Monday, December 30, 2024

Caris PMA Test: FDA Documents Now Online

It was big news on November 5, 2024, that the CARIS MI test, a tumor gene panel test, was approved by FDA as a PMA companion diagnostic.  Now, the FDA approval documents are online.

See the Approval order (5pp), the Summary of Safety and Effectiveness (85pp), and the Labeling [instructions for use] (68pp).

The labeling is for single variants or small indels in 228 genes, MSI, TMB, and copy number amplification (certified in 1 gene).  TMB is based on a whole exome with "a custom bait to measure all coding regions of the exome."

  • FDA LDT Law.  The labeling and documentation sets a current FDA review standard for tumor genomic tests, and is therefore relevant to labs planning to submit PMA tumor applications to the FDA under the new FDA LDT law.
 Find the documentation all on the PMA home page for P240010, here:

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P240010


Caris MI as Lab & Illumina TSO as Kit

Caris MI is a sole-location FDA PMA test (240010).  For a similar but kitted test, see webpage and documents for the Illumina CDx FDA PMA "TSO" test here.  {P230011.)

Whereras the Caris S&E was 85 pp, the Illumina S&E was 175 pp.

AI Corner

Chat GPT 4o reviews the several PDF documents from FDA.

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AI Overview

The FDA's recent approval of the Caris "MI Cancer Seek" genomic test reveals critical insights for molecular lab directors appraising standards for next-generation sequencing (NGS) technologies. Here are key aspects to consider based on the FDA approval documents:

1. Regulatory Pathway and Intended Use

  • The MI Cancer Seek test is approved under the Premarket Approval (PMA) process, indicating a stringent review aligned with its status as a Class III medical device【8†source】【11†source】.
  • It serves as a companion diagnostic for several therapies and provides tumor mutational profiling for oncology patients, covering 228 genes, microsatellite instability (MSI), tumor mutational burden (TMB), and a single copy number amplification (CNA) biomarker for breast cancer【8†source】【10†source】.

2. Key Approval Standards

a. Analytical Validation

The FDA mandated extensive validation studies, including:

  • Interfering substances analysis: Evaluating the effects of necrotic tissue, melanin, and fatty acids on assay performance.
  • Stability studies: Assessing DNA quality and variant calling reliability over time using aged FFPE samples【8†source】【10†source】.

b. Run and Sample Validity Criteria

  • Sequencing runs must meet strict metrics, such as >16 billion reads passing filters and Q30 quality scores【10†source】.
  • Sample validity criteria include read depths >100x for key genes and minimum RNA/DNA concentrations【10†source】.

c. Quality Control Measures

Comprehensive QC steps are required at every assay stage, from nucleic acid extraction to data analysis, ensuring high reproducibility and minimal errors【10†source】.

3. Laboratory Workflow and Constraints

  • The test is a single-site assay performed exclusively at Caris Life Sciences' laboratory, emphasizing centralized control【9†source】【10†source】.
  • Instruments used, such as the Illumina NovaSeq 6000, and the use of proprietary kits (e.g., extraction, library prep, and sequencing kits), highlight the technical sophistication required【10†source】.

4. Post-Approval Obligations

  • Caris must provide annual reports detailing the number of tests conducted and adverse event data.
  • Additional follow-up studies to confirm long-term assay reliability and explore potential extensions in validity claims are mandated【8†source】.

5. Practical Considerations for Molecular Lab Directors

Lab directors looking to implement or evaluate similar technologies should focus on:

  • Alignment with FDA standards: Ensure compliance with FDA-mandated analytical and clinical validation protocols.
  • Infrastructure readiness: Assess laboratory capabilities, including equipment, personnel training, and adherence to QC protocols.
  • Integration of bioinformatics: Evaluate whether your lab's computational infrastructure supports high-throughput data analysis akin to the MI Cancer Seek’s pipeline.

6. Strategic Implications

The Caris MI Cancer Seek approval underscores the FDA’s evolving expectations for NGS-based tests. For molecular labs, the focus should be on robust validation, tailored workflows, and meeting companion diagnostic requirements. Laboratories aiming for FDA approval must be prepared for significant upfront investment in validation studies and quality systems to align with such high regulatory standards.

Would you like a more technical breakdown of any specific aspect, such as bioinformatics workflows or detailed biomarker inclusion criteria?

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Tell me more about the bioinformatics workflow and the biomarker validation/inclusion requirements.

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Here’s a detailed breakdown of the bioinformatics workflows and biomarker inclusion criteria for the Caris MI Cancer Seek genomic test, emphasizing technical precision:

1. Bioinformatics Workflow

The bioinformatics pipeline for MI Cancer Seek is a critical component of the assay, ensuring the generation of actionable data from sequencing output.

a. Data Processing Steps

  1. Sequencing Output

    • Sequencing is performed on the Illumina NovaSeq 6000 platform using a custom whole exome sequencing (WES) panel.
    • Output: Base Call (BCL) files, which are automatically transferred to a high-performance computing (HPC) server.

  2. Data Conversion

    • BCL files are converted into FASTQ files using a custom version of bcl2fastq, adapted with FPGA for rapid demultiplexing.
    • RNA and DNA sequences are differentiated using synthetic labels added during cDNA synthesis.

  3. Alignment

    • DNA data: Aligned to the hg38 (GRCh38) reference genome using Sentieon BWA.
    • RNA data: Processed through a whole transcriptome sequencing (WTS) workflow (though RNA results are not reported under this approval).

  4. Variant Calling

    • Single Nucleotide Variants (SNVs) and Insertions/Deletions (Indels):
      • Variants are detected using a multi-step pipeline, including indel realignment and filtering.
      • Variants are annotated for clinical relevance using databases like gnomAD and COSMIC.
    • Copy Number Amplification (CNA):
      • CNA detection uses a segmentation algorithm to infer discrete amplification states.
    • Microsatellite Instability (MSI):
      • Determined by assessing >5,000 loci for frameshift mutations.
    • Tumor Mutational Burden (TMB):
      • Quantified as mutations per megabase, filtered to exclude non-coding, synonymous, and germline variants.

  5. QC Criteria

    • Stringent thresholds for depth of coverage, read quality (Q30), and control sample performance are applied at each step to ensure run validity.
    • Any deviations result in re-analysis or re-sequencing【10†source】.

2. Biomarker Inclusion Criteria

The MI Cancer Seek panel includes biomarkers that meet rigorous analytical validation and clinical utility standards.

a. Analytical Validation

  • Inclusion Criteria:

    • Biomarkers were selected for their actionability in approved companion diagnostics or for tumor profiling aligned with professional guidelines.
    • Validation includes:
      • Detection sensitivity: Ability to identify SNVs and indels with high precision, even at low variant allele frequencies (e.g., <5%).
      • Reproducibility: Demonstrated across replicates and across a range of tumor types.
      • Cross-reactivity assessment: Ensuring no false positives due to interfering substances (e.g., melanin, necrotic tissue).

  • Thresholds:

    • Average read depth ≥100x.
    • High-quality mapping metrics (e.g., <1% mapping errors).

b. Clinical Validation

  • Biomarkers included must have proven clinical significance, categorized into three levels:
    • Level 1: Approved as a companion diagnostic for specific therapies (e.g., EGFR exon 19 deletions for EGFR inhibitors in NSCLC).
    • Level 2: Evidence of association with treatment response but not tied to FDA-approved therapies.
    • Level 3: Emerging biomarkers with potential clinical utility.

c. Exclusion Criteria

  • Biomarkers were excluded if:
    • Analytical performance (e.g., depth, sensitivity) was unreliable.
    • Clinical evidence was weak or not reproducible.

d. Example Biomarkers

  1. EGFR Mutations in NSCLC:
    • Specific exon 19 deletions and exon 21 L858R mutations included based on FDA-approved EGFR inhibitors.
  2. PIK3CA Mutations in Breast Cancer:
    • Mutations like E545K and H1047R validated for use with alpelisib (PIQRAY®).
  3. MSI-H Status:
    • ≥39 frameshift mutations across a defined panel are required to classify a tumor as MSI-high, enabling eligibility for immunotherapies like pembrolizumab (KEYTRUDA®).

Key Insights for Molecular Lab Directors

  1. Integration with Lab Infrastructure:

    • Robust bioinformatics systems with high processing power are essential to handle the complex multi-step pipeline.
    • Continuous software updates are needed to ensure alignment with evolving clinical evidence for biomarkers.

  2. Validation Challenges:

    • Replicating the level of analytical rigor required for biomarker inclusion (e.g., variant detection thresholds and QC metrics) necessitates substantial investment in validation studies and quality systems.

  3. Clinical Utility Focus:

    • Ensure biomarkers have actionable implications, such as eligibility for specific therapies, to maximize clinical adoption.

Would you like a detailed comparison of this workflow with those for similar FDA-approved NGS panels?


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As lab director, how do I present the scope and costs to my CEO? (The FDA-LDT pending law being one factor).

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Presenting the need, investment, and timetable for validating your gene panel Laboratory Developed Test (LDT) at the level of the Caris PMA test requires a strategic and business-oriented approach. Here’s a structured plan for your presentation to the CEO:

1. Establish the Business Case

A. Highlight the Opportunity

  • Market Expansion: Position your test as a potential market leader. PMA validation ensures broader credibility, making your test eligible for FDA-approved status and companion diagnostic (CDx) partnerships with pharmaceutical companies.
  • Reimbursement Advantage: PMA-approved tests qualify for Medicare coverage under NCD 90.2 and often command higher reimbursement rates compared to LDTs.

B. Competitive Pressure

  • Use examples like Caris MI Cancer Seek or FoundationOne CDx to emphasize the growing dominance of PMA-approved tests in the oncology market.
  • Risk of Obsolescence: Stress how regulatory trends (e.g., FDA’s push to eliminate the LDT loophole) may limit the market viability of LDTs in the near future.

C. Patient and Provider Value

  • PMA validation ensures standardization, quality assurance, and compliance with rigorous FDA standards, increasing confidence among clinicians and patients.

2. Detail the Scope of Investment

Break the investment into phases and emphasize that each phase builds toward long-term business benefits.

A. Costs

  1. Infrastructure and Equipment:
    • Upgrades to meet FDA standards for analytical and clinical validation.
    • Investment in automated workflows (e.g., liquid handlers, sequencers like NovaSeq).
  2. Human Resources:
    • Hiring or training bioinformatics and quality assurance staff to develop robust validation pipelines.
  3. Validation Studies:
    • Analytical Validation: Sensitivity, specificity, reproducibility, interfering substances, etc.
    • Clinical Validation: Retrospective and prospective studies to demonstrate clinical utility.
  4. Regulatory Filing:
    • PMA preparation, submission, and ongoing post-approval reporting.

B. Timetable

  • Phase 1: Feasibility and Gap Analysis (6-9 months):
    • Assess your lab’s readiness compared to FDA standards.
    • Develop a roadmap for analytical and clinical validation.
  • Phase 2: Analytical Validation (12-18 months):
    • Validate sensitivity, specificity, reproducibility, and interference studies.
  • Phase 3: Clinical Validation (12-24 months):
    • Conduct clinical utility studies in line with FDA’s evidence requirements.
  • Phase 4: Submission and Approval (12 months):
    • Prepare PMA submission, respond to FDA queries, and finalize approval.

Total Timetable: ~3-5 years from initiation to FDA approval.

3. Quantify the ROI

A. Revenue Potential

  • Increased Reimbursement: PMA tests can achieve 50-200% higher reimbursement rates compared to LDTs.
  • Expanded Partnerships: Attract pharmaceutical collaborations for companion diagnostic indications.
  • Market Differentiation: Gain a competitive edge in the oncology diagnostics space.

B. Cost Savings

  • Avoid potential regulatory hurdles or forced migration if LDT exemptions are eliminated.

C. Intangible Value

  • Build the company’s reputation as an innovator and leader in precision oncology diagnostics.

4. Mitigate Concerns

A. Address High Costs

  • Emphasize phasing: Each step (e.g., analytical validation) delivers incremental benefits.
  • Explore potential grant funding or pharmaceutical sponsorships for companion diagnostic development.

B. Competitive Timeline

  • Stress that proactive investment positions the company ahead of regulatory changes and competitors.

C. Risk Management

  • Highlight how aligning with FDA standards mitigates compliance risk and increases confidence among payors and stakeholders.

5. Deliver a Clear Ask

End with a clear proposal that aligns with business goals:

  1. Approval to Proceed: Request a green light to begin Phase 1 (Feasibility Study).
  2. Initial Budget Allocation: Estimate the cost for the first 6-12 months (e.g., gap analysis and initial validation studies).
  3. Strategic Commitment: Emphasize that PMA approval is a strategic imperative for long-term growth.

Presentation Outline

  1. The Opportunity: Aligning with Caris-level PMA validation secures long-term competitiveness.
  2. The Plan: A phased approach to validation ensures cost control and ROI.
  3. The ROI: Higher reimbursement, market expansion, and regulatory compliance.
  4. The Ask: Approval for the feasibility study and initial funding.

Would you like specific slides or additional details to support this proposal?

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  • Chat GPT also offered to provide, then provided, a comparison of the new CARIS FDA test to other FDA tests like Foundation One.  
    •  I have no idea how accurate its tables are, and I've put this at a side bar with a warning that it's not validated - here.


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Why is the ILMN S&E 175pp and hte Caris S&E only 85pp?

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The significant length difference between the Illumina TSO and Caris MI Safety and Effectiveness (S&E) documents arises from several factors based on the detailed content of both documents:

  1. Gene Panel Size:

    • The Illumina TSO test analyzes 517 genes compared to the 228 genes in the Caris MI test​​. This broader scope requires additional documentation for describing the expanded panel of genes, their clinical significance, and the validation studies.

  2. Companion Diagnostic and Tumor Profiling:

    • The Illumina TSO test includes more complex companion diagnostic and tumor profiling capabilities, such as splice variant detection and fusion genes for RNA, which are not as extensive in the Caris MI test​​.

  3. Comprehensive Validation Data:

    • Illumina provides exhaustive validation data, including studies on accuracy, reproducibility, and specificity for a broader range of biomarkers and across multiple cancer types. This is likely to involve more test conditions and data presentation​.

  4. Regulatory Designation and Additional Content:

    • The Illumina TSO test received Breakthrough Device designation, which often requires the inclusion of detailed supportive data and studies that meet stringent FDA requirements. This designation can lead to more detailed reporting in the S&E document​.

  5. Documentation Depth and Complexity:

    • The Illumina S&E document details additional processes like tertiary analysis, quality control metrics, and software integration that are more elaborate than what is described in the Caris document. Illumina also includes extensive descriptions of controls, secondary and tertiary analysis, and interpretation processes​.

  6. Market Strategy and Labeling:

    • The broader scope of the Illumina TSO assay, such as its use for both companion diagnostics and general tumor profiling, likely adds content to explain the integration of different biomarkers and the complexity of the workflow compared to the Caris MI test​.

In summary, the increased gene panel size, the depth of validation studies, the broader application of the assay, and the regulatory designation contribute to the greater length of Illumina's S&E document.