Navigating Clinical Laboratories Agenda Topics A discussion of our interactions with clinical diagnostics laboratories • What makes a lab clinical? • Regulators & regulations • Clinical assays • Personnel & equipment • Dos & don’ts • Communicating boundaries & reminders Clinical Laboratories “Clinical laboratories are healthcare facilities providing a wide range of laboratory procedures which aid the physicians in carrying out the diagnosis, treatment, and management of patients.”* • Patient samples: blood, urine, tissue (FFPE) • Testing informs diagnosis, treatment & disease management • Typically don’t do research • Regulated environment (FDA, CLIA & CAP) *Bayot and Gossman StatPearls, https://www.ncbi.nlm.nih.gov/books/NBK535358/ Clinical Laboratories • Defined roles for personnel • Strict regulations: • • • • • • Personnel Samples & controls Assays Quality Assurance and Quality Control Data Results reporting • Strict policies and procedures • Quality Assurance and Quality Control (QA & QC) is continuous & regulated • Tests must demonstrate clinical utility (help the patient) CLIA + CAP = Lab Improvement • In 1988, Congress tasked The Centers for Medicare & Medicaid Services (CMS) with regulating all human non-research testing (Clinical Diagnostic Testing) through the Clinical Laboratory Improvement Amendments (CLIA) • The Division of Clinical Laboratory Improvement & Quality of CMS oversees the CLIA program • CMS allows qualified organizations (e.g. College of American Pathologists, CAP) to conduct laboratory accreditation when the organization’s requirements meet or exceed CMS requirements (i.e. stricter) • CAP’s laboratory accreditation program is the leading credentialing authority for CLIA compliant clinical (Pathology) labs in the U.S. Laboratory Accreditation VS. • CMS and States have specific regulatory authority pertaining to lab accreditation • CAP accreditation authority arises through CMS • FDA regulates Medical Devices: • Instruments & Equipment • in vitro Diagnostics (IVDs) • FDA has no specific authority regarding lab accreditation Laboratory Accreditation Overview • CAP accreditation process: • Application is for a single physical testing location & ancillary sites • Peer-based inspection process in lieu of a CMS inspection (review policies and procedures) • Accreditation lasts for two-years • Subsequent inspections maintain accreditation • States (e.g. NY) may have a separate (accreditation and inspection) process • Most clinical labs that we interact with will be CAP accredited Testing: Tools of the Clinical Lab • FDA interprets levels of test complexity (via CLIA-CMS) • High (Molecular Tests) • Moderate • Waived (Very low risk, No CLIA Number Requirement) • IVD (In Vitro Diagnostic) • ”In vitro diagnostic products are those reagents, instruments, and systems intended for use in diagnosis of disease ...” • Subject to pre and post market control by the FDA • Think of as ready to use tools for clinical labs (no validation study) • EUA (Emergency Use Authorization) • Utilize non-approved tests in emergencies (bypass regulations) • FDA has authority to authorize use of products “to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions … when there are no adequate, approved, and available alternatives” Clinical Labs May Develop their Own Tools • Laboratory Developed Tests (LDTs): • • • • Clinical labs have the ability to develop their own diagnostic assays Typically developed when no FDA approved IVD is available Typically involve use of RUO products Must comply with specific regulations • Labs utilizing LDTs must validate the performance characteristics of an LDT before incorporation into their test menu (validation study) • Large number of known samples tested • Results must align with expected outcomes • LDTs must demonstrate clinical utility (help patient) • Laboratory are ultimately responsible for LDT performance • Role of FDA in LDT development is currently unclear Inspections & Proficiency Testing Program Overview • Clinical labs are routinely inspected • Diagnostic procedures & policies • Staff qualifications & competency • Quality Control process • Inspection failures that rise to the level endangering patient safety may lead to immediate suspension of laboratory certification and cessation of laboratory testing • All diagnostic tests require Proficiency Testing (PT) • Samples with known results (testing facility blinded) • Separate from internal Quality Control process • Verifies that Day to Day Testing Results are High-Quality • A diagnostic test w/ repeated unsatisfactory PT results may lead regulators to order a suspension of the test Clinical Lab Personnel • Personnel in clinical labs have roles defined by regulations • Typically 3 Levels of personnel involved in testing • Medical Laboratory Scientists (Medical Technologists: implement assay) • General Supervisor (technical review) • Medical Director (clinical interpretation of results) • Personnel must meet regulatory defined qualifications (often discipline specific) • Testing personnel must routinely demonstrate competency to perform testing procedures • Final test results must be reviewed by a board-certified medical professional (Medical Director, i.e. a Pathologist), before reporting to the ordering physician Clinical Laboratory Equipment & Instruments • Laboratory equipment utilized in testing must meet criteria defined by regulations • All instruments must undergo a performance verification before testing patient samples • Maintenance and functional checks must be performed according to manufacturer’s specifications • There is no regulatory requirement to utilize the FDA approved version of an instrument in lieu of a RUO model for LDTs • Avoid specific advice regarding equipment regulatory requirements FDA & LDTs • FDA does provide guidance regarding IVDs vs. LDT in the context of manufacturer’s distribution practices “When determining whether non-compliance with statutory and regulatory requirements warrant a regulatory and/or enforcement action, FDA intends to consider the totality of the circumstances concerning a manufacturer’s sale and distribution of a product labeled as RUO or IUO.” • Please remember customers are responsible for all aspects of clinical performance for LDTs, when utilizing our Research Use Only (RUO) products • Customers interpret their own data (not us) • Customers are responsible for knowing & following regulations regarding LDTs & IVDs FDA & LDTs • For LDTs: outside of instrument & general NGS training, avoid specific advice • Recommend customers: • Search literature • Review regulatory documents • Interact with other customers for advice & sample exchange • Never provide aid in Clinical (Medical) interpretation of testing performance of products • Customers are responsible for all aspects of clinical performance for LDTs Drawing the red line The red line seperates - RUO from IVD - What we can do /what we can‘t do RUO (->Lab developed tests) in clinical labs What we can do Support the scientific concepts Support the analysis options Support quality measures, GLP Speak about references by quoting their science Support with training on general NGS principles Support by refering clinical customers to appropriate ThermoFisher group with clinical training What we cannot do Don‘t give concrete analysis recommendations Don‘t talk about Patient Data Don‘t speak about direct therapy indication Don‘t support how to establish SOPs including concrete thresholds Don‘t speak about references in the sense of their diagnostic practice Don‘t support clinical implementation, utility & outcomes (decisions) Don‘t refer to specific samples, controls, results, genes & mutations (beyond the references in user guides) Summary & Random Thoughts • Clinical labs are not research labs (important functional differences) • Remember our work helps clinical labs improve patient outcomes • Test data may contain sensitive information • Avoid specific advice regarding regulations • Customers are responsible for LDT performance • Currently, excepting ODxTT, our NGS products are RUO • Never speak to clinical utility of RUO products References • Description of CLIA: https://www.cms.gov/Regulations-andGuidance/Legislation/CLIA/index.html • Test Categorization (CLIA): https://www.cms.gov/Regulations-andGuidance/Legislation/CLIA/Categorization_of_Tests • CAP website: https://www.cap.org/ • FDA Website: https://www.fda.gov/default.htm • FDA Medical Devices: https://www.fda.gov/MedicalDevices/default.htm • FDA EUA: https://www.fda.gov/emergency-preparedness-andresponse/mcm-legal-regulatory-and-policy-framework/emergency-useauthorization
