By 2026, FDA expects LDT labs to comply with increasing amounts of medical device manufacturing regulations, in particular, those on "labeling." (Note that labeling for complex PMA products, such as Illumina's new TSO CDx (PMA) 500-gene test, can be over 100 pages long, including instructions for use and other labeling).
FDA held a webinar on the topic on September 24, 2024:
Here's the webpage, where you can access streaming links as well as the 55-page deck.
FDA will post the video and transcript in about a week.
- FYI, in the meantime, an instant autotranscript is here.
- FYI, in the meantime, a crude screen grab video is here.
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Here's coverage from Shannon Bennett and from Christine Bump.
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I've always understood that labeling, including intended use, can involve a complex back-and-forth with FDA near the end of the product development cycle, with the FDA ready to assert at any moment that your intended use conflicts with your data in some way. Here, labs are asked to generate the labeling unilaterally, and submit it to the FDA, before FDA has seen or reviewed the LDT product.
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Keep track of FDA's lengthy home page for FDA LDT issues:
https://www.fda.gov/medical-devices/in-vitro-diagnostics/laboratory-developed-tests
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I've provided an AI summary of the FDA webinar, in the whimsical format of a memo to your boss who's head of regulatory at your LDT laboratory.
Below that, some additional AI commentaries on the just-completed webinar.
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Chat GPT 4o: Memo to Your Boss
MEMO: FDA's New Labeling Requirements for In Vitro Diagnostic (IVD) Products, Including Laboratory Developed Tests (LDTs)
To: [Boss's Name], Head of Regulatory at Big_LDT_Lab
From: [Your Name, Director]
Date: September 25, 2024
Subject: FDA Webinar on Labeling Requirements for LDTs and IVDs under 21 CFR 809.10(b)
Background:
On September 24, 2024, the FDA hosted a webinar focusing on the new labeling requirements for In Vitro Diagnostic (IVD) products, including Laboratory Developed Tests (LDTs), under 21 CFR 809.10(b). These regulations are part of the FDA's ongoing phaseout of its enforcement discretion policy for LDTs. By May 6, 2025, most LDTs must comply with the labeling requirements under 21 CFR 809.10(b). Full compliance is expected by May 2026.
The aim of these changes is to clarify labeling rules for LDTs, which have traditionally been less regulated than other IVDs. For a large diagnostic laboratory like ours, developing and using many proprietary LDTs, understanding and complying with these new regulations is essential for maintaining FDA compliance by the 2026 deadline.
Key Labeling Requirements under 21 CFR 809.10(b):
The FDA outlined the mandatory information that must accompany any IVD, including those offered as LDTs. This labeling includes:
- Product Name – The proprietary and established name (common or usual name).
- Intended Use – A clear description of the test's purpose and its procedure, specifying whether it is qualitative or quantitative.
- Summary and Explanation – A brief history of the test's methodology, referencing the literature and outlining the test’s merits and limitations.
- Principles of the Procedure – Explanation of the test's chemical, physical, or biological principles.
- Reagents and Instruments – Comprehensive details on the reagents and instruments used, including storage conditions, preparation, and any hazards.
- Specimen Collection and Preparation – Instructions for collecting, handling, and storing specimens, including precautions to maintain integrity.
- Procedure – A step-by-step description of the test process, from specimen reception to result reporting.
- Results Interpretation – Instructions on how to calculate and interpret results, including sample calculations and expected values.
- Limitations – Statements regarding known extrinsic factors or substances that could interfere with the results.
- Performance Characteristics – Detailed data on the test’s accuracy, precision, specificity, and sensitivity.
Impact for Our Lab:
Documentation Expansion: All our LDTs will require detailed documentation covering the above aspects. While some of this information may already be part of existing internal protocols (e.g., test protocols and instrument manuals), they will need to be revised to comply with 21 CFR 809.10(b) standards. For example, specimen collection instructions must now include details on potential interfering substances, special handling, and patient preparation.
Compliance Timeline: As we approach the May 2026 compliance deadline, our regulatory team will need to prioritize tests that are frequently used and marketed. We may need to prepare labeling documents for submission as part of premarket reviews, particularly for high-risk or novel LDTs.
Clarification of Exemptions: Certain LDTs are exempt from premarket review or labeling submission. This includes LDTs for unmet needs within integrated healthcare systems and some older LDTs not modified beyond their original scope. We must assess whether any of our tests fall under these exemptions and plan accordingly/
Documenting Labeling Across Multiple Sources: Labeling for LDTs can be spread across multiple documents (e.g., test protocol, report template, test menu). This allows flexibility in how we structure compliance but also requires careful coordination to ensure completeness and clarity.
Risk of Misbranding: Tests lacking appropriate labeling will be considered "misbranded" under FDA regulations. Misbranding can lead to enforcement actions, including fines or product recalls. Ensuring accurate, truthful, and non-misleading labeling is paramount to avoid regulatory issues.
Next Steps:
Internal Review: We need to conduct a thorough internal audit of all existing LDTs to assess which ones require additional labeling or modification to meet FDA standards.
Labeling Strategy: Develop a cross-departmental labeling compliance plan. This will include input from R&D, quality control, and regulatory teams to ensure all aspects of the 809.10(b) requirements are met across various LDTs.
Training and Awareness: Train relevant teams on the new labeling requirements and the importance of consistent documentation across all platforms (test protocols, inserts, and manuals).
Engagement with FDA: We should consider submitting questions to FDA and participating in the upcoming webinars on LDTs to stay updated on additional regulatory guidance, especially regarding labeling.
By staying proactive, we can ensure that our LDTs remain compliant with FDA regulations, avoiding any disruptions in service as the labeling requirements phase in.
If you need further details or assistance with specific compliance steps, please let me know.
[Your Name]
Regulatory Compliance Director
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Please summarize the webinar.
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This FDA webinar, presented by Toby Lowe, Acting Deputy Director of the Office of Health Technology within the Center for Devices and Radiological Health (CDRH), focused on labeling requirements for in vitro diagnostic (IVD) products, including laboratory developed tests (LDTs), as specified under 21 CFR 809.10(b). The FDA is phasing out its enforcement discretion approach for LDTs, with full compliance required by May 6, 2026. The discussion emphasized the importance of accurate and comprehensive labeling to ensure the safety and effectiveness of IVDs, specifically test systems.
Overview of 21 CFR 809.10(b)
Labeling requirements under 21 CFR 809.10(b) are meant to ensure IVD manufacturers provide key information about their products, such as intended use, limitations, and performance characteristics. These requirements are a critical component of the regulatory framework for ensuring the safe and effective use of IVDs, which include LDTs. The webinar outlined how labeling encompasses more than just packaging inserts—it includes all written, printed, or graphic matter accompanying the device, including test protocols, test reports, and other documentation.
Key Labeling Components
The webinar outlined the core elements required in IVD labeling under 21 CFR 809.10(b):
- Proprietary and Established Names: The first requirement is to include both proprietary and established names of the product, which help identify the product and its manufacturer.
- Intended Use: The labeling must clearly state the purpose of the IVD, including the analyte being measured, the disease or condition it diagnoses, and the patient population. This ensures that users understand the scope of the product’s application.
- Summary and Explanation: Manufacturers must provide a brief description of the test’s methodology, as well as its merits and limitations. This helps users understand how the test fits within clinical contexts.
- Principles of Procedure: The underlying scientific mechanisms and the steps involved in conducting the test must be clearly explained.
- Specimen Handling: Proper collection, handling, and preparation of specimens are crucial for accurate test results. The labeling must specify storage and transportation requirements, as well as any additives or preservatives necessary to maintain sample integrity.
- Step-by-Step Procedures: Clear instructions on how to perform the test, from receiving the specimen to interpreting the results, must be provided to ensure the proper execution of the test.
- Performance Characteristics: The IVD’s accuracy, precision, specificity, and sensitivity must be outlined, along with any other relevant characteristics. This information allows users to assess the reliability of the test results.
Enforcement and Compliance
The FDA is particularly focused on the compliance of LDT manufacturers with these labeling requirements. Manufacturers of IVDs, including those offered as LDTs, are expected to submit labeling as part of their premarket submissions, where applicable. For LDTs not subject to premarket review, the FDA expects manufacturers to maintain compliant labeling and provide it during FDA inspections. Manufacturers using reagents or instruments not labeled for clinical diagnostic use must qualify those components under their own quality systems.
The FDA may take regulatory action if labeling is found to be false, misleading, or incomplete. This could include cases where an LDT lacks sufficient evidence to support its claimed performance characteristics. Additionally, the FDA emphasized that promotional materials, which fall under the definition of labeling, must also comply with these regulations.
Special Cases for LDTs
For LDTs approved under the New York State Clinical Laboratory Evaluation Program (CLEP) or those developed to meet unmet medical needs, the FDA will exercise enforcement discretion. However, manufacturers of these tests must still submit labeling information during the listing process, allowing the FDA to monitor the safety, effectiveness, and clinical validity of these products.
The labeling requirements outlined are intended to support consistent, safe, and effective use of IVDs in clinical settings. The FDA encourages manufacturers to review publicly available labeling examples on the FDA website, particularly those related to approved Premarket Approval (PMA) applications and humanitarian device exemptions, to guide compliance efforts.
Future Webinars
The webinar concluded with a reminder about an upcoming FDA session on the total product lifecycle approach to IVD regulation, scheduled for October 24, 2024. This session will delve deeper into how IVD products are regulated throughout their lifecycle, from development to post-market surveillance.
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Please summarize the Q&A.
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Here’s a summary of the Q&A section from the latter part of the FDA webinar:
Question 1:
What does it mean when the FDA requests labeling submission for certain IVDs offered as LDTs at the time of device listing?
- Response: The FDA will request labeling information during the listing of IVDs offered as LDTs that fall within certain enforcement discretion policies, such as those approved by the New York State Clinical Laboratory Evaluation Program (CLEP) or for unmet needs. This request is intended to monitor the safety, analytical validity, and clinical validity of the IVDs, particularly for those marketed before May 6, 2024. The FDA will scrutinize any claims of superior performance and may take action if labeling is found misleading or if the test lacks safety and effectiveness.
Question 2:
Will enforcement discretion be applied to promotional materials?
- Response: Promotional materials fall under the broader definition of labeling in the Federal Food, Drug, and Cosmetic Act. These materials must be truthful and non-misleading. The FDA will pay particular attention to performance claims and may take action if claims are not adequately substantiated. While there are some categories of LDTs (e.g., HLA tests for transplantation or forensic tests) that have broader enforcement discretion, promotional materials for most LDTs must comply with labeling requirements by May 6, 2026.
Question 3:
What are the FDA expectations regarding labeling for LDTs?
- Response: FDA expects LDT manufacturers to comply with labeling requirements under 21 CFR 809.10(b) by May 6, 2026. This includes providing a complete and clear description of the intended use, limitations, and performance of the test. While a single document like a package insert is common for traditional IVDs, LDTs may use multiple documents (e.g., test protocols, report templates) to meet labeling requirements. The FDA requires a primary labeling document, often made public, while other detailed documents may remain confidential.
Question 4:
What are the labeling expectations for reagents and instruments used as part of an LDT but not manufactured by the laboratory?
- Response: If a test system uses reagents or instruments already labeled for clinical diagnostic use, laboratories can reference this compliant labeling instead of duplicating it. However, if the reagents or instruments are not labeled for clinical use (e.g., marked as Research Use Only), the laboratory must qualify these components under their own quality system and ensure that the appropriate labeling is provided for the LDT. This might require multiple documents, including a primary labeling document and internal test protocols.
Question 5:
What are the labeling expectations around performance characteristics, and how does that differ from what is expected in a premarket submission?
- Response: The labeling for IVDs, including LDTs, must include performance characteristics such as accuracy, precision, sensitivity, and specificity, per 21 CFR 809.10(b)(12). These characteristics must be summarized in the labeling. In contrast, premarket submissions require more detailed validation data to substantiate these performance claims. Labeling provides a high-level summary, while premarket submissions include the complete validation data necessary for FDA review.
Closing Remarks:
Toby Lowe emphasized that manufacturers should ensure their labeling aligns with FDA’s requirements, and additional resources, including publicly available labeling examples, are available to assist in compliance. The FDA's next webinar will cover the total product lifecycle approach to IVD regulation.
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Will LDT stakeholders find some parts of this unsettling,
since they are used to only CLIA regulation?
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Members of the lab-developed test (LDT) community who are primarily familiar with CLIA regulation are likely to find several parts of the webinar unsettling due to the additional burdens, costs, and uncertainties that FDA regulation introduces. The following aspects of the webinar may cause significant concern:
1. FDA Labeling Requirements for LDTs
- What May Be Upsetting: The concept of "FDA labeling" is new and may seem strange to labs used to CLIA's focus on laboratory performance and validation rather than detailed labeling for external use. The FDA requires that LDTs comply with 21 CFR 809.10(b), which involves extensive requirements for labeling that go beyond internal documents. This includes defining intended use, performance characteristics, specimen handling instructions, and much more in a public-facing document, a shift from the internal-only protocols commonly followed under CLIA.
- Impact: Labs are not used to developing public-facing materials that must meet specific FDA requirements, and creating, maintaining, and potentially revising this labeling will add complexity and cost. Furthermore, the multi-document approach for LDTs, which may involve both a primary labeling document and supporting confidential documents, adds a new layer of documentation management.
2. Premarket Submission and FDA Oversight of LDTs
- What May Be Upsetting: The need for FDA premarket review for certain LDTs, especially when previously CLIA was the primary regulator, introduces significant uncertainty. LDTs that were exempt from FDA premarket review under the agency's historical enforcement discretion may now need to comply with FDA regulations, including labeling submissions, performance validation, and adherence to safety and effectiveness standards.
- Impact: The submission of materials to the FDA for premarket review is an unfamiliar process for many LDT laboratories. This could result in significant costs, delays, and concerns over whether their LDTs will be approved or if they will need to modify their processes. Many LDTs, especially those developed for rare diseases or niche applications, may face regulatory challenges that they didn’t previously encounter under CLIA.
3. FDA Review of Promotional Materials
- What May Be Upsetting: FDA's regulation of advertising and promotional materials for LDTs is likely to be seen as an onerous, unnecessary extension of oversight. Under CLIA, labs did not have to worry about how they marketed their tests or whether advertising claims were “misleading.” Now, the FDA expects compliance with labeling requirements that include promotional materials, meaning any claims in advertisements must be substantiated and truthful, subject to FDA review.
- Impact: Many LDT labs have never had to navigate the complexities of advertising compliance under FDA standards, which are strict and can lead to enforcement actions if violated. This introduces additional legal and marketing costs, along with uncertainty over whether existing marketing materials will need to be revised. Laboratories may find themselves scrambling to adjust or completely overhaul their promotional approaches.
4. Costs of Compliance with FDA Regulations
- What May Be Upsetting: Compliance with FDA regulations brings significant new costs that many labs are unaccustomed to under CLIA. These costs include not only the creation of FDA-compliant labeling and promotional materials but also the possibility of needing to conduct new validation studies for performance characteristics, hiring legal and regulatory experts, and managing premarket submissions.
- Impact: LDTs are often developed by smaller labs with limited budgets. The costs associated with meeting FDA regulatory requirements may be prohibitive for some, potentially stifling innovation or even leading to the discontinuation of certain LDTs that are not deemed financially viable under the new regulatory framework. The uncertainty around how much these changes will cost and how long the approval processes might take adds to the stress.
5. Post-Market Surveillance and FDA Inspections
- What May Be Upsetting: Under FDA regulation, LDT manufacturers are expected to maintain compliance with labeling and safety standards over time, including during FDA inspections. The prospect of FDA inspections is far more rigorous and intimidating than those from CLIA, and the FDA has the authority to enforce labeling compliance and post-market surveillance.
- Impact: Laboratories accustomed to more lenient oversight may fear the potential for FDA audits and the threat of regulatory action if they fail to meet the FDA’s labeling, safety, and effectiveness standards. This adds a layer of ongoing regulatory pressure that many labs have not had to consider under CLIA.
6. Burden of Meeting FDA's Performance Characteristic Requirements
- What May Be Upsetting: CLIA focuses on test accuracy, but the FDA goes further by requiring detailed information about test performance characteristics such as sensitivity, specificity, and precision to be included in the labeling. The FDA also reviews these characteristics during premarket submissions.
- Impact: Laboratories may have to conduct additional testing or validation studies to meet FDA's stricter requirements. This could be costly and time-consuming, especially for smaller labs that do not have the infrastructure in place to handle these rigorous standards.
7. Impact on Innovation and Flexibility
- What May Be Upsetting: The flexibility that labs currently enjoy under CLIA to quickly develop and modify tests to meet clinical needs is likely to be reduced under FDA regulation. With more stringent requirements for labeling, validation, and premarket approval, labs may find it more difficult to innovate and adapt quickly to emerging clinical challenges.
- Impact: Many in the LDT community pride themselves on their ability to rapidly create custom tests for specialized clinical needs. The FDA's regulatory framework could slow down this process, requiring more formal procedures, reducing the agility of the laboratories, and increasing the lead time for new tests to reach the market.
Conclusion
The FDA’s regulatory framework, particularly the labeling requirements, review of promotional materials, and stricter oversight, represents a significant shift for the LDT community. Labs that have operated successfully under CLIA may be upset by the financial burden, the additional layers of compliance, and the uncertainty around how these new requirements will affect their operations and test offerings. The perception that FDA regulation complicates innovation, adds cost, and introduces regulatory uncertainty is likely to be a central concern for many LDT developers.
