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The FDA Approval Process

Evidence to Support the Adoption of New BiomarkersDiagnostic Course , Queen’s College , Oxford

September 2014

Sally A. Hojvat, Ph.D, M.Sc

Director, Division of Microbiology DevicesOffice of In Vitro Diagnostic Devices and Radiological Health

Center for Devices and Radiological HealthFood and Drug Administration

sally.hojvat@fda.hhs.gov

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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

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Overview of Regulation of In Vitro Diagnostic Devices

(IVD s)

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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 …..”

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FDA’s Mission

Get safe and effective devices/systems to market as quickly as possible

Get safe and effective devices/systems to market as quickly as possible

Ensure that devices/systems on the market are safe and effective

Ensure that devices/systems on the market are safe and effective

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Total Product Life Cycle Approach

Postmarket

Manufactur.Compliance

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfTPLC/tplc.cfm

Premarket

Approval/Clearance

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FDA Organization

Center for Biologics Evaluation and

Research

Center for Devices and Radiological

Health

Center for Drug Evaluation and

Research

Center for Food Safety and Applied

Nutrition

Center for Veterinary Medicine

Center for Tobacco Products

National Center for Toxicological

Research

Office of Regulatory

Affairs

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Center for Devices and Radiological Health (CDRH)

Center Director

Office of ComplianceOffice of Science and

Engineering Technologies

Office of Device EvaluationOffice of Surveillance

and Biometrics

Office of Communication,Education and Radiation Programs

Office of In Vitro Diagnostic Device & Radiological Health

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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/SCRIPTs/cdrh/cfdocs/cfcfr/CFRSearch.cfm

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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]

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In Vitro Diagnostic Tests for :

• Detection and Diagnosis

• Screening • First Response

• Not Environmental Screening

IVDs: FDA Regulated Uses

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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

BiothreatDivision 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/ diagnosisTumour markers RadNucthreat Division of Personalized Medicine

Biomarkers submitted to all Divisions

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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

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Manufacturing Regulations

• Good manufacturing (cGMP) –

QSReg. 21CFR 820

• Applicable to any device intended for human use

• Ensures quality manufacturing of IVDs /Instruments

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Software/Hardware Regulations

• Documentation and hazard analysis required

• Claims for use on multiple amplification /detection platforms must be validated

• Guidance documents available

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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

Device Investigations and Risk (21 CFR 812)

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All Device Investigations

Studies Exempt from the IDE

Regulation-Most IVDs

Studies Subject to the IDE Regulation-Rare

for IVDs

Non-Significant Risk

Abbreviated Requirements

Significant Risk

Full Requirements

Device Classification

A device should be placed in the lowest class whose level of control will provide reasonable assurance of safety and effectiveness

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Risk Based Regulation of IVDs

Class II - Moderate likelihood of harm or risk can be mitigated

Class III - High or unknown likelihood of harm

Significant Risk

Class I Knowledge Mitigates Risk

Class III

Class I - Low likelihood of harm

Risk-based Approach to Classify and Regulate Medical Devices

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Risk Dependent on IU: Different Use, Same Test

A CFTR genotyping multiplex assay on the same instrument with the indication

for aid in diagnosisfor fetal screening PMA

A breast cancer assay to be usedfor screening, diagnosis PMA

for prognosis in already diagnosed patients510(k)

510(k)

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)

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])

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Scope of Data to Support

Approval/Clearance of an IVD Device

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• 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)]

Basics of Pre-market Device Review: Safety and

Effectiveness

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Principles of a Successful IVD Pre-Market 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)

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Intended Use of the IVDIs 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

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Device “Intended Use” Claims

• Intended Use is driving force of review and classification

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.

AnalyteIntended Population

IndicationFor Use

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• Scope of Data to Support Claims in the Intended Use Leading to

Approval/Clearance of an IVD Device

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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

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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

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• 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)

Analytical & Clinical Performance

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Analytical PerformancePrecision / 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.

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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 well-developed panel etc.

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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 deviceComparison to a clinical outcome

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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 well-developed panel etc.

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Clinical Study; Importance of Following Good Clinical Practice

FDA Pre- Submission Meeting FDA Submission

Select trial sites Identify principal Prepare for possible FDA

audit investigators Close out and audit sites

Review Protocol Data collection and analysis Negotiate contract

Interim site monitoring visitsIRB reviews protocol Source /Bank specimens Start trial-initiation visit

Essential documents in place Ship supplies / train

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FDA Guidance Relevant to In Vitro Diagnostic Device Clinical Trials

• “In Vitro Diagnostic (IVD) Device Studies- Frequently 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

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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/GuidanceDocuments/ucm078384.htm

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“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.

• Additional Regulatory Consideration - CLIA

• A Different set of Regulations

CMS 42 CFR

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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)

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CLIA Complexity CriteriaModerate and High

Seven criteria per CMS 42 CFR 493.17

1. Knowledge.2. Training and experience.3. Reagents and materials preparation.4. Characteristics of operational steps.5. Calibration, quality control, and proficiency testing (PT)

materials.6. Test system troubleshooting and equipment maintenance.7. Interpretation and judgment.

Each Criteria are scored as 1, 2, or 3Score of 1 = minimum; score of 3 = specializedTotal scores (rational) : 12 or less = moderate complexity, 13 or more = high complexity

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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

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CLIA Waiver Study DesignStudies 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

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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

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DoD SECEmergency

DETERMINATION

DHS SECEmergency

DETERMINATION

HHS SECEmergency

DETERMINATION

HHS SECEmergency

DECLARATION

FDA ISSUANCE of EUA Consultation with CDC & NIH

TERMINATIONof Declaration

and EUA

EUA PROCESS

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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”

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Regulatory Challenges Posed by New Technologies:

Multiplexed Devices & High Throughput Sequencing

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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)

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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

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5757

Individual Validation vs. Multiplex Validation

Multisite Validation Studies Single Analyte 20-plex

Combined Analytical Studies Single Analyte 20-plex

Current Validation (per analyte basis) ~700 >15,000 ~300 ~6,000

Proposed Validation Concept

(20-plex)X ~3,000 X ~1,000

Reduction

(%)X ~12,000

(80% reduction)

X ~5,000 (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.

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Recently Cleared Multiplex Micro. DevicesSponsor 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 K123274ProGastro SSCS

Salmonella, Shigella, Campylobacter (C. jejuni and C. coli, undifferentiated), and STEC (stx1 and stx2)

BioFire Diag. NAT K123620 FilmArray Respiratory Panel (RP)

Multiple viral and bacterial nucleic acids in NPS

Nanosphere NAT K122514 Verigene Staphylococcus Blood Culture Nucleic Acid Test

S. aureus, S. epidermidis, mecA

Nanosphere NAT K123197 Verigene C. Diff Nucleic Acid Test

C. Diff, tcd A, tcd B, tcd C

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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

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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)

Robust, Standardized, and High Quality Microbial Sequence Database in the Public Sector

Current Need

Cover illustration (Copyright © 2009, American Society for Microbiology. All Rights Reserved.)

• Representative Samples• Metadata

• High quality raw sequences• Assemblies• Annotation

• Public Domain

High Throughput Sequencing as a Comparator

• 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

New Device

For Regulatory Clearance

RESULT

RESULT

PERFORMANCEClinical

Specimen

HTSReference Method

(Comparator)

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Useful Resources

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ResourcesCDRH 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/ucm070274.htm

• CLIA Amendments http://www.fda.gov/medicaldevices/deviceregulationandguidance/ivdregulatoryassistance/ucm124105.htm

• CMS web site: www.cms.gov/clia http://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/index.html?redirect=/clia/

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

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