Notification Issue Date:

Policy Attachment

Attachment to Policy # MA06.017r


Policy #:MA06.017r

Description:Services that are coverable via Coverage with Evidence Development (CED), registry-based approach, or other properly-designed designs

Title:Molecular Diagnostics

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

Germline Mutations: Pharmacogenomics

Medicare regulations at 42CFR410.32(a) require in relevant part that “All diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests must be ordered by the physician who is treating the beneficiary, that is, the physician who furnishes a consultation or treats a beneficiary for a specific medical problem and who uses the results in the management of the beneficiary’s specific medical problem.”

There is scant evidence of general clinical uptake of pharmacogenomic diagnostic testing to guide patient management, which continues to lack sufficient evidence of decision impact, despite emerging supportive technical research. Additional evidence would inform Medicare Administrative Contractor (MAC) determinations that certain pharmacogenomic tests are furnished appropriately under the regulation. As further described in regulations at 42CFR411.15(k)(1) these tests would otherwise not be reasonable and necessary “for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.”

Therefore, noting an equivocal Evaluation of Genomic Applications in Practice and Prevention (EGAPP) technology assessment in the area of adjunctive treatment of depression with selective serotonin reuptake inhibitors, Cytochrome P450 CYP2C19 and CYP2D6 allele testing will be covered only in the context of approved prospective clinical studies that demonstrate the use of the results in the management of a beneficiary’s specific medical problem.

Furthermore, although the Cytochrome P450 CYP2C19 enzyme metabolizes approximately 15% of all prescribed drugs and is involved in the metabolism of several important drug classes, including, but not limited to, anti-depressants (amitriptyline), anti-epileptics (phenytoin) and proton pump inhibitors (lansoprazole), routine testing is not supported by a sufficiently robust evidence base demonstrating medical necessity. However, in the context of an FDA boxed warning for clopidogrel dosing where impaired Cytochrome P450 CYP2C19 metabolism has been reported, testing is a coverable service.

In order to properly implement this condition of coverage, it is necessary to determine the circumstances under which pharmacogenomic testing actually impacts patient management. The MAC will receive and review all submitted study protocols. Any study where coverage is sought for CYP2C19 or CYP2D6 must meet the following requirements, which may, for example, use a registry-based approach, although other properly-designed methods of investigation may be acceptable:
  • The studies do not unjustifiably duplicate existing studies, such that this above research may be appropriately substituted by equivalent, externally performed studies which could independently address these same above research questions.
  • The studies are conducted by entities capable of executing the proposed studies successfully.
  • The studies are in compliance with all applicable Federal regulations concerning the protection of human subjects found at 45 CFR Part 46.
  • All aspects of the studies are conducted according to appropriate standards of scientific integrity (see A MAC may elect to require prior approval by an independent institutional review board for greater assurance of scientific integrity (e.g., properly firewalling commercial and scientific objectives via an unbiased external entity), as well as the protection of human subjects.
  • The studies have a written protocol that clearly address, or incorporate by reference, the standards listed here as Medicare requirements for coverage.
  • The clinical studies are registered on the website at an appropriately early juncture.
  • The study protocols specify the method and timing of public release of all pre-specified outcomes to be measured, including release of outcomes if outcomes are negative or if the study is terminated early.
  • The results must be made public within 36 months of the end of data collection, and subsequent articles must be planned to be published in a peer reviewed journal, where the initial release of such results may be in an abstract that meets the requirements of the International Committee of Medical Journal Editors (
  • The study protocols must explicitly discuss how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the diagnostic test.
  • Annual progress reports on each study shall be sent to the MAC, with the expectation of at least one peer-reviewed full manuscript to be accepted by a journal for publication within 36 months of the finalization of the applicable local coverage determination (LCD). Publication of the medical evidence will be necessary to support further coverage of items and services under the study protocol.

NOTE: Alleles CYP2C9 and VKORC1 for warfarin dosing are coverable per NCD 90.1 via coverage with evidence development ( ).

Furthermore, under the aegis of the applicable MAC's LCD, surrogate measures for (the possibility of) hemorrhagic or embolic events, coupled with a non-randomized prospective registry design may be acceptable, if such a design is otherwise sufficiently robust, and it properly enables control group comparisons.
Additional clinical applications of these alleles, along with CYP450 1A2, 3A4, 3A5, and the related Mthfr gene, may be covered via CED, according to these same above listed requirements.

The following CPT codes may be covered via Coverage with Evidence Development (CED), registry-based approach, or other properly designed methods of investigation when these investigations are approved by the MAC.

Physician Interpretation and Report

HCPCS code G0452 may be covered when reported with CPT codes 81225, 81226, 81227, 81291, and 81355 when these procedure codes are covered via Coverage with Evidence Development (CED), registry-based approach, or other properly designed methods of investigation when these investigations are approved by the MAC.
G0452Molecular pathology procedure; physician interpretation and report

Version Effective Date: 01/01/2020
Version Issued Date: 01/03/2020
Version Reissued Date: N/A

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