Response to Comments: MolDX: Molecular Biomarkers to Risk-Stratify Patients at Increased Risk for Prostate Cancer

The following comments were submitted to Palmetto GBA, CGS, WPS, Noridian, and received from multiple stakeholders:

1. Clarify the tests within the scope of this policy
2. Reconsider the restriction regarding providers who can order the molecular biomarker tests
3. Reconsider the requirement of a PSA value of <10 ng/mL
4. Clarify the requirement for a repeat PSA, particularly in cases of a previous negative biopsy
5. Reconsider the restriction regarding the performance of additional biomarker tests
6. Reconsider the requirement for shared decision making

1. Clarify the tests within the scope of this policy
Tests within the scope of this policy include molecular (DNA/RNA based) biomarkers to risk-stratify patients at increased risk for prostate cancer. As such, we revised the title to specify ‘molecular’ biomarkers. Moreover, in the Summary of Evidence, we separated the discussion of molecular and non-molecular biomarkers with similar intended uses. Further, in the Analysis of Evidence, we include the following statements for additional clarity - The reference to specific biomarkers in this document does not imply coverage by MolDX®. Further, this policy is restricted in scope to molecular biomarkers only; therefore, non-molecular biomarkers for the same intended use, though not covered by this policy, may meet coverage criteria of other local coverage determinations. Finally, the associated Billing and Coding Article identifies tests that have met the coverage criteria of this policy.

2. Reconsider the restriction regarding providers who can order the molecular biomarker tests
First, some comments have likened biomarkers that risk-stratify patients at increased risk for prostate cancer to prostate specific antigen (PSA). As a result, some of the comments received suggest that any physician (as well as other primary care providers) should be able to order such a biomarker test. However, this is not an appropriate comparison. The PSA is a screening test and should not be likened to the molecular biomarker tests covered by this policy. These molecular biomarker tests are meant to be performed as follow-up to the PSA and are intended for beneficiaries who are candidates for prostate biopsy or repeat prostate biopsy.

As stated in the National Comprehensive Cancer Network® (NCCN) guidelines, “When a patient meets the standards for biopsy, sometimes the patient and physicians wish to further define the risk of cancer before proceeding to biopsy with its associated risks.”¹ This is the role served by biomarkers, but not in isolation; rather, biomarkers should be considered in combination with other variables including risk calculators, imaging, and pre-existing risk factors.

A systematic review found that prostate biomarker tests, even when combined with a pre-existing multivariable clinical risk calculator such as the Prostate Cancer Prevention Trial (PCPT) or the European Randomized Screening for Prostate Cancer (EPSRC) risk calculator, can still miss 5% to 10% of clinically significant cancers.³ Thus, a negative biomarker test must still be assessed within the appropriate risk-based context in order to provide enough confidence to safely forgo a prostate biopsy, and many higher-risk patients may still require additional tests such as multiparametric MRI (mpMRI) prior to a definitive decision on whether to biopsy. The authors concluded that “incorporating the newer prostate biomarkers and mpMRI into predictive algorithms like the PCPT and EPSRC risk calculators is likely necessary when deciding whether a patient can forego prostate biopsy.”³ They also caution against using biomarker tests in a binary fashion and note that urologists will need to decide how to use these tests to determine probability of cancer within the context of the pre-existing risk predictors, the patient’s ethnicity, life expectancy and quality-of-life goals, and cost.³

Similarly, the NCCN guidelines state that no biomarker test can be recommended over any other at this time and that the optimal order of combining biomarker tests with imaging is unknown.¹ Moreover, questions remain regarding how to interpret results of multiple tests in individual patients, particularly when results are contradictory.¹ The guidelines also do not recommend the use of a single parameter (such as a risk calculator) to determine whether a biopsy is indicated; rather, they encourage a multi-faceted approach that includes clinical judgment and patient preferences. They also cite several recent studies suggesting that biomarker testing performed in parallel with conditional MRI may be an efficient and effective way to assess those with a persistently elevated PSA. Finally, they caution that biomarker tests can be complex and should be interpreted carefully, and with referral to a specialist.¹

Primary care physicians may not have the relevant expertise to choose among the various available biomarker tests and to interpret and assess the results of the biomarker test within the multivariable clinical framework underlying the patient’s risk for cancer. Primary care physicians also do not make the determination about whether (or not) to biopsy, nor are they adequately equipped to provide nuanced alternative management options along with a comprehensive assessment and discussion of their associated risks and benefits. For example, in the case of a high or rising PSA, the patient may still benefit from referral for a MRI, a decision typically made by a urologist. Therefore, the choice of the most appropriate molecular biomarker to order and the interpretation of results belong to physician specialists in the management of prostate cancer. As stated in the NCCN guidelines “a decision to perform a biopsy should not be based on a PSA cut-point alone, but should incorporate other important clinical variables including age, family history, PSA kinetics, ancestry, health status, and patient preference, as well as results of multiparametric MRI and/or biomarker tests.”¹
Therefore, the specialist requirement is rooted in clinical evidence and in best practices. On the contrary, there is not an evidence base for the use of these tests by primary care physicians. Outcomes-based literature supporting the routine use of molecular prostate biomarker tests by primary care providers may become available in the future. As such, this contractor will continue to monitor the evidence and may reassess coverage criteria accordingly.

Finally, as we are also concerned with access to care, we have added a provision to the policy allowing for an exception to the physician specialist requirement when access to such specialists is significantly limited.

3. Reconsider the requirement of a PSA value of <10 ng/mL
First, the PSA level correlates with the risk of prostate cancer and the higher above the median PSA (for a given age group), the higher the risk for prostate cancer and aggressive prostate cancer. As noted in the NCCN guidelines, “Total PSA levels >10 ng/mL confer a >67% likelihood of prostate cancer.”¹ They further recommend that patients with a persistent and significant increase in PSA should be encouraged to undergo biopsy. As such, unless otherwise contraindicated, patients with a PSA > 10 ng/mL should be encouraged to undergo biopsy, regardless of the results of biomarker testing. This includes men being considered for repeat biopsy.

Additionally, patients with a persistent and significant increase in PSA should also be considered for multiparametric MRI (mpMRI), which increases the detection of clinically significant, higher-risk disease and can inform the decision to perform an initial or a repeat biopsy.^1,2 A negative MRI does not exclude the possibility of cancer, and biomarkers may be useful in this setting. However, an unequivocally positive finding on mpMRI obviates the need for a biomarker test.

Finally, some molecular biomarker tests are not validated in patients with PSA levels >10 ng/mL.¹ Therefore, the performance of these tests in this very high-risk population is unknown.

We have included this information in the Summary of Evidence and Rationale for Determination and have added a provision to the Coverage Criteria allowing a molecular biomarker test to be performed in men with PSA levels>10 ng/mL who are being considered for repeat biopsy IF appropriate according to consensus guidelines and according to the following: the specific biomarker test has been validated in men with PSA levels>10 ng/mL AND the multiparametric MRI (mpMRI) is negative, if performed.

4. Clarify the requirement for a repeat PSA, particularly in cases of a previous negative biopsy
First, as discussed in the Summary of Evidence, PSA levels can fluctuate for a number of reasons. As such, the PSA should be checked more than once prior to the initial biopsy. There was no disagreement from stakeholders on this point.

However, there was some confusion regarding the requirement for a repeat PSA prior to a repeat biopsy, particularly after a negative biopsy, with some stakeholders commenting that it is not necessary to perform a repeat PSA after a negative biopsy.

Regarding the requirement to repeat the PSA when considering a repeat biopsy, we maintain that if there is enough concern for the possibility of cancer to warrant consideration of a repeat biopsy (even after a negative initial biopsy), then a repeat PSA (and/or digital rectal exam (DRE) should be performed. As such, Coverage Criterion #3 states that “Patients under consideration for a repeat biopsy have first undergone repeat PSA and/or DRE testing.” This is in accordance with the most recent NCCN guidelines that state “It is well known that a negative prostate biopsy does not preclude a diagnosis of prostate cancer on subsequent biopsy. Those patients with negative prostate biopsies should be followed with DRE and PSA with consideration of multiparametric MRI and biomarker tests that improve the specificity of PSA testing.”¹ The guidelines also specify that in the case of a prior negative biopsy, repeat PSA and DRE are recommended at 6- to 24-month intervals with consideration of repeat biopsy based on results.¹

Finally, the policy does not specify when a repeat PSA or DRE must be performed relative to the biomarker test but does state that patients under consideration for a repeat biopsy have first undergone repeat PSA and/or DRE testing as recommended by consensus guidelines.

5. Reconsider the restriction regarding the performance of additional biomarker tests
We have clarified the two intended uses for molecular biomarkers when risk-stratifying patients at increased risk for prostate cancer, as discussed in this policy. Specifically, we note that a non- or minimally invasive biomarker test performed to influence the decision to biopsy (pre-biopsy) is NOT the same clinical indication as a biomarker test performed to improve specificity in the post-biopsy setting. Moreover, we agree that the use of complementary biomarkers may, in some instances, be used for the same clinical indication. As such, we have added the following clarifying language - For a given clinical indication (i.e., pre- OR post-biopsy) only one molecular biomarker may be performed UNLESS a second test, meeting all the criteria established herein, is reasonable and necessary as an adjunct to the first test, according to criteria established in this policy. Further, only one molecular biomarker test may be performed per date of service.

We also expect the test to be performed according to its intended use in the intended patient population for which the test was developed and validated.

6. Reconsider the requirement for shared decision making
Shared decision-making between physician and patient is a basic tenet of medical care and is not unique to prostate cancer. However, in prostate cancer, current screening guidelines from the US Preventive Task Force (USPSTF) and American Urological Association (AUA) have specifically called for shared decision-making regarding PSA screening (and biopsy) considerations. This is a result of the controversy and ambiguity surrounding the risk/benefit profile of prostate biopsy in men with rising or elevated PSA levels. As such, this contractor upholds the expectation for shared decision-making. However, agree that this requirement can be broadly defined and applied. Moreover, it is not intended to be an administrative burden. Therefore, we have maintained - but tempered - the language in the policy referencing shared decision-making.

References:

1. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection Version 2.2021 – July 14, 2021.
2. Sidaway P. MRI, TRUS or both? Nature Reviews Clinical Oncology. 2020;17(5):274.
3. Chang EK, Gadzinski AJ, Nyame YA. Blood and urine biomarkers in prostate cancer: Are we ready for reflex testing in men with an elevated prostate-specific antigen? Asian J Urol. 2021;8(4):343-353.

The following comment was submitted to Palmetto GBA, CGS, Noridian, and WPS:

Labcorp supports Medicare coverage for tests for risk-stratification for prostate cancer when those tests have shown evidence of clinical utility and when the tests are performed with evidence of shared decision making between the patient and provider.

We do take exception to one of the required provisions in the draft LCD which does not appear in the draft Billing and Coding Article: “The test is ordered by a physician specialist in the management of prostate cancer, such as a urologist or oncologist.”
We urge the contractor to remove this provision from the final LCD.

We have searched the medical literature and can find no evidence to support this provision. Indeed, the tests in this category are a follow-on test to a PSA. Most of the PSA tests are ordered and interpreted by primary care physicians. Primary care physicians are skilled in shared medical decision making with the patient and there is no evidence in the literature (no evidence base) to require that the follow-on test to the PSA could not be equally handled by them.

Thank you again for the opportunity to review and comment on this proposed policy. We are happy to be of assistance in providing additional clinical or other information to assist the MolDX Program with this draft LCD.

Thank you for your thoughtful comments and support of this policy. We have addressed your comments in Response 1 listed above.

The following comment was submitted to CGS:

I am writing to you and your colleagues to thank you for addressing this very important issue. Current early detection techniques that rely solely on serum Prostate Specific Antigen levels to guide specialist referral and biopsy of the prostate often result in too many unnecessary benign biopsies and in the discovery of indolent cancers. The medical community at large needs to do a better job in the early detection of clinically significant prostate cancer, and use of “reflex” biomarkers can make achieving that goal possible. Your coverage guidelines on page 3 of this proposed LCD will be very helpful to our patients and the medical community at large. I would, however, like to comment on two conditions that I think can be improved and clarified.

Condition #1: I am concerned that you have capped the Prostate Specific Antigen level at 10 ng/mL. While a PSA threshold of 10 may be a valid ceiling when considering additional tests for men who are biopsy-naive, the population of men being considered for repeat biopsy of the prostate will often have a rising Prostate Specific Antigen above this level.

Condition #7: I am concerned that restricting use of these tests to a “physician specialist” such as a urologist or oncologist is too limiting. The large majority of Prostate Specific Antigen tests in the USA are ordered by primary care physicians. If PCPs had access to these tests, patient anxiety and unnecessary referral to specialists for evaluation will be avoided, thus significantly improving the overall efficiency of PSA-based early detection of prostate cancer.

Thank you for taking these suggestions under consideration. If I may provide any additional comments for clarification please let me know.

Thank you for your thoughtful comments and support of this policy. We have addressed your comments in Response 1 listed above.

The following comment was submitted to CGS:

I would like you to consider medical coverage and reimbursement for risk stratification for patients at increased risk for prostate cancer.

I commonly not only diagnose prostate cancer but ultimately have to treat patients who are suffering from the sequelae of prostate cancer disease.

Oftentimes, the disease diagnosis has been delayed and treatment options are limited due to this disease progression.

One of the obstacles to care is inadequate reimbursement for risk stratification. In simplest terms, knowing who is at higher risk would significantly help providers diagnose and more effectively treat higher risk patients.

I sincerely hope you will consider medical coverage and reimbursement for risk stratification.

Thank you for your thoughtful comments and support of this policy. The scope of this policy includes molecular (DNA/RNA based) biomarkers to risk-stratify patients at increased risk for prostate cancer or high-grade cancer, not to risk-stratify patients with a pre-existing diagnosis of prostate cancer.

The following comment was submitted to Palmetto GBA:

I have reviewed the LCD proposal regarding Confirm MDx testing. It is indicated for a negative prostate biopsy or men with HG PIN or ASAP as you point out. However, the PSA does not need to be tested prior to sending the biopsy for methylation status. The PSA should be checked more than once prior to the initial biopsy but NOT after a negative biopsy. Also, the PSA will be falsely elevated from a biopsy for about one month. The NCCN guidelines do not suggest a repeat PSA test between a negative prostate biopsy and Confirm MDx testing. An additional PSA test would add not further utility to the algorithm.

Thank you for your consideration of this modification.

Thank you for your thoughtful comments and support of this policy. We have addressed your comments in Response 1 listed above.

The following comment was submitted to Palmetto GBA:

I applaud MolDX for its efforts to develop a comprehensive LCD that addresses molecular diagnostic tests that can be used to aid in patient risk stratification. However, some of the proposed coverage requirements of the LCD do not reflect the currently accepted standard of care for the early detection of prostate cancer.

• I recommend eliminating the requirement that only a specialist (oncologist or urologist) can order biomarker tests. Nearly 90% of PSA tests ordered are by family practice/internal medicine doctors and therefore having a requirement that to order a confirmatory molecular marker requires a specialty of urology or oncology does not support the current protocol. When these primary physicians discover an elevated blood glucose they order an A1c hemoglobin, not proceed directly to insulin or metformin. When a PSA is elevated and a concern for prostate cancer exists, we should not proceed directly to biopsy but in select cases order a marker that helps identify men who harbor significant cancers and would benefit from a biopsy. Many primary care providers are perfectly capable of ordering a molecular marker and making a decision for urologic referral. I fully support additional testing to risk stratify patients prior to referral to a urologist. It’s also my understanding that the NCCN guidelines specifically state ‘Provider’ because the intention is not to place limitations on who can order a test.
• Bullet point under Condition #2: “Patients under consideration for a repeat biopsy have first undergone repeat PSA and/or DRE testing.”

Any patient with a negative biopsy has already had >1 PSA test and/or undergone DRE prior to the cancer-negative biopsy, so it’s not clear to me why this is a condition for coverage. Is there as specific way this information should be documented? The real issue is quite simple, we biopsy because we feel there is risk of having prostate cancer and a negative biopsy does not completely eliminate that risk!

• Does MolDX intend to require repeat PSA/DRE after the prior cancer-negative biopsy, and before ordering a biomarker test? If yes, this would create unnecessary office visits and repeat testing, and also block optimal use of biomarker tests in my practice.
• If my patient already has repeat PSA and/or DRE results and a negative biopsy, no additional information is gained by another PSA test or DRE, since these methods triggered the initial biopsy. I do use PSA to monitor these patients, but that testing would occur at least 6 months later.
• If I am concerned about missed cancer, the ideal time to order a biomarker test is upon receipt of negative biopsy results (or shortly thereafter) provided that I have discussed biomarker testing with my patient. ConfirmMDx can be run immediately on cancer-negative biopsy tissue, and other tests such as ExoDx and 4Kscore can be performed as soon as the prostate has recovered from biopsy. Many of my patients experience tremendous anxiety before and after a cancer-negative biopsy, and biomarker results can help decrease uncertainty (especially if test results are negative /low-risk).
• We and others have development algorithms for when to biopsy and when to consider re-biopsy. Examples are AUA, EAU, NCCN, and other organizations. We have development a simple patient and physician algorithm.
• These organizations have focused on the concerns raised over a decade ago by the USPTF and developed sound pathways involving molecular markers. We do not want to retreat from these positive developments.
• Coverage condition #2 states that biomarker tests can be ordered for men with prior atypical small acinar proliferation (ASAP). Does MolDX consider ASAP to be synonymous with atypia suspicious for cancer? If so, please specify in the LCD to avoid confusion. ASAP/Atypia determinations can be subjective and indicate elevated risk, so patients are likely to benefit from biomarker testing.
• Please consider removing the PSA < 10 ng/mL requirement for the repeat biopsy setting. If I have a patient with one or more negative biopsies who has had stable PSA levels above 10 ng/mL, I would order a biomarker test to decrease uncertainty before recommending another biopsy. The 10 ng/mL threshold applies to biopsy naïve men who are being PSA screened.

The billing and coding article has some additional coverage conditions not found in the LCD:

• Why are different coverage conditions listed on two separate documents? It seems that this is asking for confusion. I would recommend that all coverage conditions be listed in the LCD.
• What is the rationale for disallowing more than one biomarker test for the same clinical indication? Several of these tests provide complementary information (i.e., different biomarkers and/or specimen types). I agree that ordering several biomarker tests at the same time is not appropriate, but this condition prevents me obtaining additional information based on my medical judgement.
• “Once it is determined that the test is medically reasonable” seems to be related to timing (i.e., when the treating physician can or cannot order a test). Please confirm that this is not the case per my comments on Coverage Condition 2.
• The term “shared decision making” generally applies to discussion of potential risks and benefits before a patient decides to be PSA screened. Please consider removing this wording. I cannot imagine a scenario where a patient is biopsied without first being informed. Shared decision making has been evaluated in this and other disease. The primary care physician will obtain a cholesterol on a patient with shared decision making, that occurs after an abnormal test and before instituting medications. We are doing that with molecular markers.

Thank you for your thoughtful comments and support of this policy. We have addressed your comments in Response 1 listed above.

Additionally, we agree that language concerning coverage belongs in the policy and not the Billing and Coding Article. We have revised those documents as appropriate.

The following comment was submitted to Palmetto GBA:

We appreciate the opportunity to submit comments and questions regarding this proposed local coverage determination (LCD) for biomarker testing to risk-stratify men at increased risk for prostate cancer. At Freenome, our mission is to develop tools to empower everyone to prevent, detect, and treat their disease. To this end, Freenome is developing artificial intelligence/machine learning-enabled multiomics blood tests for a variety of clinical applications, including those described in this LCD. We support this LCD to make these tests available to Medicare beneficiaries to help identify men who may benefit from a prostate biopsy.

Regarding the proposed coverage criteria (numbers listed below reflect numbering under “Coverage Indications, Limitations, and/or Medical Necessity” in the LCD), we request MolDx clarify the following:

1. The beneficiary is a candidate for prostate biopsy or repeat biopsy, according to a consensus guideline [i.e., National Comprehensive Cancer Network (NCCN)].

Is NCCN the only consensus guideline that is acceptable? For example, will consensus
guidelines from other organizations (e.g., ASCO and AUA) be acceptable as well?

5. If the test relies on an algorithm (which may range in complexity from a threshold determination of a single numeric value to a complex mathematical or computational function), the algorithm must be validated in a cohort that is not a development cohort for the algorithm.

Cross-validation is a commonly used technique in which a single cohort is iteratively divided into “training” and “test” subsets, with performance evaluation based only on the test set samples (which are not used for training). Cross-validation permits unbiased estimation of performance, but the full collection of samples used may be thought of as a single “development cohort.” We understand the guidance above to preclude use of cross-validation, and to require instead a fully independent test cohort for validation. Are we correctly interpreting your guidance?

7. The test is ordered by a physician specialist in the management of prostate cancer, such as a urologist or oncologist.

Patients with PSAs in the range described in this LCD generally are managed by non-specialists. We therefore recommend that MolDX allow non-specialists to order such MolDX-approved tests, but the non-specialist should have arrangements for referral to specialists for cases with positive results.
We sincerely commend MolDx for creating a clear and consistent path for coverage of biomarker tests for risk stratification of patients at increased risk of prostate cancer, and look forward to working with MolDx now and in the future. Freenome believes providing access to safe and effective prostate cancer risk stratification options will save and improve the lives of millions of Medicare beneficiaries, reduce burdens across the entire spectrum of stakeholders, and facilitate innovation. Thank you for considering our comments.

Thank you for your thoughtful comments and support of this policy. We have addressed your comments in Response 1 listed above.

Additionally, NCCN is not the only consensus guideline that is acceptable, which is why it was listed as ‘i.e., NCCN’ in the policy. However, for added clarity, we have now included ASCO® and the AUA as additional examples of acceptable consensus guidelines.

Finally, for a complete algorithm validation, we require an independent test cohort (beyond that of the training/development cohort).

The following comment was submitted to Palmetto GBA:

I am writing in regard to the proposed LCD addressing biomarkers for risk-stratification of patients at increased risk for prostate cancer. It is well-established that the diagnostic evaluation for prostate cancer remains an uncertain and imprecise practice, exposing a majority of patients to unnecessary procedures with inherent risks and side effects. As a clinician focused on the diagnosis and management of urologic cancers, this reality is difficult to accept in light of the currently available tools positioned to improve upon this practice.

At the same time, as an academician and researcher focused on prostate cancer biomarkers, I acknowledge the limitations of available clinical data – with analyses at times performed in heterogeneous or poorly-defined patient populations, in some cases including men that are unlikely benefit from biomarker testing. For this reason, our team has performed contemporary analyses of biomarkers with a careful focus on appropriate methodology and transparent reporting as set forth by expert guidelines.^1-3

We recently reviewed the published literature describing use of prostate cancer biomarkers in the proposed pre-biopsy setting.⁴ Limitations notwithstanding, currently available biomarkers have consistently demonstrated substantial improvements in accuracy relative to PSA- and clinical risk factor-based approaches, resulting in improved clinical outcomes. Furthermore, cost-effectiveness analyses have demonstrated superior economic value with pre-biopsy use of biomarkers as compared to current and alternative approaches.^5,6 Ultimately, the literature supports substantial improvements in the patient experience, clinical outcomes, and cost-effectiveness with pre-biopsy use of biomarker testing.

Altogether, biomarker testing appears to provide both clinical and economic value to a clinical pathway in great need of improvement. Providing coverage of these tests will enable clinicians to provide patients with the best care available, while at the same time empowering the research community to produce the thoughtfully designed studies needed to optimize the effectiveness of testing moving forward. For these reasons, I believe that providing coverage of prostate cancer biomarker tests is both appropriate and critical to achieving our shared goal of minimizing the harm caused by prostate cancer.

Thank you for your time and consideration.

References were received and reviewed.

Thank you for your thoughtful comments and support of this policy.

The following comment was submitted to Palmetto GBA:

On behalf of MDxHealth we are writing regarding MolDX: Biomarkers to Risk-Stratify Patients at Increased Risk for Prostate Cancer. Thank you for bringing this coverage policy forward and for considering our comments.

We appreciate the opportunity to propose certain clarifications to coverage conditions set forth in the current draft LCD. In addition to our detailed discussion below, we have attached a redlined draft that clearly identifies proposed suggestions and clarifications to the existing draft text.

We ask that the LCD distinguish between tests used prior to biopsy and tests performed on biopsy tissue to obtain additional clinical information.

We recommend that MolDX model coverage language for this LCD on the coverage language it used in MolDX: Molecular Testing for Solid Organ Allograft Rejection LCD. The Solid Organ Allograft testing LCD recognized that there are two very distinct kinds of tests.

1. Non-invasive tests to inform clinical management and potentially obviate the need for a biopsy and
2. Tests run on tissue to obtain additional information from molecular features that is not evident in histopathological analysis. These tests can potentially obviate the need for a repeat biopsy, but they do so by gathering additional information from a first biopsy.

We believe that the same paradigm applies to tests of prostate tissue, including ConfirmMDx for Prostate Cancer, and we encourage MolDX to apply it in this LCD as well.

Prior to a biopsy, clinicians and patients rely on noninvasively obtained biomarkers suggestive of prostate cancer, such as PSA, which has neither a high sensitivity nor specificity when moderately elevated. Some biomarker tests, such as SelectMDx, are intended to improve risk stratification of men with elevated PSA prior to pursuing a prostate biopsy, thereby helping to identify men most likely to benefit from and those who could avoid biopsy.

Prostate biopsy remains the definitive method for prostate cancer diagnosis. However, due to sampling limitations a negative biopsy does not rule out the presence of cancer, with up to 30% of men receiving an erroneous (i.e., false negative) result.¹ The fear that cancer has been missed oftentimes leads to repeat biopsies, which increase healthcare costs and expose men to potential morbidities, including post-biopsy infection and sepsis.² Importantly, the indicator(s) for initial prostate biopsy (e.g., elevated serum PSA level, suspicious DRE findings) typically persist after a cancer-negative biopsy, so these patients remain at elevated risk. If the clinician's prebiopsy suspicion for cancer is sufficiently high, the clinician may counsel his or her patient that, given the low NPV of the biopsy procedure, the patient will remain a candidate for repeat biopsy notwithstanding the absence of cancer diagnosis on the initial biopsy.

ConfirmMDx was specifically designed to address this repeat biopsy 'dilemma', and has been covered by Medicare since 2014.³ The test detects cancer-associated DNA methylation in histologically benign prostate tissue, and helps determine the probability that prostate cancer will be found on a repeat biopsy. ConfirmMDx provides clinically actionable information that is orthogonal to other methods and has been validated for predicting repeat biopsy outcome in Caucasian and African American men with normal or suspicious DRE findings and across all PSA levels.⁴ ConfirmMDx also differs from other biomarker tests in that it provides information about the state of the prostate gland at the time of the negative biopsy (other tests cannot be performed until after the prostate has recovered from biopsy-induced trauma). A test such as ConfirmMDx is intended to provide additional information from a negative tissue biopsy to help clinicians assess the probability that prostate cancer is present, even if not evident in the biopsied tissue on histopathologic evaluation.

Regarding specific coverage conditions, we agree that tissue-based testing is appropriate to inform a repeat biopsy decision within 24 months after the tested tissue was obtained. However, we ask that it be clear in the LCD that ConfirmMDx can be used whenever a treating clinician wishes to obtain information from the biopsy that will inform patient management plans, including at the time of the initial biopsy (assuming it does not show cancer).

To reflect the foregoing concerns, we propose the following coverage language, in modification to proposed conditions 1 and 2:

There are two potential applications of biomarkers to risk-stratify patients at increased risk for prostate cancer:

1. A non-invasive or minimally invasive test, the results of which are obtained prior to a prostate biopsy to inform the decision as to whether or a patient may be a good candidate for a biopsy.
2. A test performed on prostate tissue when a biopsy does not clearly indicate
   malignancy on histopathologic examination.

Tests used for Indication are covered when all of the following conditions are met:

1. The beneficiary is a candidate for prostate biopsy or repeat prostate biopsy, according to a consensus guideline [i.e., National Comprehensive Cancer Network®(NCCN)].

a. For men 75 years of age -Prostate Specific Antigen (PSA) (or adjusted PSA in special populations, i.e., patients taking Salpha-reductase inhibitors) OR repeat PSA are >3 and
<10ng/mL AND/OR Digital Rectal Exam (DRE) findings are very suspicious for cancer
b. For men> 75 years of age - PSA (or adjusted PSA in special populations, i.e., patients taking 5alpha-reductase inhibitors) OR repeat PSA are :2:4 and <10ng/mL AND/OR DRE findings are very suspicious for cancer
c. Patients under consideration for a repeat biopsy have first undergone repeat PSA and/or DRE testing

Tests used/or Indication II are covered when all of the following conditions are met:

2. The beneficiary is a candidate for repeat prostate biopsy, according to a consensus guideline [i.e., National Comprehensive Cancer Network®(NCCN)].

a. The test is performed on prostate tissue within 24-months of its collection in the prior biopsy.
b. The test must provide additional information from the tissue sample as to whether prostate cancer may be present in spite of the previous negative or non-malignant but abnormal histopathology finding.

To accommodate this paradigm for coverage language, we also recommend modifying the billing and coding article to list covered tests for each indication and covered ICD-10 codes for each indication. For Indication II, we recommend adoption of ICD-10 codes contained in MolDX's existing LCD MolDX: ConfirmMDx Epigenetic Molecular Assay for the coverage of ConfirmMDx.

We ask that SelectMDx be listed as a covered test at the time of LCP finalization.

Based on the current language in the draft LCD, it appears that MolDX agrees with NCCN guidelines that it is reasonable to consider non-invasive tests to support decision making in men with moderately elevated PSA prior to undergoing an initial biopsy. Moreover, since retirement of the draft LCD, SelectMDx has been incorporated into NCCN guidelines as one potential test that can be used to inform this decision. NCCN's decision was based on the evidence that was available to MolDX as part of draft LCD. Given that all evidence supporting the use of SelectMDx published two or more years ago, we respectfully request that Palmetto GSA not require SelectMDx to re-submit into a technical assessment process following finalization of the LCD.

We also ask that the article clearly indicate which tests are covered so that it is clear to ordering providers, Medicare beneficiaries, and Medicare Advantage plans which tests are covered under the LCD. We ask that SelectMDx be added to this list of covered tests.

We ask that tests used prior to an initial biopsy be orderable by primary care providers.

Screening for prostate cancer is typically initiated by a primary care provider, who orders the initial PSA test and may refer the patient to a urologist based on the PSA result. While there is no doubt that a urologist or oncologist is the optimal clinician to manage a patient with known prostate cancer, the primary care provider may handle the initial evaluation, which includes not only PSA, but also tests that may be ordered as a follow-up to PSA. The patient population who has difficulty accessing specialty care to have a biopsy is also a population that is likely to benefit from non-invasive testing.

We ask for certain changes to facilitate technical compliance under the Coverage Article regarding medical record documentation and shared decision making

To submit appropriate claims for reimbursement under the proposed LCD (when final), in addition to confirming that the billed service is medically reasonable and necessary, the provider must also ensure that it complies with each element of the conditions to coverage enumerated in the applicable LCD and associated Local Coverage Article (LCA). In this regard, there are several requirements in the draft LCA that may be difficult if not impossible or impractical to document or confirm.

For example, in the draft LCA, proposed wording in the last condition to coverage starts as follows:

• Once it is determined that the test is medically reasonable and necessary in a beneficiary, the medical record must support the medical necessity for the test.

The lead in wording for this last coverage condition is somewhat duplicative and, as such, may be interpreted by a claims reviewer to require both (a) that the ordering clinician document in the medical record his or her determination of medical necessity for a covered service PRIOR to even ordering that covered service, this being in addition to (b) requiring that the medical record itself contain factors establishing medical necessity for the same service. Said another way, as written, the medical record would not only need to include the necessary facts, it must also include the clinician's decision that such facts satisfy the conditions to coverage for an as yet (not) ordered test. In practice, it would be highly irregular for a clinician to take the extra step to proactively document their "ability" to order a service prior to actually ordering it. Therefore, we respectfully request that the initial clause of the lead-in for this condition be removed, since the remaining language will ensure medical necessity for an ordered service, as follows:

The medical record must support the medical necessity for the test.

In addition, there are technical compliance hurdles implicated by the second clause of the last condition to coverage of the Billing Article, which requires "documented evidence of shared decision making between the patient and provider.” While we recognize and support the value of informed decision making in the screening of men for prostate cancer, we note that the term "Shared Decision Making" references the entirety of an extended, collaborative, and complex process that requires patient education, understanding and informed participation with the involvement of multiple clinicians and clinical interactions. In addition, we wish to emphasize that this is something that should likely precede the decision to pursue PSA screening for prostate cancer in the first place.

As we discuss below, prostate cancer screening is fraught with substantial uncertainties, including whether a patient is likely to benefit from treatment if prostate cancer is detected. As such, the critical issue that shared decision making is recommended to address is not the modality of prostate cancer detection that is used, but rather whether or not a man should even start down the road of prostate cancer screening with PSA screening and DRE in the first place. However, prostate cancer screening with PSA and DRE is a statutorily covered benefit, so we do not believe that a MAC has the authority to place additional coverage conditions around such testing. It is impractical [and unduly burdensome] — not only for an independent laboratory service provider but also for the ordering clinician — to verify and collect evidence of this extended, poorly defined and disparate process, which itself should commence prior to initiation of PSA screening. By introducing the requirement of shared decision making prior to further evaluation of an elevated PSA, MolDX is not alleviating the fundamental issues at stake in prostate cancer testing, but MolDX is introducing barriers to help mitigate many of the problems that can arise once a man starts down the road of prostate cancer screening.

In 2018, the USPSTF recommended that Informed Decision Making (IDM) occur with patients "before deciding whether to be screened," for prostate cancer⁵, recognizing that the American Cancer Society (ACS), the American Urologic Association (AUA) and other organizations had years earlier recommended Shared Decision Making (SOM). The American Cancer Society explicitly notes the importance of "information about the uncertainties, risks, and potential benefits of prostate cancer screening" in the decision making process as to whether or not to even pursue prostate cancer screening in the first place.⁶ Moreover, the American Cancer Society also notes that if a man is unable to make a decision, a healthcare provider should make this decision keeping in mind patient preferences and values. In a publication by the USPSTF Shared Decision-Making Workgroup posted on the USPSTF's website⁷, the work group notes that Shared Decision Making is a complex, multi-faceted process that "differs significantly" from informed consent and informed decision making, and may extend over many clinical interactions, such that, ''The initial discussion can represent the first step in the shared decision-making process; patients can then be encouraged to review additional information at home and further consider their preferences before making a final decision at a future visit" and further that:

"Because the evidence about shared decision making is limited and the patient-clinician partnership is complex, defining how any given interaction about screening and chemoprevention should transpire is impossible."⁸

In its guidelines for Early Detection of Prostate Cancer, the AUA strongly recommends that shared decision making occur before a man first commences screening for prostate cancer. Further, the AUA, in its 2015 White Paper on Shared Decision Making, recognizes that "there is no consensus on a unified approach toward implementing SDM techniques across the range of medical practice settings," and it points to this "lack of a universally accepted definition of the concept" of SDM as a key challenge limiting its implementation by clinicians.⁹

Based on the foregoing, we are concerned not only with the lack of clarity regarding what constitutes appropriate SDM and what documentation is needed to establish appropriate SDM, but also with the ability of the ordering clinician to obtain necessary documentation from the patient's caregivers who may have initiated or continued screening for the patient. Shared decision making is not a single well-defined procedure, but rather describes many different processes that may involve different steps and timelines sharing common inputs and goals. It often differs among patients, with providers having discussing information with patients as needed to achieve the goals of the decision-making process. Given that shared decision making is very heterogeneous, we are concerned that it is something that medical reviewers of records will have difficulty recognizing, even when it is documented.

Additionally, there are clear findings reported in multiple published studies concerning both the limited implementation of SDM in clinical practice and also disparate patient access to appropriate SDM in the prostate cancer screening diagnostic continuum. In a cross-sectional study of recent patterns in shared decision making for PSA testing of US men, the authors identified that, based on pre-established SDM criteria, "the proportion of men with recent PSA testing who reported full shared decision making was still relatively small. " And that "When full shared decision making was examined according to sociodemographic factors, it was significantly less common (50%) in men without a high school diploma relative to college graduates.”¹⁰ We wish to emphasize that this implies an issue that precedes PSA testing rather than an issue on how an elevated PSA should be addressed. By introducing a requirement of documented shared decision making prior to diagnostic prostate cancer testing that follows a PSA test, MolDX is not addressing the need for shared decision making prior to PSA testing. However, MolDX is implementing a barrier to helping clinicians and patients manage the uncertainties of an elevated PSA result. Moreover, MolDX is introducing a requirement that is not likely not to be well understood by the laboratories, ordering providers, or possibly even a MAC's own medical review staff.

Based on the foregoing, we respectfully request that reference to shared decision making not be included in the LCA or the LCD.

We ask for certain changes to facilitate technical compliance under the Coverage Article regarding ordering subsequent tests

Currently the coverage article gives as one of its additional criteria, the following:
The patient has not been previously tested using the same or similar biomarker tests from the same samples OR for the same clinical indication.

We recognize the intent of this language, but we are concerned that this language will create unanticipated problems analogous to the challenges created by the initial language of NCD 90.2, which limited coverage of an NGS test to once per patient per cancer. In hindsight, it appears that CMS made this coverage decision by generalizing a very focused evidence review to the universe of NGS testing in cancer, and CMS ultimately addressed this with NCD modification.

We believe that MolDX took a thoughtful approach to its LCD concerning transplant testing that avoids this potential pitfall. As such, we ask that MolDX track coverage language that relates to ordering more than one test in this LCA on the coverage language it used in MolDX: Molecular Testing for Solid Organ Allograft Rejection. The Solid Organ Allograft testing LCD recognized that there may be circumstances when ordering an additional subsequent biomarker test may be reasonable and necessary:
For a given patient encounter, only one molecular test for assessing allograft status may be performed UNLESS a second test, meeting all the criteria established herein, is reasonable and necessary as an adjunct to the first test.

We believe that a similar paradigm applies to biomarker tests useful in the diagnosis of prostate cancer, and we encourage MolDX to apply it in this LCD and article as well to cover another test or a repeat test if it meets the other coverage requirements in the LCD.

We greatly appreciate your time and attention. Thanks in advance for your consideration of these comments.

Redline Drafts of the Policy, Billing and Coding Article, and References were received and reviewed.

Thank you for your thoughtful comments and support of this policy. We have addressed some of your comments in Response 1 listed above.

Additionally -

• We have more clearly outlined the two intended uses of molecular biomarkers to risk-stratify patients at increased risk for prostate cancer.
• Any test not already covered by the policy will be subject to a technical assessment process following finalization of the policy.
• We have revised the language referencing the medical record, as follows –“The medical record supports the medical necessity for the biomarker test.”

The following comment was submitted to Palmetto GBA:

As a Urologist with a focused practice in Urologic Oncology, I have devoted a tremendous amount of time to the care of men with prostate cancer. In additional to that, I serve on leadership committees in organized urology including the AUA where I co-chair the AUA/SOU Advanced Prostate Cancer Guidelines and I am President of the Society of Urology Oncology. As a Urologist, Educator and Leader, I am deeply invested in the improving the quality of care of men with prostate cancer. It is against this backdrop that I would like to comment and recommend consideration of some of the wording to the document as it pertains to coverage guidance.

#3. The candidate would benefit from treatment of prostate cancer.

Recommended change: The candidate would benefit from treatment of prostate cancer, and that treatment recommendation may be impacted by using a biomarker.

Rationale: While I would agree that testing should only be considered in men would benefit from treatment of their cancer, it is possible that a biomarker would add additional information that could impact management and decision making including a change in management to a more conservative or a more aggressive approach.

#7 The test is ordered by a physician specialist in the management of prostate cancer, such as a urologist or oncologist.

Recommended change: The test is ordered by a provider engaged in the management of patients with prostate cancer, such as a urologist, urologic oncologist, medical oncologist, radiation oncologist primary care provider or advanced practice provider.

Rationale: Prostate cancer patient management has evolved into a multidisciplinary care model. This approach is intended to improve the outcome of the patient with prostate cancer across the disease state and care continuum. Importantly, I would argue that allowing the treating provider to obtain important testing without unnecessary delay including biomarkers. This approach is more in line with good clinical practice and has been shown to improve the quality of care, reduce barriers to access and promote the multidisciplinary care model that we promote in our professional organizations. Including primary care providers and advanced practice providers (physician assistants and nurse practitioners) will also improve access in rural and underserved areas of the country where prostate cancer care remains challenging. In addition, in many rural areas the primary care providers are solely or comanaging the patients and their ability to order biomarkers should not be limited. They, along with APPs, are also mission critical in large group practices as well as large academic health systems and cancer centers. To not be inclusive in this would be a mistake.

I hope these comments are of value to you as you finalize your document. I would be happy to discuss on a personal level as well.

Thank you for your thoughtful comments and support of this policy. We have addressed your comments in Response 1 listed above.

Additionally, we agree with your first recommendation and have added language to the following criterion:

“The beneficiary would benefit from treatment of prostate cancer and patient management will be impacted by use of a biomarker in a manner already demonstrated in the peer-reviewed published literature to improve patient outcomes.”

The following comment was submitted to Palmetto GBA:

For nearly 30 years the Prostate Conditions Education Council (PCEC) has been dedicated to saving lives through advancing the awareness and education of men, the women in their lives, as well as the medical community about prostate cancer prevalence, testing, and treatment options across the disease continuum. The Council – comprised of a consortium of leading physicians, health educators, scientists and prostate cancer advocates – has become a global leading resource for information on prostate cancer.

On behalf of our patient centered organization, I am writing regarding MolDX: Biomarkers to Risk-Stratify Patients at Increased Risk for Prostate Cancer.

While we are pleased that MolDX has created a draft coverage policy coverage for prostate biomarker diagnostic tests that help differentiate men who may or may not benefit from a prostate biopsy, we have two important concerns.

Patients with limited access to specialty care stand to benefit the most from the kinds of testing that this LCD addresses, as the decision of whether or not to see a specialist is a significant one for them and may be a significant burden. For patients with treatable prostate cancer, this may be a burden worth undergoing, but this helpful to know ahead of time.

Finally, we would like to note that for Medicare beneficiaries, laboratory tests that provide high quality information have the advantage of having no beneficiary cost sharing. This is particularly important for older adults on fixed incomes for whom unexpected expenses can be difficult to manage. While we appreciate that a visit to a specialist may offer optimal insight and counseling regarding disease management, copayments for specialist consultation and non-laboratory diagnostic evaluations can be a significant economic burden.

We ask that Palmetto GBA permit specialists or primary care providers to order the tests that are within the scope of this LCD.

Thank you for considering our feedback. We hope that our feedback from the patient and advocacy perspective will further improve the LCD.

Thank you for your thoughtful comments and support of this policy. We have addressed your comments in Response 1 listed above.

Finally, some of the comments received included information deemed not relevant to the scope or tests pertinent to this policy.