Sunday, November 10, 2024

Now Streaming: CAP Webinar on How FDA Defines Risk (w/ Tim Stenzl MD)

CAP is running a series of major webinars on how FDA regulates laboratory-developed tests.   They remark the series is intended to follow, mirror, and translate the FDA's own webinar series on LDT regulation.

They've now posted the video stream (and 42 slide deck) from their September 18, 2024 webinar on FDA and LDT risk classification.  And their speaker is Tim Stenzl MD, who until earlier this year was head of diagnostics at the FDA.

Find the CAP webinar here:

https://www.cap.org/calendar/webinars/understanding-the-impact-of-the-fdas-ldt-risk-classification-on-your-laboratory

Get the deck here:

https://documents.cap.org/documents/CAP-webinar_Understanding-Impact-FDA-LDT-Risk-Classification.pdf



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AI Corner

Otter.ai made an auto-outline of the webinar.

 

Outline

 

Introduction to the Webinar Series and FDA Final Rule

  • Dr Karcher (CAP) introduces the webinar series aimed at preparing pathologists and laboratories for the FDA final rule on LDT oversight, emphasizing the importance of Stage One, which becomes effective in May 2025.
  • The webinar series is designed to shadow corresponding FDA webinars, making complex information more accessible to laboratorians.
  • The goal is to provide practical steps and resources for compliance with the final rule, though definitive instructions are not given.
  • Dr Karcher provides a brief introduction, highlighting their background and experience in LDT oversight.

Background and Legislative Context

  • Dr Karcher provides a historical overview of FDA oversight of LDTs, mentioning various legislative proposals and the most recent, the Verity Act, which did not pass in 2022.
  • The FDA proceeded with regulation of LDTs based on their current statutory authority, releasing a proposed rule in September 2023 and a final rule in April 2024.
  • The final rule employs a three-tiered, risk-based structure, phasing out enforcement discretion, and includes five stages ending in May 2028.
  • Stage One involves compliance with medical device reporting, correction and removal reporting, and quality system requirements for complaints regarding an LDT.

CAP's Advocacy Principles and Opposition to the Final Rule

  • Dr Karcher outlines CAP's advocacy principles, emphasizing patient protection, continued development of innovative LDTs, and a least burdensome and costly regulatory framework.
  • CAP opposes the final FDA rule and supports legislation to reduce regulatory burdens and introduce maximum flexibility in FDA oversight.
  • The organization also supports legal efforts to stop the implementation of the final rule.
  • Despite the potential changes in the rule's implementation, CAP aims to ensure laboratories are prepared to comply with the regulations.

Understanding LDTs and CLIA Regulations

  • Dr Karcher defines an LDT as an in vitro diagnostic product intended for clinical use, designed, manufactured, and used within a single clinical laboratory, and meets CLIA requirements for high complexity testing.
  • CLIA categorizes tests as moderate or high complexity, based on seven factors including knowledge needed to perform, reagents, materials, and interpretation required.
  • The FDA risk classification system is based on patient risk, classifying tests into low risk (Class 1), moderate risk (Class 2), or high risk (Class 3).
  • The intended use of the test and the risk posed to patients determine the classification.

Introduction of Dr. Tim Stenzl and His Background

  • Dr Karcher introduces Dr. Tim Stenzl, highlighting his extensive experience in molecular pathology and leadership roles at Duke University and the FDA.
  • Dr. Stenzl is the former director of the FDA Office of In Vitro Diagnostics and is not representing the FDA in this webinar.
  • Dr. Stenzl's presentation will focus on the FDA risk classification system and provide practical guidance for laboratorians.

Dr. Stenzl's Presentation on FDA Risk Classification

  • Dr. Stenzl begins by stating that he is only expressing his opinion and not representing the FDA.
  • He emphasizes the importance of understanding the FDA's approach to risk classification and provides disclaimers about the use of non-FDA language.
  • Dr. Stenzl explains the ongoing reclassification process at the FDA, focusing on companion diagnostics and other IVDs.
  • The FDA has exempted almost all Class 1 tests from FDA review, and the reclassification process involves expert panels and public comments.

Details of FDA Risk Classification and Submission Requirements

  • Dr. Stenzl explains the classification of clinical laboratory tests into Class 1 (low risk), Class 2 (moderate risk), and Class 3 (high risk).
  • The classification determines the appropriate pre-market regulatory process and the type of application needed (510(k), de novo, or PMA).
  • The intended use of the test, including the purpose, methodology, patient population, and where the test is performed, influences the classification.
  • Dr. Stenzl provides examples of intended use statements and explains how the FDA determines the risk classification based on these statements.

Examples of FDA Classification and Submission Process

  • Dr. Stenzl provides examples of Class 1, Class 2, and Class 3 tests, explaining the submission requirements for each classification.
  • He emphasizes the importance of knowing the risk classification of a test to determine the validation work needed and whether submission to the FDA is required.
  • Dr. Stenzl explains the process of creating a product code for novel tests and how subsequent similar tests can use the same product code.
  • He highlights the FDA's product classification database and how to search for similar tests to determine the classification and submission requirements.

Q&A Session with Dr. Stenzl

  • Dr. Stenzl answers questions from the audience, addressing topics such as the impact of risk classification on immunohistochemistry, validating current LDTs, and the implications of changing sample types.
  • He explains that automated staining or image analysis on non-FDA cleared reagents would require submission to the FDA.
  • Dr. Stenzl advises using the FDA's product classification database and decision summaries to validate tests and determine the appropriate regulatory controls.
  • He clarifies that not all modifications to a test require FDA submission and that the FDA has a pre-submission process for answering questions.

Final Takeaways and Next Steps

  • Dr Karcher summarizes the key points from Dr. Stenzl's presentation, emphasizing the importance of understanding the FDA's risk classification system and the differences between FDA risk and CLIA complexity.
  • The FDA recommends searching their database for similar tests to determine the appropriate regulatory controls and risk classification.
  • The webinar series will continue with five more sessions, each focusing on different aspects of the FDA final rule.
  • Dr Karcher thanks Dr. Stenzl for his insights and the CAP staff for organizing the webinar, and encourages attendees to register for the remaining sessions.  {End, Otter.ai]
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Here is a short news article written by Chat GPT.  I asked it for a short journalistic report based on an auto-transcript.   I also asked it to replace "Speaker 1" with "Dr Karcher" and to correct the spelling "Dr Stencil" to "Dr Stenzl" and it was able to do so. 
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CAP Launches Webinar Series on FDA’s Final Rule for Laboratory-Developed Test (LDT) Oversight

The College of American Pathologists (CAP) has launched a six-part webinar series to guide pathologists and clinical laboratories through the complexities of the FDA's new final rule on LDT oversight. In the inaugural session, CAP President Dr. Karcher and former FDA Office of In Vitro Diagnostics director Dr. Timothy Stenzl discussed the background, stages, and risk classifications that underpin the FDA's regulatory framework.

Dr. Karcher emphasized that while legal challenges to the FDA rule continue, CAP aims to ensure laboratories are prepared should the rule proceed. Stage One of the final rule, effective in May 2025, will introduce compliance requirements for reporting complaints and quality issues for LDTs. The remaining four stages, ending in 2028, will bring additional oversight to higher-risk LDTs. CAP has consistently opposed the final rule, advocating for a regulatory framework that balances patient safety with innovation and minimizes costs for pathologists.

Dr. Stenzl provided an in-depth review of the FDA's risk-based classification system. Unlike CLIA, which categorizes tests by complexity, the FDA evaluates LDTs based on patient risk. Using FDA-cleared platforms and reagents can sometimes exempt certain modifications from FDA submission. For laboratories developing novel tests or modifications, Dr. Stenzl recommended utilizing FDA databases to align with existing classifications and seeking FDA guidance for clarity.

With five webinars remaining, CAP's series aims to provide actionable guidance for pathologists navigating the regulatory changes. Upcoming sessions will continue to interpret FDA requirements with a laboratory-centered approach, easing the transition for clinical labs nationwide.

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That was kind of bare-bones.  I asked for a more detailed article.  

Please provide a more detailed, deep dive report on the actual issues and problems, and then, provide a summary of 15 key takeaways.

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In-Depth Analysis of CAP Webinar on FDA’s Final Rule for LDT Oversight

The CAP’s first session in a six-part webinar series provided a comprehensive overview of the FDA's final rule on LDT (laboratory-developed test) oversight, detailing the motivations behind the rule, the specifics of the regulatory framework, and its anticipated impact on clinical laboratories. This session, presented by CAP President Dr. Karcher and former FDA official Dr. Timothy Stenzl, addressed both technical and practical challenges associated with compliance, particularly under Stage One of the five-stage rule. Here is a detailed look at the core issues discussed, as well as a concise list of 15 essential takeaways.

Core Issues and Challenges

  1. Ambiguity in Classification and Compliance
    The FDA’s three-tiered risk classification for LDTs (Class I, II, and III) is not straightforward, causing confusion among laboratories about the specific regulatory requirements for each risk class. Labs face uncertainty in determining which tests require submission and what validations are necessary for compliance, particularly when test modifications are made.

  2. Overlap and Divergence from CLIA
    The FDA’s risk-based classifications for LDTs differ fundamentally from CLIA’s complexity-based categories (moderate vs. high complexity), creating potential overlap and misalignment. For laboratories already accustomed to CLIA guidelines, the FDA’s different criteria pose a challenge in adjusting protocols to meet dual standards.

  3. Stage One Compliance Requirements
    Stage One, effective May 2025, mandates that labs have a robust reporting and quality control process for complaints. Many laboratories may need to implement or modify existing complaint-handling and quality control procedures to meet the specific demands outlined by the FDA, which are more stringent than traditional CLIA protocols.

  4. Confusion Over the Scope of “Grandfathering”
    Labs are uncertain about which LDTs qualify as “grandfathered” under the rule, particularly with tests developed after May 2024 but before the final submission deadline. Tests meeting the “grandfather” criteria must avoid modifications that might trigger a new FDA classification, thus affecting compliance obligations.

  5. Challenges with Modifications and Reclassification
    Modifications to LDTs, including changes to sample types or methodologies, could reclassify a test as a new LDT under FDA rules, potentially necessitating submission or resubmission. Dr. Stenzl pointed out that this adds complexity, as minor alterations could escalate the regulatory requirements for a test that otherwise would not need FDA oversight.

  6. Risks of Non-compliance Due to Undefined Validation Standards
    Without clear FDA validation standards for each risk level, laboratories are left to reference other FDA-cleared or approved tests to approximate compliance requirements. For labs developing novel tests without an FDA-comparable precedent, this presents a significant compliance risk.

  7. Increased Documentation Burden
    The FDA’s quality system requirements necessitate extensive documentation and tracking, especially in areas such as complaint handling and adverse event reporting. This documentation increase is seen as costly and time-intensive, with smaller labs possibly struggling to keep up with resource demands.

  8. Impact on Innovation in Laboratory Testing
    CAP has expressed concerns that the final rule might stifle innovation, as stringent requirements may discourage labs from developing novel LDTs due to the regulatory burden. This could limit patient access to specialized tests, particularly in rare disease and oncology sectors where tailored testing can be essential.

  9. Cost Implications for High-Complexity Labs
    High-complexity labs accustomed to CLIA standards may incur substantial costs adapting to FDA oversight. Costs could arise from implementing new quality systems, training personnel, or hiring additional staff to manage compliance, all of which affect smaller labs disproportionately.

  10. Lack of Clear FDA Guidance on Test Modifications
    Laboratories struggle with knowing which modifications necessitate reclassification and submission. The FDA’s current approach lacks detailed guidance on this issue, leaving labs in a position of potential non-compliance or excessive caution that limits operational flexibility.

  11. Potential Liability for Errors in Test Modifications
    If modifications trigger unintended reclassifications, labs risk penalties for unauthorized use of LDTs without FDA clearance. CAP has highlighted that labs face potential liability if unrecognized reclassifications lead to the use of unapproved tests in clinical settings.

  12. Pressure to Meet Compliance Deadlines
    The timelines set by the FDA for compliance in Stage One (May 2025) and beyond are challenging for labs needing significant adjustments. While large labs may have compliance frameworks in place, smaller labs face difficulties implementing the necessary changes in time.

  13. Public Database Use and Accessibility
    Dr. Stenzl recommended labs utilize the FDA’s product classification databases, but navigating these databases is complex, especially for staff unfamiliar with FDA terminology. This complexity could lead to errors in classification that impact compliance.

  14. Impact of FDA Rule on IHC and Other Specialized Testing
    Immunohistochemistry (IHC) and other specialized tests are only exempt from FDA submission under specific conditions, creating uncertainty for labs about which tests must comply. CAP has argued that the exemptions should be expanded to reduce unnecessary compliance burdens.

  15. Administrative Burden of Pre-submission Inquiries
    The FDA’s pre-submission process can take up to 75 days to provide a determination, which delays laboratories seeking clarity on test classification and compliance. This slow turnaround can hinder labs’ ability to implement compliant protocols promptly.

15 Key Takeaways

  1. Three-Tiered Risk Structure: The FDA classifies LDTs as Class I (low risk), Class II (moderate risk), or Class III (high risk), each requiring different levels of compliance.
  2. Compliance for Stage One (May 2025): Labs must establish complaint handling, quality system procedures, and reporting for adverse events by this deadline.
  3. Distinct FDA vs. CLIA Criteria: FDA’s risk classification focuses on patient risk, contrasting with CLIA’s complexity-based standards, requiring laboratories to adapt to dual systems.
  4. Grandfathering Uncertainty: Tests developed before May 2024 may be “grandfathered,” but significant modifications could void this status and trigger compliance needs.
  5. Modification Triggers Compliance: Altering test parameters, such as sample type, could necessitate FDA submission, posing a challenge for labs using LDTs.
  6. Unclear Validation Standards: Labs are encouraged to reference similar FDA-cleared tests for validation, though exact standards remain undefined.
  7. Documentation and Quality System Demands: The final rule requires meticulous documentation, especially in complaint handling and corrective actions, adding resource strain.
  8. Costly Impact on Smaller Labs: Adapting to FDA requirements may be financially burdensome, particularly for smaller high-complexity laboratories.
  9. Innovation Risks: Strict requirements could inhibit innovation in LDT development, limiting new test offerings in high-need areas such as rare diseases.
  10. Public Database Navigation: The FDA’s product database aids classification, though its complexity may lead to compliance errors for unfamiliar users.
  11. Exemptions for IHC and Manual Tests: Some immunohistochemistry and manual tests are exempt if using FDA-cleared platforms; however, automation might require FDA submission.
  12. Pre-submission Process Delays: The 75-day pre-submission inquiry process can slow down labs seeking classification clarification and compliance advice.
  13. Penalties for Unauthorized LDT Use: Unintended test modifications could lead to unapproved LDT use and potential regulatory penalties.
  14. Reliance on FDA Database for Compliance: Labs can use the FDA database to approximate compliance but may need tailored guidance for novel or unique LDTs.
  15. Upcoming Webinars for Guidance: CAP’s remaining webinars will continue to interpret FDA requirements, aiding labs in understanding and meeting compliance obligations.

By addressing these issues, CAP’s series aims to equip laboratories with the necessary knowledge and resources to navigate the regulatory complexities of the FDA’s final rule.