FDA’s approach to regulation of in vitro diagnostic tests

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Elizabeth Mansfield, PhD, discusses the FDA’s approach to regulation …

Elizabeth Mansfield, PhD, discusses the FDA’s approach to regulation
of in vitro diagnostic tests.

Part of Dx2010, a workshop at MaRS focused on best practices and regulatory considerations for developing gene-based diagnostic and prognostic tests.

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  • 1. FDA’s Approach to Regulation of In Vitro Diagnostic Tests Elizabeth Mansfield, PhD OIVD/CDRH/FDA elizabeth.mansfield@fda.hhs.gov
  • 2. Overview • IVD regulation • Laboratory developed test policy – IVDMIA – Revisit of policy • RUO/IUO labeling • Personalized Medicine • Codevelopment/companion Dx
  • 3. What FDA regulates FFDCA Part 201(h) Devices • The term "device" (…) means an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is-- – (1) recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them, – (2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or – (3) intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.
  • 4. IVDs are devices • 21 CFR 809.3(a) – In vitro diagnostic products are those reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body. These products are devices as defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act (the act), and may also be biological products subject to section 351 of the Public Health Service Act.
  • 5. IVD regulation Cliff Notes • Regulation by risk – Risk defined by possible harm to patient of unrecognized incorrect result – Three classes from high to low risk • Compliance with general controls – Registration/listing, GMPs, premarket review, postmarket controls, etc • Labeling – Instructions for use, etc.
  • 6. Current Structure • Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD) in Center for Devices and Radiologic Health (CDRH • Four review divisions – Chem/tox – Micro (virology/bacteriology) – Immunology/hematology – Radiology • One Personalized Medicine Staff serves all divisions
  • 7. Laboratory Developed Tests • Bifurcation in oversight of IVD devices – FDA + CLIA – CLIA only • LDTs (CLIA only pathway) – No record of who is offering what – No premarket review – No requirement for clinical validation – No postmarket requirements – Taking on higher risk, more complex tests
  • 8. LDTs: the problem • Can be used as a loophole – Bad, unvalidated, or fraudulent tests on market with minimal control – High risk tests with unknown performance in use • Creates an unlevel playing field – Traditional Dx manufacturers have higher hurdle than LDT manufacturers
  • 9. Enforcement Discretion • LDTs: Currently, – Self-defined by labs – No way to know what’s out there – No regulatory definition of LDT – More-or-less blanket approach by FDA
  • 10. Time for Change • Blanket enforcement discretion no longer appropriate – risk-based approach to regulation • Need to see what is being offered – No registry of LDTs exists • Need an approach to regulation that serves public health
  • 11. Public meeting on LDTs • FDA announces public meeting and intent to make changes (FDA-2010-N-0274) – Public meeting July 19-20, 2010 – Intent to establish risk-based oversight framework for all tests – General expectations at this time • Registration and listing period will be needed • Risk-based phase in (highest risk first) • Avoid disruption to access – Low or no bar for certain tests (rare disease, etc)
  • 12. The book is not written yet • Seeking input on: – Risk assessment paradigm – Oversight mechanisms for LDTs • Evaluation of necessary info to assure safety and effectiveness • Encourage innovation • Avoid total disruption of marketplace • Provide fair field of play – Timing
  • 13. LDTs: Benefits/harms • Possible benefits – Tests available for small populations – Rapid test development and deployment – May save system $$$ • Possible harms – Patients, healthcare providers relying on useless tests – Labs think they validate better than they really do – Puts traditional mfrs with controlled design, product development, manufacture processes at disadvantage = they don’t play
  • 14. Benefits/harms explored • Emergency use authorization for H1N1 outbreak – Devices for diagnosing 2009 H1N1 needed urgently – Device regulatory bar lowered – EUA not required to offer test – Multiple applicants from traditional and LDT manufacturing sectors
  • 15. 2009 H1N1 • FDA makes EUA template available with minimum info/data requirements – “fill in the blanks” approach – Low data burden • Result – Several devices deemed appropriate – Labs—more than one had improperly designed test (already being offered), not enough validation – Mfrs—more than one “not ready for prime time”
  • 16. IVDMIA • FDA’s effort to ensure certain types of difficult-to-validate tests came under regulatory scrutiny – Easy to overfit data – Easy to introduce bias – Easy to choose incorrect validation strategy – Easy to get to market if an LDT
  • 17. Problems We’ve Seen • Inappropriate sample size • Overfit data • Bias, bias, bias • Tests not independently validated • Lack of control mechanisms – Reagents – Processes – Samples
  • 18. RUO/IUO Labeling • Manufacturers inappropriately marketing devices marked: – For research use only. Not for use in diagnostic procedures (RUO) – For investigational use only. The performance characteristics of this product have not been established (IUO)
  • 19. Legitimate Uses of RUO/IUO • RUO – Research to determine characteristics of devices to be developed – Basic scientific research • IUO – Controlled investigations to gather performance data on products • Informed consent, IRB
  • 20. RUO Inappropriate Marketing • Labeling – Includes intended use • See 21 CFR 801.4 on intent – Includes clinical information – Includes clinical interpretation guidelines – References diagnostic use • Sold for clinical use
  • 21. IUO Inappropriate Marketing • Sold for clinical use outside investigation • “investigation” has no protocol, no ending criteria
  • 22. Novel Technologies • aCGH—public meeting on validation and regulatory issues • Whole genome sequencing—still evolving quickly • Proteomics—may offer new and accessible markers • Highly multiplexed diagnostics—validation and review timing issues
  • 23. Personalized Medicine • How will OIVD handle novel technologies • What is different about codevelopment • What are the regulatory requirements for companion diagnostics • Other policy areas around emerging diagnostic issues
  • 24. Approach to Novel Issues • Different programs available – VXDS: scientific discussion only; discuss discovery/science issues related to use in drug development, etc • Not for regulatory issues • Not an early diagnostic meeting – preIDE: early diagnostic consultation • CDRH program, but can add consults from other centers • Evaluation of validation plans in context of intended use – Intended use – Analytical validation – Enrollment strategies – etc
  • 25. Codevelopment • “Coordinated” development of a drug with a diagnostic that identifies a specific treatment population – Response/non-response – Adverse events – Dose required for safety and efficacy – Population in which the drug was trialed
  • 26. Regulatory Issues in Codevelopment • Test and therapeutic review processes – Test subject to IDE/IND – Review of one or two applications? – Labeling • Drug reference to FDA approved test • Device with specific intended use • Approval – Intercenter agreement – Timing • Change management – Test performance – Technology – Labeling
  • 27. Codevelopment • Codevelopment guidance – Most likely “non-directive” but providing information about differences in approach for drug and diagnostic development – Every drug/diagnostic combination will have different issues – Planned draft publication in 2010 – Not directly related to biomarker guidance
  • 28. Codev guidance • Codevelopment guidance approach – Will describe: • general principles and provide information • when a diagnostic must be available in order for drug (or new label) to be approved • risk/benefit determinations around requiring or recommending a diagnostic in labeling • recommendations for timing of diagnostic development in drug development cycle • how drug and diagnostic performance evidence will be reviewed
  • 29. Companion Diagnostics • Those diagnostic devices that are required in order to select appropriate patients for treatment with a therapy – Established performance of drug depends on diagnostic test result – Known performance of diagnostic needed – Premarket approval indicated – Business model of test offering not critical
  • 30. Other Issues • RUO to IVD transition for instrumentation, reagents • Intercenter coordination for codeveloped products • Quality systems for laboratories
  • 31. Thanks! • Questions? • Elizabeth Mansfield • elizabeth.Mansfield@fda.hhs.gov • 301-796-4664