FDA Regulation of In Vitro
Diagnostic Tests
George Washington University
March 8, 2011
Katherine Serrano
Office of In Vitro Diagnostic Device Evaluation and Safety
Center for Devices and Radiological Health/FDA
Katherine.serrano@fda.hhs.gov
Center for Food Safety
and Applied Nutrition
Center for Devices and
Radiological Health
Office of Regulatory
Affairs
FDA
Center for Biologic
Evaluation and Research
Center for Tobacco
Center for Drug
Evaluation and Research
Center for Veterinary
Medicine
Legal Basis of Regulation
• Authority to regulate medical devices
• Public Health Services Act
• Federal Food Drug and Cosmetic Act
(FFDCA) of 1938
• Medical Device Amendments 1976
• Other legislation
• FDA Modernization acts of 1997, 2002 and
2007
Medical Devices
•
•
•
•
•
•
•
Artificial Hearts
Drug Eluting Stents
Hospital Beds
Thermometers
Tongue depressors
Insulin Pumps
In Vitro Diagnostic tests (IVDs)
What is an IVD?
In Vitro Diagnostic Tests for:
• Diagnosis
• Screening
• Prevention
• Risk Assessment
• Surveillance
• First Response
• etc…
• Not Environmental Screening
FDA IVD Regulation
• Medical Devices (including IVDs) are
regulated to an extent that is driven by the
risk of their Intended Use
(i.e. tongue depressors have a lower
regulatory bar than artificial hearts)
Intended Use
• The risk of an IVD is based on the
consequences of a false result
Examples:
High risk –
Lower risk –
Intended Use
•
The risk of an IVD is based on the
consequences of a false result
Examples:
High risk – HIV, tuberculosis
Lower risk –
Intended Use
• The risk of an IVD is based on the
consequences of a false result
Examples:
High risk – HIV, tuberculosis
Lower risk – Calcium, pregnancy
Risk-Based Classification
• The risk of an IVD is based on the
consequences of a false result
• 3 Classification levels
• Class I: common, low risk devices
• Class II: more complex, moderate risk
• Class III: most complex, high risk and novel
intended uses
Class II IVDs
• “Moderate risk” devices, tend to be more
complex
• Examples:
• Blood glucose meters
• Troponin
• General Controls
• Usually require premarket review in the form of a
premarket notification [510(k)] submission
• Special Controls
Premarket Notification: 510(k)
• 510(k) submission required of most class II devices
• Submission has 90 day review clock
• FDA clearance based on “substantial equivalence” to
legally marketed device (predicate device)
• What substantial equivalence to predicate device means:
– Similar intended use
– Similar performance characteristics
• What substantial equivalence may not mean
– Identical technology
• Submissions may require clinical data
• Summary of FDA’s review and basis for decision is
posted on the FDA website
Class III IVDs
• Represent highest risk intended uses
– Sometimes includes devices with new
intended uses, technologies/methodologies,
scientific questions
– Examples:
• Hepatitis B and C, HPV tests
• Total PSA for prostate cancer screening
• Continuous Glucose Monitoring Devices
• Premarket Application [PMA]
• Submissions often include clinical data
Premarket Application (PMA)
•
•
•
•
•
•
180 day review clock
Demonstration of safety and effectiveness
Does not use predicates
Submissions often include clinical data
Pre-approval inspection performed
FDA may seek may require advisory panel
decision prior to approval
• Summary of Safety and Effectiveness Data
(SSED) posted publicly on web
Premarket Review
•
All IVDs must establish adequate:
•
Analytical Validity
• How accurately does the test measure the analyte?
• How reliably?
•
Clinical performance
• How reliably does the test measure the clinical condition?
•
Labeling (21 CFR 809.10)
• Adequate instructions for use
• Intended use, directions for use, warnings, limitations,
interpretation of results, performance summary
Analytical Performance
• Repeatability/Reproducibility
• Will I get the same result in repeated tests over time?
• Will I get the same result as someone else testing the same
sample?
• Accuracy
• Will I get results that are the same as “Truth”?
• “Truth” – may be a reference method, clinical endpoint,
predicate device, etc…
•
•
•
•
Limit of Detection
Potential Interferences/ Cross-Reactivity
Cross-contamination / Carry-over
etc…
Other Performance:
Software/Instrumentation
• FDA regulates all software/instrumentation used in diagnostic test
systems
– Database integrity
– Cyber-security
• Engineering Considerations related to Instrumentation
– Design Robustness
• Cleaning/disinfection
• Handling
– Environmental Factors
• Temperature
• Humidity
• Altitude
Direct to Consumer
•
IVDs for consumer use (OTC) have additional
requirements:
• Data submitted to demonstrate that the tests are accurate in the
hands of lay users (including sample collection)
• Studies are performed to evaluate how well lay users can
understand the instructions without prompting, perform a selftest (or collect a sample), and obtain an accurate result
• Lay users’ ability to understand the results of the
test are also evaluated
• Human factors are also considered in the review, where
applicable
Post Market
Medical Device Reports (MDRs)
• Reports to FDA by user facility/manufacturer when a
device:
• Caused or contributed, or may have caused or may have
contributed to a death
• Caused or contributed, or may have caused or may have
contributed to a serious injury
• Malfunctioned or failed to meet specifications
(manufacturer only)
• Recurrence could result in death or serious injury
• Required timeframe for reporting
• 5-30 days, depending on severity
• Follow-ups when needed
• FDA assesses reports and decides if action is needed
Recalls
• Method of removing or correcting products that
are in violation of laws
• Products present a risk of injury or gross
deception or are otherwise defective
• Usually voluntary by manufacturer, but must be
reported to FDA
• FDA
•
•
•
•
Conducts health hazard evaluation (HHE)
Classifies recall
Posts recall information on website
Ensures manufacturer completes recall
Laboratory Developed Tests
Lab Developed Tests – Unequal Regulation
1) Commercially Distributed Test Pathway:
FDA approval
Patient
“test kit” manufactured
for distribution to
multiple labs
“Test kits” distributed to
patients, hospital, or
clinical lab
2) Lab Developed Test (LDT) Pathway:
FDA
“enforcement
discretion”
Test designed,
manufactured, and
used in a single lab
LDTs (lab developed
tests)
enter the market without
review
Patient
Enforcement Discretion:
• Definition: When FDA does not enforce some or all
applicable laws and regulations on certain categories
of products (drugs, devices, biologics, etc.)
• Key Points:
•Enforcement discretion not unique to LDTs
•Enforcement discretion does not change the fact
that the law applies
•Many different reasons for this practice (risk,
history, timing, resources, etc.)
•Practices like this do occur, but may change (often
because of changes in risk profile of the products)
History: LDTs - Then
•
Local
•
Mostly non-commercial
•
Tests generally used FDA-approved components
•
Test methods generally well established, accessible
•
Most tests were single signal tests
•
Used simple, well-defined chemical, biological, or immunological principles
(IHC, RIA, etc.)
•
Clinician/Pathologist/Patient relationships
•
Simple software – calculations
•
Performed by specialists with advanced training and require expert
interpretation (karyotype, IHC)
•
Small test volumes
History: LDTs - Now
•Volume and types of LDTs has grown significantly
•Often a mechanism for market entry of novel tests
•Higher proportion in commercial labs and biotechnology companies
•Often no clinician/pathologist/patient relationship
•Tests developed for broad, commercial use
•Tests broadly advertised
•Often require complex software
CLIA
What does CLIA stand for?
• Clinical Laboratory Improvement Amendments (1988)
• Implemented by the Centers for Medicare and Medicaid Services (CMS)
What does CLIA provide for?
• The regulation of laboratories that perform clinical testing on human
samples in the US
• Requires adequate personnel training/education, quality system for testing,
record keeping, proficiency testing, etc.
• CLIA requires that labs have adequate methods/records of analytical
validation of tests
• CLIA inspects labs to ensure that adequate testing quality is in place
LDT Enforcement Discretion
Why did FDA apply enforcement
discretion to LDTs?
Should they? Why or Why not?
Greater Oversight for LDTs?
• Oversight: Concerns
– Burden of FDA regulation is too great
– Stifle innovation
– Decreased patient access to critical tests
– Effect of regulation on rare disease testing
– Oversight already exists under CLIA
Greater Oversight for LDTs?
• Oversight: Pro
– In some cases, there is an FDA
cleared/approved alternative
– Patient protections needed
– Independent evaluation of data and claims
needed
– Innovation needs to be controlled
– Unlevel playing field and regulatory
uncertainty
Potential Framework Elements
• Risk-based, phased-in over time to allow for
predictability, planning
• Exemptions for certain categories of LDTs
– Rare Diseases
– Tests used for forensic (law enforcement) purposes
• List of who offers what
– Coordinate with NIH’s Genetic Test Registry?
• Implement modifications to current oversight
structure where appropriate
LDT Example: Her2/neu testing
Her2/neu Test
• Test determines whether a woman with
breast cancer will respond to Herceptin
treatment
• 3 FDA approved tests available
• Many LDTs also available
• Recent report – 20-50% of Her2 tests
inaccurate
Example: Her2/neu testing
• What are the potential reasons for this
inaccuracy?
• What are the potential risks of inaccurate
results?
Direct to Consumer Genetic
Testing
DTC Genetic Testing
• A number of for-profit companies now provide personal genomic
testing services directly to patients
• Companies uniformly claim “laboratory developed test (LDT)” status
• Wide range of information provided by these services ranges:
 Some usually do not meet definition of medical device
 Ancestry
 Forensics
 Non-medical information
 Some do meet definition of medical device




Pharmacogenetic profiles
Mendelian disease mutations
Risk prediction for disease/condition
Others
Challenges to DTC Oversight
 Patients require protection from misleading, false
information
 Correct measurement, valid clinical claims
 Medical device regulation must keep up with science and
technology
 Assessment of new technology (i.e. multiplexed devices)
 How to promote quality and innovation
 Healthcare community requires training in how to use
new information
 Wide variety of genetic information available, spectrum of
usefulness
DTC
• What potential benefits to patients are
there through this testing?
• What potential risks may be posed through
this type of testing?
Summary
• LDTs and genetic tests have so far avoided
regulatory oversight but this is changing
• FDA tries to minimize stifling new technology
while concentrating on areas that pose greatest
risk to patients
• If you find consumer protection in health
care important consider working at the FDA!