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.
Purchasing Controls Ch 6 p 39-42
etc
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:
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.
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.
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.
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.
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.
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.
##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:
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.
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.
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.
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.
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 .
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:
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.
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.
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.
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.
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