The FDA Approval Process
Evidence to Support the Adoption of New Biomarkers
Diagnostic Course , Queen’s College , Oxford
September 2014
Sally A. Hojvat, Ph.D, M.Sc
Director, Division of Microbiology Devices
Office of In Vitro Diagnostic Devices and Radiological Health
Center for Devices and Radiological Health
Food and Drug Administration
sally.hojvat@fda.hhs.gov
1
Presentation Outline
• Overview of Regulation of In Vitro
Diagnostic Devices (IVD s)
• Scope of Data to Support
Approval/Clearance of an IVD Device
• Regulatory Challenges Posed by
New Technologies
• Useful Resources
2
Overview of
Regulation of In Vitro
Diagnostic Devices
(IVD s)
3
FDA’s Mission
• “The FDA is responsible for protecting the
public health by assuring the safety,
efficacy, and security of …medical
devices.
• “The FDA is.. responsible for advancing
the public health by helping to speed
innovations ……..; and helping the public
get accurate, science-based information
…..”
4
FDA’s Mission
Ensure that
devices/systems
on the market are
safe and effective
Get safe and
effective
devices/systems to
market as quickly as
possible
5
Total Product Life Cycle Approach
Design
Postmarket
Postmarket
Surveillance
Manufactur.
Compliance
Quality
Systems
21CFR
§820
Premarket
Analytical
Evaluation
Approval/
Clearance
Clinical
Evaluation
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfTPLC/tplc.cfm
6
FDA Organization
Center for Biologics
Evaluation and
Research
Center for Devices
and Radiological
Health
National Center for
Toxicological
Research
Center for
Veterinary
Medicine
Center for Drug
Evaluation and
Research
Center for Food
Safety and Applied
Nutrition
Office of
Regulatory
Affairs
Center for
Tobacco
Products
7
Center for Devices and Radiological
Health (CDRH)
Center Director
Office of Compliance
Office of Science and
Engineering Technologies
Office of Device Evaluation
Office of Surveillance
and Biometrics
Office of Communication,
Education and Radiation Programs
Office of In Vitro Diagnostic
Device & Radiological Health
8
FDA Regulatory Authority over IVDs
• Federal Food, Drug and
Cosmetic Act
– Established Regulatory Controls
for Medical Devices (May 28,
1976)
• Code of Federal Regulations, Title
21, Part 800 - Includes Quality
System Regulation Part 820
• CFR available at:
– http://www.accessdata.fda.gov/S
CRIPTs/cdrh/cfdocs/cfcfr/CFRS
earch.cfm
9
Definition:
“In -Vitro Diagnostic Device”
“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. … for use in the
collection, preparation, and examination
of specimens from the human body.”
[21 CFR 809.3]
10
IVDs: FDA Regulated Uses
In Vitro Diagnostic Tests for :
• Detection and Diagnosis
• Screening
• First Response
• Not Environmental Screening
11
Office of In Vitro Diagnostic Device
Evaluation and Radiological Health:
Division of Microbiology Devices
Infectious Diseases: bacteria,viruses,yeast,pathogens,fungi
Influenza,other respiratory infections;TB
Hepatitis A,B,C,D,E, HPV
STDs, sepsis, malaria,parasites
Multiplex – devices that detect multiple organisms
Biothreat
Division of Chemistry and Toxicology Devices
General Chemistry, Glucose, Drug testing, Cardiac markers
Pharmacogenomics (AmpliChip)
Chemthreat
Division of Immunology and Hematology Devices
Cytogenetics/Fish (BCR-ABL Fish)
Cancer screening/ diagnosis
Tumour markers
RadNucthreat
Division of Personalized Medicine
Biomarkers submitted to all Divisions
12
Compliance Oversight
Embedded Within each Division
• Review PMA manufacturing sections for Quality
System Compliance
• Check on Registration and Listing
• Aid GMP Inspectors
• Aid Bioresearch Monitoring (BIMO)Audits
• Enforcement Actions-Product Recalls
• Devices being sold when not in compliance
• Import/Export issues
• Shortages
13
Manufacturing Regulations
• Good manufacturing (cGMP) –
QSReg. 21CFR 820
• Applicable to any device intended for
human use
• Ensures quality manufacturing of
IVDs /Instruments
14
Software/Hardware
Regulations
• Documentation and hazard analysis
required
• Claims for use on multiple amplification
/detection platforms must be validated
• Guidance documents available
15
FDA Human Subject
Protection Regulations
• 21 CFR Part 50: Informed consent and
limited emergency exceptions
• 21 CFR Part 56: IRB review
• 21CFR 812: Disqualification of an
Investigator (812.119)
– Regulations that apply to all FDA clinical
investigations
16
Device Investigations and Risk (21 CFR 812)
All Device Investigations
Studies Subject to the
IDE Regulation-Rare
for IVDs
Significant Risk
Full Requirements
Studies Exempt
from the IDE
Regulation-Most
IVDs
Non-Significant Risk
Abbreviated
Requirements
17
Device Classification
A device should be placed in the lowest
class whose level of control will provide
reasonable assurance of safety and
effectiveness
Risk Based Regulation of IVDs
Knowledge Mitigates Risk
Class I
Class I - Low likelihood of harm
Knowledge
Class II - Moderate likelihood of
harm or risk can be mitigated
Risk
Class III - High or unknown
likelihood of harm
Significant Risk
Class III
19
Risk-based Approach to Classify and
Regulate Medical Devices
Class I:
Low risk devices
• Most exempt
from premarket
submission
• General controls
–e.g., GMP,
registration &
listing
Class II:
Moderate risk
devices
• 510(k) or De
Novo
• Substantial
equivalence to a
marketed device
• Special controls
–e.g.,
performance
standards,
quality systems
regulations
Class III: Highest
risk devices
• Premarket
Approval [PMA]
• Demonstrate
safety and
effectiveness
• Additional
postmarketing
controls
20
Risk Dependent on IU: Different Use,
Same Test
 A CFTR genotyping multiplex assay on the same
instrument with the indication
 for aid in diagnosis510(k)
 for fetal screening PMA
 A breast cancer assay to be used
 for screening, diagnosis PMA 510(k)
 for prognosis in already diagnosed patients
21
Regulatory Classes (Class I)
Primarily devices for which any combination of general
controls are sufficient to provide reasonable assurance of
the safety and effectiveness of devices
General controls include (for example):
• Prohibition against adulterated or misbranding
• GMPs
• Registration of manufacturing facilities
• Listing of device types
• Record keeping
• Repair, replacement, refund
Regulatory Classes (Class II)
• Devices which cannot be classified into Class I
because general controls by themselves are
insufficient to provide reasonable assurance of the
safety and effectiveness of such device, and
• For which there is sufficient information to establish
special controls to provide such assurance
Regulatory Classes (Class II)
Examples of Special Controls:
•
•
•
•
•
•
•
Performance standards
Postmarket surveillance
Patient registries
Tracking requirements
Recommendations and other appropriate actions
Special labeling requirements
Note: special controls will now be part of a published
regulation. Guidances will not be published.
Regulatory Classes (Class III)
• Devices for which insufficient information exists to
determine that general and specials controls are
sufficient to provide reasonable assurance of safety
and effectiveness
• Such devices:
– Are life sustaining and/or life supporting
– Are of substantial importance in preventing
impairment of human health; or
– Present potential or unreasonable risk of illness or
injury (Sometimes a matter of perspective….)
Why is Classification Important
• Class II devices are ‘cleared’ by the 510(k)
process
– Devices are determined to be ‘substantially equivalent’ to a
preexisting device, i.e., there are no new issues of safety or
effectiveness
– Different timelines ( 90 days- FDA /FDA+Sponsor 180 days)
– Different submission requirements for sponsors (fewer)
– Different user fees (cheaper)
– Inspection not mandatory just periodic (Class III both
manufacturing facility and clinical trial site inspections)
Why is Classification Important
• Class III devices are ‘approved’ by the PMA
(Premarket Approval application process)
– Different timelines (longer- 180 days -FDA )
– Different submission requirements for sponsors (i.e., more
complete; manufacturing documentation, stability , primary
data, more expensive)
– Different user fees (higher)
– Mandatory Inspections , manufacturing and clinical trial
– Postmarketing changes all require FDA review
– Labeling changes oversight,
– Annual reports required
Classification of New Devices
• ‘New’ devices that are not ‘substantially equivalent’ to
existing devices are automatically considered Class III
• Devices remain in Class III and require premarket
approval, unless:
– The device is reclassified into Class I or II by:
– FDA decision that risks can be mitigated by special
controls and apply the de novo path
– New: A sponsor can apply directly for Class II
designation under the de novo pathway (no fee and
shorter review time [120 days])
Scope of Data to
Support
Approval/Clearance
of an IVD Device
29
Basics of Pre-market Device
Review: Safety and
Effectiveness
•
Safety
– Are there reasonable assurances, based on valid
scientific evidence that probable benefits to health
from use of the device outweigh any probable risks?
[860.7(d)(1)]
•
Effectiveness
– Is there reasonable assurance based on valid
scientific evidence that the use of the device in the
target population will provide clinically significant
results? [860.7(e)(1)]
30
Principles of a Successful IVD PreMarket Submission to FDA
Clear & precise “intended use” (IU)
Complete device description
Scientific evidence supporting the IU
Data demonstrating safety and
effectiveness of the device
 Adequate Quality System in place
 Labeling 21 CFR §809.10 (b)




31
Intended Use of the IVD
Is the driving force of the scientific review
• Understanding the disease(s)/condition(s),
integration of patient clinical management and
public health (surveillance)
– Who will be tested, where and when:
outpatients, inpatients, U.S non-U.S
populations/environments, pediatrics, adults,
acutely/chronically ill, etc.
– What are the appropriate specimens: timing,
handling and how result(s) may be used:
patient management
32
Device “Intended Use” Claims
•
Analyteof review and
IntendedIntended
Use is driving force
Indication
Population
classification
For Use
The XYZ Assay is a multiplex Real Time RT-PCR in vitro diagnostic
test for the rapid and qualitative detection and discrimination of
Influenza A Virus, Influenza B Virus, and Respiratory Syncytial
Virus (RSV) nucleic acids isolated and purified from
nasopharyngeal (NP) swab specimens obtained from
symptomatic patients. This test is intended for use to aid in the
differential diagnosis of Influenza A, Influenza B and RSV viral
infections in humans and is not intended to detect Influenza C.
A negative test is presumptive and it is recommended these results
be confirmed by cell culture. Negative results do not preclude
influenza or RSV virus infection and should not be used as the sole
basis for treatment or other management decisions.
33
• Scope of Data to Support Claims in
the Intended Use Leading to
Approval/Clearance of an IVD Device
34
Scientific Review
IVD Performance Validation
Both 510(k) and PMA Submissions
• Analytical Performance* : Internal Site
Reliability and accuracy of analyte measurements
• Clinical Performance : External/Internal Sites
Clinical sensitivity and specificity; % agreement etc
•
Labeling
Intended use, device design, directions for use,
warnings/limitations, result interpretation,
analytical & clinical performance characteristics
Other Regulatory Pathways.
EUA - Analytical rather than Clinical Performance
HDE – Rare Disease
IDE- Need Informed Consent & IRB
35
Demonstrating Evidence for
Safety: Analytical Studies
• Likelihood of false positives
– Cross-reactivity and other interferences
– Carryover and contamination
• Likelihood of false negatives
– Limits of detection
– Matrix effects
– Interference
36
Analytical & Clinical Performance
• Analytical performance measures
–
–
–
–
–
–
–
–
–
Precision (repeatability, reproducibility)
Accuracy
Sensitivity, Limit of Detection
Specificity (interference, cross-reactivity)
Sample type / matrix
Sample preparation / conditions
Performance around the cut-off
Potential for carryover, cross-hybridization
Stability
 Studies may vary depending on:
 Technology, end user
 Quantitative or qualitative assay
 What is reported (individual analytes vs. composite
score)
37
Analytical Performance
 Precision / Reproducibility
–
–
–
–
3 sites
Adequate coverage of all genotypes/tumor types
Clinical samples if available, different matrices
Include pre-analytical steps (e.g., extraction/purification)
• Limit(s) of detection
– Serial dilutions (highest to lowest conc. of input
specimen)
– Lowest concentration of target in normal background
(cancers)
• Potential interferences and cross reactivity
– Co-administered drugs
– Pre-analytical test components (e.g., extraction buffer)
– Common endogenous and exogenous substances –
differ with specimen
– Species cross reactivity etc.
38
Demonstrating Evidence for
Effectiveness: Clinical Studies
• Well-controlled clinical evaluations:
– Clinical plan and protocol
– Defined objective(s) and methods
• A test device with final standardized design and
performance
• Other evidence: case histories, literature,
reproducibility in multiple labs with a welldeveloped panel etc.
39
Clinical Performance
 Real clinical samples where feasible
 Prevalence of analyte is low? Consult with FDA
about alternative sample types
 Prospective or retrospective evaluation
 Comparison to a reference method
 Comparison to a predicate device
 Comparison to a clinical outcome
40
Demonstrating Evidence for
Effectiveness: Clinical Studies
• Well-controlled clinical evaluations:
– Clinical plan and protocol
– Defined objective(s) and methods
• A test device with standardized design and
performance
• Other evidence: case histories, literature,
reproducibility in multiple labs with a welldeveloped panel etc.
41
Clinical Study; Importance of
Following Good Clinical Practice
FDA Pre- Submission Meeting
Select trial sites
Identify principal
audit
investigators
Review Protocol
Negotiate contract
FDA Submission
Prepare for possible
FDA
Close out and audit sites
Data collection and analysis
Interim site monitoring visits
IRB reviews protocol
Source /Bank specimens
Start trial-initiation visit
Essential documents in place
Ship supplies / train
42
FDA Guidance Relevant to In Vitro
Diagnostic Device Clinical Trials
• “In Vitro Diagnostic (IVD) Device StudiesFrequently Asked Questions”
Published 10/25/07
Describes “Significant Risk and Non-Significant
Risk Studies” etc.etc
http://www.fda.gov/cdrh/oivd/guidance/1536.pdf
43
Using “Leftover Specimens”
that are Not Individually Identifiable
• 2006 FDA guidance: enforcement discretion as to
informed consent requirements for limited set of IVD
studies
– Guidance on Informed Consent for In Vitro Diagnostic Device Studies
Using Leftover Human Specimens that are Not Individually Identifiable Guidance for Sponsors, Institutional Review Boards, Clinical
Investigators and FDA Staff
– available at
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Guidanc
eDocuments/ucm078384.htm
44
“Leftover Specimen” IVD Study
Study not eligible for enforcement discretion if any
below apply:
• Study not exempt under 21 CFR 812.2(c)(3);
• Specimens are individually identifiable
• Specimens were collected specifically for the proposed investigation
– e.g., specimens not leftover from routine clinical care or analysis
or leftover from other research
• Amount of specimen needed for study is more than would be
leftover from what is usually collected for routine clinical analysis
• Test results will be reported to subject’s health care provider.
45
• Additional Regulatory Consideration CLIA
• A Different set of Regulations
CMS 42 CFR
46
CLIA Complexity
• CLIA complexity categorization is the process of
assigning commercially marketed in vitro
diagnostic test systems to one of three CLIA
regulatory categories based on their level of
complexity:
– waived tests (can be run in any testing facility)
– moderate complexity (test can be run in
moderate/highly complexity labs)
– high complexity (test can only be run in high
complexity labs)
47
CLIA Complexity Criteria
Moderate and High
Seven criteria per CMS 42 CFR 493.17
1.
2.
3.
4.
5.
6.
7.
Knowledge.
Training and experience.
Reagents and materials preparation.
Characteristics of operational steps.
Calibration, quality control, and proficiency testing (PT)
materials.
Test system troubleshooting and equipment maintenance.
Interpretation and judgment.
Each Criteria are scored as 1, 2, or 3
Score of 1 = minimum; score of 3 = specialized
Total scores (rational) : 12 or less = moderate complexity,
13 or more = high complexity
48
POC - CLIA Waiver Studies
• CLIA Waiver Process is under FDA oversight
• Studies designed to determine use of product
in non laboratory setting
– CLIA Program web site:
http://www.fda.gov/cdrh/clia/index.html
• Test Systems are waived by:
Regulation-42 CFR 493.15(c) Meeting the
statutatory criteria with valid scientific data
49
CLIA Waiver Study Design
Studies in support of CLIA waiver:
• Accuracy Study (method comparison)
–
–
–
–
–
Prospective
3 sites (selection is critical)
9 operators (selection is critical)
Best available reference method (selection is critical)
120 positives and 120 negatives
• Study with samples near the cutoff
–
–
–
–
Low positive and negative samples
3 sites
9 operators
20 aliquots of each (low pos and neg) at each site
• Flex Studies-examples of how an operator can invalidate test
• Also :
– Need quick simple Reference Instructions (QRI)
– Operator Questionnaire after study completed
50
Other Regulatory Pathways:
Emergencies
Emergency Use Authorization (EUA)
Section 564 of the Federal Food Drug and Cosmetic Act, as amended
by the Project BioShield Act of 2004
• Allows use of unapproved products or unapproved uses of
approved products during a declared emergency or
potential emergency
•
No need for informed consent or IRB approval. Data
needed but authorization is based on risk/benefit
• Used during the 2009 H1N1 influenza pandemic, MERS
CoV , Influenza H7N9 and Ebola outbreak in West Africa
51
EUA PROCESS
DoD SEC
Emergency
DETERMINATION
DHS SEC
Emergency
DETERMINATION
HHS SEC
Emergency
DETERMINATION
HHS SEC
Emergency
DECLARATION
FDA ISSUANCE of EUA
Consultation with CDC & NIH
TERMINATION
of Declaration
and EUA
52
Use of Investigational IVDs
Outside Protocol for an
Emergency
• Like other investigational devices, investigational
IVDs may be used outside the study protocol:
– “Emergency use”: patient has serious disease
or condition, no accepted alternative
diagnostic device available, no time to get
FDA approval for emergency use.
– “Compassionate” use
– “Treatment IDEs”
53
Regulatory Challenges Posed by New Technologies:
Multiplexed Devices & High Throughput Sequencing
54
Highly Multiplexed Microbiology Devices
Clinical Challenges
• Availability of positive specimens for all indications for use
• Availability of sufficient sample volume
– Determination of clinical truth (specificity)
– Reference testing
• Appropriate design/selection of targets included in the assay menu
– Intended Use of device
– Specimen type
– Relevance of targets (in context of Intended Use)
55
Multiplex Diagnostic Validation Concepts
• Held 2011 Public Workshop .Concepts implemented for
various studies over extended period
• Final Multiplex Device Guidance published 8/14
• Promoting Concepts through pre-submission
communications – numerous sponsors
• Incoming submissions and those under review have adopted
many of the Concepts
56
Individual Validation vs. Multiplex Validation
Multisite Validation Studies
Single Analyte
Current Validation
(per analyte basis)
Proposed
Validation Concept
(20-plex)
Reduction
(%)
20-plex
Combined Analytical Studies
Single Analyte
20-plex
~700
>15,000
~300
~6,000
X
~3,000
X
~1,000
X
~12,000
X
~5,000
(80% reduction)
(84% reduction)
The agreed upon CDRH concept for validation of highly multiplexed devices
provides significant reduction in the development/validation burden for assay
developers while providing the essential scientific elements to demonstrate device
safety and performance.
57
Recently Cleared Multiplex Micro. Devices
Sponsor
Type
Submission #
Device Name
Analytes
BioFire Diag.
NAT
K130914
Blood Culture Identification
Panel
Gram+, Gram-, yeast, and resistance
targets
Luminex
NAT
K121454
xTAG Gastrointestinal
Pathogen Panel with Luminex
100/200
11 gastrointestinal bacterial, parasite, and
viral organisms
Gen-Probe
Prodesse
NAT
K123274
BioFire Diag.
NAT
Nanosphere
Nanosphere
ProGastro SSCS
Salmonella, Shigella, Campylobacter (C.
jejuni and C. coli, undifferentiated), and
STEC (stx1 and stx2)
K123620
FilmArray Respiratory Panel
(RP)
Multiple viral and bacterial nucleic acids in
NPS
NAT
K122514
Verigene Staphylococcus
Blood Culture Nucleic Acid
Test
S. aureus, S. epidermidis, mecA
NAT
K123197
Verigene C. Diff Nucleic Acid
Test
C. Diff, tcd A, tcd B, tcd C
58
Summary
• Multiplex Diagnostic Concept
– Reduced the burden and developers came in to FDA
– Continued outreach at early stages of development
– Interdisciplinary approach to review - team effort
• Several already cleared for market – MANY on the horizon,
with increasing complexity and detection capabilities
• Reporting multiplexed device results – not so simple
– Information overload
– Does highlight potential co-infections, secondary bact. infection
– Colonization vs. infection
59
Microbial High Throughput Sequencing
(HTS) Based Technologies
1. Public Workshop held July 2014
2. Possible approaches to validation studies for High
Throughput Sequencing (HTS) systems
– Metagenomic vs. Targeted (custom amplicon)
– Use of sequence outputs in combination with database to
evaluate performance
– HTS as a comparator for regulatory submissions
3. Inter-Agency Working Group - Curated Data Base
4. NIST/FDA Microbial Reference Materials
Potential HTS Validation Strategies
• System approach – collection to result
• Impact of format on validation strategies
– Metagenomic vs. Targeted (custom amplicon)
Current Need
Robust, Standardized, and High Quality Microbial
Sequence Database in the Public Sector
• Representative Samples
• Metadata
• High quality raw sequences
• Assemblies
• Annotation
• Public Domain
Cover illustration
(Copyright © 2009, American Society
for Microbiology. All Rights Reserved.)
High Throughput Sequencing as
a Comparator
New Device
Clinical
Specimen
RESULT
For Regulatory Clearance
PERFORMANCE
Reference Method
HTS
(Comparator)
RESULT
• Cornerstone of all microbiology regulatory submissions
• Accomplished using a comparator device
– Can be a composite of multiple technologies
– Burden increases with increase in analytes (especially relevant
for multiplexed technologies)
– May not be uniform
A standardized method that can accurately establish the
presence/absence of a microbe in a given sample would be ideal
Useful
Resources
64
Resources
CDRH Homepage
www.fda.gov/MedicalDevices/default.htm
– Device Classification Database
– Device Advice
– Register for “What’s New”
– Guidance Documents
•
•
•
•
CLIA Guidance: http://www.fda.gov/downloads/MedicalDevices/
DeviceRegulationandGuidance/ GuidanceDocuments/ucm070889.pdf
OIR Guidances:
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/uc
m070274.htm
CLIA Amendments
http://www.fda.gov/medicaldevices/deviceregulationandguidance/ivdregulatoryassistance/
ucm124105.htm
CMS web site: www.cms.gov/clia http://www.cms.gov/Regulations-andGuidance/Legislation/CLIA/index.html?redirect=/clia/
65
More Resources
 See FDA’s Device Advice webpage at
http://www.fda.gov/medicaldevices/deviceregulationandguidance, for
useful information on regulation and review of medical
devices
 Search FDA’s 510(k) database for a predicate device with
a similar intended use as your device
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm
 Check the Decision Summary to see the kind of data
submitted for the predicate
 Search the PMA database for devices with similar
intended use as your device
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm
 Check SSED statement to see the studies performed for the
device
66
Pre-Submission Advice
• Free Consulting!
• You can (and should) meet/call FDA for nonbinding
discussions and advice: The earlier the better….
• before conducting analytical and clinical studies
• before submitting a marketing application
• Why?
• Chance to address new scientific/regulatory issues.
• Very important when developing new technologies
and there is no FDA approved similar device
• Draft Guidance on the pre-Submission process
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuid
ance/GuidanceDocuments/ucm310375.htm.
67