Tuesday, September 9, 2025

MolDX New Cancer LCD: For Non-NGS Testing in Cancer

On August 28, 2025, I flagged two new proposed LCDs from MolDx, one for thrombophilia (F5) testing, one for liver disease steatosis risk.  

MolDX released a third proposed LCD on August 28, titled, "Non-Next Generation Sequencing Targeted Molecular Panel Tests for Predictive Testing in Cancer."  

Find it here, DL40210.  There is a 2/2024 request letter from Padma Sundar and a 6/2024 request letter from Anjana Bhattacharya (Biofidelity).  The LCD has 81 citations.  Comment til October 12.

The LCD has a draft billing article DA60236 here.  (The only code listed is 81479 plus DEX Z-code.)

  • Note that this is only relevant for outpatient biopsies.   If the patient has an inpatient colectomy, for example, you're free to order PCR on Day 1 and NGS on Day 4 but both are bundled (nonpayable) under the 14 day rule for inpatients.

The Rules

MolDx opens the LCD 9 rules, some of which are general ("the test has been validated," "the patient has cancer," etc).   Specifically, the non-NGS test can be used when at least one of these is true: (1) NGS is not feasable or likely to fail, OR (2) NGS is not required by guidelines and non-NGS testing will provide management, OR (3) the test includes necessary biomarkers and precludes unnecessary NGS testing.  A negative result in a non-NGS test may be followed with a larger NGS test.   The non-NGS test includes the relevant genes for FDA-approved therapies.

  • For me, it's tempting to read the 3 restrictions as "AND" - making the gateway to PCR testing very narrow - but it's clearly written as "OR" - making the gateway pretty wide.

Genomeweb 360Dx reports the LCD is relevant for ChromaCode HDPCR, Biofidelity Aspyre Lung, and Biocartis Idylla [platform] assays.

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AI CORNER

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Playfully, I first gave Chat GPT 5 only the bibliography of the LCD, and asked it to guess what the body of the LCD (not shown) is about.

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Based on the bibliography you shared, this new MolDx draft LCD is focused on PCR-based panel testing in solid tumors (especially NSCLC and colorectal cancer) — not on broad NGS panels.

Here’s why:

1. Dominant Focus on NSCLC

  • Many references are about EGFR, ALK, ROS1, RET, MET exon 14, KRAS, BRAF and other actionable drivers in non-small cell lung cancer (e.g., Kris 2014 JAMA; Lindeman/CAP-IASLC-AMP guidelines; multiple NCCN guideline versions; numerous papers on turnaround time and reflex testing).

  • There are repeated mentions of reflex single-gene or small multiplex assays and their impact on time-to-treatment and outcomes.

2. Emphasis on PCR Platforms

  • Several papers specifically evaluate Idylla (Biocartis), ASPYRE, digital PCR, and rapid cartridge-based systems (Evrard 2019, Momeni-Boroujeni 2021, Banyi 2022, Carnero-Gregorio 2025, Buglioni 2022, Depoilly 2022, Melchior 2024, Hogarth 2025).

  • These are PCR-based methods for detecting actionable variants and fusions, positioned as alternatives or complements to NGS.

3. Secondary Focus on Colorectal Cancer

  • References to KRAS, NRAS, BRAF, and PIK3CA mutations in metastatic colorectal cancer (De Roock 2010; Therkildsen 2014; Al-Turkmani 2018).

  • Again, much of the cited literature is about PCR-based testing rather than large CGP panels.

4. Themes in the Citations

  • Speed and turnaround time: rapid results enabling earlier treatment decisions.

  • Clinical utility and cost-effectiveness of rapid PCR panels.

  • Comparisons of PCR vs. NGS (sensitivity, sample requirements, concordance).

  • Workflow integration in pathology labs (reflex testing, small FFPE samples).

✅ Interpretation:
This draft LCD (DL40210) is not about broad NGS panel coverage, but rather about coverage for rapid, multiplex PCR-based panel testing in cancer tissue — with the main clinical use cases being NSCLC driver mutations/fusions and RAS/RAF testing in colorectal cancer.

It looks like MolDx is carving out a policy lane for automated cartridge-based PCR panels (e.g., Idylla, ASPYRE, ChromaCode, etc.) as an alternative to broad CGP, emphasizing faster turnaround and use in tissue-limited scenarios.

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Now I gave Chat GPT the whole LCD to discuss.

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Here’s a structured take for your genomics industry blog readers on MolDx’s new draft LCD DL40210: Non-NGS Targeted Molecular Panel Tests for Predictive Testing in Cancer:

1. Criteria for Coverage vs. Non-Coverage

MolDx lays out a detailed set of conditions for when non-NGS (PCR or similar) multigene cancer panels are covered:

  • Patient eligibility:
    Must have a cancer diagnosis where molecular results will inform treatment.

  • When NGS is not the first choice: Coverage applies if:

    • NGS is not feasible (poor specimen, low tumor content).

    • NGS isn’t required by guidelines, and a faster non-NGS method can guide timely treatment.

    • The non-NGS test can safely identify common actionable biomarkers and help avoid unnecessary NGS.

  • Testing rules:

    • No duplicate testing of the same content; negative results may be reflexed to NGS for additional targets.

    • Panels must cover the most common guideline-recommended biomarkers (e.g., EGFR, ALK, ROS1, RET, BRAF, METex14, NTRK, KRAS/NRAS in CRC).

    • Test must be validated for the intended population and sample type.

    • Performance must be comparable to NGS, with faster turnaround (<10 business days, ideally 1–3 days).

    • Must pass MolDx technical assessment (analytical validity, clinical validity, clinical utility).

  • Non-coverage (implied):

    • Panels that duplicate NGS without a turnaround/time-to-treatment benefit.

    • Tests not validated, with poor concordance to NGS, or that miss common guideline biomarkers.

    • Platforms that only cover rare targets or provide incomplete content for standard-of-care therapy selection.

2. What MolDx’s Goals and Concerns Likely Are

Although MolDx (and CMS via NCD 90.2) strongly supports broad NGS panels, this LCD signals pragmatic flexibility. Likely goals:

  • Address Turnaround Delays:
    Long waits for NGS results (2–4 weeks) often push oncologists to start empiric chemo or immunotherapy, risking worse outcomes. Rapid PCR-based panels (Idylla, ASPYRE, ChromaCode, etc.) can deliver results in hours to days.

  • Tissue Constraints:
    Small biopsies or cytology samples often fail NGS. Cartridge-based PCR panels can run on low-input or degraded samples, rescuing otherwise “quantity-not-sufficient” cases.

  • Encourage Tiered Testing Models:
    Allow labs/clinicians to use fast PCR panels for the high-frequency drivers, then reflex to NGS if negative. This improves efficiency, tissue stewardship, and may reduce unnecessary send-out NGS.

  • Balance Innovation with Guardrails:
    MolDx insists on peer-reviewed validation, high concordance, and low false-positive rates. They don’t want rapid panels to become a loophole that undermines the rigor of CGP or leads to inappropriate therapy.

  • Cost and Utilization Control:
    Coverage is framed to prevent duplicative billing (PCR panel and full CGP for every patient). The LCD stresses that multiple assays may constitute “one service,” signaling attention to economic efficiency.

3. Big Picture Takeaway

This LCD is not a retreat from NGS CGP—MolDx and CMS continue to endorse large panels for comprehensive profiling. Instead, it’s a practical bridge policy: recognizing the clinical value of rapid, non-NGS panels in situations where speed or tissue constraints trump breadth.

Think of it as CMS acknowledging:

  • NGS = gold standard, but not always practical.

  • PCR = fast, pragmatic, and valuable in the right context.

  • Together, they form a tiered ecosystem of tumor testing, with PCR as the “first strike” in some patients and NGS as the “catch-all” for negatives and rarer events.

 

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How should major NGS test providers view this LCD? How would biopharma view it? It sounds like most of the tests are non FDA, but i might be wrong on that. How does this fit with some centers like MGH, that have advocated ultra rapid early panels (like EGFR in Lung Cancer) followed in 7-14 days by NGS panels.

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Great set of questions. Here’s how I’d unpack this for your genomics strategy blog audience:

1. How Major NGS Test Providers Should View This LCD

For the large comprehensive genomic profiling (CGP) companies (Foundation, Caris, Tempus, Guardant, etc.), this LCD is both complementary and slightly competitive:

  • Complementary:
    MolDx still affirms that NGS is the gold standard for comprehensive testing. The LCD explicitly allows non-NGS panels as a triage step, with reflex to NGS if PCR is negative. This reinforces the role of CGP in covering rare variants, resistance mutations, tumor mutational burden, MSI, and tumor-agnostic biomarkers that PCR cannot detect.

  • Competitive Risk:
    If rapid PCR panels proliferate, oncologists may be more inclined to treat based on those results alone, delaying or skipping CGP in some cases. That could shrink the immediate clinical “pull” for NGS—especially in community oncology, where the turnaround problem is most acute.

  • Strategic Opportunity:
    NGS providers may benefit by positioning themselves as the second step in a tiered pathway: e.g., “we’re the comprehensive follow-up to the rapid PCR triage.” They may also co-market with rapid PCR vendors or even acquire/licence those platforms to offer bundled solutions.

In short: NGS providers should see this as a policy endorsement of a hybrid model rather than a threat to CGP’s long-term centrality.

2. How Biopharma Should View It

For drug developers, the LCD is actually a win:

  • Faster Patient Identification: Rapid PCR panels help identify patients with common, druggable mutations (EGFR, ALK, KRAS, BRAF, etc.) much earlier. This means more patients can get on targeted therapies (often in first line) instead of missing the therapeutic window.

  • Supports Companion Diagnostic Uptake: Even if many of these PCR panels aren’t FDA-cleared CDx devices, MolDx coverage makes it easier for oncologists to order guideline-mandated biomarker testing and match patients to approved drugs.

  • Broader Access in Community Settings: Biopharma is well aware that delays and tissue inadequacy in NGS testing are barriers to adoption. This LCD lowers those barriers, particularly outside academic centers.

The caveat: most of the cited tests (Idylla, ASPYRE, ChromaCode HDPCR, etc.) are not FDA-cleared CDx assays but are LDTs running under CLIA. MolDx is effectively giving these non-FDA platforms a reimbursement pathway, as long as they pass MolDx’s technical assessment. That’s unusual but consistent with MolDx’s long history of supporting LDTs where commercial CDx tests don’t fully meet clinical needs.

3. Fit with Ultra-Rapid Panel Strategies (e.g. MGH)

Centers like Mass General/Harvard have long advocated a two-step strategy:

  • Step 1: Run a very rapid single-gene or small-panel PCR test (e.g. EGFR mutations in NSCLC), with results in 24–72 hours. This avoids empiric chemo/IO in patients who might instead benefit from immediate targeted therapy.

  • Step 2: Run full NGS (7–14 days turnaround), to capture rarer drivers, resistance mutations, and trial-eligible markers.

This LCD institutionalizes that philosophy. It validates that rapid PCR testing is clinically valuable in the early window but insists that negative or incomplete cases should reflex to NGS. In other words, MolDx has effectively translated the MGH playbook into reimbursement policy.

4. Bottom Line

  • For NGS companies: This isn’t a rollback; it’s a codified two-tier model. But they must adapt messaging: “NGS is the essential complement to rapid PCR triage.”

  • For biopharma: It helps ensure more patients get on their targeted therapies quickly—boosting adoption curves.

  • On regulatory status: Most of these rapid PCR panels are non-FDA, CLIA LDTs, but MolDx’s willingness to reimburse them (subject to technical validation) means the FDA gap is not a barrier in the Medicare population.

  • In practice: This LCD brings Medicare policy into alignment with what leading cancer centers (like MGH, MSK, MD Anderson) already do—rapid initial panel + comprehensive NGS.

Would you like me to also sketch how private payers are likely to interpret this? (Some may be less inclined than MolDx to pay for both PCR and NGS, unless carefully staged.) That might round out the blog post with a payer-market lens.

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Perfect — let’s round this out with a payer-market lens, since your readership is always alert to what happens after MolDx moves first.

1. Private Payers Will Watch Closely

Commercial insurers generally take their cues from MolDx and CMS, but with more caution on cost duplication. They’ll note two things immediately:

  • MolDx frames rapid PCR panels as reasonable and necessary only when they prevent delay or specimen failure.

  • MolDx emphasizes that multiple assays may constitute a single service — i.e., don’t expect to bill PCR panels and NGS universally for every patient.

Private payers are likely to echo this emphasis: coverage is for targeted use, not carte blanche.

2. Expect Guardrails on PCR + NGS “Double Dipping”

Commercial payers are already wary of NGS utilization growth. From their perspective:

  • PCR panel alone: Acceptable if it replaces NGS for patients with limited tissue or acute need for fast results.

  • PCR followed by NGS reflex: Acceptable if the PCR is negative or incomplete.

  • PCR + NGS in every patient: High risk of denial. Insurers will see this as duplicative and not aligned with MolDx’s intent.

So expect prior authorization requirements or medical policy language requiring documentation of why both were needed.

3. Alignment with Broader Payer Trends

  • Time-to-treatment: Payers are sensitive to oncology outcomes tied to fast biomarker results. This LCD gives them language to support “early actionable biomarker detection” while still steering patients to CGP when needed.

  • Site of care dynamics: Community oncology groups (often under value-based care contracts) may find PCR panels attractive because they’re fast, low-tissue, and potentially cheaper than NGS send-outs. Private payers will favor models that reduce unnecessary NGS but don’t miss drug-eligible patients.

  • FDA status: Unlike Medicare/MolDx, commercial payers may raise more questions about LDT vs. FDA-cleared CDx. Some already write policies preferring FDA-cleared companion diagnostics when available. They could therefore be slower to embrace some of the PCR platforms cited in the LCD (Idylla, ASPYRE, ChromaCode), unless academic validation is strong.

4. Strategic Implications

  • NGS labs: Need to educate payers that PCR-first pathways risk under-detection of rarer drivers and trial markers. Their argument: “comprehensive NGS is the definitive test, PCR is an optional triage.”

  • PCR vendors: Will push the cost-savings angle (avoid unnecessary NGS, faster therapy initiation, fewer empiric chemo/IO starts).

  • Biopharma: May advocate with payers that rapid PCR triage improves patient capture for on-label targeted therapy, reducing waste on ineffective treatments.

5. Bottom Line for Private Payers

Private insurers are likely to follow MolDx’s tiered testing framework but with tighter utilization controls. Look for policies that:

  • Require medical necessity documentation for PCR + NGS.

  • Prefer FDA-cleared tests when available.

  • Restrict broad coverage to cancers where guideline biomarkers are clear (NSCLC, CRC, melanoma, thyroid).

For the industry, this means PCR-NGS tiering is now legitimized by Medicare, but private payers will push hard to ensure it’s “either/or + reflex,” not “both, always.”

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 300 WORD SUMMARY

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Here’s a concise 300-word blog-ready summary:

MolDx’s new draft LCD DL40210 carves out a role for non-NGS (PCR or similar) multigene panels in cancer testing. Coverage is allowed when patients have cancer where results inform therapy, and when NGS is either infeasible (low tissue, poor quality), not required by guidelines, or unnecessarily delays care. Panels must cover the most common actionable biomarkers (EGFR, ALK, ROS1, RET, BRAF, METex14, NTRK, KRAS/NRAS in CRC), be validated in the intended setting, deliver results faster than NGS (<10 business days, ideally hours–days), and pass MolDx technical assessment. Non-coverage applies to tests that duplicate NGS without a turnaround benefit or miss guideline-mandated targets.

MolDx’s goals are clear: reduce delays tied to NGS send-outs, enable testing of low-yield tissue, and support tiered strategies where rapid PCR identifies high-frequency drivers, with reflex to NGS if negative. Guardrails are emphasized: avoid duplicative billing, demand strong validation, and ensure positive PCR results can directly guide therapy.

For NGS companies, this is both complementary and competitive. It reinforces CGP as the “gold standard” for rare drivers and tumor-agnostic biomarkers, but PCR triage could siphon some early treatment decisions. Strategically, NGS providers may reposition themselves as the indispensable second step in a hybrid pathway or partner with rapid PCR vendors.

For biopharma, the LCD is a win. Faster PCR identification of common drivers means more patients start on targeted therapies in first line. Even though most of these assays (Idylla, ASPYRE, ChromaCode) are non-FDA LDTs, MolDx reimbursement lowers barriers to adoption, particularly in the community setting.

Private payers will likely follow MolDx but with tighter controls: coverage for PCR alone or PCR-then-NGS reflex, not “PCR plus NGS for all.” Expect prior authorization and preference for FDA-cleared tests.

In short, MolDx is institutionalizing the MGH-style hybrid model: rapid PCR upfront, NGS for breadth—bringing policy in line with what leading cancer centers already do.

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Obviously, we can't read the mind of MOLDx, but does it seem they have a negative stance - wanting to avoid paying for both upfront PCR and later NGS - or a positive stance - wanting to be sure that patients in key scenarios can get rapid focused testing while perhaps awaiting larger panels that might, for example, support TMB.

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You’re right — we can’t know MolDx’s inner stance, but the tone of DL40210 is more positive than negative. A few signals stand out:

  • Not written as a crackdown: The LCD doesn’t frame PCR panels as wasteful or duplicative. Instead, it goes to great lengths to describe situations where PCR panels are reasonable and necessary (small specimens, urgent treatment needs, avoiding empiric chemo/IO).

  • Explicit emphasis on timeliness: They cite evidence that long NGS turnaround drives inferior outcomes, and that rapid PCR results can materially improve survival. That’s a clear endorsement of PCR’s role, not a warning shot against it.

  • Guardrails, not prohibitions: The language about multiple assays counting as “a single service” and reflex-to-NGS only after negative PCR is less about discouraging PCR, and more about preventing systematic double billing. It’s fiscal discipline layered on top of a clinically positive message.

  • Consistency with practice at leading centers: By echoing the “MGH model” (rapid PCR triage + NGS follow-up), MolDx is signaling they want Medicare policy to align with best-practice workflows, not fight them.

  • Still affirming NGS as the gold standard: They don’t minimize the importance of CGP for rare alterations or tumor-agnostic markers. The policy makes PCR panels a bridge, not a substitute.

Bottom line

The stance looks pragmatically positive: MolDx is not trying to wall off NGS or punish labs for running PCR first. Rather, they want to legitimize PCR panels in key scenarios (speed, tissue limits) while ensuring they don’t become a redundant add-on to NGS. The goal is patient-centered—get results fast when it matters most—while keeping utilization and costs in check.

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It seems potentially confusing since if I am offering an NGS test, I would look to the NGS CGP LCD for coverage rules. But I'd also have to unexpectedly look to this different PCR LCD, which has some possible restrictions on NGS CGP even though the title and topic is all about non NGS! Confusing.

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Exactly — you’ve spotted one of the more confusing features here.

On its face, DL40210 is titled as a policy for non-NGS tests, but buried inside is guidance that directly affects NGS coverage in practice. A lab offering an NGS CGP panel would naturally look to the long-standing MolDx NGS LCDs (L38045, L38047). But in reality, DL40210 sets up rules about when PCR panels should be used instead of NGS, or when PCR results should precede NGS reflex. That creates an overlap zone:

  • From the lab’s perspective: You’re required to comply with both the NGS LCD and this new PCR LCD. If you ignore DL40210, MolDx could question why you billed NGS up front when the LCD describes scenarios where PCR triage is “reasonable and necessary.”

  • From the oncologist’s perspective: It muddies the waters. The message has always been “NGS is endorsed by CMS.” Now the LCD inserts a carve-out for rapid PCR — not as a competitor, but as a preferred first step in some patients.

  • From a policy perspective: The title makes it sound like a niche non-NGS policy, but the text effectively conditions NGS coverage on considering PCR first in certain scenarios. That’s what feels unexpected.

Why this matters

For NGS companies, the risk isn’t that MolDx is retracting support — it isn’t. But it does mean payers could interpret DL40210 as a utilization management tool, nudging clinicians away from “NGS for everyone on day one” and toward a tiered model. That could complicate billing, documentation, and pre-authorization.

In short: yes, it’s confusing. A policy ostensibly about non-NGS tests ends up shaping the context for NGS CGP. Labs and oncologists will now need to read these LCDs together, not separately.

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FDA VS RUO

I don't think many of these PCR tests are fully FDA approved - but I could be wrong.  Assuming that is correct (and I'd happy to revise it), would these "kits" need to be labeled RUO in the USA?

FDA & IDYLLA see an older 510K for MSI testing for Lynch genetics, and a new 2025 PMA for MSI as a CDx.

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You’re right to flag that distinction — it’s a subtle but important one.

1. FDA Approval Status

Looking at the assays referenced in the bibliography and the LCD (Idylla™ EGFR, Idylla GeneFusion, ASPYRE, ChromaCode HDPCR, digital PCR panels, etc.):

  • FEW are FDA-cleared companion diagnostics (with the exception of the Oncomine Dx Target Test FN43, which is NGS-based and FDA-approved, but that’s not the focus of this LCD; and Idylla "MSI").

  • The rest are laboratory-developed tests (LDTs) running on commercial hardware platforms (e.g., Biocartis Idylla, ASPYRE cartridge-based systems). These are manufactured kits, but they are not cleared or approved as IVDs by FDA.

So your instinct is correct: they are not FDA kits in the CDx sense.

2. Regulatory Labeling

Because they are distributed as kits, but without FDA clearance, they must be labeled “For Research Use Only. Not for use in diagnostic procedures” (RUO) under FDA rules. That creates a paradox:

  • The physical cartridges and platforms are marketed commercially, often with CE-IVD labeling in Europe.

  • In the U.S., absent FDA approval, they are RUO kits — even though in practice they are run in CLIA labs as part of validated LDTs.

3. MolDx’s Position

What MolDx is doing here is essentially saying: “We don’t require FDA approval for these panels. If you validate them as LDTs under CLIA, and if they pass MolDx technical assessment, we will cover them.”

This is consistent with MolDx history: they’ve long reimbursed non-FDA NGS LDTs (FoundationOne before FDA approval, Tempus, Caris, etc.). The difference here is they’re extending the same policy flexibility to rapid PCR kits running as LDTs.

✅ Takeaway:
These are indeed kits running on manufactured platforms, but since they’re not FDA-cleared, they must be labeled RUO. MolDx is effectively stepping in to provide reimbursement despite the RUO labeling, relying on its own technical assessment as the arbiter of clinical validity and utility.

 

 If you enjoyed this LCD on the dynamics of PCR testing, you might enjoy:

Liu L et al. (2025) Research Trends and Development Dynamics of qPCR-based Biomarkers: A Comprehensive Bibliometric Analysis.  Molecular Biotechnology (1/22/2025).  PMID 39843617.