The FDA Approval Process Evidence to Support the

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 Surveillance Manufactur. Compliance Quality Systems 21 CFR § 820 Premarket Analytical Evaluation Approval/ Clearance Clinical Evaluation http: //www. accessdata. fda. gov/scripts/cdrh/cfdocs/cf. TPLC/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/ SCRIPTs/cdrh/cfdocs/cfcfr/CFR Search. 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 (Ampli. Chip) Chemthreat Division of Immunology and Hematology Devices Cytogenetics/Fish (BCR-ABL Fish) Cancer screening/ diagnosis Tumour markers Rad. Nucthreat 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 (c. GMP) – QSReg. 21 CFR 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 • 21 CFR 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 Knowledge Class I - Low likelihood of harm Class II - Moderate likelihood of harm or risk can be mitigated Risk Class III - High or unknown likelihood of harm Significant Risk 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 üfor aid in diagnosis 510(k) üfor fetal screening PMA § A breast cancer assay to be used üfor screening, diagnosis PMA 510(k) üfor 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 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) 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 • Analyte Intended Use is driving force of review and Intended 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 Ø Studies may vary depending on: Ø Technology, end user Ø Quantitative or qualitative assay Ø 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 Ø Real clinical samples where feasible Ø Prevalence of analyte is low? Consult with FDA about alternative sample types Ø Prospective or retrospective evaluation Ø Comparison to a reference method Ø Comparison to a predicate device Ø 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 FDA audit investigators Review Protocol Negotiate contract FDA Submission Prepare for possible 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 Studies. Frequently Asked Questions” Published 10/25/07 Describes “Significant Risk and Non-Significant Risk Studies” 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/Medical. Devices/Device. Regulationand. Guidance/Guidanc e. Documents/ucm 078384. htm 44

“Leftover Specimen” IVD 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 Bio. Shield 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 H 1 N 1 influenza pandemic, MERS Co. V , Influenza H 7 N 9 and Ebola outbreak in West Africa 51

EUA PROCESS Do. D SEC Emergency DETERMINATION DHS 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 ~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 Bio. Fire Diag. NAT K 130914 Blood Culture Identification Panel Gram+, Gram-, yeast, and resistance targets Luminex NAT K 121454 x. TAG Gastrointestinal Pathogen Panel with Luminex 100/200 11 gastrointestinal bacterial, parasite, and viral organisms Gen-Probe Prodesse NAT K 123274 Bio. Fire Diag. NAT Nanosphere Pro. Gastro SSCS Salmonella, Shigella, Campylobacter (C. jejuni and C. coli, undifferentiated), and STEC (stx 1 and stx 2) K 123620 Film. Array Respiratory Panel (RP) Multiple viral and bacterial nucleic acids in NPS NAT K 122514 Verigene Staphylococcus Blood Culture Nucleic Acid Test S. aureus, S. epidermidis, mec. A NAT K 123197 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 HTS Reference Method (Comparator) PERFORMANCE 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/Medical. Devices/default. htm – Device Classification Database – Device Advice – Register for “What’s New” – Guidance Documents • • CLIA Guidance: http: //www. fda. gov/downloads/Medical. Devices/ Device. Regulationand. Guidance/ Guidance. Documents/ucm 070889. pdf OIR Guidances: http: //www. fda. gov/Medical. Devices/Device. Regulationand. Guidance/Guidance. Documents/u cm 070274. htm CLIA Amendments http: //www. fda. gov/medicaldevices/deviceregulationandguidance/ivdregulatoryassistance/ ucm 124105. htm CMS web site: www. cms. gov/clia http: //www. cms. gov/Regulations-and. Guidance/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/cf. PMN/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/cf. PMA/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/Medical. Devices/Device. Regulationand. Guid ance/Guidance. Documents/ucm 310375. htm. 67