1. FDA oversight of in vitro diagnostics and other medical devices
Pamela L. Bradley, Ph.D.
Personalized Medicine Staff
Office of In Vitro Diagnostics and Radiological Health
Center for Devices and Radiological Health
U.S. Food and Drug Administration
NCCS Cancer Policy Advocate Training (CPAT)
November 13, 2014

2. Talk Overview What is a medical device?
FDA’s risk-based regulation of devices
Companion diagnostics
Laboratory developed tests (LDTs)
The future of cancer diagnostics

3. Medical Devices Hospital Bed Artificial Heart Drug Eluting Stent
“an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent or similar related article…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”
FFDCA 201(h)
Hospital Bed
Artificial Heart
Drug Eluting Stent
Insulin Pump
Tongue Depressor
Thermometer
Mobile Medical App
IVDs (In Vitro Diagnostic)

4. FDA Regulation of Medical Devices
Risk-based approach
Medical Devices are regulated to an extent that is driven by the risk of their Intended Use
For example: tongue depressors have a lower regulatory bar than artificial hearts
Components of oversight
Registration and Listing
Premarket review
Good Manufacturing Practices
Adverse Event Reporting
Recalls

5. What is an IVD?
“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 in man. … for use in the collection, preparation, and examination of specimens from the human body.” [21 CFR 809.3]
Can be used in clinical laboratories & other settings (e.g., Point-of-Care/Over-the-Counter)

6. IVDs Used For… Diagnosis Screening Risk Assessment Surveillance
First Response
Not Environmental Screening
Not Ancestry Information

7. IVDs: Risk and Intended Use
For IVDs, intended use is what a test measures and how to use the results
For IVDs, the risk is based on the consequences of a false result
For example:
Higher risk – HIV test
Lower risk – pregnancy test
The same IVD could have different level of risk depending on intended use:
Example: Screening asymptomatic individuals for the presence of cancer risk genes is generally higher risk than detecting the presence of a mutation in an individual diagnosed with cancer

8. Device Classification
3 Classification levels dictate required regulatory controls
Class I: common, low risk devices
Class II: more complex, moderate risk
Premarket review: 510(k), de novo
“Cleared”
Class III: most complex, high risk
Premarket review: PMAs
“Approved”

9. FDA Premarket Review
Independent review of IVD performance claims prior to clinical use
Assures test performance claims are supported by scientific evidence
Assures claims are clinically meaningful
Assures test limitations are described

10. Scientific review of IVD performance
Analytical performance characteristics
Reliability and accuracy of analyte measurements
Clinical performance characteristics
Clinical sensitivity and specificity
Positive and negative predictive values
Labeling
Intended use, device design, directions for use, warnings/limitations, result interpretation, performance
Transparency:

11. Postmarket Surveillance and Controls
Helps to identify and correct problems early
Medical Device Reports (MDRs)
Mandatory and voluntary reports submitted to MAUDE -- Manufacturer and User Facility Device Experience
Publicly available at
Recalls
Method to remove or correct products in violation,
Usually voluntary
Provides assurances of IVD performance throughout its lifecycle

12. Companion Diagnostics
Expect growing use of genetic information to suggest, and sometimes dictate, therapy decisions
“only patients positive for genetic biomarker X should receive this drug”
“patients with genetic biomarker Y should not receive this drug—use alternative therapy”
Herceptin and HER-2 status first drug/dx pair

13. Companion Diagnostics
“The success of personalized medicine depends on having accurate diagnostic tests that identify patients who can benefit from targeted therapies.”
Dr. Peggy Hamburg and Dr. Francis Collins
“The Path to Personalized Medicine” New England Journal of Medicine; July 22, 2010
Having a good test is as important as having a good drug
Need for a clear companion diagnostics policy for patient safety and to support therapeutic product approval

14. Companion Diagnostics: FDA Policy
Published Guidance: In Vitro Companion Diagnostic Devices (Draft July 2011; Final July 2014)
Defines companion diagnostics:
An IVD companion diagnostic device is an in vitro diagnostic device that provides information that is essential for the safe and effective use of a corresponding therapeutic product.
Describes expectations for codx contemporaneous approval with the therapeutic product
“How to” guidance on codevelopment coming soon

15. Companion Diagnostics: Current Status
To date: 19 different approved drug/diagnostic combinations
One imaging device
Cancer leading the way – 18/19
Many are HER-2 specific (10)
Others: ALK, B-RAF, C-KIT, EGFR, KRAS
Historically, one analyte—one test—one drug

16. Laboratory Developed Tests
An LDT is a type of IVD that is designed, manufactured and used within a single laboratory.
LDTs are marketed under enforcement discretion by FDA.
“test kit”
manufacturer
CLIA-certified
lab
FDA
“Enforcement
Discretion”
Performed in CLIA-certified lab
Performed within same lab that developed test

17. Public Health Need for Greater Oversight of LDTs
Evolution of LDT technology, marketing, and business models has increased risk associate with LDTs
Consequences
Significant adverse health consequences
Unnecessary healthcare costs
Could undermine progress of personalized medicine, which depends on tests that work

18. FDA’s Current Proposal for LDTs
On Sept. 30, 2014, FDA issued draft guidance that proposes an oversight framework for LDTs
Informed by 2010 public meeting and public comments
Goal: to work with all stakeholders to determine a framework for oversight that is in the best interest of public health

19. FDA’s Current Proposal for LDTs
Collect basic information on all LDTs through a notification process (a no-fee alternative to R&L)
Phase-in enforcement of regulatory requirements over 9 years, based on risk
Use public process to obtain input on risk and priority for enforcement
Continue some enforcement discretion for specific categories determined by FDA to be in the best interest of public health

20. FDA seeking comment on Proposed LDT Framework
Info, links, archived webinar available at:
120-day comment period opened Oct 3
Notice of Availability in Federal Register
Points out specific issues for comment
Questions?

21. The Future of Cancer Diagnostics
Liquid biopsies
Cancer panels
Combination of CoDx and novel markers
Whole exome/Whole genome sequencing
Other omics
Big data
Centralized knowledge databases
Consideration of new regulatory approaches

22. Questions? Pamela.Bradley@fda.hhs.gov