Next Generation Sequencing (NGS) Workgroup

Report to CLIAC April 11, 2019

Dr. Jordan Laser, Workgroup Chair

Workgroup Members

Chair: Jordan Laser, MD

Members:Joe Campos, PhD, DAPMM, FAMMAlexis Carter, MDMarc Couturier, PhD, D(ABMM)David Dimmock, MDTina Hambuch, PhD, FACMGSteven Hinrichs, MDGianella Garcia Hughes, PhDZahra Mehdizadeh Kashi, PhD, HCLDEric Klee, PhDJennifer LeftwichStan Letovsky, PhD

Jason Merker, MD, PhDSteve Miller, MD, PhDKevin Modarress, PhDSomak Roy, PhDErasmus Schneider, PhDMarty Soehnlen, PhD, MPH, PHLD(ABB)Colleeen Stevens, PhDFredrik Vannberg, DphilKarl Voeklerding, MD, FCAPElizabeth Worthey, PhD

HHS Workgroup Members and Subject Matter Experts Designated Federal Officer:

Heather Stang, MS, MT(AMT) Ex Officio Members:

Collette Fitzgerald, PhDZivana Tezak, PhDFelicidad Valcarcel, MS, MT(AMT)

Agency Staff Subject Matter Experts:Marie Earley, PhDRachel Jacobs, MSHS(CRA). HCM, SCT(ASCP)Shyam Kalavar, MPH, CT(ASCP)Lisa Kalman, PhDPenny Keller, BS, MB(ASCP)Ira Lubin, PhD, FACMGAmy Zale, MT(ASCP), PMP, GWCFPM

NGS Charge

Provide input to CLIAC for consideration in developing recommendations to CDC, CMS, and FDA for assuring quality of next generation sequencing based testing in clinical laboratory settings.

Workgroup Tasks: Identify challenges in applying the existing regulatory framework Identify challenges and gaps in guidance Consider and suggest strategies to address the identified gaps and

challenges Consider and suggest strategies for assuring workforce competency

Discussion Question #1What consultation or other assistance does the laboratory provide to help clinicians order the appropriate tests for their patients?

Question # 1 Discussion Points

# 1 Discussion Points

Personnel Director-Provider Genetic Counselors Client Services

Support is critical Education/ operations (PA/BI)

Small vs Large lab resources

Clinical Utility/Diagnostic Yield Needs:

Standard definitions, education

Discussion Question #2What consultation or other assistance does the laboratory provide to help clinicians understand and use NGS-based test results?

Question # 2 Discussion Points

# 2 Discussion Points Personnel MD/DO/PhD (+boards) Genetic Counselors

Scope?

Method Phone calls (pro vs reactive) Online resources Tumor board style meetings

Report “First page phenomenon” Loss of fidelity workflow

Discussion Question #3

What are the challenges with developing and performing NGS test validations?

Question # 3 Discussion Points

# 3 Discussion Points Guidelines Availablemore

Entire analytical process

Validation/Revalidation

Performance Characteristics Determined and clear

Challenging to determine

Application specific

Validation Issues Definition of test detects/limitations

Oversight by experienced professionals

Needs Inspection expertise

Minimum standards (exomes/genomes)

Specimen (GeTRM)

Discussion Question #4

What are the challenges for clinical laboratories in performing NGS quality control and quality assurance?

Question # 4 Discussion Points

#4 Discussion Points QA/QC resource intensive Traditional QM differs from NGS

+ Control/ NTC One size not fit all Current QM framework? Guidelines exist

AMP/CAP Needs

NGS appropriate QM definitionsAgile frameworktechnology

Discussion Question #5What reference materials (physical and/or electronic) are important to include for developing validation and quality control procedures?

Question # 5 Discussion Points

# 5 Discussion Points

Currently available:Genome in a Bottle ConsortiumATCC Microbiome StandardsMedical Device Innovation

ConsortiumCDC GeT-RM

Needs: In silico clearinghouseDepth of current RM

Discussion Question #6What proficiency testing programs or alternate assessment schemes are available for NGS?

Question #6 Discussion Points

# 6 Discussion PointsElementsWet/DryAvailable:

CAP, CDC PulseNet PT, Regional consortia, Precision FDA, Ass. Biomol. Resource FacilitiesGenerally too easy?

Alternative AssessmentDistributive model PT referralNeeds:

More/challenging/distributive

Discussion Question #7What are the challenges to developing, establishing quality control, and implementing a bioinformatics pipeline within a clinical laboratory setting?

Question #7 Discussion Points

#7 Discussion PointsQC in Pipelines

Regs/Standards+/- vs NGS

PersonnelBioinformaticians/Inspectors

PipelineUse case specificExternal databasesVersioning

Needs:Training setsExpertise to assist

Discussion Question #8What are the challenges associated with using and assuring the quality of external data (e.g., data annotation) to inform the bioinformatics analysis?

Question #8 Discussion Points

#8 Discussion PointsDatabases:GuidelinesData behind the data?Balance privacy vs metadata

CurationVariants interpreted each time

Needs:MetadataQC for inputMandate to share?

Discussion Question #9What are the laboratory practices and challenges to NGS software and data management with respect to: Data sharing (e.g., for QC, populating external

databases, availability to patients)

Question #9 Discussion Points

#9 Discussion Points Patient:

Federal lawFiles?

3rd party interpretationsUnvalidated data

Professionals: Criticalknowledge

Curation/metadata Interoperability

LOINC Consent:

Various (Opt in/out) Environment Privacy/curation

Discussion Question #9 Continued

What are the laboratory practices and challenges to NGS software and data management with respect to: Data and software storage/retention/upgrades

Question #9 Discussion Points continued

#9 Discussion Points continuedStorage:

No consensusCAP- 2 years, reanalysis

? Files, lossiness, latencyintentSoftware:

Mods regression / unitVersioning

Re-verify/validate:Encryption, upgrades

Needs:Why? Unity, Guidelines

Discussion Question #10What are the real world and recommended practices and challenges in reporting clinically significant secondary findings that are not related to the test that was ordered?

Question #10 Discussion Points

#10 Discussion Points Secondary vs Incidental

Secondary- Purpose A, other actionable findingsWES inherited cancer syndrome

Incidental Purpose A, findings significant for disease outside of intentKras Noonan

ACMG Guidelinesreevaluate Refine Consenting Reporting Impact Resources

Discussion Question #11What training and competencies are performed or considered essential to demonstrate that qualified personnel are testing specimens and analyzing data?

Question #11 Discussion Points

#11 Discussion PointsWet well covered CLIADry GAPS in CLIA

BioinformaticiansDeveloper vs Scientist vs Analyst

Lab vs Manufacturer Recommendations:

SurveyJDs, qualifications, education

WorkgroupDefine BI categories crosswalk

Discussion Question #12How does the laboratory determine the total annual testing volume for NGS?

Question #12 Discussion Points

#12 Discussion Points

Volume = test name / report