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

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

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)

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

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)

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

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

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”

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

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: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Databases/default.htm

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 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/search.CFM Recalls Method to remove or correct products in violation, Usually voluntary Provides assurances of IVD performance throughout its lifecycle

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

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

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

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 www.fda.gov/companiondiagnostics

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

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

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

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

FDA seeking comment on Proposed LDT Framework Info, links, archived webinar available at: www.fda.gov/LDTs 120-day comment period opened Oct 3 Notice of Availability in Federal Register Points out specific issues for comment Questions? Email: LDTframework@fda.hhs.gov

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

Questions? Pamela.Bradley@fda.hhs.gov