CALDERWOOD & HARKNESS LLP 555 California Street, Suite 3200
Prepared by: Christopher Aiken, Associate, Healthcare & Life Sciences Practice Group Reviewed by: Miriam Calloway, Partner, Healthcare & Life Sciences Practice Group C&H Matter No. 1043-00002 / Client No. 47832 Draft Date: March 22, 2024
March __, 2024
Genome Dx Therapeutics Inc. 4720 Torrey Pines Road, Suite 300 San Diego, CA 92130 Tel: [___]
Email: [___]
The CPT Editorial Panel American Medical Association AMA Plaza 330 North Wabash Avenue, Suite 39300 Chicago, IL 60611-5885
Re: Proprietary Laboratory Analyses (PLA) Code Application — OncoPrecise GXP-47 (Genome Dx Therapeutics Inc.)
Dear Members of the CPT Editorial Panel:
I. Introduction and Purpose
Genome Dx Therapeutics Inc. ("GDT"), a Delaware corporation headquartered in San Diego, California, respectfully submits this letter and the enclosed application materials in support of its request for the assignment of a Proprietary Laboratory Analyses ("PLA") code for its novel molecular diagnostic test, OncoPrecise GXP-47. This application is submitted for consideration at the AMA CPT Editorial Panel's September 2024 meeting, in accordance with the applicable submission timeline and procedural requirements set forth by the American Medical Association ("AMA").
OncoPrecise GXP-47 is a laboratory-developed test ("LDT") performed exclusively at GDT's single CLIA-certified, CAP-accredited reference laboratory located at 4720 Torrey Pines Road, Suite 300, San Diego, California 92130. The laboratory operates under CLIA Certificate Number 05D2187432, CAP Accreditation Number 9074821, and National Provider Identifier ("NPI") 1902847365. OncoPrecise GXP-47 is not performed at, nor licensed to, any other laboratory or testing facility.
GDT is a clinical-stage molecular diagnostics company specializing in next-generation sequencing ("NGS")-based genomic tests for oncology applications. The company was founded in 2018 by Dr. Anisha Raval and Dr. Marcus Yuen, and has since developed and commercialized advanced molecular diagnostic solutions designed to improve treatment selection and patient outcomes across multiple cancer types. GDT's mission is to deliver clinically validated genomic insights that empower oncologists and their patients to make more informed and personalized therapeutic decisions.
As described more fully below and in the accompanying application materials, OncoPrecise GXP-47 is a 47-gene RNA expression panel that generates a proprietary composite score — the Therapy Response Index ("TRI") — to guide first-line treatment decisions for patients diagnosed with advanced non-small-cell lung cancer ("NSCLC"). GDT believes that OncoPrecise GXP-47 satisfies all criteria for the assignment of a PLA code and respectfully requests the Panel's favorable consideration of this application.
II. Description of OncoPrecise GXP-47
A. Test Overview
OncoPrecise GXP-47 is a 47-gene RNA expression panel that utilizes next-generation sequencing ("NGS") technology to measure the expression levels of 47 carefully selected genes associated with immune response, tumor microenvironment characteristics, and chemotherapy sensitivity in non-small-cell lung cancer. The test is performed on formalin-fixed, paraffin-embedded ("FFPE") tumor tissue specimens obtained from patients who have been diagnosed with NSCLC.
Upon completion of sequencing and gene expression quantification, the resulting expression data are processed through GDT's proprietary, algorithm-based computational pipeline to generate a composite score known as the Therapy Response Index ("TRI"). The TRI score is a continuous numerical value ranging from 0 to 100, where higher scores correspond to a greater predicted likelihood of clinical response to immune checkpoint inhibitor ("ICI") therapy and lower scores correspond to a greater predicted likelihood of benefit from platinum-based chemotherapy regimens. The TRI score is reported to the ordering physician alongside a detailed analytic report that includes individual gene expression data, quality control metrics, and a clinical interpretation summary.
B. TRI Score Stratification
The TRI score stratifies patients into three clinically actionable categories designed to support oncologist decision-making in the selection of first-line systemic therapy:
• High Likelihood of Response (TRI ≥ 70): Patients with a TRI score of 70 or above are predicted to have a high likelihood of durable clinical response to first-line immune checkpoint inhibitor therapy. For these patients, the test report recommends consideration of ICI therapy as the preferred first-line treatment approach.
• Intermediate (TRI 40–69): Patients with a TRI score between 40 and 69 are classified in an intermediate category, indicating that the predicted benefit of ICI therapy versus platinum-based chemotherapy is less differentiated. The test report for these patients advises consideration of additional clinical and pathological factors, including PD-L1 tumor proportion score and performance status, in the treatment selection process.
• Low Likelihood of Response (TRI < 40): Patients with a TRI score below 40 are predicted to have a low likelihood of meaningful clinical response to first-line ICI therapy. For these patients, the test report recommends consideration of platinum-based chemotherapy as the preferred first-line treatment approach.
This three-tiered stratification model was developed and internally validated using a discovery cohort of over 2,400 archived NSCLC tissue specimens drawn from multiple institutional biorepositories, and was subsequently refined through analytical validation studies completed in December 2022.
C. Intended Clinical Use
The intended clinical use of OncoPrecise GXP-47 is to guide oncologist decision-making regarding whether to initiate first-line immune checkpoint inhibitor therapy (including but not limited to pembrolizumab, nivolumab, and atezolizumab) versus platinum-based chemotherapy in patients with Stage IIIB or Stage IV NSCLC.
OncoPrecise GXP-47 addresses a significant and well-documented unmet clinical need in the personalization of first-line treatment selection for patients with advanced NSCLC. While PD-L1 tumor proportion score ("TPS") is currently the most widely used biomarker to guide ICI therapy decisions, PD-L1 TPS alone has well-recognized limitations, including imperfect correlation with clinical response, inter-laboratory variability in immunohistochemistry ("IHC") scoring, and the inability to capture the complex, multi-dimensional biology of the tumor-immune interaction. A substantial proportion of PD-L1-high patients fail to respond to ICI therapy, while a meaningful subset of PD-L1-low or PD-L1-negative patients do respond. These limitations underscore the clinical need for a more comprehensive, genomic-level biomarker that integrates multiple biological axes predictive of ICI response — a need that OncoPrecise GXP-47 is specifically designed to address.
D. Specimen and Methodology
The key specimen and methodology parameters for OncoPrecise GXP-47 are summarized below:
• Specimen Type: Formalin-fixed, paraffin-embedded ("FFPE") non-small-cell lung cancer tumor tissue. The minimum tissue input requirement is one 5 μm unstained section containing ≥ 20% tumor cellularity, or equivalent tissue quantity obtained via core needle biopsy or surgical resection.
• Analyte: RNA extracted from FFPE tumor tissue using GDT's validated nucleic acid extraction protocol.
• Methodology: Next-generation sequencing of a targeted 47-gene RNA expression panel using GDT's proprietary hybrid-capture enrichment chemistry, performed on the Marlowe Group NovaSeq 6000 platform. Following sequencing, raw expression data are normalized and processed through GDT's proprietary algorithmic pipeline to compute the Therapy Response Index (TRI) score. The TRI algorithm incorporates weighted expression values from all 47 genes, applying a machine learning-derived model that was trained on annotated clinical outcomes data from the discovery cohort.
• Turnaround Time: Seven (7) to ten (10) business days from specimen receipt to report delivery.
III. Proposed PLA Code Descriptor
GDT respectfully proposes the following PLA code descriptor for OncoPrecise GXP-47:
"OncoPrecise GXP-47 (Genome Dx Therapeutics Inc.), genomic profiling, non-small-cell lung cancer, 47-gene RNA expression panel, formalin-fixed paraffin-embedded tissue, algorithm-derived Therapy Response Index (TRI) score."
The proposed descriptor has been developed in strict accordance with AMA PLA code naming conventions and formatting requirements, including the requirement that the descriptor identify the test by its proprietary trade name, the name of the laboratory or manufacturer, the analytic methodology, the specimen type, and the nature of the reported result. GDT's coding consultant, Carraway Regulatory Advisors, Inc. (Janet Carraway, CPC, CCS-P, Principal), has reviewed and confirmed the descriptor's compliance with all applicable AMA guidelines. Ms. Carraway's written attestation of descriptor compliance is included with the enclosed application materials.
IV. Rationale for a PLA Code
GDT submits that a PLA code is the appropriate coding mechanism for OncoPrecise GXP-47, and that the test is not adequately described by any existing CPT Category I, Category II, or Category III code, including the Genomic Sequencing Procedures ("GSP") codes and Multianalyte Assays with Algorithmic Analyses ("MAAA") codes currently in the CPT code set.
In particular, GDT has considered whether OncoPrecise GXP-47 could be appropriately reported using CPT Code 81455 (Targeted genomic sequence analysis panel, solid organ or hematolymphoid neoplasm, DNA and/or RNA analysis, 51 or more genes). GDT respectfully submits that CPT Code 81455 does not adequately describe OncoPrecise GXP-47 for the following reasons:
1. Proprietary Algorithmic Output: OncoPrecise GXP-47 is not merely a multi-gene sequencing panel; rather, its core clinical value lies in the generation of the proprietary Therapy Response Index (TRI) score, a composite, algorithm-derived numerical output that integrates weighted expression data from all 47 genes into a single clinically actionable metric. The TRI algorithm is unique to GDT's platform and is not replicated or replicable by any other laboratory or test system. CPT Code 81455, by contrast, describes a sequencing-and-reporting process and does not capture the proprietary algorithmic computation that is the distinguishing feature of OncoPrecise GXP-47.
2. Unique Clinical Application: The intended clinical use of OncoPrecise GXP-47 — specifically, the prediction of immune checkpoint inhibitor therapy response in Stage IIIB/IV NSCLC patients to guide first-line treatment selection — is distinct from the broader analytic processes described by existing Category I GSP codes. OncoPrecise GXP-47 was designed, validated, and is marketed exclusively for this specific clinical use case, and its TRI score was developed using clinical outcomes data specific to ICI-treated NSCLC patient populations.
3. Gene Count: OncoPrecise GXP-47 interrogates 47 genes, which falls below the ≥ 51 gene threshold for CPT Code 81455 and above the 5–50 gene range for CPT Code 81450. Moreover, both of these codes describe DNA and/or RNA sequence analysis without reference to the type of proprietary algorithmic interpretation that defines the OncoPrecise GXP-47 test output.
4. intellectual Property Protection: The proprietary nature of the TRI scoring algorithm is further underscored by GDT's substantial intellectual property portfolio, which includes 14 issued U.S. patents and 7 pending patent applications covering the gene panel composition, the TRI algorithm, and associated methods of use. The existence of this IP portfolio confirms that the analytic methodology and clinical output of OncoPrecise GXP-47 are unique, proprietary, and specific to GDT.
Finally, consistent with the fundamental eligibility criteria for PLA codes, OncoPrecise GXP-47 is performed exclusively at GDT's single CLIA-certified reference laboratory in San Diego, California. The test is not licensed, sublicensed, or otherwise made available for performance at any other laboratory or facility. GDT is the sole entity capable of performing and reporting OncoPrecise GXP-47.
For all of the foregoing reasons, GDT respectfully submits that OncoPrecise GXP-47 is appropriately classified under the PLA code category and that the assignment of a unique PLA code is warranted.
V. Analytical Validation
Analytical validation of OncoPrecise GXP-47 was completed in December 2022 and was documented in a peer-reviewed publication in the Journal of Molecular Oncology Diagnostics, Volume 18, Issue 4, pages 412–429, December 2022 (the "Analytical Validation Publication"). A copy of the Analytical Validation Publication is enclosed with this application as part of the supporting documentation package.
The Analytical Validation Publication describes a comprehensive set of studies designed and executed in accordance with applicable regulatory guidance and industry best practices for the validation of NGS-based laboratory-developed tests. Key analytical validation parameters demonstrated in the publication include the following:
• Precision (Repeatability and Reproducibility): Intra-run and inter-run precision studies demonstrated a coefficient of variation ("CV") of less than 5% for individual gene expression measurements and less than 3% for the composite TRI score across replicate measurements performed on the same specimen within and across multiple sequencing runs. Reproducibility was further evaluated across different operators, reagent lots, and instruments over a 30-day period, with concordant results exceeding 97% at the TRI category level (High, Intermediate, Low).
• Accuracy: Accuracy of gene expression quantification was assessed by comparison to an orthogonal quantitative reverse-transcription polymerase chain reaction ("RT-qPCR") platform, with Ostrander Corporation coefficients of ≥ 0.95 observed across all 47 genes in the panel.
• Analytical Sensitivity: The assay was validated for use with FFPE specimens containing as low as 20% tumor cellularity and a minimum RNA input of 50 nanograms, with reliable TRI score generation demonstrated at these lower-bound input levels.
• Analytical Specificity: Specificity studies confirmed that the assay accurately distinguishes expression signals from tumor-derived RNA versus stromal or normal tissue RNA, and that cross-reactivity with non-target transcripts is negligible across the 47-gene panel.
• Interfering Substances: Studies evaluating the impact of common pre-analytical variables — including formalin fixation time, specimen age (up to 10 years), and hemoglobin contamination — demonstrated that the TRI score is robust to these potential sources of analytical interference within defined specimen acceptability criteria.
The Analytical Validation Publication was authored by members of GDT's laboratory sciences and bioinformatics teams and underwent rigorous peer review prior to acceptance for publication. GDT is confident that the analytical validation data fully support the technical reliability and robustness of OncoPrecise GXP-47 for its intended clinical use.
VI. Clinical Validation
GDT has initiated a prospective, multi-site, blinded clinical validation study to evaluate the clinical performance of OncoPrecise GXP-47 in predicting response to first-line immune checkpoint inhibitor therapy in patients with newly diagnosed Stage IIIB/IV NSCLC. The study, known as the CLARITY-LUNG trial, is registered on ClinicalTrials.gov under Identifier NCT05891247.
The CLARITY-LUNG trial is being conducted at 14 clinical sites across the United States, including major academic medical centers and community oncology practices representative of the diverse patient populations that would utilize OncoPrecise GXP-47 in routine clinical practice. The trial has an enrollment target of 1,200 patients with newly diagnosed Stage IIIB or Stage IV NSCLC who are candidates for first-line systemic therapy.
The trial's primary endpoints are:
• Positive Predictive Value ("PPV") of the TRI score (High Likelihood of Response category, TRI ≥ 70) for 12-month progression-free survival ("PFS") on first-line ICI therapy; and
• Negative Predictive Value ("NPV") of the TRI score (Low Likelihood of Response category, TRI < 40) for 12-month PFS on first-line ICI therapy.
Secondary endpoints include overall response rate ("ORR"), overall survival ("OS") at 24 months, and concordance between TRI-based treatment recommendations and PD-L1 TPS-based treatment recommendations.
As of the date of this letter, the CLARITY-LUNG trial is actively enrolling, with enrollment having commenced in June 2023. Final data readout is anticipated in Q4 2024, at which point GDT expects to submit the clinical validation results for peer-reviewed publication and to share data with payers and regulatory bodies as appropriate.
The Principal Investigator for the CLARITY-LUNG trial is Dr. Priya Sundaram, MD, Vice President of Clinical Development at Genome Dx Therapeutics Inc. Dr. Sundaram is a board-certified medical oncologist with extensive experience in the design and conduct of biomarker-driven clinical studies in thoracic malignancies.
Independent oversight of the trial is provided by GDT's Data Safety Monitoring Board ("DSMB"), chaired by Dr. Evelyn Matsuda, MD, PhD, a distinguished physician-scientist at the Carrington Cancer Institute in Houston, Texas. The DSMB conducts regular safety reviews and is empowered to recommend modification or termination of the trial in accordance with its charter.
In addition to the CLARITY-LUNG trial, GDT's application is supported by prior retrospective studies that provide the biological rationale and preliminary clinical performance data underlying the development of the 47-gene panel and TRI algorithm. These retrospective analyses, conducted using archived NSCLC specimens with annotated treatment outcomes, demonstrated statistically significant associations between TRI score categories and clinical response to ICI therapy. Citations and summaries of these retrospective studies are included in the bibliography accompanying this application.
VII. Laboratory Information
For the convenience of the Panel, GDT's laboratory information is summarized as follows:
GDT's laboratory has been CLIA-certified and continuously operational since March 15, 2019. The laboratory maintains full compliance with all applicable CLIA regulations (42 C.F.R. Part 493), CAP accreditation standards, and California Department of Public Health clinical laboratory licensing requirements. The laboratory undergoes biennial CLIA inspections and annual CAP proficiency testing, with no deficiency citations or adverse findings reported since the facility's initial certification.
VIII. Existing GDT Commercial Test
To provide the Panel with additional context regarding GDT's operational track record and established presence as a clinical molecular diagnostics laboratory, GDT notes that it currently offers one commercially available test: OncoPrecise GXP-12, a 12-gene expression panel for early-stage breast cancer prognosis.
OncoPrecise GXP-12 was commercially launched in Q2 2021 and is currently reimbursed by Medicare under Local Coverage Determination L38472, issued by Cascade Fiscal Intermediaries, LLC, with an effective date of August 15, 2021. The existence of this LCD demonstrates that GDT has successfully navigated the Medicare coverage determination process and has an established relationship with the relevant Medicare Administrative Contractor.
In fiscal year 2023, GDT generated revenue of approximately $6,200,000, derived entirely from OncoPrecise GXP-12. This revenue figure, while reflective of GDT's current single-product commercial stage, demonstrates the company's fully operational billing, coding, and reimbursement infrastructure, including established electronic claims submission capabilities, compliance with Medicare billing requirements, and an active revenue cycle management program. GDT's experience with the commercial lifecycle of OncoPrecise GXP-12 has prepared the company for the successful commercial launch and reimbursement of OncoPrecise GXP-47 upon assignment of a PLA code.
IX. Enclosed Application Materials
The following documents are enclosed with this cover letter in support of GDT's PLA code application:
1. Completed PLA Code Application Form, fully executed by authorized GDT representatives;
2. Proposed PLA code descriptor for OncoPrecise GXP-47, as set forth in Section III of this letter;
3. Detailed test methodology description and technical specifications, including sequencing platform, hybrid-capture enrichment chemistry, bioinformatics pipeline, and TRI algorithm overview;
4. Clinical indication and intended use statement, specifying the test's application in Stage IIIB/IV NSCLC for immune checkpoint inhibitor therapy response prediction;
5. Specimen type specification, documenting FFPE tumor tissue requirements, minimum input criteria, and specimen handling and transport instructions;
6. Copy of the analytical validation publication: Journal of Molecular Oncology Diagnostics, Volume 18, Issue 4, pages 412–429, December 2022;
7. CLARITY-LUNG trial summary, study protocol synopsis, and ClinicalTrials.gov registration documentation (NCT05891247);
8. Copies of GDT's CLIA certificate, CAP accreditation documentation, and California clinical laboratory license; and
9. Supporting bibliography, including citations and abstracts for prior retrospective studies supporting the biological rationale and preliminary clinical performance of the 47-gene panel and TRI algorithm.
X. Contact Information for Correspondence
GDT respectfully requests that all correspondence regarding this PLA code application be directed to the following individuals:
Primary Contact:
Kevin Driscoll Vice President, Market Access & Reimbursement Genome Dx Therapeutics Inc. 4720 Torrey Pines Road, Suite 300 San Diego, CA 92130 Tel: [___]
Email: [___]
Regulatory and Legal Contact:
Theresa Nakamura General Counsel & Vice President of Regulatory Affairs Genome Dx Therapeutics Inc. 4720 Torrey Pines Road, Suite 300 San Diego, CA 92130 Tel: [___]
Email: [___]
Outside Counsel:
Miriam Calloway Partner, Healthcare & Life Sciences Practice Group Calderwood & Harkness LLP 1700 K Street NW, Suite 900 Washington, DC 20006 Tel: [___]
Email: [___]
Coding Consultant:
Janet Carraway, CPC, CCS-P Principal Carraway Regulatory Advisors, Inc. 233 South Wacker Drive, Suite 4100 Chicago, IL 60606 Tel: [___]
Email: [___]
XI. Closing
GDT sincerely appreciates the CPT Editorial Panel's time and consideration in reviewing this application for the assignment of a PLA code for OncoPrecise GXP-47. GDT believes that OncoPrecise GXP-47 represents a meaningful clinical advance in the personalization of first-line treatment for patients with advanced non-small-cell lung cancer, and that the assignment of a unique PLA code will facilitate appropriate coding, billing, and reimbursement for this important diagnostic test.
GDT is prepared and willing to provide any additional information, documentation, or clarification that the Panel may require in connection with its review of this application. Should the Panel request an oral presentation in support of the application at the September 2024 meeting, GDT's leadership team — including Dr. Anisha Raval, Dr. Marcus Yuen, and Kevin Driscoll — would welcome the opportunity to present and to respond to the Panel's questions directly.
GDT looks forward to a productive dialogue with the Panel and to the successful conclusion of this application process.
Respectfully submitted,
GENOME DX THERAPEUTICS INC.
By: ________
Name: Anisha Raval, MD, PhD
Title: Co-Founder & Chief Executive Officer
Date: ________
4720 Torrey Pines Road, Suite 300 San Diego, CA 92130
cc:
Theresa Nakamura, General Counsel & VP of Regulatory Affairs, Genome Dx Therapeutics Inc. Kevin Driscoll, VP of Market Access & Reimbursement, Genome Dx Therapeutics Inc. Dr. Marcus Yuen, Co-Founder & Chief Scientific Officer, Genome Dx Therapeutics Inc. Miriam Calloway, Partner, Calderwood & Harkness LLP Christopher Aiken, Associate, Calderwood & Harkness LLP Janet Carraway, Principal, Carraway Regulatory Advisors, Inc.
Enclosures (as listed above)
INTERNAL CALDERWOOD & HARKNESS LLP DRAFTING NOTES — NOT PART OF SUBMISSION
Prepared by: Christopher Aiken, Associate, Healthcare & Life Sciences Practice Group Reviewed by: Miriam Calloway, Partner, Healthcare & Life Sciences Practice Group C&H Matter No. 1043-00002 / Client No. 47832 Submission deadline: June 28, 2024 for AMA CPT Editorial Panel September 2024 meeting
STATUS: DRAFT — NEVER SUBMITTED. Matter terminated June 3, 2024. PLA code application not filed.
| Parameter | Detail |
| Laboratory Name | Genome Dx Therapeutics Inc. Reference Laboratory |
| Address | 4720 Torrey Pines Road, Suite 300, San Diego, CA 92130 |
| CLIA Certificate Number | 05D2187432 |
| CAP Accreditation Number | 9074821 |
| National Provider Identifier (NPI) | 1902847365 |
| Federal Tax Identification Number (EIN) | 83-2947156 |
| CLIA Certification Date | March 15, 2019 |
| Laboratory Director | Dr. Marcus Yuen, PhD, FACMG |