Laboratory Administration & Management of Pathology Practices

Images hosted on other servers:


Comparison: FDA versus CLIA / CMS oversight of testing (FDA: Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories - Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs) [Accessed 4 March 2024])

U.S. FDA oversight	CLIA '88 / CMS oversight
Focus on devices themselves and how they perform	Focus on laboratory processes to use devices, not device quality
Review of analytic validity performed before test may be used on patients	Review of analytic validity performed during a 2 year inspection cycle; test may be in use for 2 years before assessment of data and test use
Analytic validity large in scope with thousands to tens of thousands of data points	Analytic validity may be performed on the smallest number of patients required for statistical significance
Requires assessment of clinical validity / utility of testing	Does not require clinical validity / utility
Review requires assessment of patient safety	Review does not require assessment of patient safety
Required demonstration of effectiveness in determining presence / absence of condition being assessed	No required demonstration of effectiveness in determining presence / absence of condition being assessed
Requires adverse event reporting to identify inaccurate, unsafe and ineffective devices	Does not require adverse event reporting
Requires removal of unsafe devices from market	Does not remove devices from the market

European Union (EU) (European Commission: Questions and Answers - Stronger Rules for Placing Medical Tests on the Market [Accessed 18 March 2024], Ther Innov Regul Sci 2022;56:47)

• Regulation on in vitro diagnostic medical devices (IVD regulation)
  • Entered into force May 2017 and applicable on May 26, 2022 with staggered grace periods extending to May 26, 2025 for high risk IVDs and May 26, 2027 for lower risk IVDs
  • Updates first EU level rules for placing IVDs on the market in 1998
  • Response to substantial technological and scientific progress over the last 20 years
    • To improve the safety of IVDs
    • To modernize regulations and the sector
    • Ensure a high level of public health and safety
    • Ensure smooth operation of a single market for these devices
• IVD Regulation (EU-IVDR) - EU Regulation 2017/746 on in vitro diagnostic medical devices
  • Clear obligations for economic operators
  • Risk based classification system with 4 risk classes of IVDs
    • Class A: low individual risk and low public health risk (e.g., buffer solutions)
    • Class B: moderate individual risk or low public health risk (e.g., pregnancy home tests)
    • Class C: high individual risk or moderate public health risk (e.g., cancer tests)
    • Class D: high individual risk and high public health risk (e.g., hepatitis and HIV tests)
  • Stricter control of high risk IVD with new premarket scrutiny mechanism
  • Oversight by independent third party conformity assessment bodies (notified bodies)
  • Improved transparency through comprehensive EU database
  • Traceability system based on unique device identifier
  • Reinforced rules on clinical evidence and performance evaluation
  • Strengthened postmarket surveillance requirements
  • Improved coordination mechanisms among EU countries on vigilance and surveillance
  • Specific regime for devices manufactured and used in the same health institution (in house devices or LDT)
    • Not marketed or transferred to other legal entities
    • Not CE marked
    • General safety requirements must be met
    • Requirements of health institution using an LDT
      • Must have an appropriate quality management system
      • Must comply with international standards setting out the quality and competency requirements of the laboratory (EN ISO 15189) or other national provisions
      • Must justify that the target patient group's specific needs cannot be met by an equivalent IVD available on the market

Canada (CMAJ 2020;192:E1166, CMAJ 2019;191:E1067)

• Health Canada, a federal institution, is responsible for
  • Helping Canadians maintain and improve health
  • Ensuring high quality health services are accessible
  • Reducing health risks
• Federal Food and Drugs Act
  • Oversees IVD devices under Medical Devices Regulation
  • Has oversight of diagnostics developed as test kits only
  • Does not address LDT
• Other regulation of laboratory testing is overseen by public and private entities with oversight from provincial governments, nongovernmental organizations and professional societies
• No single entity is formally responsible across Canada for independent evaluation of LDT or assessment of development, validity and adverse effects
• Standards Council of Canada, Canadian Standards Association Technical Committee Z252.11 for Lab Developed Tests, April 2018
  • Voluntary standard
  • In concert with Medical Devices Bureau of Health Canada and laboratory partners Siemens and Roche
  • Provides high level guidelines for test validation
  • Distinguishes testing performed for clinical use versus research

Definitions

• Device master record (DMR): the definitive instruction manual in the compliant manufacture of a device, an all encompassing collection of documents and records required by regulation
• Corrective and Preventative Action (CAPA): a process used to address and prevent quality problems

Essence of the FDA final rule (Federal Register: Food and Drug Administration - 21 CFR Part 809 [Docket No. FDA-2023-N-2177] [Accessed 10 June 2024])

• The FDA issued a final rule on May 6, 2024 to amend its regulations to make explicit that IVDs are devices under the Federal Food and Drug Cosmetic Act (FD&C Act), including when the manufacturer of the IVD is a laboratory
• The remainder of the Final Rule document is the proposed draft guidance for
  • Schedule for implementation of the rule
  • Description of the application of the rule
  • Exceptions to the rule where enforcement discretion will continue
• FDA may alter its draft guidance at any time
• Proposed draft schedule for implementation (FDA: FDA’s Final Rule Including a Phaseout Policy Regarding Laboratory Developed Tests [Accessed 10 June 2024]) (see Figure 2)
  • Unless specifically exempt, all LDTs will be required to meet the reporting and performance requirements for stages 1 and 2
  • A subset of LDTs will be required to meet the requirements for subsequent stages
• Specific FDA required reporting / documentation elements that differ from CLIA required reporting
  • Design controls: a structured approach that manufacturers must adhere to throughout the device development lifecycle; this typically follows a traditional waterfall model
    • Requirements for a device are developed / identified
    • Device is designed
    • Design evaluated, produced and manufactured
    • Iterative feedback at each stage
  • Purchasing controls: a requirement that manufacturers develop and maintain procedures to ensure that all purchased or otherwise received products and services adhere to specific requirements
  • Acceptance criteria: this refers to the numerical limits, ranges or other criteria for tests that are used for making a decision to accept or reject a unit, lot or batch of a test or its products
    • The activities required in the DMR are completed
    • Associated data and documentation reviewed
    • The release is authorized by signature of designated individual
    • The authorization is dated
  • Records required in DMR are complete and maintained
  • CAPA: a specific system for evaluating any issues or complaint, with specific documentation and reporting requirements (FDA: Corrective and Preventive Actions (CAPA) [Accessed 10 June 2024])
• The FDA may take action against any LDT that it determines is dangerous or too high risk to the public
• Continued enforcement discretion includes the following categories of tests
  • 1976 type LDTs
    • Use of manual techniques performed by laboratory personnel with specialized expertise
    • Use of components legally marketed for clinical use
    • Design, manufacture and use within a single CLIA certified laboratory that meets CLIA high complexity testing requirements
  • Certain human leukocyte antigen tests for transplantation
    • Designed, manufactured and used within a single CLIA certified laboratory
    • Used for organ, stem cell and tissue transplantation
  • Forensic tests
  • Department of Defense and Veterans Health Affair LDTs
  • LDTs approved by New York State's Clinical Laboratory Evaluation Program (CLEP)
  • Certain modified versions of another manufacturer’s 510(k) cleared or de novo authorized test
    • Laboratory certified under CLIA
    • Modification follows design controls and other quality system requirements of FDA
    • Does not significantly affect the safety or effectiveness of the test
    • Does not constitute a major change or modification in the intended use of the test
    • Modified test is performed only in the laboratory making the modification
  • Certain LDTs for unmet needs
    • Manufactured and performed by a laboratory integrated within a healthcare system to meet an unmet need of patients receiving care within that same healthcare system
    • Once an FDA approved test is available for the same indication, the LDT may not be used, unless the LDT is not available to that patient population at that location
  • Currently marketed IVDs offered as LDTs
    • Were being offered prior to the May 6, 2024 issuance of the final rule
    • Are not altered / modified after that date
    • Note that some limited alterations may be permitted
  • Certain nonmolecular antisera LDTs for rare red blood cell antigens for transfusion compatibility
• Questions yet to be clarified in this guidance include
  • What is the definition of a high risk LDT that will require a laboratory to go beyond the first 2 stages of the implementation?
  • What modifications to a manufacturer’s test or LDT would require additional submission of data as a new LDT?
  • What are unmet patient needs?
  • How is “within a healthcare system” defined? Is it the same corporation or could it be an independent lab contracted to that healthcare system?
  • Will data previously collected during the validation of an LDT prior to May 6, 2024 be accepted as part of the FDA data submission?
  • What will the fee structure be for?
    • Laboratories registering new LDTs that do not require premarket approval or 510(k) clearance?
    • Laboratories only offering LDTs where continued enforcement discretion will be followed?
• Implementation of the FDA Final Rule on LDTs may still be impacted by
  • Legislation
  • Litigation
  • Federal intervention

Which of the following is required by both the U.S. Food and Drug Administration (FDA) and Clinical Laboratory Improvement Act (CLIA) in the oversight of laboratory testing?

1. Demonstration of diagnostic effectiveness
2. Demonstration of patient safety
3. Requirement for analytic validity
4. Requirement for clinical validity

C. Requirement for analytic validity. Analytic validity is required by both the FDA and CLIA before a test may be put into use; however, the FDA requires large scale population studies and CLIA allows analytic validity to be performed on the smallest number of patients that can be used for statistical significance. Answers A, B and D are incorrect because these are mandatory only under FDA regulatory oversight of medical testing and not CLIA.

Comment Here

Reference: Laboratory developed tests

Which of the following characteristics describes the original (1976) definition of laboratory developed tests (LDT)?

1. Are based on manual methods requiring scientific expertise
2. Are used by reference laboratories across the U.S.
3. Require complex and proprietary algorithms for interpretation
4. Widely screen for disease

A. Are based on manual methods requiring scientific expertise. The original definition of LDT in 1976 included primarily manual methods of testing, performed in a single high complexity CLIA certified laboratory for the local population, in small volume and to diagnose rare diseases. Answers B, C and D are incorrect because they describe some of the changes that have occurred in LDT processes over the years. These changes have led to the FDA seeking to establish greater oversight of these tests.

Comment Here

Reference: Laboratory developed tests