Contract analysis

I. PURPOSE AND SCOPE OF REVIEW This memorandum summarizes Calderwood & Harkness LLP's review of the health economics and outcomes research ("HEOR") analysis prepared by Larkfield Health Economics, LLC ("Larkfield") for potential incorporation into the MolDx Technical Assessment Dossier (Version 1.0) being prepared for submission to Ridgeline Administrative Services, LLC ("Ridgeline" or "RAS"), the contractor administ

II. BACKGROUND ON ONCOPRECISE GXP-47 AND CLINICAL CONTEXT A. Test Description 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, CA 92130. The laboratory holds CLIA Certificate No. 05D2187432 and CAP Accreditation No. 9074821. The laboratory's National Provider Iden

III. SUMMARY OF LARKFIELD HEOR DELIVERABLES A. Clinical Utility Evidence Report Larkfield's Clinical Utility Evidence Report presents a systematic review and synthesis of the evidence supporting the clinical utility of genomic-based ICI response prediction in NSCLC. The report is structured to address the clinical utility framework that MolDx reviewers apply when assessing molecular diagnostic tests for coverage, and

IV. CRITICAL OBSERVATIONS AND AREAS REQUIRING REVISION Our review of the Larkfield HEOR deliverables has identified several significant issues that must be addressed before the analysis can be incorporated into the MolDx Technical Assessment Dossier. These issues are discussed in detail below, together with our specific recommendations for revision. A. Reliance on CLARITY-LUNG Interim Data — Evidentiary Sufficiency C

V. REGULATORY COMPLIANCE CONSIDERATIONS A. CMS/MolDx Evidentiary Standards The MolDx program, administered by Ridgeline on behalf of participating MACs, requires that clinical utility and cost-effectiveness claims for molecular diagnostic tests be supported by evidence meeting specific evidentiary standards. These standards are articulated in the MolDx program's published technical assessment framework and in guidanc

VI. MARK-UP RECOMMENDATIONS — SPECIFIC SECTIONS The following section-specific mark-up recommendations are provided for transmission to Larkfield through GDT (Kevin Driscoll). These recommendations supplement the broader observations in Section IV above with targeted, actionable editorial guidance. A. Clinical Utility Section We recommend the following revisions to the Clinical Utility Evidence Report:

1. Add a dedicated subsection on clinical actionability of TRI score categories. This subsection should specify how each TRI score category (High, Intermediate, Low) corresponds to a distinct clinical management decision. The subsection should describe the clinical decision pathway that would be followed for a patient in each TRI category, including the specific treatment options that would be recommended or avoided,

2. Revise the discussion of analogous tests. The current framing of analogical evidence from breast cancer, colorectal cancer, and other oncology indications should be revised to clearly characterize these as supporting precedent for the general proposition that gene expression-based treatment selection panels can demonstrate clinical utility, rather than as primary evidence for the clinical utility of OncoPrecise GX

3. Add a limitations subsection. A new subsection should be added to the Clinical Utility Evidence Report explicitly acknowledging the current status of the CLARITY-LUNG trial, the interim nature of the available clinical validation data, and the limitations that this status imposes on the strength of the clinical utility evidence. The subsection should note that the interim results have not met pre-specified perform

4. Incorporate the CLARITY-LUNG trial design as evidence of clinical utility intent. The report should reference the CLARITY-LUNG trial protocol (NCT05891247) as evidence of GDT's commitment to generating robust prospective clinical utility data and should describe the trial's design features — including the pre-specified treatment decision algorithm, the multi-site design, and the blinded assessment — as structural

1. Revise test cost assumptions. Replace the single-point test cost assumption of $3,850 with a range reflecting crosswalk comparator variability ($2,919 to $4,206) in the sensitivity analysis, as detailed in Section IV.B above. If the base case retains the $3,850 target rate, include a methodological note explaining the basis for this assumption and its provisional nature.

2. Add a tornado diagram. Include a tornado diagram (one-way sensitivity analysis summary plot) showing the key drivers of ICER variability. This is a standard feature of published cost-effectiveness analyses and is expected by health economics reviewers. The tornado diagram should include, at minimum, the following parameters: test PPV, test NPV, test cost, ICI drug cost, chemotherapy cost, adverse event incidence r

3. Revise the base case test performance inputs. The base case should use the interim PPV (0.68) and NPV (0.71) as the primary inputs, clearly identified as interim values from an ongoing clinical validation trial. The pre-specified target values (PPV ≥ 0.75, NPV ≥ 0.80) should be modeled as a scenario analysis representing the "target performance" scenario, rather than being presented as the base case — which could

4. Source all model inputs. Ensure that all Markov model inputs — including transition probabilities, adverse event rates, costs, and utilities — are sourced to peer-reviewed publications or, where proprietary data is used, are clearly identified as such with accompanying methodology descriptions. Unsourced "internal GDT data" citations should be replaced with specific references to the underlying datasets and analyt

5. Remove revenue and commercial data. Remove all market-size, revenue projection, commercial uptake, and volume forecast data from the cost-effectiveness analysis section, as discussed in Section IV.E above. These data are not relevant to the clinical cost-effectiveness question and should be maintained separately for GDT's internal use.

6. Add a budget impact analysis. Add a dedicated budget impact analysis ("BIA") from the Medicare payer perspective. MolDx reviewers frequently consider the budgetary implications of new molecular diagnostic tests alongside cost-effectiveness, and the inclusion of a BIA strengthens the economic evidence package. The BIA should estimate the incremental cost to Medicare of covering OncoPrecise GXP-47 over a defined tim

VII. COORDINATION WITH OTHER WORKSTREAMS The Larkfield HEOR analysis must be consistent with and fully integrated into the broader MolDx Technical Assessment Dossier (Version 1.0), which Calderwood & Harkness has been retained to prepare. The dossier framework was delivered to GDT on April 30, 2024, and the HEOR sections — specifically Sections 4 (Clinical Utility) and 5 (Health Economics) of the dossier — will incor

VIII. SUMMARY OF RECOMMENDED REVISIONS The following is a consolidated list of all specific revisions recommended for the Larkfield HEOR analysis, as discussed in detail in Sections IV, V, and VI above:

1. Characterize CLARITY-LUNG interim data as preliminary. The analysis should clearly identify the interim PPV (0.68) and NPV (0.71) as preliminary estimates from an ongoing clinical validation trial. Model sensitivity scenarios should be run using both the observed interim values and the pre-specified target values (PPV ≥ 0.75, NPV ≥ 0.80), as well as a downside scenario with values below interim estimates.

2. Add sensitivity analyses for test cost. The cost-effectiveness model should be run at the weighted average crosswalk comparator rate ($3,622.33), the lowest comparator rate ($2,919), and the highest comparator rate ($4,206), in addition to the GDT target rate of $3,850. The base case assumption should be clearly documented and justified.

3. Strengthen direct clinical utility evidence. The Clinical Utility Evidence Report should strengthen the evidence specific to OncoPrecise GXP-47, including incorporation of CLARITY-LUNG trial design data and available retrospective analyses. Reliance on analogical evidence from other tumor types should be reduced and reframed as supporting precedent.

4. Source all Markov model inputs to peer-reviewed publications. Transition probabilities, cost inputs, utility values, and other model parameters cited to "internal GDT data" should be accompanied by methodology descriptions and, where possible, supplemented or replaced with published data. All proprietary data inputs should be clearly identified and labeled.

5. Update adverse event modeling. The adverse event component of the Markov model should be updated to reflect the most current published ICI safety data for NSCLC, including differentiation between ICI-associated irAEs and chemotherapy-related toxicities.

6. Add discount rate discussion. The model documentation should include an explicit discussion and justification of the discount rate assumptions (3% for costs and outcomes), with reference to applicable CMS and AHRQ guidance.

7. Remove all revenue projections and commercial data. All revenue projection, market sizing, commercial uptake, and volume forecast data should be removed from the dossier-facing sections of the HEOR analysis. These data should be maintained separately for GDT's internal commercial planning purposes.

8. Cross-reference the complete 43-publication bibliography. Larkfield should review and incorporate additional relevant publications from the master bibliography compiled by Calderwood & Harkness, particularly in the clinical utility and health economics categories. Any publications cited by Larkfield that are not in the master bibliography should be flagged for inclusion.

9. Map evidence to MolDx evidence hierarchy. The analysis should explicitly map its evidence base to the MolDx technical assessment evidence hierarchy, identifying where the current evidence falls for each domain.

10. Address the "reasonable and necessary" standard. The cost-effectiveness analysis should be framed within the context of the Social Security Act § 1862(a)(1)(A) "reasonable and necessary" standard, demonstrating that OncoPrecise GXP-47 is reasonable and necessary for the diagnosis or treatment of NSCLC.

11. Add limitations subsection. The Clinical Utility Evidence Report should include a limitations subsection acknowledging the interim nature of the CLARITY-LUNG data and the current evidentiary gaps.

12. Add budget impact analysis. A dedicated budget impact analysis from the Medicare payer perspective should be added to the cost-effectiveness section, using conservative volume assumptions.

13. Add tornado diagram. A tornado diagram (one-way sensitivity analysis summary plot) should be added to the cost-effectiveness section, illustrating the key drivers of ICER variability.

14. Note LDT regulatory status. The analysis should clearly note that OncoPrecise GXP-47 is marketed as a laboratory-developed test under CLIA authority without FDA clearance or approval, and should avoid any claims or language that could be construed as implying FDA authorization.

IX. CONCLUSION AND NEXT STEPS Based on our review, the Larkfield HEOR analysis provides a reasonable foundation for the clinical utility and cost-effectiveness components of the MolDx Technical Assessment Dossier, but requires the material revisions summarized in Section VIII above before it is suitable for incorporation into the dossier. The most significant concerns relate to (a) the reliance on CLARITY-LUNG interi