and some tests, such as FISH and NMP22 are, in fact, appropriately covered with 2B recommendations.
We don’t believe that a 15% minority on a panel should determine access to a technology for the Medicare population. Now, the NCCN guidelines for bladder cancer were updated in 2019 as I showed to reflect a broader acceptance of the use of biomarkers for the evaluation of recurrent bladder cancer. In the draft LCD summary of evidence, the reviewer notes that there is no shared commonality between the Cxbladder test and the FGFR family of genes. This is not a relevant comparison. Relevant changes, as I showed previously, are on Page MS13 in the section, Non-Muscle Invasive Bladder Cancer Surveillance.
The reviewer seems to reference FGFR testing, which is a companion diagnostic for erdafitinib such as shown on Page MS24. Cxbladder provides a risk assessment as to the presence or absence of UC. It's not intended to predict response to erdafitinib. There's no reason to expect shared commonality of these biomarkers.
Now, we also submitted the paper by Davidson which is a real world utility measurement of prospectively collected data from 571 patients with hematuria being evaluated for bladder cancer. The reviewer noted that the patients were coached about the test. We don’t know where this statement came from or what it means as there's no reference to coaching patients in the manuscript.
A single mid-stream urine sample was collected from each patient, preferably from the second void of the day as per the instructions for use and we don’t see any bias introduced by instructing appropriate sample collection. The reviewer also noted that there's no documented clinical utility in this study but rather healthcare insurer utility and we don’t understand the distinction between clinical utility and insurer utility and we disagree that clinical utility is not demonstrated.
The study documented the elimination of cystoscopy in one third of patients with the use of the mandatory protocol pathway allowing them to safely avoid the social disruption and discomfort of an invasive procedure. Where Cxbladder is non-invasive, cystoscopy produces pain, anxiety, discomfort and risk of infection and urethral strictures eliminating unnecessary cystoscopies is clinical utility.
This statement from the American Urologic Association further supports the fact that the reduction in unnecessary invasive procedures is a reflection of clinical utility. Now, the reviewer also notes that the study is not generalizable to the Medicare population. This statement is incorrect. Given that the median age in the study, as shown in Table 1, is 66 years old, more than 50% of the study population is in the Medicare age group. The study pathway was used on all patients with hematuria regardless of age and these results are, in fact, generalizable to the Medicare population.
The reviewer also notes that there was little follow-up in the study and that less than one year of data is not enough data to support a change of decision. These statements are factually incorrect. The non-referred cohort was followed for a minimum of two years to ensure that no malignancies were missed. The study was compelling enough that the health board, which includes 12% of the country’s population, implemented it into their clinical pathway in early 2018 and as noted in the conclusions it has been continuously audited since then; an additional 18 months. They prospectively managed approximately 890 patients as of the time of this publication and will report on that in a follow-up study.
In fact, now, 11 out of the 20 district health board providers in New Zealand, encompassing 62.5% of the total population, have adopted Cxbladder into their pathways. This means that more than three million people in New Zealand are being managed with this new pathway. This has resulted in greater than a 40% reduction in cystoscopies nationally.
We also submitted the paper by Konety (SP) which is a retrospective analysis from 1784 patients pulled from four separate cohorts of patients with hematuria or being evaluated for recurrence. Evaluating the ability of Cxbladder to adjudicate atypical cytology; a common diagnostic dilemma. The reviewer stated that the limitation is this was open access and not peer reviewed with a significant conflict of interest by the authors. This is factually incorrect as this journal is peer reviewed.
European Urology is a platinum journal, it's the official journal of the European Association of Urology, has an impact factor greater than 17 and the acceptance rate is approximately 10% of the nearly 2000 annual submissions. By comparison, acceptance rate for JAMA is between 5% and 11% depending on the type of submission and the admission rate at Harvard is 5.4%.
All authors appropriately disclosed any potential conflicts of interest and the publication was peer reviewed with no evidence or bias from the authors. The reviewer again notes with this study that the generalizability to the Medicare population was not specified. We disagree. Table 3 from the supplement shown in the lower left here, as noted by the reviewer, shows the age for the patients that were included in the Konety study, extracted from four different cohorts. From this data, we can see that 64% of the samples are from patients in the Medicare population. Furthermore, in the surveillance cohort, which is indicated as Study 2 in the table, it was a multi-centered trial performed in the U.S. and previously published and submitted to Novitas. Table 3 from that study, shown on the right side, shows that actually the sensitivity of the test improves with age.
And as for the clinical utility, the authors note that the atypical cytology is a common diagnostic dilemma. Clinical utility is not theoretical. Nearly all patients with atypical cytology are subjected to additional invasive procedures in the current system and Cxbladder correctly adjudicated all atypical cytology samples in the study providing clinical utility by avoiding repeat cystoscopies in over a third of patients.
Now, in the rationale for determination; the reviewer again notes that there's no commonality in the genes between Cxbladder and FGFR and that the recommendations for biomarkers are only 2B. Again, this references the incorrect portion of the NCCN guidelines. As noted already, there's no reason to expect Cxbladder to share commonality with a companion diagnostic; rather, urine molecular tests, which include Cxbladder, NMP22, BTA, FISH and ImmunoCyt via referenced meta-analysis are recommended with Level 2B consensus for consideration during surveillance of high risk non-muscle invasive bladder cancer. A 2B recommendation is a majority consensus and it should be sufficient to positively impact coverage. An 85% panel vote is too stringent.
Finally, the reviewer states that the clinical utility and clinical validity were not supported in the literature and were not generalizable to the Medicare population. As noted above, the Medicare population constitutes more than half of the study population in these studies and the results are clearly generalizable to that population.
Clinical utility is demonstrated through improved patient care with a reduction in invasive procedures with no increase in adverse events and by removing the diagnostic dilemma associated with atypical cytology. In conclusion, we believe that we've already submitted sufficient evidence to support inclusion of Cxbladder and LCD 35396. Additionally, ongoing clinical utility data will continue to be published in both the hematuria evaluation and surveillance settings confirming the above data.
Cxbladder improves patient outcomes through a reduction in unnecessary invasive evaluations and it is recommended by a majority of NCCN panel members. We respectfully disagree with several aspects of the current LCD reconsideration review and recommend that Novitas should cover CPT codes 0012M and 0013M in LCD 35396 and our proposed coverage language is shown here. We will be formally submitting these comments as well.
Thank you, I was also allotted a couple of extra minutes to read a comment letter from Dr. Mark (SP) in relation to the Davidson (SP) publication and the implementation in the New Zealand Health System and the success they're having with Cxbladder there.
I am the urologist in Christ Church New Zealand within the public healthcare provider Canterbury DHB and president of the Urologic Society of Australia and New Zealand. I had the opportunity to review your comments on the paper Davidson -- was referenced in Novitas draft LCD DL35396 submitted as evidence of clinical utility. I would like to address your comments regarding Cxbladder implementation. This paper is a real world audit of the clinical utility following the adoption and use of Cxbladder into the standard patient pathways at a large public healthcare provider, Canterbury DHB. In this audit, all, 100% of patients that presented to clinic with hematuria were evaluated and all patients received both appropriate radiology and the standard workup, Cxbladder Plus flexible cystoscopy. As all patients had standard assessment, there was no selection bias and each patient was their own control. Physicians were blinded to the results of Cxbladder when carrying out the conventional workup using cystoscopy. Our primary goal was to look at the safe removal of flexible cystoscopy from the patient pathway for all patient results with a negative Cxbladder score.
The objective was successfully met with 40% of patients were shown to safely avoid cystoscopy. We now have a further two years of data following implementation of Cxbladder in our standard pathway which is also supportive of the addition of Cxbladder. The post-implementation data to be published, has confirmed the initial published finding with greater than 95% negative predictive value of a negative Cxbladder score. We here at Christ Church have 100% community capture and have had no cases present with a previous negative Cxbladder and progressive bladder cancer. A second large public healthcare provider in New Zealand, Auckland DHB, has implemented the test in over 500 patients with similar sensitivity and negative predictive value.
A total of 11 public healthcare providers are now commercially using Cxbladder covering approximately 62.5% of New Zealand's population. As we implemented the test in a whole of population review; the age range was as expected; median 66, range 18 to 95 with a significant proportion over 65 years of age as listed in Table 1 of the published paper. In summary, we looked at Cxbladder test implementation, negative predictive value and the gain in clinical utility from reduced flexible cystoscopy. Post implementation, there has been ongoing safe reduction of flexible cystoscopy in 40% of the referrals with significant clinical utility for patients through the removal of unnecessary invasive investigations.
If you would like any more clarification, please feel free to contact me. Yours sincerely, Stephen Mark, FRACS Urologist and President of USAMZ. Thank you.
Dr. Jyme Schafer
Thank you, Dr. Nifong. Dr. Whites, do you have any questions?
Dr. Barry Whites
No, just please go ahead and, as you said, present this in writing with unique references you would like to add.
Dr. Thomas Nifong
Okay, thank you. We will.
Dr. Jyme Schafer
Thank you, sir. All right, I believe this concludes the presentation. I want to thank everyone for listening on the phone and certainly being here in person and one more thing, please submit your comments in writing. We'll look forward to it. Thank you very much and everyone have a great day. Thank you.
Today's open meeting has concluded. Thank you for attending, you may now disconnect.