Pacific Edge Releases Submissions on Medicare LCD
11 September 2023
PACIFIC EDGE RELEASES SUBMISSIONS ON MEDICARE LCD
DUNEDIN, New Zealand – Cancer diagnostics company Pacific Edge (NZX, ASX: PEB) today
releases details of written submissions on the draft local coverage determination (LCD) that
proposes non-coverage of Cxbladder tests by Medicare, the US national health insurance
provider.
The written submissions argue Cxbladder Triage, Detect and Monitor tests should retain
Medicare coverage based on the clinical value they offer to patients, clinicians, and healthcare
payers.
Written submissions are the second element of the notice and comment period required when
proposing a new LCD. The details released today concern the draft LCD DL39365 proposed
by Novitas the Medicare Administrative Contractor (MAC) with jurisdiction for Pacific Edge’s
US laboratory on July 27, 2023, and its sister MAC First Coast Service Options (FCSO).
Pacific Edge Chief Executive Dr Peter Meintjes said: “Pacific Edge believes there is no new
information in these submissions, but they provide further context of a sensitive process and
show the weight of opinion supporting the arguments for continued Medicare coverage
Cxbladder.”
The material released can be found attached and includes:
• A Pacific Edge letter to Novitas Medical Director Dr Patrick Mann MD summarizing the
submissions on the draft LCD of which the company is aware.
• Pacific Edge’s medical rebuttal of Novitas’ evidentiary review of the clinical evidence
supporting Cxbladder tests.
• A letter from the American Urological Association (AUA), the Large Urology Group
Practice Association (LUGPA), and the American Association of Clinical Urologists
(AACU) - the three most influential urological organizations in the US, covering every
practicing urologist in the country. The letter includes unpublished non-peer-reviewed
results from Kaiser Permanente that shows Cxbladder Triage safely excluded 78% of
the patients presenting with hematuria from a cystoscopy. It also showed similarly
positive results for Cxbladder Monitor for patients under surveillance for the recurrence
of bladder cancer.
• A submission from the diagnostic technology industry group ‘The Coalition for 21st
Century Medicine’ which provides a detailed critique on the structure and approach of
the draft LCD.
• An open letter from long-time Pacific Edge research collaborator Dr Yair Lotan
Professor of Urology at University of Texas Southwestern Medical Center, and 13 other
key urologic opinion leaders supporting the use of urine bladder cancer markers. This
letter has also been accepted for publication in the journal “Bladder Cancer”, the official
journal of the US advocacy group, the Bladder Cancer Advocacy Network.
The written submissions follow the presentations made during the open public meetings held
in August. The written comments are important, because MACs are required to respond to all
comments in a process that is also reviewed by the Centers for Medicare and Medicaid
Services (CMS).
Written submissions closed in the US on 9 September. Novitas and FCSO may take up to 365
days from the original US publication date (27 July 2023) to withdraw or finalize the LCD
including a response to written comments. When finalized, the MACs must provide a minimum
of 45 days’ notice before the LCD becomes effective.
For more information:
Investors: Media:
Dr Peter Meintjes Richard Inder
Chief Executive The Project
Pacific Edge P: +64 21 645 643
P: 022 032 1263
OVERVIEW
Pacific Edge: www.pacificedgedx.com
Pacific Edge Limited (NZX/ ASX: PEB) is a global cancer diagnostics company leading the way
in the development and commercialization of bladder cancer diagnostic and prognostic tests
for patients presenting with hematuria or surveillance of recurrent disease. Headquartered in
Dunedin, New Zealand, the company provides its suite of Cxbladder tests globally through its
wholly owned, and CLIA certified, laboratories in New Zealand and the USA.
Cxbladder: www.cxbladder.com
Cxbladder is a urine-based genomic biomarker test optimized for the detection and surveillance
of bladder cancer. The Cxbladder evidence portfolio developed over the past 14 years includes
more than twenty peer reviewed publications for primary detection, surveillance, adjudication
of atypical urine cytology and equivocal cystoscopy. Cxbladder is the focal point of numerous
ongoing and planned clinical studies to generate an ever-increasing body of clinical utility
evidence supporting adoption and use in the clinic to improve patient health outcomes.
Cxbladder has been trusted by over 4,400 US urologists in the diagnosis and management of
more than 100,000 patients, including the option for in-home sample collection. In New
Zealand, Cxbladder is accessible to 75% of the population via public healthcare and all
residents have the option of buying the test online.
---
Submitted via email to ProposedLCDComments@fcso.com and
ProposedLCDComments@novitas-solutions.com
Dear Drs. Schaening-Perez and Stevens,
The American Urological Association (AUA), the Large Urology Group Practice Association
(LUGPA), and the American Association of Clinical Urologists (AACU) extend their appreciation
for the opportunity to submit joint comments in response to the proposed Local Coverage
Determination (“Draft LCD”) DL39365, Genetic Testing for Oncology. The Draft LCD has a high
potential to negatively impact patient care and, therefore, we advise that it be modified to
provide broad coverage of these indispensable tools for the timely identification and
management of bladder cancer.
The AUA, with a membership of over 18,000 medical professionals in the United States
including physicians, physician assistants, and advanced practice nurses, holds an esteemed
position in the landscape of urologic care in the United States. Through its commitment to
education, research, and health policy development, the AUA upholds the highest standards in
urologic care, benefiting the urology community and Medicare recipients alike. LUGPA unites
over 150 urology group practices, accounting for than 2,100 physicians, who collectively
provide approximately 35% of the nation's Medicare urology services and works in tandem with
the AUA to achieve the shared vision of improved quality, expanded patient access and
reduction in costs. The AACU, established in 1968, is dedicated to addressing socio-economic
and political matters within the urology field, bridging the gap between urologists and
legislators to ensure optimal legislative outcomes that benefit clinical patient care.
It is our belief that the proposed modifications to coverage criteria are incorrectly applied to
urine-based tumor markers, and thus finalizing the draft policy as written will have adverse
impacts on the provision of high-quality patient care while ultimately increasing system costs.
The guidelines utilized in the Draft LCD do not adequately consider the differences between the
urine-based tumor markers and genetic biomarker tests. As discussed in our presentations to
Novitas and First Coast, CPT coding recognizes FISH tests as cytopathology (pathology) tests
coded as 88120. This is the same coding family as a PAP smear; CPT codes 88141-88175.
Genetic testing is found in the 812XX, 813XX and 814XX code families. The AUA, LUGPA and
September 9, 2023
Juan Schaening
-
Perez
, MD
Contractor Medical Director
First Coast Service Options,
Inc.
Medical Affairs
2020 Technology Parkway
,
Suite 100
Mechanicsburg, PA 17050
Leslie Stevens, MD
Acting Executive Contractor Medical Director
Novitas Solutions, Inc.
Medical Affairs
2020 Technology Parkway
,
Suite 100
Mechanicsburg, PA 17050
AACU are anxious to participate in conversations regarding guidelines surrounding these tests
in a separate LCD, but they do not belong in the Draft LCD and are not truly genetic tests.
Furthermore, the Draft LCD does not utilize the widely accepted standards for these tests found
in guidelines promulgated by the AUA and Society of Urologic Oncology (SUO). AUA guidelines
are the specialty of urology’s well established and accepted governing resource and should be
included when promulgating an LCD of this nature. Considering the panel’s failure to
incorporate the AUA/SUO guidelines: Diagnosis and Treatment of Non-Muscle Invasive Bladder
Cancer and their choice to base their recommendations solely on National Comprehensive
Cancer Network (NCCN) guidelines that do not address the clinical scenario in which urine-
based tumor markers are most commonly deployed, urine-based tumor marker tests should be
removed from the Draft LCD entirely.
i
Beyond the patent miscategorization, our organizations have several significant concerns with
the Draft LCD rationale.
The Draft LCD introduces a proposal that significantly limits coverage for urine-based tumor
markers, citing the following key observations:
1. Insufficient Study in the Medicare Population: Concerns arise due to the markers'
limited study within the Medicare population.
2. Low Positive Predictive Value (PPV): The markers exhibit a relatively low PPV, raising
concerns about possible false positives.
3. Cost Considerations: The cost associated with these markers is deemed significant.
The argument that the markers' limited study within the Medicare population justifies a lack of
coverage raises questions. Notably, the Medicare population largely comprises older adults, a
demographic with an elevated susceptibility to bladder cancer. Research involving urine-based
tumor markers has extensively included older adults. For example, In the study evaluating
CxBladder Monitor, 82% of patients were over the age of 60.
ii
Furthermore, a study of 15,779
patients evaluated for hematuria found that the mean age was 60.9 (14.6) years.
iii
Similarly, the notion that the markers' low PPV should dictate non-coverage warrants further
examination. The inherent question is what the purpose is of using the marker in clinical
decision making. It is recognized that diagnostic tests are developed with a balance of
sensitivity and specificity and that both positive and negative predictive value are driven by the
prevalence of disease. In patients with a low likelihood of disease presence, the PPV is going to
be low. For many urine markers the current utility is either to exclude the presence of cancer
which is driven by a high negative predictive value (NPV) or to adjudicate patients with atypical
cytology or equivocal cystoscopy. While these clinical questions are important to clinicians and
patients, they are not addressed in many guidelines such as the NCCN. Most urine markers
including Cxbladder monitor have a high NPV which helps exclude the presence of cancer in
patients undergoing surveillance for bladder cancer. Studies such as Kamat et al. (2012)
iv
,
Mengual et al. (2007)
v
, and Whitson et al. (2009)
vi
provide valuable insights into the utility of
fluorescence in situ hybridization (FISH) for predicting response to Bacillus Calmette-Guerin
(BCG) therapy and for surveillance of bladder cancer patients treated with BCG therapy.
For example, the European Urology Journal (2019) highlighted a study showcasing the urine-
based tumor marker Cxbladder had an NPV 97% (95% confidence interval [CI] 94-98%)
compared with 93% (95% CI 91-94%) for cytology; Cxbladder correctly adjudicated all patients
with both atypical cytology and equivocal cystoscopy.
vii
Additionally, studies like those by
Schlomer et al.
viii
and Lotan et al.
ix
underscore the challenges of atypical and equivocal cytology
readings and the potential of urine markers like ImmunoCyt™ and UroVysion® FISH to aid in
reducing unnecessary diagnostic evaluations. In both of these studies, the Urovysion FISH
assay had a much higher PPV in the setting of atypical cytology or equivocal cystoscopy which
allowed detection of cancer recurrence while avoiding biopsies in all patients with these
findings. This selective use of urine markers can reduce cost and morbidity by reducing
unnecessary surgery while avoiding delay of diagnosis of recurrence. There are other
specialized uses of markers such as predicting response to common treatments such as
intravesical BCG.
Most notably, Kaiser Permanente, one of this nation’s largest healthcare networks, with 12.7M
covered lives, has recently evaluated and published its clinical findings for CxBladder in the
hematuria screening, as well as its bladder cancer surveillance population. In Southern
California, 2326 Cx Bladder home urinary tests were performed:1932 CxBladder Triage tests
were resulted on patients referred to Urology for hematuria; 394 CxBladder Monitor tests were
resulted on patients with a history of bladder cancer. Of the 1932 hematuria patients tested,
1200 resulted with "low probability" and avoided cystoscopy (78%). 358 patients resulted with
"high probability" (22%). 280 of the 358 patients underwent cystoscopy and 18 bladder cancers
were diagnosed. Cancer detection rate in the CxBladder positive screening cohort who
underwent subsequent endoscopic evaluation was 6.4%. Of the 394 bladder cancer follow up
patients tested with CxBladder, 284 resulted with "low probability" and avoided cystoscopy
(72%). 105 patients resulted with "high probability" and 98 underwent cystoscopy. 16 bladder
cancers were detected in this group, with a cancer detection rate of 16.3%. Overall, 77% of
patients evaluated with CxBladder tested as low probability and avoided cystoscopy, and of the
378 patients who tested high probability and underwent cystoscopy 34 bladder cancers were
identified with an overall detection rate of 9%. Internal regional estimates of cystoscopies
performed within the healthcare network number approximately 25,000 annually. The
subsequent expenditures and impact to capacity from hematuria and bladder cancer
monitoring have broad implications with the use of a novel urinary biomarker that addresses
both types of urologic populations.
x
The cost of tumor marker testing is remarkably insignificant when considered in the context of
the massive spend associated with the surveillance and treatment of bladder cancer patients.
An average FISH test costs less than 1% of the $55,267 median attributed cost after two years
of bladder cancer treatment. A study published in the Journal of the American Medical
Association Network (2020) underscored total median costs at 1 year were $29 459; at 2 years,
$55 267 and at 5 years, $117 361. Patients with progressive disease had significantly higher
median 5-year costs ($232 729 vs $94 879), with outpatient care, pharmacy, and surgery-
related costs contributing.
xi
A FISH test costs approximately $500.
In conclusion, we firmly believe the implications of the Draft LCD will detrimentally impact
access to urine-based tumor markers in the context of bladder cancer, thereby compromising
patient care. If urine-based tumor markers are to be included in an LCD, their coverage should
be determined through appropriate use criteria widely recognized by the specialty of urology
and guided by expert input and stakeholders. We implore you to reconsider the inclusion of
these tests in the proposed LCD and stand ready to engage in further discussions about the
merits of these tools in patient care.
Thank you for your attention to this matter.
Sincerely,
Eugene Rhee, MD, MBA
Chair, Public Policy Council, American Urological Association (AUA)
Mara R. Holton, MD
Chair, Large Urology Group Practice Association (LUGPA)
Terrance Regan MD
Health Policy Chair, American Association of Clinical Urologists (AACU)
William C. Reha, MD, MBA
President, American Association of Clinical Urologists (AACU)
i
Chang SS, Boorjian SA, Chou R et al: Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO
guideline. J Urol. 2016; 196: 1021.
ii
Kavalieris L, O'Sullivan P, Frampton C, et al. Performance Characteristics of a Multigene Urine Biomarker Test for
Monitoring for Recurrent Urothelial Carcinoma in a Multicenter Study. J Urol. Jun 2017;197(6):1419-1426.
doi:10.1016/j.juro.2016.12.010
iii
Woldu SL, Ng CK, Loo RK, Slezak JM, Jacobsen SJ, Tan WS, Kelly JD, Lough T, Darling D, van Kessel KEM, de Jong JJ,
van Criekinge W, Shariat SF, Hiar A, Brown S, Boorjian SA, Barocas DA, Svatek RS, Lotan Y. Evaluation of the New
American Urological Association Guidelines Risk Classification for Hematuria. J Urol. 2021 May;205(5):1387-1393.
doi: 10.1097/JU.0000000000001550. Epub 2020 Dec 24. PMID: 33356483.
iv
Kamat AM, Dickstein RJ, Messetti F et al: Use of fluorescence in situ hybridization to predict response to bacillus
Calmette-Guerin therapy for bladder cancer: results of a prospective trial. J Urol 2012; 187: 862.
v
Mengual L, Marin-Aguilera M, Ribal MJ et al: Clinical utility of fluorescent in situ hybridization for the surveillance
of bladder cancer patients treated with bacillus Calmette-Guerin therapy. Eur Urol 2007; 52: 752.
vi
Whitson J, Berry A, Carroll P: A multicolour fluorescence in situ hybridization test predicts recurrence in patients
with high-risk superficial bladder tumours undergoing intravesical therapy. BJU Int 2009; 104: 336.
vii
Konety B, Shore N, Kader AK, Porten S, Daneshmand S, Lough T, Lotan Y. Evaluation of Cxbladder and Adjudication
of Atypical Cytology and Equivocal Cystoscopy. Eur Urol. 2019 Aug;76(2):238-243. doi:
10.1016/j.eururo.2019.04.035. Epub 2019 May 16. PMID: 31103391.
viii
Schlomer BJ, Ho R, Sagalowsky A, Ashfaq R, Lotan Y. Prospective validation of the clinical usefulness of reflex
fluorescence in situ hybridization assay in patients with atypical cytology for the detection of urothelial carcinoma
of the bladder. J Urol. 2010 Jan;183(1):62-7. doi: 10.1016/j.juro.2009.08.157. PMID: 19913822.
ix
Lotan Y, Bensalah K, Ruddell T, Shariat SF, Sagalowsky AI, Ashfaq R. Prospective evaluation of the clinical
usefulness of reflex fluorescence in situ hybridization assay in patients with atypical cytology for the detection of
urothelial carcinoma of the bladder. J Urol. 2008 Jun;179(6):2164-9. doi: 10.1016/j.juro.2008.01.105. Epub 2008
Apr 18. PMID: 18423745.
x
Raman JD, Kavalieris L, Konety B, et al. The Diagnostic Performance of Cxbladder Resolve, Alone and in
Combination with Other Cxbladder Tests, in the Identification and Priority Evaluation of Patients at Risk for
Urothelial Carcinoma. J Urol. 2021;206(6):1380-1389.]
xi
Williams SB, Howard LE, Foster ML, et al. Estimated Costs and Long-term Outcomes of Patients With High-Risk
Non–Muscle-Invasive Bladder Cancer Treated With Bacillus Calmette-Guérin in the Veterans Affairs Health System.
JAMA Netw Open. 2021;4(3):e213800. doi:10.1001/jamanetworkopen.2021.3800
---
September 7, 2023
VIA Electronic Mail to: ProposedLCDComments@novitas-solutions.com
Novitas Solutions
Medical Affairs
Suite 100
2020 Technology Parkway
Mechanicsburg, PA 17050
RE: Proposed LCD – Genetic Testing for Oncology (DL39365)
Dear Dr. Mann:
On behalf of the Coalition for 21st Century Medicine (C21), thank you for the opportunity to
submit comments regarding the above-captioned proposed local coverage determination (LCD).
C21 comprises many of the world’s most innovative diagnostic technology companies, clinical
laboratories, physicians, venture capital companies, and patient advocacy groups. C21’s mission
is to improve the quality of health care by encouraging research, development, and
commercialization of innovative diagnostic technologies that will personalize patient care,
improve patient outcomes, and substantially reduce health care costs.
For the reasons outlined below, C21 respectfully recommends that Novitas withdraw the
draft LCD at the end of the comment period, and convene one or more Contractor
Advisory Committee (CAC) meetings before engaging in future LCD development in
genetic testing for oncology – both with respect to such tests in general, as well as the 13
specific tests evaluated in the proposed LCD. Engagement with the CAC would allow
Novitas to obtain input from healthcare professionals, beneficiary representatives, and
representatives of medical organizations to obtain meaningful feedback that would “ensure an
unbiased and contemporary consideration of ‘state of the art’ technology and science” and would
support the development of a clinically appropriate LCD.
1
By considering the CAC’s input (as
well as that from interested stakeholders, like C21), Novitas could address key clinical questions
and develop an updated proposal to ensure that Medicare beneficiaries will continue to have
timely access to advanced molecular diagnostic tests.
Alternatively, if Novitas elects to finalize the LCD, C21 recommends that Novitas modify the
LCD to remove the presumption against coverage for tests not supported in at least one of the
three listed compendia, and convene a CAC meeting before finalizing non-coverage for the 13
specifically-referenced tests.
1
Medicare Program Integrity Manual ch. 13, § 13.2.4.3.
September 7, 2023
Page 2 of 10
2
* * * *
1. SUPPORT FOR NOVITAS’S LONGSTANDING APPROACH TO COVERAGE OF DIAGNOSTIC
TESTING SERVICES
For more than sixteen years, C21 has worked with the Centers for Medicare & Medicaid
Services (CMS) and Medicare Administrative Contractors (MACs) on the development,
promulgation, and implementation of policies intended to facilitate appropriate Medicare
coverage and payment for high-quality clinical laboratory tests. C21 appreciates the work of
Novitas over the past decade in reviewing novel advanced diagnostic tests and establishing LCD
policies, including its current LCD for oncology tests, “Biomarkers for Oncology” (L35396).
C21 strongly supports the current LCD, and appreciates Novitas’s willingness to identify
individual tests as covered services based on its assessment of the analytical validity, clinical
validity, and clinical utility evidence supporting each test. As we noted in our Open Meeting
presentation, we are concerned that the proposed “Genetic Testing for Oncology” LCD would, if
finalized, significantly limit beneficiary access to advanced diagnostic tests, including many tests
performed by C21 members with longstanding Medicare coverage following a previous test-
specific evidence review by Novitas.
Historically, it has been both CMS’ and Novitas’ position that unless an LCD explicitly
identifies a test as a non-covered service following an individualized review of the evidence for
that test, such test would be eligible for Medicare coverage on a case-by-case basis. C21
strongly supports this position. Moreover, in recent years this requirement has been codified in
federal law, as the 21
st
Century Cures Act prohibits Medicare contractors from implementing
non-coverage policies unless the contractor makes an evidence-based determination that a test
does not meet the statutory/regulatory criteria for Medicare coverage.
2
2. CONCERNS WITH PROPOSED LCD FRAMEWORK
a. Novitas should not issue a final LCD that delegates coverage decisionmaking
authority to external databases – particularly insofar as the the LCD does not
contain a viable, timely alternative pathway to coverage.
Under the proposed LCD, a genetic test must have adequate support in one of three databases to
be covered: (i) National Comprehensive Cancer Network’s (NCCN) database, (ii) National
Institutes of Health (NIH)-sponsored clinical genome resource, ClinGen, or (iii) Memorial Sloan
Kettering’s tumor mutation database, OncoKB
TM
. All tests not supported in one or more of these
compendia would be presumptively non-covered, unless/until they successfully complete the
LCD reconsideration process. This proposed coverage framework raises several concerns,
including:
• While third-party guidelines/recommendations can provide useful information when
deciding whether to cover a test, relying solely on such determinations is not a
2
Social Security Act § 1862(l)(5)(D).
September 7, 2023
Page 3 of 10
3
permissible substitute for evidence-based, test-specific review. Under the 21
st
Century
Cures Act, MACs must include a “a summary of evidence that was considered by the
contractor during the development of such determination and a list of the sources of
such evidence” (emphasis added) as well as “[a]n explanation of the rationale that
supports such determination.”
3
Furthermore, while the Medicare Program Integrity
Manual allows MACs to “supplement their research... with clinical guidelines, consensus
documents, or consultation by experts,” the Manual does not allow the MACs use these
sources as a substitute for its own review.
4
Therefore, the decision to cover or not cover
a particular test must be based on evidence reviewed by Novitas, and Novitas must
memorialize its rationale by publishing an explanation for the decision. Relying on a
third-party database without itself engaging in a test-specific evaluation or offering a test-
specific rationale – as proposed – would be contrary to the Act, and amount to a
preemptive non-coverage determination without the requisite test-specific, evidence-
based review. Such reliance is particularly problematic insofar as there is no assurance
that any of the compendia will have reviewed any individual test, particularly for novel
assays.
• Novitas does not have authority to delegate coverage decisions to third parties. Congress
delegated to the HHS Secretary the authority to “enter into contracts with any eligible
entity to serve as a [MAC]” and establish LCDs.
5
Congress did not, however, grant the
Secretary or the MACs the authority to delegate powers to other private parties. The U.S.
Court of Appeals for the District of Columbia Circuit has stated that that “subdelegations
to outside parties are assumed to be improper absent an affirmative showing of
congressional authorization.”
6
The court’s concern is particularly relevant here. When private entities (like NCCN or
MSK) update their databases, or NIH updates ClinGen, they are not required to comply
with any of the procedural controls that normally apply to the development of LCDs.
Specifially, they are:
o Not required to issue a proposed decision that explains their rationale;
o Not required to accept public comments on those proposals;
o Not required to hold an open meeting to collect stakeholder feedback; and
o Not required to consider and respond to public comments when finalizing their
decisions.
As a result, the decisions made by NCCN, MSK, and/or NIH are not subject to the same
procedural controls and safeguards – and may be made with a different set of substantive
considerations – than those that would have been required had the government’s
authorized delegate (Novitas) made the decision via the process required by law.
3
Id.
4
Medicare Program Integity Manual ch. 13, § 13.2.3.
5
42 U.S.C. §§ 1395kk-1(a)(1), (a)(4).
6
U.S. Telecom Ass’n v. F.C.C., 359 F.3d 554, 565 (D.C. Cir. 2004).
September 7, 2023
Page 4 of 10
4
In support of its ability to delegate coverage decisions to third parties, Novitas points to
Medicare’s use of third-party compendia when deciding whether to cover certain
chemotherapy drugs off-label.
7
However, this precedent is distinguishable from the
diagnostic testing in three key respects.
o First, the Social Security Act explicitly requires Medicare to consider certain
compendia when determining coverage for off-label uses for cancer
chemotherapy drugs.
8
There is no analogous instruction that allows Novitas to
use the compendia in the same way for clinical laboratory tests.
o Second, in the cancer drug context, the compendia are used to expand coverage
beyond FDA-approved labeling for certain drugs – not to restrict coverage.
o And lastly, even if a particular off-label use is not supported in the compendia,
Medicare explicitly retains the ability to review other published literature – i.e.,
Medicare is not solely bound based on the compendia’s decision.
9
• Availability of the LCD reconsideration process is not an adequate alternative pathway
to coverage. Novitas states that interested stakeholders may request coverage for a test
not supported in one of the three compendia via the LCD reconsideration process.
However, this framework would not give test developers and other stakeholders an
opportunity for public comment prior to implementation of non-coverage based on the
compendia – even if the compendia themselves have not reviewed the evidence
supporting a test. Therefore, reliance on the reconsideration process alone does not
satisfy the requirement that MACs may not impose a policy restricting coverage for an
item or service absent an evidentiary review. Rather, Novitas must review evidence, hold
a public meeting, and consider public comment before making a non-coverage decision.
Furthermore, Novitas makes no commitments regarding the timeframe on which it will
substantively consider reconsideration requests, or how often it intends to update the
LCD to reflect new evidence. MACs have 60 calendar days to determine whether a
reconsideration request is valid.
10
Once determined to be valid, however, CMS does not
require the MACs to substantively respond to a reconsideration request within any
specific period of time. As such, reconsideration requests may remain in a MAC’s queue
for several months, if not longer, depending on MAC workloads and priorities.
Furthermore, even once a MAC decides to substantively respond to a reconsideration
request issuing a proposed LCD, that MAC has up to 365 calendar days to issue a final
LCD.
11
As a result, tests not meeting compendia requirements may remain non-covered
for multiple years, even if they otherwise have strong evidence supporting assay
performance.
7
Article – Response to Comments: Genetic Testing for Oncology (A59417).
8
See Social Security Act § 1861(t)(2)(B) ( applicable to Part B drugs); 1860D-2(e)(4) (applicable to Part D drugs);
1927(g)(1)(B) (applicable to drugs delivered to Medicaid beneficiaries).
9
See Medicare Benefit Policy Manual ch. 15, § 50.4.5(C).
10
See Medicare Program Integrity Manual ch. 13, §13.3.3.
11
Id. §13.5.1.
September 7, 2023
Page 5 of 10
5
• NCCN is the only pathway to coverage for multianalyte algorithmic tests to obtain
coverage. Two of the three databases referenced by Novitas in the proposed LCD –
ClinGen and OncoKB – do not review multianlayte algorithmic tests that may combine
these variants with an empirically derived algorithm. These databases’ restriction to
single gene assays is plainly stated in their public-facing materials:
o ClinGen: “We then use this data to answer a number of key curation questions: Is
this gene associated with a disease, and by which mechanisms do variation cause
this disease? Is this variant causative? Will this information affect medical
management?”
12
(emphasis added)
o OncoKB: “Alteration- and tumor type-specific therapeutic implications are
classified using the OncoKB™ Levels of Evidence system, which assigns clinical
actionability to individual mutational events.”
13
(emphasis added)
(At the Open Meeting, a speaker from MSK/OncoKB explained that database does
account for certain concurrent gene-gene interactions in its reporting. The speaker did
not, however, refute the point that OncoKB does not include recommendations
multianlyte algorithmic tests.) As a result, multianalyte tests would only be eligible for
coverage if supported in NCCN.
Reliance on NCCN is not an appropriate substitute for evidence-based, test-specific
review, as NCCN guidelines are largely consensus-based and may not reflect input from
certain specialties or subsets of healthcare providers.
14
Indeed, NCCN itself
acknowledges the limitations of this approach:
The NCCN Guidelines® are a statement of evidence and consensus of
the authors regarding their views of currently accepted approaches to
treatment. Any clinician seeking to apply or consult the NCCN
Guidelines is expected to use independent medical judgment in the
context of individual clinical circumstances to determine any patient’s
care or treatment. The National Comprehensive Cancer Network®
(NCCN®) makes no representations or warranties of any kind regarding
12
https://clinicalgenome.org/start/.
13
https://www.oncokb.org/about.
14
NCCN, Development and Update of Guidelines, https://www.nccn.org/guidelines/guidelines-
process/development-and-update-of-guidelines ( last visited August 2023) (“Recommendations within the NCCN
Guidelines are derived from critical evaluation of evidence, integrated with the clinical expertise and consensus of a
multidisciplinary panel of cancer specialists, clinical experts and researchers in those situations where high-level
evidence does not exist. Panels are charged with evaluating the efficacy of treatment, utility of tests or evaluations,
and toxicity of the various interventions. Recommendations (or changes to existing recommendations) are agreed
upon by Panel Members following review and discussion of the evidence during the Panel meetings. The Panel
Members deliberate on the interpretation of the clinical evidence, and vote on how the evidence should be
incorporated into the existing Guidelines. The Panel Chair and Panel Members then develop the wording to denote
the specific recommendations within the Algorithms.”)
September 7, 2023
Page 6 of 10
6
their content, use or application and disclaims any responsibility for their
application or use in any way.
15
Furthermore, updates to NCCN can be irregular, varying by disease state,
16
and standards
for inclusion may vary significantly between different types of cancer (e.g., breast,
bladder, prostate, cutaneous melanoma, and uveal melanoma). And lastly, NCCN
guidelines may be challenging for providers (and Novitas itself) to faithfully translate
into coverage policy, since certain guidelines are routinely updated, and the documents
do not lend themselves to easy implementation of coverage policy (e.g., 84 guidelines
consisting of 218 algorithms, as described by NCCN at the 2022 Open Meeting).
* *
Given the issues outlined above, we respectfully recommend that that Novitas withdraw the draft
LCD at the end of the comment period, and convene one or more CAC meetings before engaging
in future LCD development in this area. In the event that Novitas elects to finalize the draft
LCD, however, we offer the following additional comments for your consideration:
• The proposed LCD would identify tests supported by a majority of NCCN panel members
as non-covered. Novitas proposes to non-cover tests with a Category “2B” rating in
NCCN. NCCN assigns a “2B” rating to tests for which there is NCCN “consensus” –
i.e., 50-85% agreement – that the “intervention is appropriate” based on lower-level
evidence.
17
It is unclear why Novitas believes tests supported by a majority (or
potentially, a substantial majority) of NCCN panel members should be automatically
non-covered. We encourage Novitas to remove the presumption against coverage for
“2B” rated tests, and at minimum, review claims for such tests on a case-by-case basis
consistent with longstanding Novitas practice.
• The proposed LCD defines “screening” tests in a manner inconsistent with longstanding
CMS policy. The proposed LCD requires patients to have an “established a diagnosis of
cancer or found significant evidence to create suspicion for cancer in their patient via a
clinical evaluation and abnormal results (cancer or suspicious for cancer) from histologic
and/or cytologic examination.” In the “Response to Comments” article associated with
the now-withdrawn version of L39365, Novitas takes the position that oncology tests
performed prior to the availability of such evidence are “screening” tests:
Oncologic genetic testing is considered screening if it is performed before
the ordering provider either establishes a diagnosis of cancer or a
15
See, e.g., NCCN Guidelines Version 3.2023: Bladder Cancer,
https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf
, at 3 (emphasis added).
16
For example, the NCCN guidelines for rectal cancer have been updated 4 times since the start of 2023, while the
guidelines for primary cutaneous melanoma have been updated just once (on January 5
th
, 2023).
17
NCCN, Development and Update of Guidelines, https://www.nccn.org/guidelines/guidelines-
process/development-and-update-of-guidelines ( last visited August 2023).
September 7, 2023
Page 7 of 10
7
substantiated suspicion of cancer through histologic, cytologic, and/or
flow cytometric testing.
Novitas’s position is not consistent with CMS’s longstanding definition of a “screening”
test – i.e., a test for patients without “signs or symptoms” of the underlying condition.
18
Indeed, such signs or symptoms of cancer may exist without evidence from a “histologic
and/or cytologic examination” – e.g., hematuria in patients suspected of bladder cancer.
Therefore, if Novitas elects to finalize the LCD, we urge Novitas to remove the
requirement for histologic and/or cytologic results, and permit evidence-based coverage
for assays when run on patients with “signs or symptoms” of cancer.
• Novitas’s rationale for limiting coverage to these three specific databases – to the
exclusion of all others – is not clear. C21 appreciates the detailed assessment that
Novitas conducted of each of the three databases, and agrees that all three databases may
provide useful information to Novitas when evaluating the totality of the evidence
supporting an individual test. However, dozens of other professional societies and
guideline developers also make evidence-based recommendations regarding molecular
diagnostic tests that reflect and/or inform the applicable standard of care, yet do not
appear to have been evaluated for inclusion in the LCD. It is unclear why Novitas
believes a favorable recommendation in an alternative evidence-based database or
professional society guideline would not be sufficient to support a favorable coverage
determination.
b. Evidentiary review of 13 specifically listed tests
In addition to our comments about the proposed LCD framework more generally, we offer the
following comments in response to the test-specific evidentiary review for the 13 tests:
• Novitas should restrict longstanding coverage only where supported by new evidence.
Several tests proposed for non-coverage in the draft LCD have been covered by Novitas
for many years, including several for which Novitas initially decided to initiate coverage
following a detailed review of the available evidence:
Test Medicare Coverage Effective Date
DecisionDx-Melanoma December 2018 (Palmetto)
DecisionDx-SCC April 2022
Cxbladder Detect July 2020
18
See, e.g., Screening for Colorectal Cancer – Stool DNA Testing (CAG-00440N), https://www.cms.gov/medicare-
coverage-database/view/ncacal-decision-memo.aspx?proposed=N&ncaid=277 ( last visited August 2023) (“This
decision memorandum does not address the use of stool DNA testing as a diagnostic test to evaluate signs or
symptoms of colorectal disease. (...) When making national coverage determinations concerning the scope of the
CRC screening benefit under Medicare Part B, CMS evaluates relevant clinical evidence to determine whether or
not the evidence is of sufficient quality to support a finding that a test is appropriate for general screening in
individuals with no signs or symptoms of colorectal cancer.”)
September 7, 2023
Page 8 of 10
8
Test Medicare Coverage Effective Date
Cxbladder Monitor July 2020
Cxbladder Triage January 2023
PancraGEN November 2010
UroVysion July 2014
Colvera January 2021
C21 agrees that Medicare coverage decisions should be made on the basis of the best
available evidence, and therefore, it may be necessary to restrict or remove coverage.
That being said, patients and providers alike rely on longstanding coverage
determinations, particularly insofar as as such coverage was based on a review of the
evidence supporting those tests. Therefore, existing test-specific coverage should be
restricted only (a) if new evidence becomes available that reasonably questions whether
an assay remains reasonable and necessary, (b) Novitas clearly identifies this new or
updated evidence in a draft LCD, and (c) subjects any new or updated conclusions to
public scrutiny via the LCD notice and comment process. Insofar as Novitas believes it
has such grounds, we request that Novitas reissue the draft LCD to clarify these
considerations.
• Novitas must apply a consistent standard of review to all tests within the scope of the
proposed LCD – not a different (higher) standard for specifically reviewed tests. For
compendia-supported tests, Novitas assumes that tests are analytically valid if run in a
CLIA-certified laboratory, because “CLIA includes an analysis of accuracy, precision,
analytical sensitivity, analytical specificity, reportable range, reference interval, and any
other performance characteristics required for the test system in the laboratory that
intends to use it.”
19
However, this same presumption is not afforded to any of the
thirteen tests that underwent Novitas’s test-specific evidentiary review, even though each
of these tests is also performed in a CLIA-certified laboratory. Insofar as Novitas
believes performance in a CLIA laboratory is sufficient to establish analytical validity for
compendia-supported tests, it should make similar assumptions when it conducts a test-
specific evidentiary review.
• Novitas must consider and substantively respond to stakeholder comments on its test-
specific evidentiary review of the 13 tests. At the Open Meeting, Novitas stated that it is
particularly interested in reviewing “new evidence” not already listed in the bibliography
of the LCD. C21 agrees that evidence not previously considered would be highly
probative, but also believes Novitas must review and respond to all comments submitted
on the LCD, including comments regarding:
o The overarching framework for review of evidence (e.g., overall approach, level
of evidence required);
19
Article – Response to Comments: Genetic Testing for Oncology (A59417).
September 7, 2023
Page 9 of 10
9
o Novitas’s interpretation of the literature cited in the proposed LCD (e.g., if a cited
article does not reflect the intended use population of the test, or has some other
limitation that explains reported performance characteristics);
o Published literature not included in the LCD;
o Other clinical guidelines and consensus statements not referenced in the proposed
LCD; and
o Clinician experience with such tests (even if unpublished).
Notwithstanding Novitas’s prior review of certain documentation, nothing in the Program
Integrity Manual allows Novitas to ignore or not respond to public comments supported
by evidence, even if such evidence relates to data the MAC may have already considered.
• Novitas must consider and respond to stakeholder feedback, even if unpublished. While
C21 agrees that published evidence is an important component of any evidentiary review
for an LCD, nothing in the Program Integrity Manual explicitly prohibits MACs from
considering unpublished feedback. Indeed, the Manual actually suggests that such
review and response is required, as it requires MACs to respond to “all timely received
public comments” in the comment/response article.
20
c. Concerns with coding article
In the proposed coding article (DA59125), Novitas does not identify any “unspecified” laterality
codes or codes for cancer of unknown origin as covered when reported for genetic testing
services. Insofar as Novitas decides to finalize the LCD, we urge Novitas to add both sets of
codes for the reasons set forth below.
When treating physicians are considering genetic testing for oncology patients, they are looking
for specific genetic variants or signatures in the tumors in order to guide treatment. The specific
location where the tumor originated is generally no longer relevant by the time patients are
referred for genetic testing to guide treatment. For example, when a patient presents with
advanced non-small cell lung cancer, the location of the original tumor (e.g., right upper lobe
versus left lower lobe) is irrelevant to selecting an appropriate chemotherapeutic or
immunotherapeutic regimen to be guided by genetic testing.
In addition, by the time a patient presents to an oncologist with advanced cancer, it may not
always be clear at that point where the tumor originated. Therefore, when the treating physician
refers patients for genetic testing at that point in the course of their disease, the treating physician
may not specify the originating site of the tumor nor provide an ICD-10-CM code as the
referring diagnosis that is specific to the laterality or location of the originating tumor. Novitas’s
proposal to exclude ICD-10-CM codes from the list of covered codes that describe unspecified
sites (e.g., ICD-10-CM C34.00, C34.10, C34.30, C34.80, and C34.90 for malignant neoplasm of
lung)
21
would negatively impact access to medically necessary genetic testing in such cases
20
Medicare Program Integrity Manual ch. 13, §13.5.5.
21
C34.00 “Malignant neoplasm of unspecified main bronchus”
C34.10 “Malignant neoplasm of upper lobe, unspecified bronchus or lung”
C34.30 “Malignant neoplasm of lower lobe, unspecified bronchus or lung”
September 7, 2023
Page 10 of 10
10
where the treating physician is unable to or otherwise does not provide more specific information
to determine the laterality of the original tumor. And, as noted above, knowing and reporting the
laterality of the original tumor is generally irrelevant to the purpose and use of genetic testing for
patients with cancer. The testing is medically necessary consistent whether or not the originating
site of the tumor was on the right or left or in an upper lobe or lower lobe.
Furthermore, some patients present with advanced cancer where the origin of the tumor is
unknown (commonly referred to as Cancer of Unknown Primary). Under these circumstances,
genetic testing can still help help guide treatment decision making. Exclusion of codes C80.0
“Disseminated malignant neoplasm, unspecified” and C80.1 “Malignant (primary) neoplasm,
unspecified” would block access to genetic testing in this patient population for whom genetic
testing may be critically important to guide therapy.
Consistent with our request, CMS covers both unspecified laterality codes and Cancer of
Unknown Primary codes, where appropriate, for next generation sequencing tests covered under
NCD 90.2.
22
* * * *
C21 is grateful for the opportunity to comment on the proposed LCD, and would be pleased to
meet with Novitas if it has any questions. Please contact me at hmurphy@c21cm.org
or
(916) 835-5117 should you have any questions or if we can provide you with further
information.
Sincerely,
Hannah Murphy
C34.80 “Malignant neoplasm of overlapping sites of unspecified bronchus or lung”
C34.90 “Malignant neoplasm of unspecified part of unspecified bronchus or lung”
22
See Transmittal 12184 (Change Request 13278) (Aug. 3, 2023), r12184otn.pdf (cms.gov), at pgs. 12-69.
---
Commentary on Novitas LCD
Yair Lotan
1
, Daniel A Barocas
2
, Sam S Chang
2
, Siamak Daneshmand
3
, Badrinath
Konety
4
, Joshua J Meeks
5
, Sima Porten
6
, Jay D. Raman
7
, Charles J Rosser
8
, Kristen R
Scarpato
2
, Wade J Sexton
9
, John P Sfakianos
10
, Neal D Shore
11,
Robert S Svatek
12
1
University of Texas Southwestern, Dallas, Texas.
2
Department of Urology, Vanderbilt University Medical Center, Nashville, Tennessee.
3
Department of Urology, USC/Norris Comprehensive Cancer Center, University of
Southern California, Los Angeles, California.
4
Allina Health Cancer Institute, Minneapolis, MN and University of Minnesota,
Minneapolis, MN
5
Department of Urology and Biochemistry, Feinberg School of Medicine, Northwestern
University, Chicago, IL
6
Department of Urology, University of San Francisco, California
7
Department of Urology, Penn State Health Milton S. Hershey Medical Center, Hershey,
Pennsylvania.
8
Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
9
Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, FL
10
Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY.
11
Carolina Urologic Research Center, Myrtle Beach, SC, USA
12
Department of Urology, University of Texas Health Science Center at San Antonio,
San Antonio, TX, USA.
Conflicts of Interest:
Yair Lotan: Consultant
Nanorobotics, C2I genomics, Photocure, Astra-Zeneca, Merck, Fergene, Abbvie,
Nucleix, Ambu, Seattle Genetics, Hitachi, Ferring Research, verity pharmaceutics,
virtuoso surgical, Stimit, Urogen, Vessi medical, CAPs medical, Xcures, BMS, Nonagen,
Aura Biosciences, Inc., Convergent Genomics, Pacific Edge, Pfizer, Phinomics Inc, CG
oncology, Uroviu, On target lab
Daniel Barocas: Pacific Edge, Ambu, Lantheus, Pfizer, On target labs
Sam Chang: Consultant
Astellas, Merck, Janssen, Pfizer, Virtuoso Surgical, Photocure, Tu Therapeutics,
Nonagen, Pacific Edge , Urogen, Prokarium, Valar Science
Siamak Daneshmand
Consultant for: Janssen, Ferring, Photocure, Taris, Spectrum, Pacific Edge, BMS,
Sesen, Protara, Pfizer, CG Oncology
Badrinath Konety: Consultant for Pacific Edge, Astrin Biosciences, Asieris
Pharmaceuticals, Convergent Genomics, Illumina, Ferring Pharmaceuticals, Styx
Biotechnology, Geneverify.
Joshua Meeks: Consultant: Merck, AstraZeneca, Incyte, Janssen, BMS, UroGen,
Prokarium, Imvax, Pfizer, Seagen/Astellas, Research Funding: VHA, NIH, DoD,
Compensation for talks/educational courses: AUA, OncLive, Olympus, UroToday,
Clinical Trials: SWOG, Genentech, Merck, AstraZeneca, Incyte
Sima Porten: Research with, KDx, Nonagen and Signatera, Consultant with Pacific
Edge.
Jay Raman: Education Chair for American Urological Association; Investment interest in
United Medical Systems; Ongoing research with MDxHealth, Pacific Edge, Urogen
Pharma, Steba Biotech
Charles Rosser: Executive team for Nonagen Bioscience Corp.
Kristen Scarpato: Photocure, CxBladder
John P Sfakianos: Natera and pacific edge.
Wade J. Sexton: Pacific Edge, Urogen Pharmaceuticals
Neal Shore: Arquer,Astra Zeneca, Aura biosciences, Diacarta, Ferring, Janssen,
MDxHealth, Merck, Pacific Edge, Photocure, Protara, Roche
Robert Svatek: Consultant CG Oncology and Verity Pharma
The role of biomarkers (aka, markers) in detecting and managing cancer is an evolving
field. It is crucial to develop biomarkers robustly that mirror drug development in the
pharmaceutical industry. The goal for markers should be to provide a clear benefit in
managing patients that is additive to both clinical and laboratory information. Markers
should be developed in phases, with initial assay development and validation followed
by clinical studies to evaluate the marker's performance characteristics in assessing
specific clinical conditions (e.g., sensitivity, specificity, predictive value) and ability to
improve a clinically meaningful outcome. Ultimately, economic validation is also
warranted, especially as we move forward with value-based healthcare. Trials should
focus on answering specific clinical questions and thereby demonstrate the incremental
value of the marker in predicting the benefit of a treatment or detection of a defined
disease state. Additionally, the benefits of the marker need to be balanced by any
harmful interpretation that can occur from false positive and false negative results,
which could lead to patient anxiety, unnecessary costs, and as well as potentially
incorrect clinical decision making predicated on test result.
While clinical utility is arguably the most important parameter to judge the value of a
marker in managing a patient, acceptable reimbursement is a critical component for the
viability of a marker. A marker with evidence-based utility which is not reimbursed will
thus render it unavailable for patients and clinicians thereby forfeiting a valuable tool(s)
in clinical decision making. Novitas Solutions, Inc. (Novitas) provides administrative
services for government-sponsored healthcare programs and serves as a Part A/B
Medicare Administrative Contractor (MAC) under multiple contracts for the Centers for
Medicare and Medicaid Services (CMS). As a MAC, Novitas serves as a single point-of-
contact entity processing Medicare Part A and B claims from hospitals and other
institutional providers, physicians and practitioners. Novitas serves the Medicare
Program in Jurisdiction L, which encompasses Delaware, New Jersey, Pennsylvania,
Maryland, as well as the District of Columbia, and Jurisdiction H which includes
Arkansas, Colorado, Louisiana, Mississippi, New Mexico, Oklahoma and Texas. The
recent release of a draft local coverage determination (LCD Genetic Testing for
Oncology) by Novitas proposes a fundamental change to the criteria Novitas would use
to determine coverage for molecular diagnostic tests.
In the draft LCD, Novitas proposed a new external review model for coverage
determined only by including or excluding the tests or biomarkers in one of a limited
number of external databases and published guidelines (references to ClinGen, NCCN,
and OncoKB). Before the draft LCD, the established determination process was for
MACs to determine coverage and reimbursement through a product-specific internal
review of the published literature. Such a change in the LCD would drastically impact
urine-based tumor marker use and accessibility since Novitas proposes to severely limit
coverage for a variety of markers.
While this draft specifically focused on a few urine markers (among other molecular
tests) including the Cxbladder urinary tests (detect, triage, and monitor urine-based
markers) and UroVysion fluorescence in situ hybridization (FISH), this approval process
change could have a profound ripple effect with significant deleterious impact on other
current and future urine marker tests. Hence, it is of paramount importance to consider
the implication of such a ruling for additional biomarker accessibility, the merits of the
decision and, most importantly, its implication for optimized clinical care.
When considering urine marker development for bladder cancer, there has been
considerable effort to identify candidate markers or panels of markers to improve the
evaluation of at-cancer risk patients, especially those with hematuria, and to enhance
surveillance of bladder cancer specifically.
1-3
It is important to delineate the specific
clinical scenario which in turn can significantly impact the type of marker needed. A
comprehensive marker evaluation may not always capture the specific value in
answering a clinical question. For example, a marker used to help determine which
patients with hematuria should undergo further evaluation would optimally have a high
negative predictive value (NPV) so that cancer is not missed rather than a high positive
predictive value (PPV) which limits evaluation to only a small percentage of patients.
The rationale for the aforementioned approach being that if patients meet the criteria for
microhematuria with current recommendations to perform cystoscopy in most cases,
then excluding patients at extremely low risk for cancer could be an excellent way to
improve compliance (and decrease costs) with evaluation while limiting unnecessary
procedures (cystoscopy and imaging).
2,4,5
Furthermore, any positive marker result (whether true or false) would be followed up
with a cystoscopy, thereby avoiding incremental testing beyond current standard of
care. In other clinical scenarios, such as patients with abnormal cystoscopy or cytology
that is atypical but not conclusive for cancer, a marker with a high PPV would be
valuable since the goal would be to biopsy those patients who are likely to have cancer
but avoid unnecessary surgery in patients who may have inflammation or other benign
changes. The American Urologic Association (AUA)/ Society of Urologic Oncology
(SUO) guidelines for non-muscle invasive bladder cancer (NMIBC) already state that a
clinician may use biomarkers to assess response to intravesical BCG (UroVysion®
FISH) and adjudicate equivocal cytology (UroVysion® FISH and ImmunoCyt™).
6
A
recent publication also found that CxBladder Monitor could adjudicate patients with
atypical cytology or equivocal cystoscopy
7
, showing up to 35% of patients can avoid
unnecessary further procedures.
There are several concerns with the types of criticisms raised by Novitas in the draft
LCD (Genetic Testing for Oncology). The first is based on limited published guidelines
(references to ClinGen, NCCN, and OncoKB). The NCCN guidelines are focused on
patients with a known diagnosis of cancer, and their only statement on pre-diagnosis is
a recommendation for all patients with hematuria to undergo cystoscopy. As such, they
do not focus on evaluating hematuria or managing unique scenarios like atypical
cystoscopy or cytology, which urologists routinely must manage. The AUA has
developed guidelines for managing hematuria in conjunction with the Society of
Urodynamics Female Pelvic Medicine and Urogenital Reconstruction (SUFU)
5
.
Similarly, the AUA and SUO developed guidelines for the management of NMIBC
6
.
These guidelines include standardized methodology and evaluation of all available data
with recommendations based on robust levels of evidence. They evaluate the role of
urine markers and other tests for detecting and managing bladder cancer. It would be
inappropriate for Novitas to ignore the recommendations of these widely accepted
guidelines in making decision regarding reimbursement/coverage.
Novitas did not specify why it was excluding the Urovysion FISH assay, which has been
FDA-approved for more than two decades and whose use has been supported by the
AUA guidelines to assess response to intravesical BCG and adjudicate equivocal
cytology (as noted above). They had specific concerns regarding the Cxbladder line of
tests. While Novitas focused on these markers, many criticisms could be applied to
other urine markers.
One comment focused on the fact that the tested patient population included a strong
bias towards male patients of European ancestry and that the Cxbladder tests have not
been adequately investigated in the context of the Medicare population. The focus on
male patients is inherent in all studies related to bladder cancer because there are more
than three times as many bladder cancer cases in men relative to women. In 2023, of
the 82,290 newly diagnosed bladder cancer patients, there were 62,420 men versus
19,870 women
8
. There is a significantly higher rate
9
of bladder cancer in whites relative
to non-white populations. The average annual age-standardized incidence in the US
was 0.49, 0.61, 0.4, and 0.46 relative to whites for black, American Indian, and Alaska
Native, Asian American and Pacific Islander, and Hispanic, respectively. Moreover, it is
challenging to enroll many minority patients in large bladder cancer trials since they
represent a smaller percentage of the prevalence population and have a lower relative
cancer rate.
It is also unclear why Novitas asserted that Cxbladder tests were not vetted in the
context of Medicare patients since the average age of bladder cancer patients is over
70. In the study evaluating CxBladder Monitor, 82% of the patients were over 60
10
years of age. Thus, it seems this marker is particularly focused on the Medicare
population, as is the case for most markers used for bladder cancer surveillance.
Another area of concern raised by Novitas pertained to issues related to false positive
tests. There is no question that most urine markers suffer from a low PPV, impacting
their clinical performance, interpreting Clinical scenarios where a patient undergoes a
surveillance cystoscopy with no demonstrable tumor albeit with a positive urine marker
presents a clinical conundrum. In such cases, whether the white light cystoscopy
“missed” cancer or the marker is falsely positive is a dilemma. The use of enhanced
cystoscopy has illustrated the fact that white light cystoscopy can miss some papillary
tumors and carcinoma in situ, which may result in a positive marker
11
. Multiple papers
have been published on “anticipatory” positive results for many different markers
12-14
,
finding that patients with a positive marker are more likely to recur during an extended
follow up than patients with a negative marker. The important question is the role of the
marker in this setting. For example, the PPV of markers is much higher if there are
equivocal findings on cystoscopy which resulted in the AUA guidelines supporting the
use of markers in that setting
15
. In the case of the Cxbladder monitor test, the design of
the test was to focus on NPV and not PPV. Since the marker was designed to optimize
sensitivity, it is not surprising that the specificity is lower. If one tries to avoid
cystoscopy in some patients, the high NPV will facilitate reducing the number of
cystoscopies. Similarly, an attempt to reduce cystoscopy in patients with low-risk
clinical features with microscopic hematuria would also benefit from a marker with high
NPV. There is still a need for ongoing trials to support this latter use. A randomized trial
is underway to obtain the evidence needed to result in guideline recommendations for
the use of a marker in the hematuria evaluation (NCT03988309). In summary, the
performance characteristics of markers may vary in terms of optimizing PPV or NPV
and they should be judged on their clinical utility.
Another concern raised in the Novitas draft document focuses on how the studies were
funded. Novitas notes that most of the primary literature regarding Cxbladder test
development and performance is funded, if not directly underwritten, by the test’s parent
company, Pacific Edge Diagnostics. This should be fully addressed as the development
of almost all US markers, devices, and pharmaceuticals is funded by industry. Conflict
of interest should indeed be considered in reviewing papers. Still, marker development
is usually performed at tertiary medical centers and advanced community care centers.
The company is blinded to the results of cystoscopy when analyzing markers, and the
urologist is blinded to the results of the marker when performing cystoscopy. To
suggest that there is a bias in testing performance suggests an incomplete
understanding of prospective observational biomarker study designs. Furthermore,
there is a “catch” for validating markers independent of company support early in
marker development. Namely, until there is coverage for markers, it would be almost
impossible to use markers in routine clinical practice given cost to individual patients.
Thus, the imperative for outsourced funding, whether industry or government, to obtain
data across a cohort of patients. Also, until there is payor coverage, there are only a
limited number of laboratories who will perform the assay. As such, marker companies
must be involved in development and validation of their assays.
This commentary is not meant to be a broad appeal for the indiscriminate coverage for
all urine markers for detection and management of bladder cancer. We acknowledge
that many of the authors of this commentary have consulted with Pacific Edge and other
urine marker companies. However, the authors are clinical scientists who have a strong
interest in improving the care of patients suspected to have or with bladder cancer and
have been involved in research with urine markers and continue to evaluate new
markers. While that can be perceived as a conflict, we are not intending to endorse a
particular marker with this commentary. Our goal is to encourage fair evaluation of
bladder cancer markers for their intended use. There should also be balanced
assessment of markers across the disease spectrum. In table 1, the performance
characteristics of prostate and bladder cancer-related markers are enumerated, and
one can see that there are not many differences in performance characteristics between
some of the covered prostate cancer markers compared to the uncovered bladder
cancer markers. Future decisions on coverage should take into consideration the
available marker data published in the literature, intended use of marker, expert opinion,
and stated position of stakeholders such as the AUA, SUO, SUFU, etc. through their
guideline and expert opinion panels.
Table 1: Performance Characteristics of Prostate and Bladder Cancer Related Markers
Molecular
marker AUC
Sensitivit
y
Specificit
y PPV NPV Medicare LCD references
Prostate
Biomarker
Test
Serum-Based Biomarkers
Prosate-
Specific
Antigen PSA
0.55
1
6
60%
17
79%
17
22%
1
8
93.8%
1
8
LCD - Biomarker
Testing for
Prostate Cancer
Diagnosis
(L37733)
(16) Auprich M, et al. Eur Urol. 2011;60: 1045-1054.,
(17) Oto Jet al. Sci Rep. 2020; 10: 2463. (18) de la
Calle C, et al., J Urol. 2015 Jul;194(1)
PHI
total PSA, Free-
PSA, p2PSA
isoform
0.71
1
9
82%
20
80%
20
27%
2
1
97%
21
LCD - Biomarker
Testing for
Prostate Cancer
Diagnosis
(L37733)
(19) Nordström T, et al. Eur Urol.2015; 68: 139-146.
(20) Al Saidi SS, et al. Oman Med J. 2017; 32: 275-
283. (21) White J, et al. Prostate Cancer Prostatic Dis.
2018; 21:
78-84.
4KScore
total PSA, Free-
PSA, intact PSA,
hK2
0.8-
0.9
22
75%
19
65%
19
LCD - Biomarker
Testing for
Prostate Cancer
Diagnosis
(L37733)
(19) Nordström T, et al. Eur Urol.2015; 68: 139-146.
922) Zappala SM, et al. Rev Urol. 2017; 19: 149-155.
Urine-Based Biomarkers
ExoDx
Prosate
IntelliSore
(EPI)
Exosomal RNA -
SPDEF, PCA3,
ERG 0.7
23
92%
23
34%
23
35%
2
3
91%
23
LCD - Biomarker
Testing for
Prostate Cancer
Diagnosis
(L37733)
(23) McKiernan J, et al. JAMA Oncol. 2016; 2: 882-
889.
MiPS
Michigan
Prostate
Score
PCA3 and
TMPRS52 mRNA
0.69
2
4
93%
25
33%
25
LCD - Biomarker
Testing for
Prostate Cancer
Diagnosis
(L37733)
(24) Tomlins SA, et al. Eur Urol. 2016;70: 45-53. (25)
Gene-based tests for screening, detection, and/or
management of prostate cancer. Medical Policy
Manual Genetic Testing. 2020; Policy No. 17
http://www.policy.asuris.com/geneticTesting/gt17.p
df
Progensa
(PCA3)
Long Non-coding
RNAs
0.73
2
6
69%
26
65%
26
34%
2
7
90 %
27
LCD - Biomarker
Testing for
Prostate Cancer
Diagnosis
(L37733)
(26) Nicholson A, et al., Health Technol Assess. 2015;
19: 1-191. (27) Physician Brochure for the
PRoGensa® PCa3 assay
SlectMDX
HoXC6 and DLX1
mRNA
0.71-
0.83
2
8
91%
28
36%
28
45%
2
9
95%
29
LCD - Biomarker
Testing for
Prostate Cancer
Diagnosis
(L37733)
(28) Van Neste L, et al. Eur Urol. 2016; 70:740-748.
(29) Haese A et al., J Urol. 2019 Aug;202(2):256-263.
Tissue-Based Biomarkers
ConfirmMD
X
DNA
Hypermethylatio
n - GsTPA, APC,
RASSF1
0.74
3
0
68%
30
64%
30
96%
30
LCD - Biomarker
Testing for
Prostate Cancer
Diagnosis
(L37733)
(30) Van Neste L, et al. Prostate. 2016; 76: 1078-
1087.
Bladder
Biomarker
Test
Urine-Based Biomarkers
Cytology Cell Phenotype 38%
31
98%
31
64.%
32
88%
32
Lab:
Bladder/Urothelia
l Tumor Markers
(L36678)
(31) Blick, C.G., et al., BJU Int. 2012, 110, 84–94. (32)
Dimashkieh H, et al.,Cancer Cytopathol. 2013
Oct;121(10):591-7
UroVysion FISH 72%
33
83%
33
46%
3
2
92%
32
Lab:
Bladder/Urothelia
l Tumor Markers
(L36678)
(32) Dimashkieh H, et al.,Cancer Cytopathol. 2013
Oct;121(10):591-7 (33) T.Hajdinjak, T. UroVysion FISH
Test for Detecting Urothelial Cancers: Meta-Analysis
of Diagnostic Accuracy and
Comparison with Urinary Cytology Testing; Elsevier:
Amsterdam, The Netherlands, 2008; pp. 646–651.
(20)Dimashkieh H, et al., Cancer Cytopathol. 2013
Oct;121(10):591-7
CxBladder
(Detect)
mRNA -IGFBP5,
HOHA13, MDK,
CDK1, CXCR2
0.87
3
4
82%
34
85%
34
25%
3
5
97%
35
(34) O’Sullivan, P. et al.,J. Urol. 2012, 188, 741–747.
(35) Lotan et al., J of Urology April 2023; 209:762-772
NMP-22
Nuclear matrix
protein 22 ELISA
0.73
3
4
(17) 69%
36
77%
36
87%
37
Lab:
Bladder/Urothelia
l Tumor Markers
(L36678)
(34) O’Sullivan, P. et al.,J. Urol. 2012, 188, 741–747.
(36) Hu, X. et al., Cancers 2022, 14, 3181. (37) Lotan
et al., 2017
NMP-22
BladderChe
k point of care test 58%
36
88%
36
86%
37
Lab:
Bladder/Urothelia
l Tumor Markers
(L36678)
(36) Hu, X. et al., Cancers 2022, 14, 3181. (37) Lotan
et al., 2017
CxBladder
(Monitor)
2 clinical features
and mRNA -
IGFBP5, HOHA13,
MDK, CDK1 ,
CXCR2 91%
37
96%
37
(37) Lotan et al., 2017
ImmunoCyt IHC
0.79
3
8
73%
36
66 %
36
26–
67%
3
9
91–
96%
39
Lab:
Bladder/Urothelia
l Tumor Markers
(L36678)
(36) Hu, X. et al., Cancers 2022, 14, 3181. (38) He
H,et al., Oncol Lett. 2016 Jul;12(1):83-88. (39) Fradet
Y, Lockhard C., Can J Urol. 1997;4:400–405.
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doi:10.1016/j.ucl.2022.09.009
2. Woldu SL, Souter L, Boorjian SA, Barocas DA, Lotan Y. Urinary-based tumor markers enhance
microhematuria risk stratification according to baseline bladder cancer prevalence. Urol Oncol. Nov
2021;39(11):787.e1-787.e7. doi:10.1016/j.urolonc.2021.03.022
3. Chou R, Gore JL, Buckley D, et al. Urinary Biomarkers for Diagnosis of Bladder Cancer: A
Systematic Review and Meta-analysis. Ann Intern Med. Dec 15 2015;163(12):922-31. doi:10.7326/m15-
0997
4. Woldu SL, Ng CK, Loo RK, et al. Evaluation of the New American Urological Association
Guidelines Risk Classification for Hematuria. J Urol. May 2021;205(5):1387-1393.
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5. Barocas DA, Boorjian SA, Alvarez RD, et al. Microhematuria: AUA/SUFU Guideline. J Urol. Oct
2020;204(4):778-786. doi:10.1097/ju.0000000000001297
6. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder
Cancer: AUA/SUO Guideline. J Urol. Oct 2016;196(4):1021-9. doi:10.1016/j.juro.2016.06.049
7. Konety B, Shore N, Kader AK, et al. Evaluation of Cxbladder and Adjudication of Atypical
Cytology and Equivocal Cystoscopy. Eur Urol. Aug 2019;76(2):238-243.
doi:10.1016/j.eururo.2019.04.035
8. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. Jan
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9. Schafer EJ, Jemal A, Wiese D, et al. Disparities and Trends in Genitourinary Cancer Incidence and
Mortality in the USA. Eur Urol. Jul 2023;84(1):117-126. doi:10.1016/j.eururo.2022.11.023
10. Kavalieris L, O'Sullivan P, Frampton C, et al. Performance Characteristics of a Multigene Urine
Biomarker Test for Monitoring for Recurrent Urothelial Carcinoma in a Multicenter Study. J Urol. Jun
2017;197(6):1419-1426. doi:10.1016/j.juro.2016.12.010
11. Daneshmand S, Patel S, Lotan Y, et al. Efficacy and Safety of Blue Light Flexible Cystoscopy with
Hexaminolevulinate in the Surveillance of Bladder Cancer: A Phase III, Comparative, Multicenter Study. J
Urol. May 2018;199(5):1158-1165. doi:10.1016/j.juro.2017.11.096
12. Cowan B, Klein E, Jansz K, et al. Longitudinal follow-up and performance validation of an mRNA-
based urine test (Xpert(®) Bladder Cancer Monitor ) for surveillance in patients with non-muscle-invasive
bladder cancer. BJU Int. Dec 2021;128(6):713-721. doi:10.1111/bju.15418
13. Gopalakrishna A, Fantony JJ, Longo TA, et al. Anticipatory Positive Urine Tests for Bladder
Cancer. Ann Surg Oncol. Jun 2017;24(6):1747-1753. doi:10.1245/s10434-016-5763-5
14. Seideman C, Canter D, Kim P, et al. Multicenter evaluation of the role of UroVysion FISH assay in
surveillance of patients with bladder cancer: does FISH positivity anticipate recurrence? World J Urol.
Sep 2015;33(9):1309-13. doi:10.1007/s00345-014-1452-9
15. Schlomer BJ, Ho R, Sagalowsky A, Ashfaq R, Lotan Y. Prospective validation of the clinical
usefulness of reflex fluorescence in situ hybridization assay in patients with atypical cytology for the
detection of urothelial carcinoma of the bladder. J Urol. Jan 2010;183(1):62-7.
doi:10.1016/j.juro.2009.08.157
16. Auprich M, Bjartell A, Chun FK, et al. Contemporary role of prostate cancer antigen 3 in the
management of prostate cancer. Eur Urol. Nov 2011;60(5):1045-54. doi:10.1016/j.eururo.2011.08.003
17. Oto J, Fernández-Pardo Á, Royo M, et al. A predictive model for prostate cancer incorporating
PSA molecular forms and age. Sci Rep. Feb 12 2020;10(1):2463. doi:10.1038/s41598-020-58836-4
18. de la Calle C, Patil D, Wei JT, et al. Multicenter Evaluation of the Prostate Health Index to Detect
Aggressive Prostate Cancer in Biopsy Naïve Men. J Urol. Jul 2015;194(1):65-72.
doi:10.1016/j.juro.2015.01.091
19. Nordström T, Vickers A, Assel M, Lilja H, Grönberg H, Eklund M. Comparison Between the Four-
kallikrein Panel and Prostate Health Index for Predicting Prostate Cancer. Eur Urol. Jul 2015;68(1):139-
46. doi:10.1016/j.eururo.2014.08.010
20. Al Saidi SS, Al Riyami NB, Al Marhoon MS, et al. Validity of Prostate Health Index and Percentage
of [-2] Pro-Prostate-Specific Antigen as Novel Biomarkers in the Diagnosis of Prostate Cancer: Omani
Tertiary Hospitals Experience. Oman Med J. Jul 2017;32(4):275-283. doi:10.5001/omj.2017.55
21. White J, Shenoy BV, Tutrone RF, et al. Clinical utility of the Prostate Health Index (phi) for biopsy
decision management in a large group urology practice setting. Prostate Cancer Prostatic Dis. Apr
2018;21(1):78-84. doi:10.1038/s41391-017-0008-7
22. Zappala SM, Scardino PT, Okrongly D, Linder V, Dong Y. Clinical performance of the 4Kscore Test
to predict high-grade prostate cancer at biopsy: A meta-analysis of us and European clinical validation
study results. Rev Urol. 2017;19(3):149-155. doi:10.3909/riu0776
23. McKiernan J, Donovan MJ, O'Neill V, et al. A Novel Urine Exosome Gene Expression Assay to
Predict High-grade Prostate Cancer at Initial Biopsy. JAMA Oncol. Jul 01 2016;2(7):882-9.
doi:10.1001/jamaoncol.2016.0097
24. Tomlins SA, Day JR, Lonigro RJ, et al. Urine TMPRSS2:ERG Plus PCA3 for Individualized Prostate
Cancer Risk Assessment. Eur Urol. Jul 2016;70(1):45-53. doi:10.1016/j.eururo.2015.04.039
25. Gene-Based Tests for Screening, Detection, and Management of Prostate or Bladder Cancer.
Medical Policy Manual Genetic Testing2022.
26. Nicholson A, Mahon J, Boland A, et al. The clinical effectiveness and cost-effectiveness of the
PROGENSA® prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate
cancer: a systematic review and economic evaluation. Health Technol Assess. Oct 2015;19(87):i-xxxi, 1-
191. doi:10.3310/hta19870
27. Physician Brochure for the PRoGensa® PCa3 assay.
https://www.hologic.com/sites/default/files/package-
insert/Progensa%20PCA3%20Physician%20Brochure-USA.pdf
28. Van Neste L, Hendriks RJ, Dijkstra S, et al. Detection of High-grade Prostate Cancer Using a
Urinary Molecular Biomarker-Based Risk Score. Eur Urol. Nov 2016;70(5):740-748.
doi:10.1016/j.eururo.2016.04.012
29. Haese A, Trooskens G, Steyaert S, et al. Multicenter Optimization and Validation of a 2-Gene
mRNA Urine Test for Detection of Clinically Significant Prostate Cancer before Initial Prostate Biopsy. J
Urol. Aug 2019;202(2):256-263. doi:10.1097/JU.0000000000000293
30. Van Neste L, Partin AW, Stewart GD, Epstein JI, Harrison DJ, Van Criekinge W. Risk score predicts
high-grade prostate cancer in DNA-methylation positive, histopathologically negative biopsies. Prostate.
Sep 2016;76(12):1078-87. doi:10.1002/pros.23191
31. Blick CG, Nazir SA, Mallett S, et al. Evaluation of diagnostic strategies for bladder cancer using
computed tomography (CT) urography, flexible cystoscopy and voided urine cytology: results for 778
patients from a hospital haematuria clinic. BJU Int. Jul 2012;110(1):84-94. doi:10.1111/j.1464-
410X.2011.10664.x
32. Dimashkieh H, Wolff DJ, Smith TM, Houser PM, Nietert PJ, Yang J. Evaluation of urovysion and
cytology for bladder cancer detection: a study of 1835 paired urine samples with clinical and histologic
correlation. Cancer Cytopathol. Oct 2013;121(10):591-7. doi:10.1002/cncy.21327
33. Hajdinjak T. UroVysion FISH test for detecting urothelial cancers: meta-analysis of diagnostic
accuracy and comparison with urinary cytology testing. Urol Oncol. 2008;26(6):646-51.
doi:10.1016/j.urolonc.2007.06.002
34. O'Sullivan P, Sharples K, Dalphin M, et al. A multigene urine test for the detection and
stratification of bladder cancer in patients presenting with hematuria. J Urol. Sep 2012;188(3):741-7.
doi:10.1016/j.juro.2012.05.003
35. Lotan Y, Raman JD, Konety B, et al. Urinary Analysis of FGFR3 and TERT Gene Mutations
Enhances Performance of Cxbladder Tests and Improves Patient Risk Stratification. J Urol. Apr
2023;209(4):762-772. doi:10.1097/JU.0000000000003126
36. Hu X, Li G, Wu S. Advances in Diagnosis and Therapy for Bladder Cancer. Cancers (Basel). Jun 29
2022;14(13)doi:10.3390/cancers14133181
37. Lotan Y, OʼSullivan P, Raman JD, et al. Clinical comparison of noninvasive urine tests for ruling
out recurrent urothelial carcinoma. Urol Oncol. Aug 2017;35(8):531.e15-531.e22.
doi:10.1016/j.urolonc.2017.03.008
38. He H, Han C, Hao L, Zang G. ImmunoCyt test compared to cytology in the diagnosis of bladder
cancer: A meta-analysis. Oncol Lett. Jul 2016;12(1):83-88. doi:10.3892/ol.2016.4556
39. Fradet Y, Lockhard C. Performance characteristics of a new monoclonal antibody test for bladder
cancer: ImmunoCyt trade mark. Can J Urol. Sep 1997;4(3):400-405.
---
DM_US 199122940-1.098494.0012
Dear Dr. Mann,
We are writing in response to your open request for comment on DL39365. This letter also
addresses the draft LCD from First Coast Service Options. We have numerous concerns regarding
the LCD, but most critically, the evidentiary review associated with the non-coverage
determination of Cxbladder products.
EXECUT IVE SUMMARY :
• This letter contains Pacific Edge’s response to the LCD for our Cxbladder Triage (0363U)
and Detect (0012M) tests which are indicated for the hematuria evaluation in patients
with no prior diagnosis of urothelial carcinoma (UC) as well as the Cxbladder Monitor test
(0013M) which is indicated for surveillance of patients diagnosed with non-muscle
invasive bladder cancer (NMIBC).
• We maintain that our published clinical data supports the inclusion of Cxbladder Triage
and Detect for specific patient populations in the clinical pathway for hematuria
evaluation, and the published clinical data supports the inclusion of Cxbladder Monitor
into the clinical pathway for surveillance of patients diagnosed with non-muscle invasive
bladder cancer(1-4).
• The letter also references three Cxbladder tests (Cxbladder Resolve, Enhanced Detect,
and Enhanced Triage) referenced in the LCD that are in development and not
commercially available and therefore are not appropriate for an evidentiary review or
inclusion/exclusion from coverage(5).
• We share our medical rebuttal to many of the points made in the evidentiary review on
the LCD that we believe do not reflect the clinical value of the tests and the substantial
clinical evidence developed to validate them.
• Pacific Edge respectfully makes the following requests for changes to the LCD.
REQUESTS
1. We request Cxbladder Triage, Detect, and Monitor be included as covered tests in the
final LCD language for the specific patient populations outlined below. The published
clinical evidence and the demonstrated real world clinical value of these tests with high
negative predictive value affirms the need for continued access of these tests to the
Medicare population (see appendix for specific evidence).
2. If Novitas does not support the request above:
a. We request that all tests in the hematuria evaluation pathway be completely
removed from this LCD as they do not fit the inclusion criteria which requires an
DM_US 199122940-1.098494.0012
established diagnosis or significant suspicion of cancer. This removal would
include Cxbladder Triage and Detect.
b. We request that once removed from LCD DL39365, Cxbladder Triage and Detect
continue to be covered per the guide and documentation requirements of LCA
58917 as currently covered when the tests are documented as medically
necessary by the treating physician.
c. We request that Novitas convene a Contractor Advisory Committee session to
determine if urinary biomarkers should be included in an existing or new LCD.
3. We request that all mentions of Enhanced Cxbladder Detect, Resolve or Enhanced
Cxbladder Triage be removed from the LCD as these tests are not available for clinical
use. The data supporting the analytic validity, clinical validity, and clinical utility of these
tests is still under development.
SUPPORT FOR RE QUE STS:
Support for Request #1
We request Cxbladder Triage, Detect, and Monitor be included as covered tests in the final LCD
language for the specific patient populations outlined below. The published clinical evidence and
the demonstrated real world clinical value of these tests with high negative predictive value
affirms the continued access of these tests to the Medicare population.
Rationale:
Cxbladder Detect
Clinical Scenario and Patient Population
Cxbladder Detect is intended for use with patients presenting with any microhematuria to risk
stratify those patients into low, intermediate, and high risk of bladder cancer. This stratification
can reduce the burden of investigations for the low and intermediate risk patients after shared
decision making with the patient and prioritize those with high risk for full investigation. The
test can also be used to adjudicate diagnostic dilemmas when cytology is equivocal, or
cystoscopy is un-informative in both microscopic and gross hematuria patients.
There are approximately 7 million patients in the US that present annually with hematuria, of
which 75% present with microhematuria (defined as ≥3 RBC/HPF and with no visible blood in
urine).
DM_US 199122940-1.098494.0012
These patients are risk stratified by AUA guidelines into low, intermediate, and high risk
microhematuria based on clinical and demographic factors with the approximate percentages
being 5%, 12%, and 83% respectively(6).
Studies have shown that most of these patients do not have UC, with prevalence data showing
approximately 5% of patients having UC(6).
The current standard of care for those patients is dependent on their risk stratification, where
only low risk patients are counseled to return in 6-8 months for another urine analysis (UA) to
determine if they need a full workup. Intermediate and high-risk patients on the other hand are
provided a full workup, including a cystoscopy, to assess the bladder and CT (Computerized
Tomography) urography to assess the upper tract. The risks associated with this standard of care
are those associated with any invasive procedure including infections, urethral damage, and any
allergic reactions to contrast agents used for CT urography to name a few.
The clinical utility of Detect is driven by the high negative predictive value that identifies the
patients that present with microhematuria that are at significantly lower risk of currently having
UC so that they can be given lower intensity diagnostic evaluations. The value to the Medicare
population of adopting Detect prior to cystoscopy is the reduction of unnecessary cystoscopy and
imaging procedures for patients who do not need it, while simultaneously improving the yield of
cancer diagnoses within the patients that do receive the full workup.
Proposed Eligibility Criteria for Cxbladder Detect
• Microhematuria (MH) patients referred to the urology office for evaluation.
o MH is defined as ≥3 RBC/HPF with no visible blood in urine.
o Gross hematuria for adjudication of diagnostic dilemmas.
• Non-malignant or gynecologic causes ruled out by urologist prior to ordering the test.
o UTI (urinary tract infections), kidney stones, etc..., ruled out.
The diagram below illustrates the two clinical pathways for Cxbladder Detect:
DM_US 199122940-1.098494.0012
Conclusion
Cxbladder Detect should be a covered benefit for Medicare patients under the LCD because:
• It has demonstrated analytical validity, clinical validity, and clinical utility in published
studies (see appendix for specific studies).
• The current standard of care drives significant overuse of diagnostic procedures,
specifically invasive and unpleasant cystoscopy. For lower risk patients, this has a
DM_US 199122940-1.098494.0012
disproportionate impact on the elderly given the higher rates of complications in patients
with multiple co-morbidities.
The clinical value of expanded use of tests with high negative predictive value also benefits
patients as it reduces the financial burden on the health care system by removing patients from
unnecessary procedures with no impact on patient outcomes.
Cxbladder Triage
Clinical Scenario and Patient Population
Triage is indicated to risk stratify and identify lower-risk hematuria patients to reduce the burden
of unnecessary investigations. It is intended for use by primary care physicians or at the urology
office to prioritize patients and manage unnecessary referrals for more invasive evaluation at the
urology office.
The clinical utility of Triage is to identify the patients that present with microhematuria that have
significantly lower risk of currently having UC so that they can be managed according to the low
risk AUA guidelines recommendation rather than given a full workup that is unnecessary for those
patients.
The value to the Medicare population of adopting Triage prior to cystoscopy is reduction of
unnecessary cystoscopy and imaging procedures for patients at lower risk, while simultaneously
improving the yield of cancer diagnoses within the patients that do receive the full workup.
Proposed Eligibility Criteria for Cxbladder Triage
• Microhematuria (MH) patients at the Primary care office, or low risk patients referred to
the urology office.
• MH is defined as ≥3- 25 RBC/HPF with no previous incidence of gross hematuria.
• Non-malignant or gynecologic causes ruled out by urologist prior to ordering the test.
o UTI, kidney stones, etc..., ruled out.
Conclusion
Cxbladder Triage should be a covered benefit for Medicare patients under the LCD because:
• It has demonstrated analytical validity, clinical validity, and clinical in published studies
(see appendix for specific studies).
• The current standard of care drives significant overuse of diagnostic procedures,
specifically invasive and unpleasant cystoscopy. For lower risk patients, this has a
disproportionate impact on elderly patients given the higher rates of complications in
patients with multiple co-morbidities.
The clinical value of expanded use of tests with high negative predictive value also benefits
patients as it reduces the financial burden on the health care system by removing patients from
unnecessary procedures with no impact on patient outcomes.
DM_US 199122940-1.098494.0012
Cxbladder Monitor
Clinical Scenario and Patient Population
The Cxbladder Monitor test is intended for use in patients with prior diagnosis of NMIBC that
are on a surveillance protocol for follow up for recurrence of disease. The test is intended for
use starting at 9 months post diagnosis of either primary or recurrent disease with no
recurrence in between. The test should be used in an alternating fashion with cystoscopy to
reduce the diagnostic burden on these patients. Patients with a negative test (NPV (Negative
Predictive Value) 97%) can defer the cystoscopy to the next scheduled surveillance visit with no
impact in identifying recurrence. Those patients with a positive test should continue with the
normal surveillance protocol.
There are approximately 800,000 patients that are seen annually for UC recurrence in the U.S.
Bladder cancer has a high rate of recurrence with a 1-year recurrence rate of 15-61%, and a 5-
year recurrence rate of 31-78%(7). Therefore, patients are subjected to a frequent and intensive
monitoring schedule. These patients generally follow a surveillance protocol that calls for
cystoscopy at regular intervals depending on the risk classification of those patients (AUA
guidelines table below). High and intermediate risk patients are followed up every 3 months for
the first two years of surveillance, every 6 months for years 3-4, then annually afterwards with
no set limit to stop surveillance. Low risk patients are recommended for follow up at 3 months
post diagnosis, 9-12 months after that, then annually for the next 5 years. It is important to note
that all these recommendations are restarted if recurrence of disease occurs, and cystectomy is
not recommended.
The risks associated with this standard of care are similar to those described above for the
hematuria evaluation, with the added risk of repeat incidence of the same problems over a
prolonged period of surveillance.
The clinical utility of Monitor is to identify the patients that are at a low enough risk of recurrence
so that they can safely alternate cystoscopy with Cxbladder Monitor test within the timeframes
of standard of care.
The value to the Medicare population of alternating Monitor with cystoscopy during standard
surveillance protocols is to reduce the burden of invasive procedures on the patient and health
care system and improve patient compliance with the surveillance protocols. If low risk patients
can safely defer the surveillance visit and alternate with the test, the higher risk patients will have
priority at the urology office and early detection of any recurrence will be standard of care.
DM_US 199122940-1.098494.0012
The chart below is AUA guideline for NMIBC.
Proposed eligibility criteria for Cxbladder Monitor test:
• Patients with previously diagnosed urothelial cancer (primary or recurrent, any risk
classification) have at least 9 months of recurrence free follow up. Those patients may
alternate the Cxbladder Monitor test with regular cystoscopy and can prolong the
duration between cystoscopies based on a negative Monitor test.
DM_US 199122940-1.098494.0012
• Low risk patients who have no recurrence for 3 years. Those patients can be setup to
receive a Cxbladder Monitor test every 6-12 months in place of regular cystoscopy.
Positive Monitor test should be referred for cystoscopy.
• Intermediate and High-risk patients who have no recurrence for 5 years. Those patients
can be setup to receive a Cxbladder Monitor test every 6 months in place of regular
cystoscopy. Positive Monitor test should be referred for cystoscopy.
Conclusion
Cxbladder Monitor should be a covered benefit for Medicare patients under the LCD because.
• It has demonstrated analytical validity, clinical validity, and clinical utility in published
studies (see Appendix for specific studies)
• The current standard of care drives significant overuse of diagnostic procedures,
specifically invasive and unpleasant cystoscopy. For lower risk patients the overuse of
invasive procedures has a disproportionate impact on elderly patients given the higher
rates of complications in patients with multiple co-morbidities. These benefits are
exaggerated in the surveillance population due to the repetitive nature of surveillance.
The more patients can avoid unnecessary procedures, the better quality of life for those
patients.
DM_US 199122940-1.098494.0012
• The clinical value of expanded use of tests with high negative predictive value also
benefits patients as it reduces the financial burden on the health care system by removing
patients from unnecessary procedures with no impact on patient outcomes(8).
Support for Request #2
Request 2a -The focus of this LCD is on genetic tests that are performed after a biopsy-proven
(histologic or cytologic) diagnosis of cancer or substantiated suspicion of cancer based on
histology or urine cytology. As Cxbladder Triage and Cxbladder Detect are indicated for patients
with hematuria prior to a diagnosis of cancer. Hematuria appears not to meet the requirements
for suspicion of cancer set forth in the draft LCD, yet hematuria is a key factor in determining if a
full diagnostic workup for urothelial cancer is warranted according to the urology community
standard of care. If in the final LCD hematuria is not recognized as a substantiated suspicion of
bladder cancer, then Cxbladder Triage and Cxbladder Detect tests as well as any other tests
performed for the evaluation of hematuria where a diagnosis of bladder cancer has not yet
been substantiated based upon histologic or cytology findings should not fall under such LCD.
Neither a coverage determination nor a non-coverage determination is appropriate under this
LCD for Cxbladder Triage and Detect because it is not the intended purpose of these tests to be
ordered in patients for whom the diagnosis of bladder cancer has already been made. It is also
worth noting that the NCCN (National Comprehensive Cancer Network) guidelines, which are
used as one of the criteria for coverage in this LCD, do not address hematuria evaluation at all—
these guidelines focus on the evaluation and management of patients with bladder cancer. As
such, inclusion of tests for the evaluation of hematuria in this proposed LCD is not appropriate
given that three knowledge bases referenced in the LCD would not include RNA based test
indicated for hematuria evaluation.
Request 2b – If Novitas and First Coast concur that Cxbladder Triage and Detect should not be
included in the LCD, we respectfully request that Medicare coverage continue as it has been
since July 2020. This coverage should include a specific reference in LCA 58917 or other
appropriate articles providing clarity to clinicians and Medicare Advantage payers on the positive
coverage of Triage and Detect. It would cause significant confusion in the marketplace if Triage
and Detect were removed from the current LCD and not referenced in another Novitas document.
Any such confusion would be detrimental to Medicare beneficiaries given that these tests have
been consistently covered for multiple years.
Request 2c - If Novitas and First Coast determine that Cxbladder Triage and Detect’s use falls
outside of the current LCD, it will be important to develop an LCD for urinary biomarkers for the
evaluation and management of patients with hematuria as that is a critical part of the bladder
cancer diagnostic process. It is our recommendation that a new LCD should be developed with
the support of convening a Contractor Advisory Council to ensure that input from clinician
experts treating Medicare beneficiaries is part of the LCD development.
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Request 3 - Cxbladder Resolve, Cxbladder Enhanced Triage, and Cxbladder Enhanced Detect are
not currently clinically available in the U.S. These tests have not been fully validated at this point.
Therefore, we believe it is premature and inappropriate to include a detailed evidentiary review
of these tests resulting in preemptive non-coverage in the draft LCD and that these tests should
be excluded from the LCD.
The Novitas/FCSO review included evaluation of Cxbladder Resolve and the "enhanced"
Cxbladder tests that include single nucleotide polymorphisms. These are tests under
development and have not been validated for clinical use at this time. None of these are
commercially available in the US. Indeed, large prospective multicenter clinical trials are currently
underway (Appendix) to provide evidence of clinical validity and clinical utility of those tests and
their clinical applications. When these tests have been fully validated and are being offered for
clinical use, then it may be appropriate for Novitas/FSCO to evaluate the evidence and determine
if these tests meet the requirements to be medically reasonable and necessary.
We thus believe the criticism of these tests as having insufficient evidence is premature and
should not influence the assessment for coverage of the commercially available tests, specifically,
Triage, Detect, and Monitor.
Request Summary
We respectfully request that Novitas re-evaluate the important clinical role that Cxbladder Triage,
Detect, and Monitor have in the hematuria evaluation and recurrence monitoring pathways for
bladder cancer. We believe that our requests are supported by the clinical evidence and the needs
of clinicians and patients. Our requests are consistent with the LCD and supported by the primary
clinical organizations and societies within the urology community.
COMMENTS ON EVIDE NTIARY REV IEW OF CXBLADDER P UBLIS HE D LITERAT URE:
Detailed comments responding to the evidentiary review in the draft LCD are presented below
for Cxbladder Triage, Detect, and Monitor. These comments form a significant portion of the
rationale for inclusion of the Cxbladder tests as covered test in the LCD as the review of the
published literature included several incorrect assumptions and misunderstandings. Taken as a
whole, the comments below show that the published data on the Cxbladder products surpasses
the level of evidence required for Medicare coverage as medically reasonable and necessary.
1) THE HOLYOAKE STUDY IS A BIOMA RKE R DEVELOPMENT STUDY, N OT A VALIDAT ION
STUDY
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Novitas/FSCO considered the Holyoake study to be the initial development study for Cxbladder
Triage and Detect and conclude that the study does not show that the tests distinguish among
various types of cancers. This assessment is then used as the basis for determining that none of
the Cxbladder tests meet the reasonable and necessary coverage criteria because they were built
on a faulty foundation. However, the evidentiary review does not reflect the fact that the
Holyoake study was designed to identify potentially relevant biomarkers to help inform
development of the Cxbladder assays – it was not designed as an initial study supporting the
validity of the assays themselves.
In their review, Novitas has claimed that our initial development study(9) was flawed in its design:
“This means that a well-designed test will be able to not only discriminate between cancer
and normal tissue, but also between different types of malignancy.”(10)
(p.32)
In another portion of the review Novitas states:
"One very notable gap included a lack of details or definition for non-urothelial cancers,
of which many would feed into the urinary system, including prostate cancers, renal
cancers, and metastatic or locally invasive cancers from other organs(10)."
* * *
"This first paper from 2012 also does not sufficiently address Cxbladder’ s ability to
distinguish between urothelial carcinoma and other malignancies, which is of particular
relevance when a majority of the patient population were male (78%) with a median
patient age of 64 years and thus, with higher risk of prostate carcinoma.”(10)
(p.33)
The Holyoake (2008)(9) paper is fundamentally misinterpreted to be a “development study” for
clinical assays. This study was a “biomarker discovery” study aimed to identify which biomarkers
play a role in various cancers that could subsequently inform the development of the Cxbladder
assays which then would be assessed in future studies to determine the analytical validity, clinical
validity, and clinical utility of the specific assays developed. Concluding that the Cxbladder assays
do not meet criteria for reasonable and necessary based on a biomarker discovery study is not
appropriate because such a study does not evaluate any specific test nor is it intended to provide
evidence of the analytical validity, clinical validity, or clinical utility of any test developed
comprising any biomarkers discovered in such a study.
Furthermore, these excerpts above from the review show an unfamiliarity with the established
clinical pathway for the management of patients presenting with hematuria that supports the
clinical utility and intended use of our tests. The Cxbladder Triage and Detect tests were
developed to determine if a urine-based test can distinguish between presence or absence of
urothelial cancer with the stated goal of reducing the burden of unnecessary invasive procedures
(cystoscopy, CT-Urogram, ureteroscopy) for patients presenting with hematuria.
The purpose of the development study was not to develop a test to distinguish between urothelial
carcinoma and other types of cancer. We also point out that prostate cancer does not typically
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present with hematuria and neither prostate nor renal cancers are diagnosed by cystoscopy. Both
of these cancers have their own presentation symptoms and signs and have pre-defined
diagnostic pathways that best represent how they are diagnosed. The Cxbladder tests were
developed specifically to address the clinical management of patients presenting with hematuria
in the absence of other known benign or malignant disease where there is suspicion of bladder
cancer and more invasive evaluation for bladder cancer (i.e., cystoscopy) is being considered. The
Cxbladder tests were not designed to address other clinical questions, such as patients presenting
with an elevated PSA (Prostate Specific Antigen) being evaluated for prostate cancer or patients
presenting with a renal mass being evaluated for renal cell carcinoma. We have heard from the
urology community that use our tests are helpful in the clinical evaluation of patients with
hematuria and monitoring for recurrence as these tests address the likelihood that the patient
has bladder cancer, which is the key question in the evaluation of these patients. We have been
told by several urology stakeholders that they plan to comment on the draft LCD reinforcing these
points.
Our tests were developed for the purpose of reducing the investigative burden on patients with
substantiated suspicion of disease by standard of care, i.e., those patients presenting with
hematuria, and for these purposes, Cxbladder tests perform exactly as intended. The tests should
remain covered accordingly.
2) THE DRAFT L CD DOE S NOT REFLE CT THE ESTABL IS HED CL INICA L PATHWAYS IN
WHICH T HE CX BL ADDER TESTS ARE USED
Novitas appears to have misunderstood the clinical value and benefits of our tests in their review
of literature. In our response above, we have included both written and graphic descriptions of
the clinical scenarios in which the Cxbladder products are used to benefit patients. The written
descriptions are copied below for your reference. Pacific Edge would strongly support assembling
a Clinical Advisory Committee (CAC) comprising experts in the management of patients
presenting with hematuria to inform the development of any coverage policy addressing the use
of urinary biomarkers in the management of hematuria. Pacific Edge is willing and ready to
collaborate with the Novitas/FCSO medical team at any time to provide appropriate additional
information on the utility and benefit of the Cxbladder Triage and Detect tests in the Medicare
population.
We provide here the intended clinical pathways for the Cxbladder Triage and Detect tests together
with the data supporting their Analytical Validation (AV), Clinical Validation (CV), and Clinical
Utility (CU).
a- Cxbladder Triage Test: Intended to risk stratify and identify lower risk microhematuria
patients to reduce the burden of unnecessary investigations. It is intended for use by
primary care physicians or advanced practice clinicians (e.g., NPs or PAs) to prioritize
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patients and manage unnecessary referrals for more invasive evaluation at the urology
office.
b- Cxbladder Detect Test: Intended for use in urology practices with any microhematuria
patient to risk stratify those patients into low, intermediate, and high risk of bladder
cancer. It is intended to reduce the burden of investigations for the low and intermediate
risk patients after shared decision making with the patient and prioritize those with high
risk for full investigation. The test can also be used to adjudicate diagnostic dilemmas
when cytology is equivocal, or cystoscopy is un-informative in both microscopic and gross
hematuria patients.
c- The Cxbladder Monitor Test: Intended for use in patients with prior diagnosis of NMIBC
that are on a surveillance protocol for follow up for recurrence of disease. The test is
intended for use starting at 9 months post diagnosis of either primary or recurrent disease
with no recurrence in between. The test should be used in an alternating fashion with
cystoscopy to reduce the burden on these patients. Patients with a negative test (NPV
97%) can defer the cystoscopy to the next scheduled surveillance visit, those with a
positive test, should be referred for cystoscopy.
The Appendix summarizes the studies used to provide the validation and utility of these tests in
these specific patients.
3) Patient demographics
The Novitas/FCSO review included a concern that there is a male bias in the studies supporting
the use of the Cxbladder Triage and Detect tests. We disagree with this critique of the evidence
base. Bladder cancer has a much higher incidence in men than women with diagnoses in the USA
3-4x more frequently in men than women (https://www.cancer.org/cancer/types/bladder-
cancer.html). If the studies had an equal balance of men and women, then the studies would not
be representative of the target population.
4) Discr imination between Urothelial Cancer and Other Cancer Types
As discussed above, the LCD does not reflect the intended use and clinical value of Cxbladder
Triage and Detect. These tests are not designed to distinguish between multiple cancers or serve
as multi-cancer early detection (MCED) tests trying to answer whether the patient has a cancer
anywhere. These are risk stratification tests that specifically attempt to reduce the use of
unnecessary, invasive, and potentially harmful investigations (cystoscopy, CT Urogram,
ureteroscopy) in populations with substantiated suspicion of urothelial cancer(11). In the case of
Cxbladder Triage this includes patients presenting with hematuria that have a high chance of
normal evaluation, but for whom American Urological Association (AUA) guidelines advocate
more invasive investigations. Prostate cancer is not diagnosed through cystoscopy or CT Urogram
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and rarely presents with hematuria unless very advanced. The fundamental question answered
by Cxbladder tests is "can a negative test identify a patient with a low enough risk of the presence
of urothelial cancer that can avoid further unnecessary evaluation" and for that question the test
has performance characteristics that provide high clinical value. In addition, patients presenting
with other types of urogenital cancers have a unique set of symptoms and signs that are specific
to those cancers. Urological societies have separate diagnostic pathways in their respective
guidelines for evaluation of those patients. In the case of prostate cancer, initial workup depends
on an elevated level of PSA and not hematuria. If the PSA level is elevated, patients can undergo
multiple imaging studies (U/S, MRI) prior to a decision for biopsy which would be the only true
diagnostic step for prostate cancer(12). In the case of renal cell carcinoma, patients will usually
present with dull aching pain in their loin with or without a palpable mass. These patients are
referred to CT scan to identify the lesion and are managed completely differently than UC in the
upper tract(13).
5) Criti cism for la ck o f studies done independently of Pacific Edg e
We do not believe that company sponsorship of clinical trials is a valid criticism of our studies as
that practice is common in the industry. The Novitas review mentions that part of the problem is
lack of confidence in Pacific Edge data since many of the studies reviewed were either funded or
performed by Pacific Edge Limited. Most new drugs, biologicals, devices, and diagnostics have the
development studies funded by the sponsor because there is no other entity who is likely to
conduct the necessary studies to determine the safety/effectiveness (drug/biological/device) or
AV/CV/CU (diagnostic). If these studies have appropriate trial designs for the intended uses and
the data is analyzed consistent with prospectively established analysis plans, then these studies
can be considered appropriate for coverage review. It is imperative for our company and others
to maintain the highest quality of evidence by supporting such studies to ensure that patients
and physicians have access to high quality data. We would also maintain that although many of
the studies were funded by Pacific Edge, there were many well respected thought leaders in the
field that participated in the design and execution of these studies to prove the value of these
tests for their patients, including Medicare patients. All published data was subject to peer review
and external editor questions that is designed to confirm the validity of the data. Finally, Novitas
does not mention in its review that several of our recent, most powerful real-world evidence for
the clinical utility of Cxbladder tests were done with no company support. Specifically, for
Cxbladder Triage in Davidson et al (2019 and 2021)(14, 15) and for Cxbladder Monitor in Li et al
(2023)(8) were all conducted completed independently of Pacific Edge with no financial support
and no provision of testing resources by the company.
6) Short follow up
Another criticism of the data supporting the use of Cxbladder tests was the short follow up time.
The suite of Cxbladder tests address a relative short-term clinical question—when patients
present with hematuria, can the tests identify patients with such low risk of bladder cancer that
more invasive testing can be avoided at that time. The Cxbladder tests are not intended for
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treatment predictive or prognostic uses. Foundationally, this means that they are designed to
inform an immediate decision regarding whether invasive procedures, e.g., cystoscopy, CT
Urogram, ureteroscopy that are mandated by the guidelines can be safely omitted or not for a
defined patient population. As they are neither predictive nor prognostic tests, they are not
designed to assess the risk of developing cancers in the future. Therefore, the follow-up included
in each study is appropriate for the intended clinical use.
In the case of Triage and Detect tests, the intended clinical use is for patients presenting with
primary or recurrent microhematuria. In the clinical application of these tests, the risk
stratification can either determine that the patient has a “Low Probability of UC” (Cxbladder
Triage report; see Appendix) or “Normal gene expression score” (Cxbladder Detect report; see
Appendix). In each case such a report enables the physician and patient to safely defer a full
evaluation for Urothelial cancer if they choose to do so. A “not negative” Cxbladder Triage result
of “Standard clinical workup” is an indication to follow standard of care. A Cxbladder Detect result
of “high gene expression score” is a higher likelihood of disease with a recommendation to follow
AUA guidelines evaluation steps and initiate a full workup. In AUA guidelines, the
recommendation of low-risk patients with hematuria would be to bring them back at 6-9 months
for a repeat urine analysis to assess if the hematuria persists. This means that the follow up
provided in our studies is appropriate for those patients.
7) Criti cism of low po sitive predicti ve valu e
In the draft LCD, Novitas/FCSO raise concerns about the PPV (Positive Predictive Value) for the
Cxbladder Triage and Detect tests. This concern reflects a misunderstanding of the intended use
of our tests as a rule out bladder cancer tests. The draft LCD states,
"These values are significant in that false test results, particularly false positives, can lead
to patient anxiety and distress among other procedural issues related to follow up for an
inaccurate result." (10)
(p.35)
As explained previously in the document, these tests were optimized for high sensitivity and high
NPV intended to help identify low risk patients that can be safely ruled out from a diagnosis of
bladder cancer in order to reduce the burden of unnecessary procedures on patients. The clinical
value of our tests in the hematuria evaluation population (Triage and Detect) is to identify those
patients that have the low likelihood of urothelial cancer and thus can defer further unnecessary
workup. If any of our tests are positive, the patient is to continue with the normal guidelines
recommended investigations for their hematuria. In the absence of such high NPV tests, all
patients presenting with hematuria would be subject to a full invasive workup even though the
prevalence of UC is low. Thus, if the value of the test is fully understood, no additional burden of
testing or morbidity from a positive test will be encountered.
Furthermore, all our marketing materials along with our scientific medical exchanges explain
clearly to physicians that point and provide recommended explanations for patients on the value
of the negative to reduce the anxiety that may be caused by a non-negative result. In addition,
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the evidentiary review included in the draft LCD did not include the fact that the guideline
directed standard of care has many more patients receiving a full workup, with many of those
patients being disease free, which translates to a much higher rate of anxiety and concern on the
part of the patients, as well as an increased financial burden on the system and patients alike(16).
8) Lack of data on patients with Inflammatory proces ses
The LCD review also notes that our studies excluded patients with inflammatory processes
(exclusion of active UTI, UT manipulations, etc.). We find this to be a lack of understanding of how
our test is developed and how it is being utilized by over 4,000 physicians in the marketplace. Our
Cxbladder Triage and Detect tests are indicated for patients that present with hematuria where
inflammatory or infectious causes have been ruled out and the clinical concern is focused on the
diagnosis of bladder cancer and the extensive evaluation required.
Cases with high inflammation can negatively impact the test results and may cause an
unwarranted false positive or false negative and therefore we exclude patients with conditions
that can be associated with inflammation (see below). We attempted to reduce the impact of
high inflammation samples by adding the 5
th
gene (CXCR2) which is an inflammatory gene to
reduce that risk(2). Although the inclusion of the 5
th
gene did reduce the impact of inflammation
considerably(2), along with many other minor changes we had made to the process, it did not
eliminate it completely. Therefore, in accordance with our commitment to the highest standards
and to maintain the best outcomes for our patients, we do not accept any commercial samples
from patients with any of these issues. In fact, here are our exclusions for our commercial
samples:
Exclusions for COLLECTION PROCESS: (see appendix)
• Visible blood
• Dip sticks cannot be left in urine cup before transferring to Cxbladder tube.
WAIT 6 WEEKS FROM:
• BCG (Bacillus Calmette Guérin) therapy
• Mitomycin therapy
• Radiation therapy
• Any bladder manipulation
WAIT 2 WEEKS FROM:
• Catheterization
• Cystoscopy
• Bladder infection or UTI (should finish antibiotics and wait 2 weeks)
• Trace leukocytes
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Thus, we are consistent in our inclusion and exclusion criteria for both our studies and our
commercial usage. We excluded those patients from our studies and from our commercial
acceptance criteria to provide the highest level of service for the other patients that would benefit
from our tests.
SUMMARY OF COM MENTS ON EVIDENTIA RY REVIEW
The comments above represent a response to the criticisms Novitas found in their evidentiary
review of the Cxbladder data. We believe that Novitas misinterpreted important aspects of our
published literature which led to incorrect conclusions about the strength of our data in the
clinical care of patients at risk or with confirmed bladder cancer. We respectfully suggest that the
criticisms should be re-examined in light of our comments and should not invalidate the clinical
data that has been developed for Cxbladder tests.
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Appendix - Summary of clinical evidence
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Appendix: – Cxbladder Test reports
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References:
1. Kavalieris L, O'Sullivan P, Frampton C, Guilford P, Darling D, Jacobson E, et al. Performance
Characteristics of a Multigene Urine Biomarker Test for Monitoring for Recurrent Urothelial
Carcinoma in a Multicenter Study. J Urol. 2017;197(6):1419-26. Epub 20161214. doi:
10.1016/j.juro.2016.12.010. PubMed PMID: 27986532.
2. O'Sullivan P, Sharples K, Dalphin M, Davidson P, Gilling P, Cambridge L, et al. A multigene
urine test for the detection and stratification of bladder cancer in patients presenting with
hematuria. J Urol. 2012;188(3):741-7. Epub 20120719. doi: 10.1016/j.juro.2012.05.003. PubMed
PMID: 22818138.
3. Lotan Y, OʼSullivan P, Raman JD, Shariat SF, Kavalieris L, Frampton C, et al. Clinical
comparison of noninvasive urine tests for ruling out recurrent urothelial carcinoma. Urol Oncol.
2017;35(8):531.e15-.e22. Epub 20170331. doi: 10.1016/j.urolonc.2017.03.008. PubMed PMID:
28366272.
4. Kavalieris L, O'Sullivan PJ, Suttie JM, Pownall BK, Gilling PJ, Chemasle C, et al. A segregation
index combining phenotypic (clinical characteristics) and genotypic (gene expression) biomarkers
from a urine sample to triage out patients presenting with hematuria who have a low probability
of urothelial carcinoma. BMC Urol. 2015;15:23. Epub 20150327. doi: 10.1186/s12894-015-0018-
5. PubMed PMID: 25888331; PubMed Central PMCID: PMC4391477.
5. Lotan Y, Raman JD, Konety B, Daneshmand S, Schroeck F, Shariat SF, et al. Urinary Analysis
of FGFR3 and TERT Gene Mutations Enhances Performance of Cxbladder Tests and Improves
Patient Risk Stratification. J Urol. 2023;209(4):762-72. Epub 20221230. doi:
10.1097/JU.0000000000003126. PubMed PMID: 36583640.
6. Woldu SL, Ng CK, Loo RK, Slezak JM, Jacobsen SJ, Tan WS, et al. Evaluation of the New
American Urological Association Guidelines Risk Classification for Hematuria. J Urol.
2021;205(5):1387-93. Epub 20201224. doi: 10.1097/ju.0000000000001550. PubMed PMID:
33356483.
7. Teoh JY, Kamat AM, Black PC, Grivas P, Shariat SF, Babjuk M. Recurrence mechanisms of
non-muscle-invasive bladder cancer - a clinical perspective. Nat Rev Urol. 2022;19(5):280-94.
Epub 20220331. doi: 10.1038/s41585-022-00578-1. PubMed PMID: 35361927.
8. Li KD, Chu CE, Patel M, Meng MV, Morgan TM, Porten SP. Cxbladder Monitor testing to
reduce cystoscopy frequency in patients with bladder cancer. Urol Oncol. 2023;41(7):326.e1-.e8.
Epub 20230302. doi: 10.1016/j.urolonc.2023.01.009. PubMed PMID: 36868882.
9. Holyoake A, O'Sullivan P, Pollock R, Best T, Watanabe J, Kajita Y, et al. Development of a
multiplex RNA urine test for the detection and stratification of transitional cell carcinoma of the
bladder. Clin Cancer Res. 2008;14(3):742-9. doi: 10.1158/1078-0432.ccr-07-1672. PubMed PMID:
18245534.
10. Proposed LCD - Genetic Testing for Oncology (DL39365). https://www.cms.gov/medicare-
coverage-database/view/lcd.aspx?lcdId=39667&ver=92023.
11. Rai BP, Luis Dominguez Escrig J, Vale L, Kuusk T, Capoun O, Soukup V, et al. Systematic
Review of the Incidence of and Risk Factors for Urothelial Cancers and Renal Cell Carcinoma
Among Patients with Haematuria. Eur Urol. 2022;82(2):182-92. Epub 20220405. doi:
10.1016/j.eururo.2022.03.027. PubMed PMID: 35393159.
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12. Edward M. Schaeffer RHL, Sandy Srinivas, Nabil, Adra YA, Daniel Barocas, Rhonda Bitting,
Alan Bryce, Brian Chapin, Heather, H. Cheng AVDA, Neil Desai, Tanya Dorff, James A. Eastham,
Thomas, A. Farrington Xin Gao SG, Thomas Guzzo, Joseph E. Ippolito, Michael, R. Kuettel JML,
Tamara Lotan, Rana R. McKay, Todd Morgan, George, Netto JMP-S, Robert Reiter,, et al. NCCN
Guidelines Version 4.2023 Prostate Cancer. 2023.
13. Neeraj Agarwal SA, Hilary Bagshaw, Michael, Baine KB, Marian, Birkeland NB, Maria Carlo,
Toni Choueiri, Brian Costello, Ithaar, Derweesh AD, Tanya Fischer, Yasser, Ged SG, John Gore,
Kristina Gregory, Andrew Gunn, Naomi Haas, Evelyn, Handel EH, Anne Holbrook, Michael
Johnson, Eric Jonasch, Payal Kapur,, et al. NCCN Guidelines Version 1.2024 Kidney Cancer. 2023.
14. Davidson PJ, McGeoch G, Shand B. Inclusion of a molecular marker of bladder cancer in a
clinical pathway for investigation of haematuria may reduce the need for cystoscopy. N Z Med J.
2019;132(1497):55-64. Epub 20190621. PubMed PMID: 31220066.
15. Davidson PJ, McGeoch G, Shand B. Assessment of a clinical pathway for investigation of
haematuria that reduces the need for cystoscopy. N Z Med J. 2020;133(1527):71-82. Epub
20201218. PubMed PMID: 33332329.
16. Barocas DA, Boorjian SA, Alvarez RD, Downs TM, Gross CP, Hamilton BD, et al.
Microhematuria: AUA/SUFU Guideline. J Urol. 2020;204(4):778-86. Epub 20200723. doi:
10.1097/ju.0000000000001297. PubMed PMID: 32698717.
---
Peter Meintjes
Pacific Edge Diagnostics USA
1214 Research Blvd #2000
Hummelstown, PA 17036
peter.meintjes@pelnz.com
September 5, 2023
Dr Patrick Mann
Novitas Solutions
2020 Technology Pkwy Suite 100
Mechanicsburg, PA 17050
Sent via email
RE: Summary of Comments on DL39365
Dear Dr Mann and Novitas Team,
Thank you for the opportunity to provide comments on DL39365. This letter supports,
augments and summarizes the feedback to Novitas concerning DL39365 “Genetic Testing for
Oncology”.
Pacific Edge is significantly (and adversely) impacted by the changes Novitas proposes to
introduce, both in the general sense of relying on certain third party databases to make
coverage decisions – of which only NCCN is applicable to MAAA tests like Cxbladder – and
in the specific sense regarding the conclusions Novitas reached after conducting an
evidentiary review resulting in a non-coverage determination for all of the Cxbladder products.
Since July 2020 Pacific Edge has relied on the unambiguous documented conclusion from
Novitas on A58529 “the CxBladder test is now covered utilizing the reasonable and necessary
guidelines”. Novitas made this decision following a review of the available evidence for the
assay and documented this decision in a public comment/response article that remains
available on the CMS website, and via e-mail correspondence to Pacific Edge officials in
response to questions. For more than two years this sufficed for appropriately guiding
coverage and Novitas supported Pacific Edge for positive coverage determinations for
Medicare Advantage appeals on this basis. When A58529 was retired, Novitas advised Pacific
Edge by email that:
“The Review and Comment documents should not be used to determine coverage. The Medicare
Advantage plan should be using LCDs and/or LCA for coverage determinations. Since 0012M and 0013M
is listed in A58917; Billing and Coding: Molecular Pathology and Genetic Testing, that is the article
that should be referenced in determining coverage.”
A58917 continues to appropriately guide coverage of Cxbladder tests, such that for more than
three years, Medicare patients have benefitted from the improvements that Cxbladder offers
to the standard of care in urology. In particular, Medicare patients that present to the physician
with blood in the urine were offered non-invasive Cxbladder testing to determine whether or
not cystoscopy and imaging (that have associated comorbidities) are necessary as part of
further evaluation. However, if finalized, the non-coverage determination in DL39365 would
eliminate Cxbladder and all non-invasive alternatives to cystoscopy for physicians to order for
their Medicare patients with hematuria – a dramatic removal of benefits that may result in
more patients receiving unnecessary invasive procedures such as cystoscopies and imaging
that have known patient morbidities, thus causing unnecessary harm to Medicare patients.
Simultaneously over the last three years Pacific Edge has continued to generate evidence
that supports the adoption of Cxbladder, and continues to a) confirm the performance
characteristics of existing tests while b) continuing to develop new tests, thus further
highlighting our commitment to clinical evidence generation and the urology community we
serve. This new evidence further supports the performance of the assays, and none of it
supports a decision to remove longstanding coverage. We are not aware of any new evidence
or adverse reporting event that Novitas can rely on to reverse the established, evidence-based
position it established in July 2020.
While Pacific Edge is concerned with the proposed LCD’s reliance on 3
rd
party databases,
which have been largely communicated by industry associations, e.g. ACLA and The Coalition
for 21
st
Century Medicine, we are most concerned by the content of the evidentiary review
undertaken for our Cxbladder products. Some of the Novitas criticisms indeed have merit –
before standardizing our commercial approach, there were occasions where Pacific Edge was
ambiguous about which product was the target of the study and some patient cohorts were
used to establish the AV and CV on multiple related products. However, this has been clarified
through more recent publications (see Appendix in our Medical Rebuttal) and with respect to
each product, the necessary requirements for analytical validation and clinical validation have
been either peer-reviewed or were submitted to other clinical certification bodies including
CLIA and New York State, and the appropriate patient population and use of our tests is
articulated in our Test Request Form, while the correct interpretation of results is clearly
outlined on our Test Results. These points are all noted in detail in our medical rebuttal.
In the Novitas review there are substantial misunderstandings regarding the appropriate use
of our tests, the appropriate patient population in which to use them and the applicable
standard of care. The misunderstandings appear to have driven Novitas to the conclusion that
our tests do not add value and have been described as ‘not medically reasonable and
necessary’. In response, our Medical Affairs Team prepared a detailed rebuttal in which we
explain in detail why Novitas should reconsider its position, as the reframing of our peer-
reviewed publications in the context of the standard of care provide a consistent message that
Cxbladder is analytically valid, clinically valid and clinically useful for urologists.
The physicians that use our tests in clinical practice have echoed these sentiments; indeed,
more than 20 plan to provide feedback in support of the Cxbladder tests, because they also
believe the evidence supporting the tests is sufficient to support continued patient access. All
of the largest associations in urology – AUA, LUGPA and AACU – have submitted comments
separately regarding this LCD to you, and more than a dozen key opinion leaders have
independently co-authored an opinion piece, expected to be published in an appropriate
journal at the conclusion of this process.
Regarding the appropriateness of relying solely on NCCN to make Medicare coverage
decisions for molecular algorithmic tests, Pacific Edge notes two points. The first is that pre-
emptive non-coverage for tests not supported with at least a 2a rating in the NCCN guidelines
(or higher) appears to be a re-definition of ‘medically reasonable and necessary’. NCCN
guidelines aim to develop a consensus of the standard of care – a definition that far
supersedes that of ‘medically reasonable and necessary’. The current reliance on NCCN
substitutes a higher standard, i.e. ‘consensus standard of care’ for the requirements of the
Social Securities Act defined as ‘medically reasonable and necessary’. The second point is
that this leaves tests with 2b recommendations non-covered, even if such assays have 50-
85% support from the guidelines committee. We urge Novitas to reconsider whether NCCN
2b recommendations should at a minimum not be automatically non-covered, allowing
Medicare beneficiaries continued access to the tests. This point is significant, as Cxbladder
Monitor peer-reviewed evidence was used in the determination of an NCCN 2b
recommendation for urinary biomarkers and consequently carries an NCCN 2b
recommendation by name.
As a diagnostic testing provider, Pacific Edge is both patient-centric and value-based in its
approach to addressing unmet clinical needs. As the average age of patients presenting with
hematuria is ~73 years old (American Urological Association), hematuria patients are majority
Medicare patients, and a primary consideration in everything that we do. Consequently, a
small number of patients have connected with us as we prepared our written comments and
have also sent those comments to you. Pacific Edge also understands that BCAN – a patient
advocacy organization well known for keeping out of medical policy discussion – has also
submitted comments. They too recognize the impact of the test on Medicare beneficiaries.
While separate from clinical evidence considerations, value-based considerations are
important for the healthcare system as a whole. The Medicare allowable for Cxbladder tests
is $760/test and a recently developed budget impact model (abstract accepted at the WSAUA
conference on 10/1-5, 2023) highlights a saving of >$500 per patient for a Cxbladder Detect
clinical pathway when compared to the standard of care pathway. The combination of clinical
utility and economic utility provides an excellent example of value-based care regarding how
new technologies can benefit patients, physicians and payers alike.
Pacific Edge remains committed to contextualizing the clinical value of Cxbladder for Novitas,
CMS or any other payor, and providing the peer-reviewed evidence to support our claims. I
am personally available to discuss at any time, have members of my team engage with the
Medical Affairs Team at Novitas or assist with assembling independent urology experts from
among our customer base.
Respectfully,
Peter Meintjes, PhD
Chief Executive Officer
Pacific Edge
+1 (203) 947 2772
Peter.meintjes@pelnz.com
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