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.

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