Medical Policy

 

Subject: In Vitro Companion Diagnostic Devices
Document #: GENE.00022 Current Effective Date:    09/27/2017
Status: Reviewed Last Review Date:    08/03/2017

Description/Scope

This document addresses the use of U.S. Food and Drug Administration (FDA) approved companion diagnostic testing and targeted drug or biologic therapy.

Position Statement

Medically Necessary:

In Vitro Companion Diagnostic Devices (IVD) (for example, diagnostic molecular tests) are considered medically necessary when all of the following criteria are met:

  1. The IVD was approved through the FDA In Vitro Companion Diagnostic Devices process; and
  2. The Associated Therapeutic Product (ATP) (for example, pharmaceutical or biologic treatment) would be considered medically necessary for the diagnosis and specific clinical situation under review; and
  3. The IVD is being used to determine whether the associated ATP would be a medically necessary therapy.

Investigational and Not Medically Necessary:

Use of an IVD which does not meet any of the criteria above is considered investigational and not medically necessary.

Note: Documents that address coverage of a specific ATP or IVD supersede GENE.00022, unless those documents do not specifically address the FDA approval (for example, because the FDA approval occurred since the last review date). In those situations, per GENE.00022, the IVD is considered medically necessary when used in accordance with the FDA labeled indications.

Rationale

Increased understanding of the human genome has made it possible to identify genomic variation in both normal and malignant tissues. Newer therapies may be targeted to specific mutations ("targeted biologic therapy") and may not have been evaluated in individuals without the specific mutation or be considered unlikely to benefit individuals without the specific mutation. In 2011, the FDA developed a process to evaluate both a targeted biologic therapy and a related diagnostic molecular test.

On August 6, 2014, the FDA released an industry guidance titled In Vitro Companion Diagnostic Devices, intended to:

…assist (1) sponsors who are planning to develop a therapeutic product (either a novel product or an existing product with a new indication) for which the use of an in vitro companion diagnostic device (or test) is essential for the therapeutic product's safe and effective use and (2) sponsors planning to develop an in vitro companion diagnostic device that is intended to be used with a corresponding therapeutic product.

The FDA guidance (2014) intends to accomplish the following:

An example of a companion diagnostic test in clinical use is the Vysis ALK Break Apart FISH Probe Test (Abbott Molecular, Inc, Abbott Park, Illinois), used to detect variations (rearrangements) in the anaplastic lymphoma kinase (ALK) gene in individuals with non-small cell lung cancer (NSCLC) who are eligible for treatment with crizotinib (Xalkori® , Pfizer Inc., New York, NY). The FDA granted premarket approval (PMA) to this molecular diagnostic test kit that uses fluorescence in situ hybridization (FISH) technology to detect rearrangements of the ALK gene on the 2p23 chromosome, offering clinicians a standardized, clinically validated method to identify individuals most likely to benefit from drug therapy. Soda and colleagues (2007) found that an acquired translocation of EML4 with ALK within chromosome 2p led to the expression of an EML4-ALK oncoprotein in NSCLC. ALK has also been identified in the oncogenesis for hematopoietic and nonhematopoietic malignancies. Therefore, ALK inhibition would be beneficial as a targeted therapy against cancers with oncogenic alterations of ALK (Li, 2011). Since EML4-ALK NSCLC represents approximately 5% of all NSCLCs in a younger, non-smoking population (Kwak, 2010), diagnostic testing must be able to identify specific genomic variation for successful targeted therapy.

Background/Overview

Genomic testing for specific biological markers prior to drug treatment provides data that can indicate if a drug will be of therapeutic value in the treatment of disease. Types of tests include first-generation amplification, DNA probes, FISH, second-generation biochips and microfluidics, next-generation signal detection and gene expression profiling using microarrays.

Examples of targeted therapies include those that:

According to the FDA (2017), an IVD could be essential for the safe and effective use of a corresponding therapeutic product to:

The following is a list of FDA cleared or approved Companion Diagnostic Devices (In Vitro and Imaging Tools) (FDA, 2017). For additional information and periodic updates (that is, new approvals/clearances), visit the FDA website at: http://www.fda.gov/medicaldevices/productsandmedicalprocedures/invitrodiagnostics/ucm301431.htm.

 

Drug Trade Name
Generic Name

Companion Diagnostic
Device

Device
Manufacturer

Cotellic® (cobimetinib) in combination with vemurafenib cobas® 4800 BRAF V600 Mutation Test Roche Molecular Systems, Inc.
 

Erbitux® (cetuximab)

 

 

cobas® KRAS Mutation Test/cobas® 4800 System Roche Molecular Systems, Inc.
DAKO EGFR PharmDx™ Kit Dako North America, Inc.
(Agilent Technologies)
therascreen ® KRAS RGQ PCR Kit Qiagen Manchester, Ltd.
 
Exjade® (deferasirox) FerriScan® R2-MR1 Analysis System Resonance Health Analysis Services Pty Ltd
 
Gilotrif® (afatinib) therascreen EGFR RGQ PCR Kit Qiagen Manchester, Ltd.
 
Gleevec® (imatinib mesylate) KIT D816V Mutation Detection by PCR for Gleevec Eligibility in Aggressive Systemic Mastocytosis (ASM) ARUP Laboratories, Inc.
PDGFRB FISH for Gleevec Eligibility in Myelodysplastic Syndrome/Myeloproliferative Disease (MDS/MPD) ARUP Laboratories, Inc.
 
Gleevec® /Glivec® (imatinib mesylate) DAKO c-KIT pharmDx™ Test Kit Dako North America, Inc. (Agilent Technologies)
 

Herceptin® (trastuzumab)

 

Bond Oracle Her2 IHC System Leica Biosystems
HER2 CISH pharmDx™ Kit Dako Denmark A/S
(Agilent Technologies)
HER2 FISH pharmDx™ Test Kit Dako Denmark A/C
HercepTest™ Dako Denmark A/C
INFORM HER2 Dual ISH DNA Probe Cocktail Assay Ventana Medical Systems, Inc.
(Roche)
INFORM HER-2/NEU Ventana Medical Systems, Inc. (Roche)
InSite Her-2/neu Mouse Monoclonal Antibody (Clone C1B11) Kit BioGenex Laboratories, Inc.
PATHVYSION HER-2 DNA Probe Kit Abbott Molecular Inc.
PATHWAY ANTI-HER-2/NEU (4B5) Rabbit Monoclonal Primary Antibody Ventana Medical Systems, Inc. (Roche)
SPOT-Light® HER2 CISH™ Kit Invitrogen™ Corporation
therascreen ® EGFR RGQ PCR Kit Qiagen Manchester, Ltd.
 
Idhifa® (enasidenib) Abbott RealTime IDH2 Abbott Molecular, Inc.
 

Kadcyla®

(ado-trastuzumab emtansine)

HER2 FISH pharmDx™ Test Kit Dako Denmark A/C
HercepTest™ Dako Denmark A/C
 
Keytruda® (pembrolizumab)

PD-L1 IHC 22C3 PharmDx™ Test

 

Dako North America, Inc.
(Agilent Technologies)
 
Lynparza™ (olaparib) BRACAnalysis CDx™ Myriad Genetic Laboratories, Inc.
 
Mekinist® (trametinib) Oncomine Dx Target Test Life Technologies Corporation
THxID™ BRAF Test bioMérieux Inc.
 
Perjeta® (pertuzumab) HER2 FISH pharmDx™ Test Kit Dako Denmark A/C
HercepTest™ Dako Denmark A/C
 
Rubraca® (rucaparib) FoundationFocus CDxBRCA Assay Foundation Medicine, Inc.
 
Rydapt® (midostaurin) LeukoStrat® CDx FLT3 Mutation Assay Invivoscribe Technologies, Inc.
 
Tafinlar® (dabrafenib) Oncomine Dx Target Test Life Technologies Corporation
THxID™ BRAF Test bioMérieux Inc.
 
Tagrisso® (osimertinib) cobas® EGFR Mutation Test v2 Roche Molecular Systems, Inc.
 
Tarceva® (erlotinib) cobas® EGFR Mutation Test Roche Molecular Systems, Inc.
cobas® EGFR Mutation Test v2 Roche Molecular Systems, Inc.
 

Vectibix® (panitumumab)

 

cobas® KRAS Mutation Test/ cobas® 4800 System Roche Molecular Systems, Inc.
DAKO EGFR PharmDx™ Kit Dako North America, Inc.
(Agilent Technologies)
Praxis Extended RAS Panel Illumina, Inc.
therascreen ® KRAS RGQ PCR Kit Qiagen Manchester, Ltd.
 
Venclexta® (venetoclax) VYSIS CLL FISH Probe Kit Abbott Molecular Inc.
 
Xalkori® (crizotinib) Oncomine Dx Target Test Life Technologies Corporation
VENTANA ALK (D5F3) CDx Assay Ventana Medical Systems, Inc. (Roche)
Vysis ALK Break Apart FISH Probe Test Abbott Molecular, Inc.
 

Zelboraf® (vemurafenib)

 

cobas® 4800 BRAF V600 Mutation Test Roche Molecular Systems, Inc.
     
     

 

Definitions

Associated Therapeutic Product (ATP): The therapeutic, preventive, and prophylactic drugs and biological products approved in association with an IVD (FDA, 2017).

Biological therapy: A treatment that uses the body's immune system to fight cancer cells rather than attacking those cells directly. For carefully selected people, biological therapy may target cancer cells (that is, targeted biologic therapy or targeted cancer therapy) to avoid damage to normal cells, prevent or slow tumor growth, and prevent the spread of cancer cells (National Cancer Institute [NCI], 2013).

In Vitro Companion Diagnostic Devices (IVD): An in vitro device or an imaging tool that provides information 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 FDA labeling of both the diagnostic device and the corresponding therapeutic product, as well as in the FDA labeling of any generic equivalents and biosimilar equivalents of the therapeutic product (FDA, 2017).

Targeted cancer therapy: Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules ("molecular targets") that are involved in the growth, progression, and spread of cancer. They recognize a specific feature of the cancer cell, attach to it, and destroy it. Targeted cancer therapies are sometimes called "molecularly targeted drugs," "molecularly targeted therapies," "precision medicines," or similar names (NCI, 2014).

Coding

Specific coding does not apply to this document.

References

Peer Reviewed Publications:

  1. Gerber DE, Minna JD. ALK inhibition for non-small cell lung cancer: from discovery to therapy in record time. Cancer Cell. 2010; 18(6):548-551.
  2. Kalia M. Personalized oncology: recent advances and future challenges. Metabolism. 2013; 62(Suppl 1):S11-S14.
  3. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010; 363(18):1693-1703.
  4. Li Y, Ye X, Liu J, et al. Evaluation of EML4-ALK fusion proteins in non-small cell lung cancer using small molecule inhibitors. Neoplasia. 2011; 13(1):1-11.
  5. Philip R, Carrington L, Chan M. US FDA perspective on challenges in co-developing in vitro companion diagnostics and targeted cancer therapeutics. Bioanalysis. 2011; 3(4):383-389.
  6. Shaw AT, Solomon B. Targeting anaplastic lymphoma kinase in lung cancer. Clin Cancer Res. 2011; 17(8):2081-2086.
  7. Stricker T, Catenacci DV, Seiwert TY. Molecular profiling of cancer--the future of personalized cancer medicine: a primer on cancer biology and the tools necessary to bring molecular testing to the clinic. Semin Oncol. 2011; 38(2):173-185.
  8. Vincent MD, Kuruvilla MS, Leighl NB, Kamel-Reid S. Biomarkers that currently affect clinical practice: EGFR, ALK, MET, KRAS. Curr Oncol. 2012: 19(Suppl 1):S33-S44.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Agency for Healthcare Research and Quality (AHRQ). Addressing Challenges in Genetic Test Evaluation: Evaluation Frameworks and Assessment of Analytic Validity. June 16, 2011. No. 11-EHC048-EF. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?productid=704&pageaction=displayproduct. Accessed on July 10, 2017.
  2. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med. 2013; 137(6):828-860.
  3. NCCN Clinical Practice Guidelines in Oncology® . © 2017 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on July 10, 2017.
  4. Raman G, Avendano EE, Chen M. Update on Emerging Genetic Tests Currently Available for Clinical Use in Common Cancers. Evidence Report/Technology Assessment. No. (Prepared by the Tufts Evidence-based Practice Center under Contract No. 290-2007-10055-I.). Rockville, MD: Agency for Healthcare Research and Quality (AHRQ). July 2013. Available at: https://www.cms.gov/Medicare/Coverage/DeterminationProcess/Downloads/id92TA.pdf . Accessed on July 10, 2017.
  5. U.S. Food and Drug Administration (FDA). Office of In Vitro Diagnostics and Radiological Health. Accessed on July 10, 2017.
  6. U.S. Food and Drug Administration (FDA). Premarket Notification Database. Vysis ALK Break Apart FISH Probe Kit; Vysis Paraffin Pretreatment IV and Post Hybridization Wash Buffer Kit; ProbeChek ALK Negative Control Slides; and ProbeChek ALK Positive Control Slides. No. P110012. Rockville, MD: FDA. August 26, 2011. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cftopic/pma/pma.cfm?num=p110012. Accessed on July 10, 2017.
Websites for Additional Information
  1. National Cancer Institute (NCI). FactSheet. Accessed on July 10, 2017.
  2. National Institutes of Health (NIH). National Human Genome Research Institute. Frequently Asked Questions About Genetic and Genomic Science. Available at: http://www.genome.gov/19016904. Accessed on July 10, 2017.
Index

Deoxyribonucleic acid (DNA)
Genomics

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
Reviewed 08/03/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Updated content and revised format of the Companion Diagnostic Device table. Updated References and Websites for Additional Information sections.
Reviewed 05/04/2017 MPTAC review.
Reviewed 05/03/2017 Hematology/Oncology Subcommittee review. Updated Companion Diagnostic Device table, Definitions, References, and Websites for Additional Information sections.
Reviewed 11/03/2016 MPTAC review.
Reviewed 11/02/2016 Hematology/Oncology Subcommittee review. Updated formatting in Position Statement section. Updated References and Websites for Additional Information sections.
Reviewed 08/04/2016 MPTAC review. Updated Companion Diagnostic Device table, Definitions, References and Websites for Additional Information sections.
Reviewed 05/05/2016 MPTAC review.
Reviewed 05/04/2016 Hematology/Oncology Subcommittee review. Updated Background, Companion Diagnostic Device table, References and Web Sites for Additional Information sections.
Reviewed 11/05/2015 MPTAC review.
Reviewed 11/04/2015 Hematology/Oncology Subcommittee review. Updated Rationale, References, and Websites for Additional Information sections. Added Companion Diagnostic Device table to the Background section.
Reviewed 11/13/2014 MPTAC review.
Reviewed 11/12/2014 Hematology/Oncology Subcommittee review. Updated Description, Rationale, Background, Definitions, References, and Websites for Additional Information sections.
Reviewed 11/14/2013 MPTAC review.
Reviewed 11/13/2013 Hematology/Oncology Subcommittee review. Updated Description, Rationale, Definitions, References, and Websites for Additional Information and Index sections.
Reviewed 11/08/2012 MPTAC review.
Reviewed 11/07/2012 Hematology/Oncology Subcommittee review. Updated Description, Rationale, Definitions, References, and Websites for Additional Information.
Reviewed 11/17/2011 MPTAC review.
Reviewed 11/16/2011 Hematology/Oncology Subcommittee review. Clarification of note addressing implementation.
New 10/03/2011 MPTAC review.
New 09/27/2011 Hematology/Oncology Subcommittee review. Initial document development.