NIST-FDA Genome Editing Workshop

Zivana Tezak, PhD

FDA – CDRH - OIR

Gaithersburg, MD

April 23, 2018
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Overview

• Personalized Medicine Efforts

• Next Generation Sequencing Based Tests

– Final Guidances

– Recent Approvals (Oncopanels)

• CDRH Strategic Priorities

– Collaborative Communities

Disclaimer: Thoughts on regulatory issues and policies are preliminary and do not 

represent finalized FDA policy
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FDA Personalized Medicine Efforts

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• Targeted Therapeutic 

Development

– Pharmacogenetics

• 192 drugs with PGx in label 

(as of 7/29/17) across 18 

therapeutic areas

– Immunotherapies

• Personalized Biologics

– 3D printed organs

– Genome editing

• Food Safety

– Outbreak tracking

• Genetic Testing

– Oncopanels

– Next-Generation Sequencing 

(NGS) 

– Liquid Biopsy
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Scientific Review : IVD Performance 

• Analytical Performance Characteristics

– Reliability and accuracy of analyte measurements

– Studies specific to the assay technology such as accuracy for 

molecular assays

• 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

www.fda.gov
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FDA’s Vision for Regulation of NGS-Based IVDs 

for Diagnosing Germline Diseases
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Final Guidances Issued (04/12/2018)

https://www.fda.gov/download

s/MedicalDevices/DeviceRegula

tionandGuidance/GuidanceDoc

uments/UCM509837.pdf

https://www.fda.gov/download

s/MedicalDevices/DeviceRegula

tionandGuidance/GuidanceDoc

uments/UCM509838.pdf
www.fda.gov

Analytical Guidance overview:

• Scope: germline WES or panels

• Makes a series of technical recommendations for how NGS-test 

developers can design and validate their tests

• Accommodates different test designs, components, indications, etc.

• Can form the basis for future FDA-recognized standard(s) and/or special 

controls

• Discusses potential for an expedited path to market for tests that meet 

these standards

2018: Finalization of NGS Guidances

Scope:

The guidance applies only to targeted or whole exome sequencing NGS-based tests 

intended to aid in the diagnosis of individuals with suspected germline diseases or 

other (germline) conditions
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Recommendations for 

Design, Development, and Validation

• Test design considerations: 

– Approach to test design

– Recommendations are flexible, to accommodate different 

test designs, components, indications, etc.

• Test performance characteristics 

– Accuracy, precision, LoD, analytical specificity

• Test run quality metrics 

– Including read depth, completeness

• General recommendations for performance evaluation 

studies

Can form the basis for future FDA-recognized consensus 

standard(s) and/or special controls
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• Discussion on supplemental procedures such as trio testing 

or orthogonal confirmation

• Variant annotation and filtering considerations

• Recommendations for presentation of test performance / 

labeling such as:

– Identify regions of the genome in which sequence meeting prespecified performance specifications can be generated by the NGSbased test

– Types of sequence detected and reported by the test

– Types of sequence variants test cannot detect with adequate 

accuracy and precision

– Performance summary

– The relationship between reported variants and the clinical 

presentation, as applicable

• How to address NGS test modifications

Additionally, guidance includes:
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Significance of NGS Standards Guidance

• Provides key considerations for designing, developing, 

and establishing analytical validity of NGS-based tests 

for suspected germline diseases 

• Informs the development of consensus standards by 

experts in the community

• Recommendations in this guidance and/or standards 

that address these recommendations may form the 

basis of special controls, allowing these tests to be 

candidates for down-classification

– Could be considered for exemption from premarket 

notification if they meet certain criteria
www.fda.gov

Database Guidance overview:

• Scope: publicly accessible databases of genetic variants

• Recommendations for administrators of databases to 

demonstrate that the database can be considered a source of 

“valid scientific evidence”

• Evidence from databases could support the clinical validity of 

NGS-based tests

• Voluntary database recognition pathway (similar to 

standards recognition)

2018: Finalization of NGS Guidances
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Benefits of Using Data from Publicly 

Accessible Genetic Databases

• Evidence generated by multiple 

parties

• Aggregated data provide a stronger 

evidence base (i.e., current state of 

scientific knowledge)

• As clinical evidence improves, new 

assertions could be supported

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Webinar

• On Thursday, May 24 from 2:00 – 3:30PM ET, we will have a 

webinar about these final guidances. You can find more 

information about the webinar at 

http://www.fda.gov/CDRHwebinar.

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Intended Use Analytical Performance Clinical Performance

MiSeqDx 

Platform

targeted sequencing of human genomic DNA. • Clinical and cell line samples

• Well-standardized panel with 

known variants

• Performance demonstrated 

on a representative set of 

variants

NA

Universal Kit 1.0 use with the MiSeqDx instrument. See above NA

Cystic Fibrosis 

Clinical 

Sequencing Assay

re-sequences the protein coding regions and 

intron/exon boundaries of the CFTR gene; reports 

any variant in the cystic fibrosis gene

Validation of both specific variants 

and CFTR normal sequence

Well-established association of 

CFTR and CF; expert interpretation

Cystic Fibrosis 

139 Variant Assay

simultaneously detect 139 clinically relevant cystic 

fibrosis disease-causing mutations and variants of 

the CFTR gene;

reports only a discrete number of variants with 

established clinical significance

Specific validation of 139 variants Use of the CFTR2 database (JHU) 

for evidence

First FDA Authorizations of NGS 

Platform and Assays
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• FoundationFocus CDxBRCA Assay (Foundation Medicine, Dec 2016): First NGS CDx

• Oncomine Dx Target Test (Thermo Fisher, June 2017): First CDx to simultaneously 

evaluate multiple biomarker/therapy for NSCLC) - 3 CDx claims, 23 genes

• Praxis Extended RAS Panel (Illumina, June 2017): First NGS CDx based on “negative” 

mutation finding

CDx test provides essential information for the safe and effective use of the 

therapeutic product. 

Summary of Safety and Effectiveness Data (SSED) for each device approval:

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm?id=P160018

https://www.accessdata.fda.gov/cdrh_docs/pdf16/p160045b.pdf

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P160038

Approvals of NGS-based Companion Diagnostics
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Recent NGS-based test approvals

• MSK-IMPACT

– Solid tumor panel

– 468 genes + MSI

– De Novo set up Class II 

pathway, potential 3rd

party review

• Foundation Medicine’s F1CDx

– Solid tumor panel

– 15 CDx claims in 5 cancer 

types

– 324 genes + MSI, TMB

• FDA authorized the first NGS Tumor Profiling 

Oncopanel (MSK-IMPACT) on November 15, 2017. 

• The De Novo authorization established a new class II 

regulatory pathway for NGS tumor profiling tests. 

Future NGS tumor profiling tests are eligible for 510(k)

clearance process, either by applying directly to FDA or

through an accredited third-party reviewer (such as 

NYSDOH).

1st Breakthrough-Designated Test to Detect 

Extensive Number of Cancer Biomarkers

• Parallel review – received a NCD from CMS
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Three Tiered Approach 

for Reporting Biomarkers in Cancer Panels

CDx

Cancer 

Mutations with 

Evidence of 

Clinical 

Significance 

Cancer Mutations 

with Potential 

Clinical Significance

Level 1 companion diagnostics: AV for each 

biomarker; CV established by clinical study or 

clinical concordance with a previous CDx

Level 2 biomarkers: AV either per biomarker or 

representative; CV established in professional 

guidelines, but NOT demonstrated with the test.

Level 3 biomarkers: AV by representative 

approach; CV validity not demonstrated either in 

professional guidelines or with the test, but 

suggestive based on clinical/biological evidence.

EVIDENCE
www.fda.gov

CDRH Strategic Priorities

https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedi

calProductsandTobacco/CDRH/CDRHVisionandMission/UCM592693.pdf

Collaborative Communities

The hallmark of a Collaborative 

Community is a continuing forum where 

public and private sector members 

proactively work together to solve both 

shared problems and problems unique 

to other members in an environment of 

trust and openness, where participants 

feel safe and respected to communicate 

their concerns.

➢ Goal to create 10 new Collaborative 

Communities by 2020. 
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• Gene editing – methodologies for detection of mutations that 

were created? 

– Potential of using NGS for evaluating “off-target” editing effects such as 

insertions or deletions at unintended genetic loci?

Questions?

Personalized Medicine Staff: 

OIRPMGroup@fda.hhs.gov

zivana.tezak@fda.hhs.gov
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• First NGS-based CDx approved by FDA

• CDx that detects BRCA1/2 variants in tumor tissue – Rubraca (rucaparib)

• NGS-based assay performed on DNA (200ng) from FFPE biopsy or surgical 

resection specimens

• Uses the Illumina HiSeq 4000 platform, hybrid-capture-selected libraries 

sequenced to median 500X with >99% of exons at coverage >100

• Custom-developed analysis 

pipeline identifies BRCA1/2 

SNVs, short indels up to 13 bp,

large rearrangements and 

homozygous deletions
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Praxis Extended RAS Panel

• First single NGS test to detect multiple RAS mutations 

approved by FDA

• The PraxisTM Extended RAS Panel is a qualitative in vitro diagnostic test 

using targeted high throughput parallel sequencing for the detection of 

56 specific mutations in RAS genes [KRAS (exons 2, 3, and 4) and NRAS 

(exons 2, 3, and 4)] in DNA extracted from formalin-fixed, paraffinembedded (FFPE) colorectal cancer (CRC) tissue samples.

• The PraxisTM Extended RAS Panel is indicated to aid in the identification of 

patients with colorectal cancer for treatment with Vectibix®

(panitumumab) based on a no mutation detected test result. The test is 

intended to be used on the Illumina MiSeqDx® instrument.

June 2017