ADLM Webinar on FDA LDT - Sept 25 2024

ADLM held an excellent 1 hour webinar on the FDA LDT compliance issues that labs are racing.  ADLM will post a link to the webinar in a few days.

Here is an AI summary.

FDA's New Lab Industry Requirements: Navigating the Regulatory Landscape

In May 2024, the FDA issued a sweeping final rule that significantly impacts laboratories developing Laboratory Developed Tests (LDTs). This new regulation is poised to shift how clinical labs operate, imposing FDA oversight traditionally reserved for commercial test manufacturers. While the rule promises to standardize safety and quality, it places laboratories in uncharted territory, with new compliance requirements and hefty penalties for non-compliance.

The Association for Diagnostics and Laboratory Medicine (ADLM) recently held a webinar to help laboratories decode the FDA’s regulatory roadmap. Here’s what labs need to know to prepare for these transformative changes.

The Five-Stage Regulatory Framework

The FDA's LDT rule is rolled out in five stages, gradually introducing more complex requirements. Stage 1, which takes effect in May 2025, is quickly approaching and primarily focuses on adverse event reporting, product corrections, and complaint files. Stages 2 and 3 will follow in 2026 and 2027, respectively, requiring formal registration, device labeling, and compliance with FDA’s Quality System Regulations (QSRs). Stages 4 and 5, beginning in 2027 and 2028, will introduce even stricter oversight, including pre-market approval for high-risk LDTs and FDA clearance for moderate-risk tests.

Stage 1: Immediate Requirements

Medical Device Reporting (MDR): Starting in May 2025, labs must report serious adverse events (e.g., deaths or injuries) and device malfunctions to the FDA within 30 days. In cases of urgent remedial actions to prevent harm, reports must be submitted within 5 days. Labs will need to establish formal procedures for MDR compliance, including using FDA’s MedWatch Form 3500A and assigning an FDA Establishment Identifier (FEI) number. Notably, the FDA now views labs as "manufacturers," a designation that brings new regulatory burdens.

Corrections and Removals: If a laboratory identifies a flaw in its LDT (e.g., a contaminated reagent or faulty device), it must notify the FDA and follow specific correction or removal protocols. A simple buffer replacement could trigger these rules, making labs susceptible to public recalls under the FDA’s expansive recall system.

Complaint Files: Labs must create a system to document, review, and respond to complaints about their LDTs. Any complaint, including those received orally, must be documented, and labs must assess whether complaints trigger MDR obligations. This system must be set up by May 2025 and will be subject to future FDA inspections.

Stage 2: Registration, Labeling, and Investigational Devices

Registration and Listing: By May 2026, laboratories must register with the FDA as manufacturers, a process that includes paying user fees (currently set at $9,280 per year). Labs will also need to list all of their LDTs with the FDA, breaking down the assays they use and specifying whether each is modified from an FDA-approved test or a pure LDT. Compilation of these lists will require substantial internal audits.

Device Labeling: The FDA expects each LDT to be fully documented with comprehensive device labeling—akin to a package insert for commercially marketed diagnostic tests. This includes not only assay performance data but also detailed patient and provider instructions. Labs should begin familiarizing themselves with FDA labeling requirements, as the process is complex and cannot be completed at the last minute.

Investigational Device Exemptions (IDE): For labs conducting clinical trials with LDTs, IDE regulations will come into play. Labs using LDTs as part of clinical trials must ensure their tests comply with investigational device rules unless exempt.

Stage 3: Quality System Regulations (QSR) Compliance

In May 2027, the FDA’s QSRs will take effect, marking a seismic shift for labs. Traditionally designed for device manufacturers, QSRs include stringent design controls, purchasing controls, and corrective and preventive actions (CAPA). Labs developing new LDTs or modifying existing tests will need to document these processes meticulously. Labs that fail to follow QSR requirements may face regulatory action, even for LDTs that have been safely used for years.

One of the most significant changes in Stage 3 is the requirement for design controls, which mandates that all test validations follow a stepwise, FDA-approved process. Labs that develop or modify LDTs will need to maintain detailed design history files for each test. This means that any LDT development done without following these protocols will need to be revalidated under the new system, adding an enormous administrative burden.

Stages 4 and 5: Premarket Approvals and FDA Submissions

By November 2027, labs developing high-risk LDTs will need to submit them for pre-market approval, mirroring the approval process for traditional medical devices. Low- and moderate-risk LDTs must be submitted through FDA's 510(k) or de novo pathways by May 2028.

The FDA estimates that bringing an LDT through this process could cost between $250,000 and $4.5 million per assay, a prohibitive price for many smaller laboratories. Labs will need to weigh these costs against their clinical utility and volume of use.

Challenges and Considerations for Labs

While some aspects of the rule are clear, the FDA has left many questions unanswered, leading to considerable uncertainty within the lab community. Key challenges include:

• Enforcement Scope: The FDA must inspect thousands of clinical labs to ensure compliance, but the agency's capacity to handle such oversight is questionable. Labs are also grappling with how dual regulation under CLIA and FDA will play out, particularly when standards between the two overlap.
• Resources and Costs: Complying with the new rules will be resource-intensive, and labs need to start budgeting now. User fees, staff training, and the potential costs of revalidating LDTs under FDA standards will weigh heavily on smaller labs.
• Turnaround Time: Labs may apply for enforcement discretion under the "unmet need" category if LDTs provide critical, time-sensitive results that FDA-approved tests cannot match. However, these labs will not be able to serve external customers under this category, limiting their reach.

Looking Ahead: Lawsuits and Legislative Uncertainty

The FDA’s final rule is being challenged in court by the American Clinical Laboratory Association (ACLA) and the Association for Molecular Pathology (AMP). These lawsuits, currently being heard in Texas, could alter the scope of FDA authority over LDTs. Additionally, the recent Supreme Court ruling striking down the Chevron deference doctrine may reduce the FDA’s leeway in interpreting the rule, making future legislative action a critical battleground for the lab community.

While Congress has shown interest in intervening, the specifics of any legislative proposal could either alleviate or exacerbate the regulatory burden. For now, labs must proceed under the assumption that the FDA’s rule will stand, making compliance preparation urgent.

Conclusion

The FDA’s final rule on LDTs represents a sea change for laboratories, bringing them under stricter scrutiny and imposing costly compliance measures. While the aim is to ensure safety and effectiveness, the practical realities of implementing these changes will place a heavy burden on the industry. Laboratories must start preparing now, even as they await potential relief from lawsuits or legislative action.

As the deadlines loom, the lab community will need to navigate these new regulations carefully, ensuring both compliance and continued access to critical diagnostic tests.

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Focus on the Q&A sessions.

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Summary of Q&A from the Webinar on FDA’s New Lab Industry Requirements

The Q&A session during the webinar covered various clarifications regarding the FDA’s new rules for Laboratory Developed Tests (LDTs). Below is a summary of each key question addressed:

1. Minor vs. Significant Modifications of Currently Marketed Tests

   • Question: What constitutes a minor modification versus a significant modification to a currently marketed test?
   • Answer: Significant modifications, as defined by the FDA, include changes to a test’s operating principle, technology (e.g., from AI to machine learning), or indications for use (e.g., a new specimen type). Minor modifications are less defined but might involve adjustments like slight protocol changes. Significant modifications trigger the full FDA approval process.

2. Revalidating an Out-of-Service LDT

   • Question: If an assay was developed but has been out of service before the final rule, can it be revalidated and considered an existing LDT?
   • Answer: This depends on how much modification has been done. If the assay remains unchanged and is simply being revalidated, it may qualify as an existing LDT. However, if modifications were made, the FDA might consider it a new test, subject to the new rules.

3. FEI Number for Multiple Labs in a Health System

   • Question: Does each lab need a separate FDA Establishment Identifier (FEI) number, or can a health system use one for all labs?
   • Answer: It is unclear whether a single FEI number can cover multiple labs within a health system. Labs may need to apply individually, though there might be synergies for reporting certain types of events.

4. Turnaround Time as a Justification for Unmet Need

   • Question: Does turnaround time justify the unmet need category?
   • Answer: Yes, if the turnaround time impacts clinical care, it can justify using the unmet need category. For example, rapid testing for metabolic crises would qualify. However, cost and convenience alone do not meet the unmet need criteria.

5. FDA’s Capacity to Enforce the New Rules

   • Question: Can the FDA realistically inspect and enforce the rules for all laboratories?
   • Answer: The FDA faces challenges in scaling its oversight. The agency is relying on user fees to increase resources but may also prioritize high-risk LDTs and focus on listing and labeling to identify where enforcement is most needed.

6. Fees per Assay, Lab, or Healthcare System

   • Question: Are the FDA fees per assay, lab, or health system?
   • Answer: Fees are levied in multiple ways. Establishment registration fees apply per lab (based on the lab’s address), while submission fees for 510(k) or premarket approval are per assay.

7. Impact on Laboratory Director’s Discretion

   • Question: How will FDA oversight impact laboratory directors’ discretion in operations?
   • Answer: While laboratory directors will still have clinical discretion under CLIA, FDA oversight adds a regulatory layer that limits flexibility. Directors will need to balance medical judgment with compliance risks, especially for tests placed on the lab’s official menu.

8. Responsibility for Reporting Errors with FDA-Approved Tests

   • Question: Who is responsible for reporting issues when a lab modifies an FDA-approved test but an error occurs with the unmodified test?
   • Answer: If the error occurs with the FDA-approved test (e.g., the approved specimen type), the vendor would be responsible for reporting. However, if the error involves the modified LDT (e.g., a new specimen type), the lab assumes reporting responsibility.

9. Requirement to Switch to FDA-Approved Tests

   • Question: If an FDA-approved test becomes available, do labs have to stop using their currently marketed LDT?
   • Answer: No. If the LDT was in use before May 6, 2024, it can continue under existing LDT enforcement discretion, even if an FDA-approved test becomes available later. However, new LDTs developed after that date may not qualify for unmet need exemptions if an FDA-approved alternative exists.

10. Manufacturer's Role in LDT Modifications

    • Question: Can labs put pressure on manufacturers to address regulatory burdens for LDT modifications, like new specimen types?
    • Answer: Labs can advocate for manufacturers to address these needs, especially for modifications like specimen types, to avoid hundreds of labs independently seeking FDA approval. However, manufacturers have limited bandwidth, and their priorities may not always align with individual labs' needs.

11. Line Between Lab and Vendor Responsibility

    • Question: Where is the line drawn between a lab and a vendor's responsibility for reporting issues with FDA-approved tests?
    • Answer: For FDA-approved specimen types, the vendor remains responsible for reporting. For modifications developed by the lab (e.g., different specimen types), the lab assumes responsibility. There’s some gray area that will need clarification.

These Q&A responses underscore the complexity of FDA’s new regulations and the myriad challenges labs will face in complying with the evolving landscape.

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What might a compliance officer report to the lab owner or board of directors, as his biggest concerns?

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Here are the top six most concerning or alarming aspects of the FDA changes, based on the webinar, that you may want to report to your lab director, owner, and board of directors:

1. Redefining Labs as “Manufacturers”:
   The FDA’s classification of laboratories performing LDTs as “manufacturers” places labs under the same regulatory scrutiny as medical device companies. This means labs must comply with extensive requirements, including adverse event reporting and medical device corrections/removals, which significantly alters how labs have operated under CLIA. Labs will be subject to FDA inspections and are now obligated to manage compliance with federal regulations meant for device manufacturers.

2. Medical Device Reporting (MDR) Requirements:
   Starting in May 2025, laboratories will be required to report adverse events, including serious injuries and device malfunctions, to the FDA within 30 days (or within 5 days for urgent public health risks). The expansive scope of what constitutes a “device malfunction” could create a heavy administrative burden, requiring constant monitoring and quick responses. This also means labs need to implement formal MDR policies and designate personnel to manage this responsibility.

3. Extensive Complaint File Documentation:
   The FDA mandates that labs maintain a formal complaint handling system, requiring detailed documentation and investigation of all complaints, including oral complaints. Complaint management must follow formal procedures and involve a designated team or individual. The records must be available for future FDA inspections, creating another level of operational and record-keeping responsibility that could overwhelm labs without sufficient resources.

4. Cost and Resource Implications of Compliance:
   Compliance with the FDA rule will require significant financial and human resources. For example, labs must budget for user fees (currently $9,280 per year per lab) as part of the registration process, and compliance with pre-market approval and device labeling requirements could cost millions per assay. Many labs will need to hire regulatory personnel, train staff, and develop new internal procedures to handle the administrative burden, which could strain operational budgets and delay testing services.

5. Labeling and Device Registration Requirements by May 2026:
   Labs will need to submit detailed labeling for all LDTs, including assay performance data, instructions for use, and detailed specimen collection procedures. This is not just a simple process but involves a package insert-like document with comprehensive information. The time and resources required to prepare accurate, FDA-compliant labeling are substantial, and errors could result in non-compliance. Furthermore, labs must register all LDTs with the FDA, which introduces new overhead in tracking and managing tests.

6. Quality System Regulation (QSR) Compliance:
   By May 2027, labs will need to comply with FDA’s Quality System Regulations (QSRs), which impose stringent controls on test design, purchasing, and quality control processes. The design control requirements, in particular, will force labs to change how they develop and validate LDTs, requiring extensive documentation of every stage of test development. For labs that do not already operate under a QSR framework, this will require a complete overhaul of their current processes, adding significant operational complexity and cost.

These six concerns are critical to understanding the profound impact these regulatory changes will have on the lab’s operations, compliance, and financial health. They will require immediate attention and strategic planning to ensure smooth transitions and avoid penalties

CLSI Handbook on Supplier Requirements, FDA > CLIA

Much talk about conflicts or overlaps between CLIA regs and new FDA application of Device Manfacturer regs (2025, 2026, 2027).

Here is the State Operations Manual (Appendix C - CLIA) from CMS:

https://www.cms.gov/regulations-and-guidance/guidance/manuals/downloads/som107ap_c_lab.pdf

Last update 2017.

CLSI LDT Library here:

https://clsi.org/ldt-perspective/

Here is the new CLSI 130 page manual about how to take existing "manufacturer" FDA regulations and implement them in your laboratory.  (Hint: It's hard).

https://clsi.org/standards/products/quality-management-systems/documents/qsrldt/

Blog notes follow.  See esp CLSI Ch 6 (matching FDA 820.50) on purchasing (supplies) regulations.

The chapter runs several pages.  

File copy: 2024 CLSI QSR FOR LABS...130pp.pdf

Purchasing Controls Ch 6 p 39-42

etc

https://clsi.org/standards/products/quality-management-systems/documents/qsrldt/

LSI QSRLDT

Quality System Regulations for Laboratory-Developed Tests: A Practical Guide for the Laboratory, 2nd Edition

This practical guide, compiled with the help of experts from the in vitro diagnostics industry, is intended for the laboratory that is creating laboratory developed tests that may be subject to the US Food and Drug Administration (FDA) regulations, specifically the Quality System Regulation (QSReg), 21 CFR Part.

This report is available in electronic format only.

Member price: $0.00 → $0.00

List Price: FREE

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Details

Chairholder: Corrisa Miliander; Shannon Bennett, MS, MBA, CMQ/OE (ASQ)

Date of Publication: September 16, 2024

Order Code PDF: CLSI QSRLDTEd2E

ISBN Number: 978-1-68440-248-9

Order Code Print: print not available

Edition: Second

Pages: 130

CHAT GPT

The guide for laboratory operations under FDA requirements focuses on how labs that develop laboratory-developed tests (LDTs) must now comply with FDA’s Quality System Regulation (QSReg), traditionally applied to medical device manufacturers under 21 CFR Part 820. This shift classifies LDT labs as medical device manufacturers, requiring compliance with decades-old device manufacturing standards, which may be overwhelming for labs accustomed to Clinical Laboratory Improvement Amendments (CLIA) regulations.

Key Concerns for Lab Directors:

1. Broader Scope of Regulation:

   • CLIA focuses primarily on lab operations and quality control for clinical testing, but QSReg emphasizes product design, manufacturing, and risk management, framing lab tests as "medical devices."
   • Labs will now need to create and maintain extensive documentation, such as design history files (DHF) and device master records (DMR), to prove their tests meet regulatory standards.

2. Management Responsibility:

   • Lab directors, now under FDA QSReg, must establish a quality policy and ensure that management reviews occur regularly to maintain compliance with the system.
   • Management must appoint a representative responsible for the quality system and ensure adequate staffing and resources to meet FDA requirements.

3. Personnel and Training:

   • Laboratories must provide sufficient training not only on CLIA compliance but also on FDA device defects that could arise from improper job performance. These training programs must be documented and regularly updated.

4. Design Controls:

   • A significant new burden is placed on labs to manage design controls for LDTs, including comprehensive design inputs and outputs, validation, and verification processes. This goes far beyond traditional CLIA practices, requiring labs to treat their tests as products to be designed, tested, and validated like medical devices.
   • Every step in the test’s lifecycle, from conception to validation and risk assessment, must be documented in the DHF, and formal design reviews must occur at various stages to ensure compliance.

5. Quality Audits and Corrective Action:

   • Audits must now ensure that the lab’s quality system (not just testing processes) is compliant with QSReg. Audits need to cover the full spectrum of test development, including nonconforming product management and corrective actions.
   • Unlike CLIA's focus on laboratory processes, the FDA audit must ensure that design and manufacturing processes for the LDTs meet federal regulations. Audits must be performed by independent personnel who are not involved in the design process.

6. Risk Management and CAPA:

   • Labs must implement Corrective and Preventive Action (CAPA) systems to address nonconformances in product quality, ensuring that test errors or risks are thoroughly investigated and resolved.

Implications for Labs:

Labs accustomed to the CLIA framework, which emphasizes the quality of laboratory procedures and test performance, will now need to adopt a more rigorous manufacturing approach. This involves formalized processes for test design, production, documentation, and audits, reflecting the FDA’s broader focus on ensuring the safety and effectiveness of devices used in clinical practice.

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I am a lab director and buy genomic RUO kits and validate under CLIA, such as supplier and reagent validation.   I understand I must now meet "manufacturer" rules, coming from FDA, not CLIA, for supply and component validation.  What does it say about that (Chapter 6 esp.)

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Chapter 6 of the guide details the Purchasing Controls that apply to labs developing LDTs, now considered medical device manufacturers. Under FDA regulations, there are specific requirements for the evaluation and control of suppliers, contractors, and consultants to ensure the quality of products and services impacting the laboratory-developed test.

Key Requirements for Supply and Component Validation:

1. Supplier Evaluation and Selection:

   • Laboratories must evaluate and select suppliers based on their ability to meet specified quality requirements. The evaluation must be documented, and the lab must establish how suppliers will be controlled going forward.
   • This is similar to CLIA reagent validation but adds the requirement to assess whether suppliers are capable of providing high-quality products consistently in the future.

2. Supplier Classification:

   • Suppliers are classified based on the risk their products pose to the lab's processes. For example, critical suppliers are those whose components (like antibodies, enzymes, or reactive chemicals) could cause test failure if they do not meet specifications. The level of control, monitoring, and audit frequency varies by this classification.

3. Monitoring Supplier Performance:

   • Labs must monitor supplier performance by assessing data such as on-time delivery, nonconforming materials reports, and the results of audits. A supplier’s classification affects how frequently their performance is reviewed. Consistent failures or nonconformance may result in a supplier being removed from the approved supplier list.

4. Change Control:

   • Labs must establish procedures to manage changes made by suppliers that could affect product quality. Any changes must be evaluated and approved before they are accepted, often requiring additional validation to ensure that the product still meets the required specifications.

5. Purchasing Data and Specifications:

   • Laboratories must maintain purchasing data that describe the requirements for all materials received. Suppliers should notify the lab of any changes to products or services, and the lab must evaluate whether these changes could affect the LDT’s quality. Specifications for materials (e.g., chemical formulations, performance criteria) must be clearly communicated and updated as necessary.

This process ensures that all procured components and services meet regulatory standards, which goes beyond traditional CLIA reagent validation by requiring a more formalized and comprehensive supplier qualification process .

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Compare our familiar CLIA controls for products like RUO products, and their validation, with the new general FDA manufacturer controls (Ch 6).

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Chapter 6 of the document confirms that FDA's Purchasing Controls under §820.50 are more complex than CLIA rules. 

Although CLIA already includes supplier and reagent validation requirements, FDA regulations extend beyond by requiring manufacturers (including labs using LDTs) to qualify suppliers in more depth. Specifically:

• Supplier Qualification: Manufacturers must not only test incoming components but also evaluate and document whether the supplier can consistently meet the specified requirements. This additional step is vital to ensure future supplies maintain quality.
• Supplier Monitoring: The FDA requires labs to monitor supplier performance through continuous reviews, such as analyzing delivery records and conducting audits. These monitoring processes must be documented, and poor performance can result in removal from the approved supplier list.
• Change Control: A new process must be in place for managing supplier changes to products or services, ensuring these do not negatively impact the quality of LDTs. This control is stricter than typical CLIA procedures, requiring thorough evaluations before accepting any changes from a supplier.

These added layers of complexity help ensure that suppliers maintain a robust quality system and deliver consistent materials, which is crucial for maintaining LDT accuracy and reliability .

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Many lab directors think CLIA is fully sufficient and time tested.

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Many CLIA lab directors share the sentiment that LDTs (laboratory-developed tests) are already well validated and safe under existing CLIA guidelines, and they often see FDA regulations as redundant and burdensome. Their main arguments include:

1. CLIA Already Covers Key Aspects:

   • Under CLIA, labs are required to validate the performance of tests (precision, accuracy, sensitivity, specificity, etc.) before they are used for patient testing. This includes controls on reagents and processes to ensure reliable results.
   • Lab directors argue that CLIA’s focus on quality control (QC) and quality assessment programs is sufficient to ensure patient safety without additional oversight from the FDA.

2. Redundancy of FDA Rules:

   • The FDA’s Quality System Regulation (QSReg), which now applies to LDTs, requires similar activities such as validation and verification, but in a more formalized and often more extensive manner. Many directors believe this duplicates efforts they are already performing under CLIA, adding unnecessary paperwork and regulatory hurdles without a clear improvement in test quality.

3. Burdensome Requirements:

   • FDA’s supplier qualification and monitoring, detailed design controls, and documentation requirements introduce new administrative burdens. These steps—although critical for manufacturing medical devices—are seen as overkill for labs that develop and use their own tests under highly controlled conditions.
   • Smaller labs may find these requirements particularly challenging, as they lack the resources or infrastructure to implement FDA-style supplier audits, maintain design history files (DHF), or conduct corrective action/preventive action (CAPA) programs at the level required for device manufacturers.

4. Innovation Slowdown:

   • Some lab directors argue that the additional FDA compliance measures will slow down innovation. LDTs have historically been developed and implemented quickly to address unmet clinical needs, particularly in the fields of oncology, genetics, and infectious disease. The longer timelines imposed by FDA oversight could delay the availability of new, potentially life-saving tests.

Counterpoint by FDA:

The FDA, however, insists that its rules ensure a uniform safety and effectiveness standard across all diagnostics, arguing that risk-based regulation is necessary as the complexity of LDTs increases, especially with the growing use of genomic and molecular tests.

While CLIA focuses on lab performance, FDA’s rules add product-level regulation, including supplier and component validation, to prevent systemic risks in manufacturing and supply chains that could impact patient safety across multiple settings.

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ASR regs have been in place since 1997 and thereunder, FDA publicly recognized for 25-30 years that they would be subject to CLIA supply validation and no more.  

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You’ve pointed out a significant historical context—the FDA's stance in 1997 on analyte-specific reagents (ASRs), where the agency publicly acknowledged that CLIA validation was sufficient for supply validation. This acknowledgment reflected trust in CLIA’s ability to ensure the quality and safety of lab-supplied reagents. For nearly 30 years, labs operated under this framework, and CLIA’s regulations worked well for the validation of ASRs.

Now, with the 2024 regulations, the FDA has imposed a new layer of compliance that aligns LDT labs with the same supply and component validation rules required of general medical device manufacturers. This approach demands that labs treat their suppliers as if they were manufacturing high-risk devices, such as pacemakers or other critical medical equipment, which comes with a far more complex regulatory burden.

This dramatic shift feels like a substantial imposition for lab directors who have successfully validated their supplies under CLIA for decades. The mountain of new requirements—more suited to traditional device manufacturing—may feel disconnected from the practical realities of clinical lab environments, where LDTs have a strong safety track record under the existing framework.

It highlights the broader struggle between ensuring safety through stringent regulations and allowing labs the flexibility to innovate and operate efficiently.

Decibio webinar "Oncologist's Role in Digital Pathology Revolution"

https://www.linkedin.com/posts/decibio_digitalpathology-precisionmedicine-oncology-ugcPost-7240012342288130051-bZ4e/?utm_source=share&utm_medium=member_ios

 

https://www.decibio.com/insights/the-oncologists-role-in-the-digital-pathology-revolution-webinar

This webinar was recorded on Thursday, 5th September 2024.

Digital pathology tools, such as predictive and prognostic algorithms, can help facilitate increased efficiencies and improved patient outcomes. To date, conversations around digital pathology tools have understandably focused on the pathologist and lab. However, emerging DP tools are increasingly targeting clinical questions (rather than pathologist efficiencies), creating opportunities to include oncologists in discussions.

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During this webinar, we will discuss different perspectives on the hurdles to tool adoption, offer suggestions on how we can overcome these, and share insights from a lab medicine perspective, where we believe digital tools, such as workflow and diagnostics tools, can improve health outcomes.

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Speakers:

• Charles Gaulin, MD, Hematologist Oncologist at Dartmouth

• Joseph Annunziata, MD, Medical Director, Molecular Pathologist

• Omar Perez, PhD, Head of Medical Diagnostics at AstraZeneca

• Heinz-Josef Klümpen, MD, Medical Oncologist, Consultant at Amsterdam University Medical Center

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Moderators:

• Katie Maloney, DeciBio Consulting
• Esther Abels, SolarisRTC

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Learn more about DeciBio's Digital Pathology Market Report here: https://www.decibio.com/product/digital-pathology-market-report

‍

View the webinar recording below:

*Note that due to an error with Zoom—Katie Maloney has been incorrectly labeled as Omar Perez in the recording.

View the Webinar Recording

In cased you missed our webinar, "The Oncologist's Role in the Digital Pathology Revolution" last week, you can now watch the full session on demand on our website here: https://lnkd.in/gX3TZmws

Moderated by Esther Abels and Katie Maloney

Thank you to our panelists Omar Perez, Joseph Annunziata, M.D., Heinz-Josef Klümpen, and Charles Gaulin for sharing their invaluable perspectives and to our engaged audience for your thought-provoking questions.

hashtag#DigitalPathology hashtag#PrecisionMedicine hashtag#Oncology

tagcsd taglungevity

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Decibio Webinar Review: Integrating Oncologists into the Digital Pathology Revolution

Decibio’s September 5, 2024 webinar, The Role of the Oncologist in the Digital Pathology Revolution, brought together key thought leaders from oncology, pathology, and biopharma to discuss the future of digital pathology. The discussion provided a comprehensive look at how emerging tools, such as diagnostic algorithms and digital slide sharing, are breaking the traditional boundaries of pathology labs and increasingly involving oncologists in the conversation.

Dr. Charles Gaulin, a hematologist oncologist from Dartmouth, began by acknowledging that while digital pathology (DP) has primarily focused on pathology lab efficiencies, the field is shifting. Today’s digital tools are targeting clinical questions that can directly improve patient outcomes, and oncologists now have a growing role to play in adopting and using these technologies. Gaulin pointed out that for oncologists, the primary hurdle remains diagnostic delays caused by information bottlenecks. He noted that approximately half of his patients come to him with incomplete pathology information, requiring additional review and sometimes delaying the start of life-saving therapies. Digital pathology, particularly slide sharing for remote consultations, could cut days out of this process, providing a faster path to treatment.

This theme of reducing time-to-treatment was echoed by multiple panelists. Dr. Joseph Annunziata, a molecular pathologist and lab director, emphasized the importance of integrating DP to facilitate faster workflows, especially in community hospitals, where digital tools are often not yet in place. He also stressed the need for reflex testing panels, which allow pathologists to automatically order crucial molecular tests, such as next-generation sequencing (NGS), without needing separate oncologist input each time. This streamlining of diagnostic procedures, according to Annunziata, can significantly improve turnaround times, especially in cases requiring complex molecular profiling.

Omar Perez, PhD, from AstraZeneca’s medical diagnostics team, provided a perspective from the pharmaceutical industry, highlighting the role digital pathology plays in identifying patients for personalized treatments, such as companion diagnostics. He observed that digital pathology is not only a laboratory tool but is becoming integral in clinical decision-making, particularly for evaluating biomarkers that guide precision treatments. Perez made the compelling point that for advanced-stage cancers, where time is a critical factor, digital tools could be vital in expediting the analysis of biopsy results and molecular data, enabling oncologists to initiate appropriate therapies sooner.

The discussion touched on the barriers to adopting digital pathology more broadly, particularly in terms of infrastructure and cost. Dr. Gaulin and Dr. Annunziata noted that while larger academic institutions may have the necessary infrastructure, community hospitals and smaller institutions are often left out of the equation due to high costs and lack of IT integration. Gaulin emphasized that this divide needs to be addressed if the full potential of digital pathology is to be realized. Dr. Annunziata also pointed out that although digital tools can save days in consult times, their financial benefits might not always be immediately clear to administrators, which can slow adoption in cost-sensitive environments.

Perhaps one of the most enlightening aspects of the webinar was its emphasis on collaboration. Dr. Perez and the other panelists stressed that oncologists, pathologists, and pharmaceutical companies must collaborate more closely to standardize diagnostic tools, reduce fragmentation, and ensure patients have access to the best possible care. By integrating molecular tumor boards and embracing digital consultations, institutions can unify their decision-making processes, improving both the accuracy and speed of diagnosis.

In closing, the panelists emphasized that while digital pathology adoption has been slow, the evidence supporting its clinical and financial value is growing. With more studies on the horizon—particularly focusing on how digital tools can improve turnaround times and patient outcomes—the panel suggested that we may be at the cusp of a broader revolution in how oncology and pathology interact.

Here are ten key takeaways from the The Role of the Oncologist in the Digital Pathology Revolution webinar:

• 1. Expanding Role of Oncologists: Oncologists are becoming key stakeholders in digital pathology, particularly as tools shift from lab efficiencies to answering clinical questions.

• 2. Faster Consultations: Digital pathology can speed up the consultation process by enabling remote slide sharing, potentially shaving off several days from diagnostic delays.

• 3. Reflex Testing for Efficiency: Automatic reflex testing panels, particularly for molecular markers, streamline workflows, allowing pathologists to order critical tests upfront without waiting for oncologist input.

• 4. Predictive and Prognostic Tools: Digital pathology tools are increasingly linked to companion diagnostics and predictive algorithms, which can guide personalized cancer treatments.

• 5. Cross-Disciplinary Collaboration: Greater collaboration between pathologists, oncologists, and pharmaceutical companies is crucial for the successful implementation and utilization of digital pathology.

• 6. Centralized Tumor Boards: Digital tools enhance multidisciplinary tumor boards by allowing pathologists to participate remotely, sharing insights and contributing to faster treatment decisions.

• 7. Financial Barriers: The high costs of implementing digital pathology, especially for smaller or community hospitals, remain a significant barrier to widespread adoption.

• 8. Infrastructure Challenges: IT integration and the lack of unified systems across hospitals further slow the adoption of digital pathology tools.

• 9. Patient Impact: For patients with late-stage cancers, faster diagnostic turnaround times enabled by digital pathology could lead to quicker initiation of treatments and better outcomes.

• 10. Future Research: Ongoing studies are expected to provide more evidence on how digital pathology improves clinical outcomes, which may drive broader adoption in the coming years.

FDA and Why HLA Tests Won't Be Regulated Right Now

 AI discussion then original FDA text follows.

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The FDA has decided to exercise enforcement discretion for HLA tests used in the context of organ, stem cell, and tissue transplantation, allowing them to operate without direct FDA regulation. Several key reasons contribute to this decision:

1. Urgency and Need for Rapid Adaptation: HLA tests for transplantation are performed in urgent situations where prompt decisions are crucial. When an organ, stem cell, or tissue becomes available, physicians must quickly assess the compatibility between the donor and recipient. Because new HLA alleles are continuously being identified, modifications to these tests need to be made rapidly to address specific mismatches and respond to the unique needs of each transplant case.

2. Customization and Individualization: These tests are highly individualized within each medical facility. Laboratories often develop HLA tests that account for local HLA polymorphisms and patient demographics, leading to a level of customization that is necessary for effective transplantation outcomes. This individualization means that a one-size-fits-all approach to regulation may not be suitable for these tests.

3. Existing Oversight Programs: Several federal programs already provide oversight and help mitigate the risks of harm from inaccurate or unreliable HLA tests:

   • National Organ Transplant Act (NOTA): This act established the Organ Procurement and Transplant Network (OPTN), which sets standards for the safe and equitable allocation of organs. The OPTN has requirements for the performance of HLA typing, antibody screening, and crossmatching tests.
   • National Marrow Donor Program (NMDP): The NMDP supports patients needing bone marrow or umbilical cord blood transplants and sets minimum requirements for organizations facilitating these transplants. It mandates HLA typing for donors and recipients and requires reporting of test results to maintain quality and accuracy.
   • Accreditation Requirements: Both OPTN and NMDP require histocompatibility laboratories to be accredited by either the American Society for Histocompatibility and Immunogenetics (ASHI) or the College of American Pathologists (CAP). These standards have provisions that specifically address OPTN and NMDP requirements, which add a layer of quality control.

4. Risk Mitigation: The combination of oversight programs like OPTN and NMDP, along with CAP and ASHI accreditation requirements, helps mitigate the risk of inaccurate results. While the FDA does not view CAP or ASHI accreditation alone as sufficient for all in vitro diagnostics (IVDs), it considers the additional protections provided by these programs and the urgency of the situation to justify continued enforcement discretion.

5. Highly Standardized HLA Tests for Blood Transfusion: The FDA's enforcement discretion does not extend to HLA tests used for blood transfusion, which are more standardized across institutions. This differentiation underscores the unique nature of HLA tests for transplantation and the need for flexibility in their regulation.

In summary, the FDA's decision not to regulate HLA tests for transplantation directly is based on the need for rapid, individualized testing in urgent situations, the presence of existing oversight mechanisms, and the high level of customization required for these tests.

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FDA HLA TESTS DISCRETION

 

 

89 FR 37297-8     May 6, 2024

 

 

[FDA discusses “1976 type tests”

and how they are defined and foresees further

clarification in the future.]

 

FDA intends to consider whether

guidance containing additional

discussion and examples of tests that

may fall within this category would be

helpful, and would issue any such

guidance in accordance with good

guidance practices (see § 10.115).

 

# # #

 

Another category of such

[enforcement discretion]

tests is HLA tests

that are designed, manufactured,

and used within a single laboratory

certified under CLIA that meets the

requirements to perform high-

complexity histocompatibility testing

when used in connection with

 

·        organ,

·        stem cell, and

·        tissue transplantation

·        to perform HLA allele typing,

·        for HLA  antibody screening and monitoring,

·        or

·        for conducting real and ‘‘virtual’’ HLA crossmatch tests

·        (hereinafter ‘‘HLA tests  for transplantation’’).

 

[Bullets BQ]

 

Physicians must

often make prompt decisions about

transplantation based on medical

judgment regarding their patient’s

condition and degree of mismatch

between the donor and patient should

an organ, stem cells, or tissue become

available. Because new alleles are

continuously identified, and the need

for assessing degree of crossmatch is

generally urgent, modifications to HLA

tests for transplantation are often made

rapidly in response to urgent situations.

 

Further, these tests are often

individualized within each medical

facility; for example, they include

reagents that reflect local HLA

polymorphisms and patient

demographics.

 

 

In addition, oversight under certain

Federal programs helps to mitigate the

risks of harm from inaccurate and

unreliable HLA tests for transplantation.

 

For example, the National Organ

Transplant Act (NOTA) of 1984 created

the Organ Procurement and Transplant

Network (OPTN).

 

NOTA, as amended

(42 U.S.C. 273 et seq.), and the OPTN

Final Rule, 42 CFR part 121, establish a

comprehensive system for the safe and

equitable allocation, distribution, and

transplantation of donated organs.

 

The OPTN Final Rule and OPTN bylaws and

policies govern operation of all member

transplant hospitals, organ procurement

organizations, and histocompatibility

laboratories in the United States. The

Stem Cell Therapeutic and Research Act

of 2005 (Pub. L. 109–129), as amended,

authorizes a national registry (‘‘Be the

Match Registry’’) to support patients in

need of bone marrow or umbilical cord

blood transplants, which is operated

under Federal contracts by the National

Marrow Donor Program® (NMDP) (Ref.

45).

 

NMDP sets forth minimum

requirements for organizations working

through the NMDP to facilitate stem cell

transplants (Refs. 46 and 47).

 

OPTN has requirements for

performance of HLA typing, antibody

screening, and crossmatching tests, and

NMDP requires HLA typing for donors

and potential recipients for stem cell

transplants facilitated by the Be the

Match Registry, as well as reporting of

test results to NMDP (Refs. 47 and 48).

Both OPTN and NMDP have procedures

in place for identifying, investigating,

and reporting discrepant tests results

(Refs. 48 and 49).

 

 

In addition to these safeguards

designed to identify and resolve

potentially inaccurate results, each

OPTN member histocompatibility

laboratory must, among other things,

meet specified American Society for

Histocompatibility and Immunogenetics

(ASHI) and/or College of American

Pathologists (CAP) standards as a

condition of OPTN membership (Ref.

50). NMDP similarly requires

histocompatibility laboratories used by

U.S. transplant centers and donor

centers to be accredited by CAP and/or

ASHI (Refs. 46, 51 and 52). Both ASHI

and CAP standards have provisions that

specifically address OPTN and/or

NMDP requirements for

histocompatibility laboratories that

perform tests for those programs.

Importantly, as discussed below, FDA

does not believe that a CAP or ASHI

accreditation of a laboratory, on its own,

is sufficient to mitigate risk and provide

assurance of the safety and effectiveness

for all IVDs offered as LDTs by the

accredited laboratory.

 

However, we consider the fact that OPTN and NMDP

require adherence to CAP and/or ASHI

standards, including provisions specific

to OPTN and NMDP requirements, to be

one factor that helps mitigate risk of

inaccurate results or unreliable HLA

tests for transplantation.

 

After considering this factor in combination

with the protections provided through

 

the programs described above and the

urgent circumstances in which HLA

tests for transplantation may be

modified and performed, as well as the

comments received on our proposed

approach to HLA tests for

transplantation, FDA intends to

continue the general enforcement

discretion approach for these tests. We

note that this enforcement discretion

policy does not apply to HLA tests used

for blood transfusion, which are highly

standardized across institutions, nor

does it apply to any IVDs identified in

section V.A.2 as falling outside the

scope of the phaseout policy or as

discussed in section V.B.