a cms mmedicare a administrative contractor - … cms mmedicare a administrative contractor clinical...

A CMS MMedicare A Administrativve Contracttor

CClinical

Version

Tes (CT

n 5.0

st Ev EP)

valu M0

uatio 0009

on P 96

Nov

Proce

vembe

ess

er 20155

MolDX: CTEP Table of Contents

DOCUMENT VERSION CONTROL Version No. Date Purpose / Changes Author 1.0 Original document Elaine Jeter, MD

Dane Dickson, MD Girish Putcha, M.D., Ph.D.

2.0 Standardized format Becke Turner, RN 3.0 6/2/15 Removed Section 5 reference to

specialty society list Becke Turner, RN

4.0 7/29/15 Updated corporate logos for cover page Becke Turner, RN 5.0 10/19/15 Updated with new MolDX icon Kathy Brannon

TABLE OF CONTENTS Section 1: Background.................................................................................................................. 1

1. Background ............................................................................................................................ 1 1.1. Objective ............................................................................................................................. 1 1.2 CMS Instructions ................................................................................................................. 1

Section 2: Clinical Utility (CU) Test Tracks ............................................................................... 2

Section 3: Analytical and Clinical Validity (AVCV) Test Tracks ............................................ 3

Section 4: Expedited FDA CU and AVCV for FDA Companion Diagnostics......................... 4

Section 5: Expedited CU for Partner Professional Societies or Groups (PSS CU)................. 5

Section 6: Traditional Clinical Utility (CU)................................................................................ 6

6.1. MolDX Clinical Trial Designations (mCTD) ..................................................................... 6 6.2. Preliminary MolDX Level of Evidence Determination ...................................................... 6 6.3. Establishing the Final MolDX Level of Evidence (mLOE) ............................................... 7

Section 7: MolDX Final Review ................................................................................................... 8

7.1. MolDX Executive Committee (EC) Review ...................................................................... 8

Section 8: MolDX Review Steps ................................................................................................... 9

Section 9: MolDX Final Review Appeal.................................................................................... 10

Section 10: Figures ...................................................................................................................... 11

Section 11: Selected References ................................................................................................. 15

Palmetto GBA Page i Version 5.0, November 2015

f

MolDX: C TEP Secction 1

SEC CTION 1 : BACKG GROUNDD

1. Bacckground 1.1. Objective The MolDDX Clinical l Test Evalua ation Process (CTEP) de escribes the mmethod Palmmetto GBA uuses in its techhnical assess sment processs to evaluatte newly dev veloped testss or for estabblished tests that have not been validatted for clinic cal utility (CCU) and anal lytical and cllinical validiity (AVCV) . In order to ddetermine if a test meets s the Medicaare reasonabl le and neces sary criteriaa, a test mustt demonsttrate CU and d AVCV. Al lthough CU and AVCV are separateely addressedd in this documennt, the MolD X Team wil l evaluate thhe two comp ponents at thee same time.. This documment further deefines the ev valuation pro ocess and dooes NOT reprresent a chaannge to the TTA process ass stated in the active M Molecular Di agnostic Tessting (MDT) ) LCD.

1.2. CMS Instru uctions The Centters for Med dicare and M Medicaid Servvices (CMS) ) emphasizedd the need too follow the ACCE crriteria develo oped by the Centers for DDisease Con ntrol and Preevention (CDDC).

“TThe methodoology will u use an evidennce framewo ork that is coonsistent withh the ACCEE crriteria develooped by the CDC for thee evaluation of genetic teests as articuulated from 22009 onnward in the e application n of the ACCCE criteria to o Medicare ccoverage in iits national cooverage dete erminations (NCDs) perttaining to moolecular diaggnostic testss.”

In additioon to these c criteria, the M MolDX proccess strives to o utilize provven and accepted industtry standardss currently in n place. This s document ddetails these e additional sstandards to enhance understannding.

CC enters for DD isease Cont rol (CDC) AC CCE Criteria Overview

Palmetto GGBA Page 1 Version 55.0, Novembe r 2015

MolDX: CTEP Section 2

SECTION 2: CLINICAL UTILITY (CU) TEST TRACKS (See Section 10 Figure 1)

Once the MolDX team determines a submitted dossier is complete, the test is categorized into one of the following three tracks for CU:

1. Expedited CU for FDA Companion Diagnostics (FDA CU): Applies when a clinical test has been submitted as part of a successful new drug application (NDA) and is the exact test specified in the FDA-approved package insert (PI) of the associated drug, or is appropriate based on the FDA-approved labeling for the companion diagnostic.

2. Expedited CU for Partner Specialty Societies or Group Approved Test (PSS CU): Applies when a test has already been formally reviewed by a MolDX-designated specialty society or other group, which has recommended the test as a “standard of care.”

3. Traditional CU (CU): Modeled after the FDA New Drug Application (NDA) process; approval is based on published, peer-reviewed trial information.

Palmetto GBA Page 2 Version 5.0, November 2015


SECTION 3: ANALYTICAL AND CLINICAL VALIDITY (AVCV) TEST TRACKS

(See Section 10 Figure 4)

To demonstrate the AVCV, the test is categorized into one of the following two tracks:

1. Expedited AVCV for FDA Companion Diagnostics (FDA AVCV): Applies only when a test has been approved by the FDA as a companion diagnostic and adheres to the intended use (IU) and indication(s) for use (IFU) approved by the FDA.

2. Traditional AVCV: All tests must demonstrate AVCV as evaluated by both subject matter experts (SME) and the MolDX executive committee. This track includes the review of evidence as outlined in MolDX CTEP: Analytical and Clinical Validation Guidelines.



SECTION 4: EXPEDITED FDA CU AND AVCV FOR FDA COMPANION DIAGNOSTICS


When the FDA has already performed a systematic review of the proposed clinical intervention and associated companion diagnostic and has identified the appropriate indicated use (IU) and indications for use (IFU) for the test and treatment, evaluation by MolDX of the same information is unnecessary. Therefore, the MolDX Team will confirm FDA approval for CU and AVCV. As for all Medicare services, the drug and the test must meet the Medicare reasonable and necessary criteria prior to final approval.

From the FDA’s website:

“A companion diagnostic device can be in vitro diagnostic device or an imaging tool that provides information that is essential for the safe and effective use of a corresponding therapeutic product. The use of an IVD companion diagnostic device with a particular therapeutic product is stipulated in the instructions for use in the labeling of both the diagnostic device and the corresponding therapeutic product, as well as in the labeling of any generic equivalents and biosimilar equivalents of the therapeutic product.”

Because the nuances of testing (including, but not limited to, differences in analytical and clinical sensitivity and specificity, reproducibility, etc.) can impact results or their interpretation, the final coverage decision may be based on specific FDA approved labeling. When the FDA does NOT specify the platform for the companion diagnostic, the test must follow the Traditional CU and AVCV tracks.



SECTION 5: EXPEDITED CU FOR PARTNER PROFESSIONAL SOCIETIES OR GROUPS (PSS CU)


Many professional societies and academic groups consistently promote cost-effective, evidenced-based healthcare and publish guidance documents to educate and standardize treatment protocols. Whenever possible, Palmetto GBA will collaborate with specialty groups and societies to advance appropriate molecular testing. When possible, existing guidelines may be applied to the review and approval process. (Figures 1 and 2)



SECTION 6: TRADITIONAL CLINICAL UTILITY (CU) (See Section 10 Figure 3)

6.1. MolDX Clinical Trial Designations (mCTD) The MolDX Team will review each clinical utility trial included in the dossier and assign a MolDX Clinical Trial Designation (mCTD). These designations are as follows:

mCTD 3A - Randomized, Prospectively Controlled Trials (PCT) directly demonstrate that therapeutic intervention based on test results leads to statistically and clinically significant improvement in patient outcomes compared to a currently accepted standard of care. End points of the trial must be widely considered to be clinically appropriate by the medical community (e.g., overall survival). The trial must be adequately powered to address the outcome of the intervention based on the test.

mCTD 3B - Prospective-Retrospective Trials (PRT) use archived samples from a previously reported prospective controlled trial to demonstrate that treatment based on a molecular test result in a specified patient population is associated with improved outcomes in a statistically and clinically significant manner versus a currently accepted standard of care. The chosen samples and study design must be sufficiently characterized and powered to permit definition of the indications for use and the intended use population for the test.

mCTD 2A - Prospective Observational Studies (POS) involve prospectively enrolling patients in a registry, treating according to a defined pathway using the molecular test as an integral part of the care plan, and demonstrating statistically and clinically significant improvement in healthcare outcomes versus a currently accepted standard of care as shown by contemporary, although historical controls.

mCTD 2B – Retrospective Data Modeling (RDM) involves complex data modeling using large data sets to demonstrate statistically and clinically significant improvement in healthcare outcomes when a given molecular test is used to guide treatment versus a standard of care approach.

mCTD 1 - Retrospective Observational Studies (ROS) do not stipulate treatment pathways or follow-up based on results from the molecular test.

mCTD 0 - Preclinical Studies (PS) involve only preclinical data (e.g., animal or in vitro experiments), or related studies or trials.

6.2. Preliminary MolDX Level of Evidence Determination A preliminary MolDX level of evidence (mLOE) will be calculated based solely on the mCTD of the submitted trials according to Table 1. If the preliminary mLOE is below IIB, then the application will be rejected with an explanation of the findings. If the mLOE is IIB or greater, the test will undergo a full clinical review (Figure 3).

Table 1: MolDX Level of Evidence

mLOE IA

Strongest CU Trial mCTD 3A

Other CU Trial(s) mCTD 3A or 3B

IB 3A 2A or 2B IB 3B 3B IIA 3B 2A or 2B IIB 2A 2A or 2B IIC 2B 2B III 2A or 2B 1 IV 1 1



6.3. Establishing the Final MolDX Level of Evidence (mLOE) During the full clinical review process, subject matter experts (SME) review the submitted clinical trials and assign a final mLOE based on the trial type and its clinical relevance. Upon completion of their analysis, the assigned SME will supply a written report to the MolDX Executive Committee for final review.



SECTION 7: MOLDX FINAL REVIEW

7.1. MolDX Executive Committee (EC) Review Once the CU and AVCV analyses have been completed, the EC will review all information and apply Medicare reasonable and necessary criteria to make a final coverage decision and rationale for the findings. Final decisions may include noncovered, covered, limited coverage, or coverage with data development (CDD).

Although Palmetto GBA considers the work performed by the FDA, the PPS and such groups, in addition to findings from the SME, the final coverage determination resides with the EC in compliance with current regulation. Every effort will be made to achieve consensus prior to the finalization of coverage decisions.



SECTION 8: MOLDX REVIEW STEPS The MolDX Team and MolDX consultants perform the following steps during a technical assessment to demonstrate CU:

1. Review dossier to determine if all required documents are included and identified with MolDX ID, which creates a valid TA submission

2. Categorize test by appropriate track for CU and AVCV assessment

3. MolDX Team reviews submitted clinical trials and assigns a MolDX Clinical Trial Designation (mCTD).

4. If the mLOE is greater than IIB, redacted test information assigned to at least two SME for CU evaluation and clinical recommendation

5. MolDX Team assigns and sends redacted test information to up to two SME for AVCV evaluation and recommendation using the elements outlined in the MolDX CTEP: Analytical and Clinical Validation Guidelines

6. SME recommendations reviewed by EC

7. EC makes final determination regarding the CU and AVCV

8. EC review tests that demonstrate CU and AVCV for Medicare reasonable and necessary criteria.

9. EC determines one of the following for test: covered, limited coverage, CDD, noncoverage

10. Tests determined as covered, limited coverage, or CDD, progress for pricing determination



SECTION 9: MOLDX FINAL REVIEW APPEAL At the developer’s request, the EC will meet with the developer to discuss the completed review and initial coverage decision. The developer will have 60 days after issuance of the initial decision to ask for redetermination of the initial coverage decision. A final written response from MolDX will be provided within 60 days of receipt of the developer's request for redetermination.


MolDX: C TEP Sectiion 10

Figu

S ure 1: MolDX

SECTION X Clinical Util

N 10: FIG lity Algorithm

GURES m for a New CClinical Testt


Figure 2: PSSS Expedited d Clinical Utiility Review P Process

Palmetto GGBA Page 12


Version 55.0, Novembe r 2015


Palmetto GGBA

Figure 3: Traditional C

Page 13

Clinical Utilitty Review Pro

Version 5

ocess

5.0, Novembe r 2015


iew ProcesssFiguure 4: Analytical and Clinnical Validity (AVCV) Revv



SECTION 11: SELECTED REFERENCES 1. Altman DG, McShane LM, Sauerbrei W, et al. Reporting Recommendations for Tumor

Marker Prognostic Studies (REMARK): Explanation and Elaboration. BMC Medicine 2012; 10:51.

2. Berger ML, Dreyer N, Anderson F, et. al. Prospective observational studies to assess comparative effectiveness: The ISPOR good research practices task force report. Value Health 2012; 15:217-230.Centers for Disease Control and Prevention (CDC). Accessed 29 March 2014. http://www.cdc.gov/genomics/gtesting/ACCE/index.htm

3. Centers for Medicare and Medicaid Services. Decision Memo for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N). 2013 Sept.

4. Center for Medical Technology Policy (CMTP). Evaluation of Clinical Validity and Utility of Actionable Molecular Diagnostic Tests in Adult Oncology. 2013 May. http://www.cmtpnet.org/resource-center/view/egd-on-mdx/

5. Febbo PG, Ladanyi M, Aldape KD, et. al. NCCN Task Force Report: Evaluating the Clinical Utility of Tumor Markers in Oncology. J Natl Compr Canc Netw 2011; 9:S1-S32.

6. Food and Drug Administration. Accessed 29 March 2014. http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm 301431.htm

7. Food and Drug Administration (FDA). Guidance for Industry Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products. 1998 May. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/u cm078749.pdf

8. Hayes DF, Bast RC, Desch DE, et. al. Tumor Marker Utility Grading System: A Framework to Evaluate Clinical Utility of Tumor Markers. J Natl Cancer Inst 1996; 88:1456-1466.

9. Simon R, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 2009; 101:1446-52.

10. Williams PM, Lively TG, Jessup JM, et al. Bridging the gap: Moving predictive and prognostic assays from research to clinical use. Clinical Cancer Research 2012; 18:1531-1539.


http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/u

http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm

http://www.cmtpnet.org/resource-center/view/egd-on-mdx

http://www.cdc.gov/genomics/gtesting/ACCE/index.htm

a cms mmedicare a administrative contractor - … cms mmedicare a administrative contractor clinical...

Documents