Program Guide Decipher Certification and Training Registry (Decipher CTR)

Transcription

1 Program Guide (Decipher CTR) This Program Guide provides a step- by- step overview of the operational aspects of the Decipher CTR, including how to (1) enroll as a healthcare provider and receive training on appropriate use of Decipher testing, (2) report any adverse events as a result of using Decipher (3) counsel and appropriately monitor your Medicare patients who have received Decipher testing. Because of the complicated nature of management decisions utilizing the Decipher assay and the potential for missing prostate cancer that could be salvaged with appropriate management at the appropriate time, testing must be furnished only by physicians who are enrolled in Decipher CTR program for Medicare Beneficiaries. The Decipher CTR program serves as a control to assure the appropriate selection of patients, compliance with management decisions and stringent follow up to ensure the benefits of the test outweigh its risks. The goals of the Decipher Certification and Training Program are as follows: To ensure that physicians understand the limitations of the test based on its validation through retrospective and heterogeneous patient populations, and To inform prescribers and patients on the safe- use conditions for Decipher, and To avoid missing clinically relevant development of metastatic prostate cancer or cancer related death with associated increased morbidity and mortality in Decipher low risk patients Decipher CTR Materials: Page A. Program Guide B. Training Package C. Sample Test Requisition Form (TRF) D. Healthcare Provider Enrollment (Form 1).. 11 E. Post- Test Treatment (Form 2).. 12 F. Adverse Event Report (Form 3). 13 G. Patient Guide. 14 H. As the sponsor of Decipher CTR, GenomeDx Laboratory has committed to working with healthcare providers to ensure compliance with the registry requirements and to assist in gathering and reporting relevant data to the MolDX program within Palmetto GBA. Page 1 of 14

2 Program Guide (Decipher CTR) 1. Healthcare Provider Enrollment: A. Carefully review all Decipher CTR program documents. B. Complete necessary training by reviewing all the materials on DecipherCTR.com. C. Complete Healthcare Provider Enrollment form (page 11) and give to your GenomeDx representative, fax to GenomeDx Laboratory at (855) , to or complete form on DecipherCTR.com. 2. Decipher Testing: A. Decipher testing is covered by Medicare for high- risk patients (post- radical prostatectomy), based on post- operative adverse pathology. B. The healthcare provider must be enrolled in the Decipher CTR and complete a Test Requisition Form to order Decipher for Medicare Beneficiaries. C. Patients should be appropriately counseled on: a. Benefits and risks of Decipher testing b. Decipher test results c. Need for additional follow- up and appropriate treatment options D. Report adverse outcomes for Medicare beneficiaries tested with Decipher, as required by the CTR. 3. Observational Data Collection/Reporting: A. Upon determining a treatment plan after running the Decipher test, fully complete the Post- Test Treatment Form (page 12) and fax to GenomeDx laboratory at (855) or to customersupport@genomedx.com. This form can also be downloaded on DecipehrCTR.com. B. Immediately report any distant metastases or prostate cancer related deaths in patients who were deemed low risk by the assay. C. A cumulative list will be sent to each enrolled healthcare provider every six months, showing their tested patients with low Decipher scores for use in checking for adverse events. D. Fully complete the Adverse Event Report (AER) Form (page 13) and fax to GenomeDx Laboratory at (855) or to customersupport@genomedx.com. This form can also be downloaded on DecipherCTR.com. E. GenomeDx has support services for completing the Post- Test Treatment Form or AER. Contact GenomeDx or your Genomic Specialist to learn if our complimentary Pathology and Registry Manager Program may be right for you. 4. Program Compliance: A. The LCD(s) providing coverage for Decipher require healthcare providers to comply with all obligations of the Decipher CTR in order to maintain their certification. B. As sponsor of the Decipher CTR, GenomeDx may contact you from time- to- time to assure your continued compliance with the Decipher CTR and to provide any necessary ongoing provider and/or patient education. C. In the event of a continued failure to remain in compliance with the terms of the LCD and the Decipher CTR, GenomeDx is charged with taking appropriate measures to bring registered healthcare providers into compliance, including by instituting corrective actions up to and including de- certification. Page 2 of 14

3 Training Package (Decipher CTR) The Decipher Certification and Training Registry (CTR) has been established to enable Medicare coverage for eligible patients. Under Local Coverage Determination (LCD) L36343, the Decipher test is considered reasonable and necessary for Medicare patients meeting identified coverage criteria only when ordered by a physician certified in the CTR. Section 1. Overview of Decipher Prostate Cancer Classifier Decipher Test Description The Decipher prostate cancer assay, a 22- biomarker expression signature using oligonucleotide microarray technology, interrogates 1.4 million RNA markers extracted from formalin fixed paraffin embedded (FFPE) prostate cancer tissue samples to assess a patient s risk for developing metastasis. The biomarkers that comprise the Decipher test include cell cycle progression, androgen signaling, cell adhesion, tumor cell motility, migration and immune evasion functions. The Decipher test provides an independent, individualized continuous estimate of risk of 5- year metastasis (0.3%- - 67%) with higher sensitivity and specificity than the population based average risk currently available with clinical risk factors. Decipher Test Performance The clinical performance of this assay was assessed in several blinded, retrospective, clinical validation studies, enrolling more than 2,500 patients. Validation studies included a wide diversity of patients with high- risk prostate cancer who underwent radical prostatectomy (RP), many of whom subsequently developed metastatic disease. Decipher was developed using the metastasis end point, not a surrogate end point such as PSA recurrence. The test results have been shown to reclassify 8 out of 10 clinically high- risk men tested into lower or significantly elevated risk of metastatic disease progression. Section 2. Limitations of the Decipher Test There are heterogeneities in the patients included in the analysis both inside the trials and between trials. While a prospective trial with randomization and treatment based on the Decipher GC score would solve these biases, and recognizing that long- term prospective data would require 10 years or more, Noridian and the CMS MolDX contractor (Palmetto GBA) believe that clinical utility can be extrapolated from these robust retrospective clinical validity trials. The strength of this data is the consistency with which the Decipher GC score predicts metastasis across high- risk patients who may or may not have had a BCR. Section 3. Important Safety Information When applying retrospective analysis to prospective treatment there is the fear that the treatment that normally would have been given is altered based on a test result. Consequently, education on the appropriate use of this test and resulting treatment outcomes must be clearly understood by ordering physicians. Page 3 of 14

4 Section 4. Patient Eligibility Indications for Use Under Decipher LCD ID L36343 The Decipher test is covered by Medicare only when the following clinical conditions are met: Patient with prostate cancer who has undergone a RP within the previous 60 months and is being considered for postoperative secondary therapy due to one or more cancer- recurrence risk factors, AND Patient must have achieved initial PSA nadir (defined as undetectable PSA) within 30 days of RP surgery, AND Patient must not have any evidence of distant metastasis, AND Patient must not have received any neo- adjuvant treatment prior to surgery, AND Decipher GC is performed on a patient s RP specimen, AND Patient s surgical pathology report or medical records must have documented presence of adverse pathology: o Pathological stage T2 disease with a positive surgical margin, OR o Pathological stage T3 disease (e.g., extraprostatic extension, seminal vesicle invasion, bladder neck invasion), OR o Rising PSA after initial PSA nadir, AND Testing has been ordered by a physician who is certified in the GenomeDX Decipher Certification and Training Registry (CTR) Section 5. Patient Management As part of the CTR requirements, to ensure the benefits of the Decipher test outweigh any risks, physicians should discuss risks and appropriate monitoring with their patient. Interpretation of Decipher Results At post- operative setting (Adjuvant): Decipher low risk patients can safely delay/defer radiation treatment (RT) and avoid the adverse side effects of radiation treatment after radical prostatectomy. Decipher low risk patients have excellent prostate cancer specific outcomes after radical prostatectomy, with % five- year metastasis- free survival (95-100% ten- year cancer- specific survival), across multi- institutional cohorts treated with diverse postoperative treatment regimens (adjuvant or salvage or no treatment at all prior to metastatic onset) as reported in 10 peer- reviewed publications Decipher high risk patients can benefit from early RT. Decipher high risk patients who received adjuvant radiation showed an 80% reduction in metastasis risk compared to salvage radiation 6. At post- BCR setting (Salvage): Post biochemical recurrence (BCR), Decipher low risk patients may be treated with salvage radiation alone, while Decipher high risk patients may require intensification of the treatment with a systemic therapy 8,9. Additionally, Decipher high risk patients who received early salvage RT (PSA 1 ng/ml) showed significantly better outcomes than those who received late salvage RT (PSA > 1 ng/ml) (10- year metastasis 15% vs 35%, p=0.031) 9. Safe Use The Decipher test does not detract from your physician s treatment recommendations and other clinical and pathological indicators. Regardless of your treatment decision, it is crucial that you continue to monitor your prostate cancer closely by maintaining follow- up appointments regularly. Page 4 of 14

5 Section 6. Decipher Peer Reviewed Scientific Evidence Decipher Clinical validity The Decipher test was developed using archived formalin- fixed paraffin embedded (FFPE) blocks of tumors selected from 621 patients that had undergone a radical prostatectomy (RP) at the Mayo Clinic Comprehensive Cancer Centre between the years , providing a median of 18 years follow- up 1. The endpoint used for the discovery was clinical metastasis, not a surrogate endpoint such as BCR. Moreover, the patients that developed metastasis after BCR were compared to two control groups of patients, the first group with BCR- only but no metastasis (with at least 5 years of follow up) and the second group without BCR and no evidence of disease (with at least 7 years of follow up). The premise of using metastasis as an endpoint in the development of Decipher was critical to increasing the specificity of the test for identifying patients truly at risk of developing metastasis. This is because not everyone who experiences BCR develops metastasis, as discussed in a recently published study (Alshalalfa et al. BJU Intl, 2015) that further supports using clinical and genomic analysis that BCR is a poor, non- specific surrogate for lethal disease. In addition to the well- defined study design, the comprehensive transcriptomic- wide survey for the most prognostic markers, which led to the identification of the 22 Decipher markers, also played an important role in improving the robustness of the test. These markers represent a network of biological pathways associated with tumor progression including cell proliferation, cell adhesion and motility, immune system modulation, cell cycle progression, and androgen signaling. Also, nearly half of the Decipher markers are non- coding RNA highlighting their pivotal role in prostate cancer progression (Alshalalfa et al. Biology of the Cell, 2015). Subsequent to the discovery and the initial validation in the Mayo cohort, Decipher was clinically validated to predict the probability of metastasis after surgery in multiple patient cohorts with postoperative high- risk features, such as pathological stage pt2 with positive margins or pt3 disease or a rising serum prostate- specific antigen (PSA) as reported in 10 published independent validation studies Decipher test showed consistent performance in the indicated testing population (87-100% of studied patients had adverse pathology or PSA rise) with over 2,500 patients studied in prospectively- designed blinded evaluations by leading academic and NCI- designated cancer centers (Mayo Clinic, Thomas Jefferson University, Johns Hopkins University and Cleveland Clinic) and outperformed clinical variables currently used in standard practice such as preoperative PSA and Gleason score. The Decipher test provided independent individualized information for a patient s risk assessment after surgery and stratified the indicated population. Therefore, identifying those patients with good prognosis who are unlikely to benefit from additional therapeutic intervention after surgery, and additionally identifying patients most likely to benefit from adjuvant radiation therapy as opposed to delayed (salvage) therapy. In summary, the eight validation studies have demonstrated that: Decipher low risk patients can safely delay/defer treatment and avoid the adverse side effects of radiation treatment after radical prostatectomy. o Decipher low risk patients have excellent outcomes with radical prostatectomy, with % five- year metastasis- free survival (95-100% ten- year cancer- specific survival), across multi- institutional cohorts treated with diverse postoperative treatment regimens (adjuvant or salvage or no treatment at all prior to metastatic onset) as reported in nine peer- reviewed publications 1-9. Page 5 of 14

6 o Post biochemical recurrence (BCR), salvage therapy with no concurrent hormones, was sufficient in Decipher low risk patients 8,9. Decipher high risk patients can benefit from early radiation. o Decipher high risk patients who received adjuvant radiation showed an 80% reduction in metastasis risk compared to salvage radiation 6. o Post biochemical recurrence (BCR), Decipher high risk patients may require intensification of the treatment with a systemic therapy, and those who received early salvage RT showed significantly better outcomes than those who received late salvage RT (10- year metastasis 15% vs 35%, p=0.031) 8,9. Decipher Clinical Utility Five published studies of clinical management investigated the influence of the Decipher test on physicians post- surgery treatment decisions for the intended use population - postoperative high- risk prostate cancer patients The Decipher test was consistently shown to influence treatment decisions of over 120 physicians from 60 tertiary and community cancer centers across the United States. Decipher changed treatment management for approximately one in three patients, redirecting postoperative treatments for Decipher high- risk and observation for Decipher low- risk patients. In addition, a decision analysis study showed in two independent cohorts of high- risk men that compared to standard care, Decipher - guided treatment decisions led to a 12% relative increase in 5- year recurrence- free survival (16% at 10 years) and a 4% relative reduction in the 5- year probability of metastatic disease or death. Importantly, these gains in survival are achieved with overall lower burden of postoperative therapy in the population. In summary, the five clinical utility studies have demonstrated that: Decipher reclassifies 60% of clinically high risk men to genomic low risk men who by current clinical practice guidelines are ALL recommended to receive 6-8 weeks of for costly and toxic intensity- modulated radiation therapy. Compared to the average clinical risk of metastasis, Decipher low risk patients (60% of men) had significantly lower than average clinical risk (~2- times lower) whereas Decipher high risk patients (20% of men) had significantly higher than average clinical risk (>3- times higher). Decipher- based treatment models consistently showed a higher net benefit (balance of benefits and harms) on patient outcome for postoperative treatment decision- making compared with pathological risk models (i.e., Gleason, CAPRA- S, Eggener, Kattan and Stephenson nomograms) or clinical scenarios where no risk prediction model would be used (i.e. treat all or treat none with adjuvant radiation) 2-8. Decipher test results transform physician decision- making o Decipher low risk (~60% of men tested) 90% opt for active observation (e.g., PSA monitoring) instead of additional therapy. o Decipher high risk (~20% of men tested) 64% recommend adjuvant radiation for these patients most at risk and consequently most likely to benefit. The most impactful aspect of clinical utility for patients getting the Decipher test is around optimal timing of postoperative treatment, enabling physicians to decide whether it can be delayed/deferred or avoided altogether and when is it most beneficial. Consequently, as reported in the clinical validity studies, Decipher- based treatment models consistently showed a higher net benefit (balance of benefits and harms) on patient outcome across a wide range of risk compared with scenarios in which clinical only models (i.e. CAPRA- S and Stephenson nomograms) or no prediction model would be used for a postoperative radiation therapy treatment decision (i.e. treat all or treat none). Page 6 of 14

7 Decision analytic outcomes modeling further shows that Decipher directed individualized care is associated with a 16% relative increase in the 10- year recurrence- free survival probability 14. References 1. Erho, N., et al., Discovery and validation of a prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy. PLoS One, (6): p. e Karnes, R.J., et al., Validation of a Genomic Classifier that Predicts Metastasis Following Radical Prostatectomy in an At Risk Patient Population. The Journal of urology, : p Klein, E.A., et al., A Genomic Classifier Improves Prediction of Metastatic Disease Within 5 Years After Surgery in Node- negative High- risk Prostate Cancer Patients Managed by Radical Prostatectomy Without Adjuvant Therapy. European Urology, (4): Cooperberg, M.R., et al., Combined Value of Validated Clinical and Genomic Risk Stratification Tools for Predicting Prostate Cancer Mortality in a High- risk Prostatectomy Cohort. European Urology, (2):p Den, R.B., et al., Genomic prostate cancer classifier predicts biochemical failure and metastases in patients after postoperative radiation therapy. Int J Radiat Oncol Biol Phys, (5): p Robert B. Den, K.Y., Edouard J. Trabulsi, Firas Abdollah, Voleak Choeurng, Felix Y. Feng, Adam P. Dicker, Costas D. Lallas, Leonard G. Gomella, Elai Davicioni and R. Jeffrey Karnes, A genomic classifier identifies men with adverse pathology after radical prostatectomy who benefit from adjuvant radiation therapy. Journal of Clinical Oncology, : Ross AE, Yousefi K, Trock B, Choeurng, V., Lam, L.L.C., Fedor, H.L., Ghadessi, M., Buerki, C. Glavaris, S., Sundi, D., Tosoian, J., Han, M., Humphreys, E.B., Partin, A.W., Netto, G.J., Davicioni, E. Schaeffer, E.M., Tissue Based Genomics Augment Post- Prostatectomy Risk Stratification in a Natural History Cohort of Intermediate- and High- Risk Men. European Urology 2015; doi: /j.eururo Ross, A.E., Feng, F.Y., Ghadessi, M., Erho, N., Crisan, A., Buerki, C., Sundi, D., Mitra, A.P., Vergara, I.A., Thompson, D.J.S., Triche, T.J., Davicioni, E., Bergstralh, E.J., Jenkins, R.B., Karnes, R.J. and Schaeffer, E.M., A genomic classifier predicting metastatic disease progression in men with biochemical recurrence after prostatectomy. Prostate cancer and prostatic diseases 2014; 17(1): Freedland S.J, Choeurng V., Howaerd L., De Hoedt A., du Plessis M., Yousefi K., Lam L.L., Buerki C., Ra S., Robbins B., Trabulsi E.J., Shah N.L., Abdollah F., Feng F.Y., Davicioni E., Dicker A.P., Karnes R.J., Den R.B. Utilization of a genomic classifier for prediction of metastasis following salvage radiation therapy after radical prostatectomy. European Urology In press. 10. Yamoah, K., Johnson, M.H., Choeurng, V., Faisal, F.A., Yousefi, K., Haddad, Z., Ross, A.E., Alshalafa, M., Den, R., Lal, P., Feldman, M., Dicker, A.P., Klein, E.A., Davicioni, E.,Rebbeck, T.R., Schaeffer, E.M., A novel biomarker signature which may predict aggressive disease in African- American men with prostate cancer. Journal of Clinical Oncology 2015; doi: /JCO Page 7 of 14

8 11. Glass, AG., Leo M.C., Haddad Z., Yousefi K., Du Plessis M., Chen C., Choeurng V., Abdollah F., Robbins B., Ra A., Richert- Boe KE. Buerki C., Pearson K., Davicioni E., Weinmann S., Validation of a genomic classifier for predicting post- prostatectomy recurrence in a community- based healthcare setting. Journal of Urology In Press. DOI: /j.juro Badani, K.K., Thompson, D.J.S., Buerki, C., Davicioni, E., Garrison, J., Ghadessi, M., Mitra, A.P., Wood, P.J., and Hornberger, J., Impact of a genomic classifier of metastatic risk on postoperative treatment recommendations for prostate cancer patients: a report from the DECIDE study group. Oncotarget 2013; 4(4): Michalopolous, S.N., Kella, N, Payne, R., Yohannes, P., Singh, A., Hettinger, C., Yousefi, K., and Hornberger, J., Influence of a genomic classifier on post- operative treatment decisions in high- risk prostate cancer patients: results from the PRO- ACT study. Curr Med Res Opin 2014; 30(8): Lobo, J.M., Dicker, A.P., Buerki, C., Davicioni, E., Karnes, R.J., Jenkins, R.B., Patel, N., Den, R.B., and Showalter, T.N., Evaluating clinical impact of a genomic classifier in prostate cancer using individualized decision analysis. PLoS One Apr 2;10(3):e doi: /journal.pone ecollection Badani, K.K., Thompson, D.J., Brown, G., Holmes, D., Kella, N., Albala, D., Singh, A., Buerki, C., Davicioni, E., and Hornberger, J., Effect of a genomic classifier test on clinical practice decisions for patients with high- risk prostate cancer after surgery. British Journal of Urology Intl 2014; 115(3): Nguyen, P., Shin, H., Yousefi, K., Thompson, D.J., Hornberger, J., Hyatt, A.S., Badani, K.K., Morgan, T., and Feng, Y.F., Impact of a Genomic Classifier of Metastatic Risk on Post- Prostatectomy Treatment Recommendations by Radiation Oncologists and Urologists. Urology 2015; 86(1): Featured on the cover of Urology July Page 8 of 14

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