Title XVIII of the Social Security Act, §1862(a)(1)(A). Allows coverage and payment for only those services that are considered to be reasonable and necessary.

42 Code of Federal Regulations (CFR) 410.32(a). Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions.

CMS On-Line Manual, Publication 100-02, Medicare Benefit Policy Manual, Chapter 15, §§80.0, 80.1.1, 80.2. Clinical Laboratory services.

Noridian will provide limited coverage for the ConfirmMDx epigenetic assay for prostate cancer (MDxHealth, Irvine, CA) to reduce unnecessary repeat prostate biopsies. The MolDX Contractor recognizes that evidence for clinical utility for ConfirmMDx in males with previous negative prostate biopsy who are being considered for repeat biopsy is promising with evidence of some clinical utility at the current time.  The MolDX Contractor believes the clinical studies planned will generate sufficient additional data to demonstrate the utility of ConfirmMDx in males with previous negative prostate biopsy who are being considered for repeat biopsy.  Continued coverage of ConfirmMDx for males with previous negative prostate biopsy who are being considered for repeat biopsy will be dependent on semi-annual review of interim data, and/or peer-reviewed publications and/or presentations of clinical utility data demonstrating ConfirmMDx for males with previous negative prostate biopsy directs patient management as measured using clinical endpoints in one or more studies.

ConfirmMDx assesses the methylation status of 3 biomarkers (GSTP1, RASSF1, APC) associated with prostate cancer. ConfirmMDx is intended for use in patients with high-risk factors such as elevated/rising prostate-specific antigen (PSA) or abnormal digital rectal examination (DRE), with a negative or non-malignant abnormal histopathology finding (e.g., atypical cell or high grade prostate intraepithelial neoplasia (HGPIN)) in the previous biopsy, and is being considered for repeat biopsy. Several case/control studies in archived biopsy core tissue blocks demonstrated the sensitivity, specificity and high negative predictive value (NPV) of these biomarkers to predict cancer detection in a repeat biopsy procedure. Single biopsy cores, using as little as 20 microns from formalin-fixed, paraffin embedded (FFPE) tissue blocks or sections cut from blocks fixed on glass slides are used in this assay. 

The performance of this assay in a large, blinded clinical validation study demonstrated a NPV of 90% for all prostate cancer and 96% for high-grade disease, which is considerably higher than that afforded by standard histopathology review. A mathematically-based budget impact model using the assay in urologic practices to decide upon the need for repeat biopsies reported significant cost and medical resource savings by avoiding unnecessary, invasive biopsies over current standard of care methods. Further logistic regression models using all pertinent risk factors for prostate cancer detection (patient age, serum PSA level, digital rectal exam, histopathological findings on the previous cancer-negative biopsy and the assay) from the clinical validation trial were analyzed to compare various metrics separately and in combination. Assay results and prior histopathology were the strongest predictors of missed cancers and these two measures combined had a higher performance than either alone. Further analysis demonstrated that the assay test results combined with traditional clinical risk factors improved patient risk stratification and significantly outperformed current risk prediction models such as the Prostate Cancer Prevention Trial Risk Calculator (PCPTRC 2.0) and PSA.

The repeat biopsy rate for patients with an initial negative biopsy was reported to be approximately 40% in the Prostate, Lung, Colorectal, and Ovarian screening trial suggesting that a majority of the patients undergoing repeat biopsies did not have cancer detected. A recently completed field observation study was conducted in 138 patients with negative biopsies and managed by the urologist receiving negative ConfirmMDx for Prostate Cancer assay findings from those patient’s tissues. Only 6 of the 138 patients in that series had received a repeat biopsy yielding a 4.5% repeat biopsy rate.

Level of Evidence 

Quality of the Evidence: Moderate 

Strength of the Evidence:  Low 

Weight of the Evidence:  Low

ConfirmMDx is covered under the following conditions:

1. Males aged 40 to 85 years old that have undergone a previous cancer-negative prostate biopsy within 24 months and are being considered for a repeat biopsy due to persistent or elevated cancer-risk factors, and
   
   
2. The previous negative prostate biopsy must have collected a minimum of 8 tissue cores (but not have received a saturation biopsy of > 24 tissue cores) and remaining FFPE tissue from all cores is available for testing, and
   
   
3. Minimum tissue volume criteria of 20 microns of prostate biopsy core tissue is available (40 microns preferable), and
   
   
4. Previous biopsy histology does not include a prior diagnosis of prostate cancer or cellular atypia suspicious for cancer (but may include the presence of high-grade prostatic intraepithelial neoplasia (HGPIN), proliferative inflammatory atrophy (PIA), or glandular inflammation), and
   
   
5. Patient is not being managed by active surveillance for low stage prostate cancer, and
   
   
6. Tissue was extracted using standard patterned biopsy core extraction (and not transurethral resection of the prostate (TURP), and
   
   
7. Patient has not been previously tested by ConfirmMDx from the same biopsy samples or similar molecular test.