FDA Watch: Agency Issues New Guidance to Ease Approval of NGS Tests & IVD Devices

April 13 was a red letter day for FDA guidance with the agency issuing a pair of final guidances on the design, development and validation of next-generation sequencing (NGS) tests, as well as a draft guidance outlining a proposed new voluntary, streamlined submission process for evaluating the risks of investigational in vitro diagnostics (IVDs) being codeveloped alongside a trial cancer drug. Here is the lowdown on all three sets of guidance:

Final Guidance 1: Using Public Genetic Variant Repositories to Show Clinical Validity of NGS Tests
The two final guidances are designed to make it easier and more efficient to develop NGS tests. The first final guidance, which bears the catchy title “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic & Genomic-Based In Vitro Diagnostics,” explains how test developers can rely on FDA-recognized public genetic variant repositories to support the accuracy of their tests and related marketing claims.

A “genetic variant database” means a publicly accessible database of human genetic variants that aggregates and curates reports of human genotype-phenotype relationships to a disease or condition with publicly available documentation of evidence supporting those linkages, the guidance explains. While as a best practice, such databases should follow an open-access model, databases that use licensing models and charge fees for commercial use may also qualify and be used to support clinical validity of genetic or genomic tests, the guidance continues.

Criteria of reliability includes a genetic variant database that:

  • Operates so as to provide sufficient information and assurances regarding the quality of source data and its evidence review and variant assertions;
  • Offers transparency regarding its data sources and operations, particularly on how variant evidence is evaluated;
  • Collects, stores and reports data and conclusions in compliance with all applicable requirements regarding protected health information, patient privacy, research subject protections and data security; and
  • Houses genetic variant information generated by validated methods.

Final Guidance 2: Design of NGS Tests for Diagnosing Germline Diseases
The other final guidance (“Considerations for Design, Development, and Analytical Validation of Next Generation Sequencing (NGS)–Based In Vitro Diagnostics (IVDs) Intended to Aid in the Diagnosis of Suspected Germline Diseases”) explains to test developers the types of data the FDA is looking for in premarket submissions for such tests. Such tests do not include NGS-based tests for aid in the diagnosis of microbial infection, cell-free DNA testing, direct-to-consumer uses, fetal testing, microbial genome identification and detection of antimicrobial resistance and virulence markers, pre-implantation embryo testing, risk assessment, risk prediction, RNA sequencing, screening, stand-alone diagnostic purposes, tumor genome sequencing or use as a companion or complementary diagnostic, the guidance explains.

The guidance then lists recommendations covering different aspects of NGS test development and quality including:

  • NGS test design considerations;
  • Test performance and accuracy;
  • Test run quality metrics;
  • Performance and evaluation studies;
  • Supplemental procedures;
  • Variant annotation and filtering;
  • Presentation of test performance in labeling; and
  • Test reports.

Draft Guidance: Determining Risk of Investigational IVDs
The new draft guidance lays out a streamlined process for evaluating investigational IVDs in oncology drug trials, specifically whether the investigational IVD is considered significant risk (SR), nonsignificant risk (NSR) or exempt. The guidance says that the FDA device division would make this risk determination alongside the drug division’s evaluation of the investigational new drug application. It also calls on sponsors to submit information on how the test results will be used in the clinical trial, discuss the prevalence of the biomarker in the patient population and any risks the biopsy collection process has on study subjects.

If the drug and device divisions find that an investigational IVD in a particular study confers non-significant risk, the FDA will issue a letter instructing sponsors to proceed with the trial ensuring that biopsy procedures do not carry significant risks and report any unanticipated adverse events. If the test is found to carry significant risks, FDA will tell the sponsor to submit an IVD exemption application and wait to start the trial until it is approved. Trials of invasive biopsy procedure presenting serious health risk to study participants would not be eligible for the new streamlined submission process, the guidance notes.

The deadline to comment on the draft guidance is 60 days from the April 13 publication date.

New FDA Approvals
Meanwhile, here’s a rundown of the key new FDA approvals announced from late March through mid-April:


Manufacturer(s) Product(s)
Roche Premarket approval for expanded use of Cobas EGFR Mutation Test v2 as companion diagnostic test with AstraZeneca’s Tagrisso (osimertinib) for non-small cell lung cancer
Roche 510(k) clearance for Cobas CT/NG assay for use on Cobas 6800 and 8800 systems
Cancer Genetics Special 510(k) clearance for Tissue of Origin gene expression test
EKF Diagnostics Holdings 510(k) clearance and CLIA waiver for use of DiaSpect Tm hand-held reagent-free hemoglobin analyzer in point-of-care settings
AESKU Group Clearance of AESKUSLIDES ANCA Ethanol and ANCA Formalin vasculitis test on the Helios automated IFA system
Curetis De novo clearance of Unyvero molecular diagnostic platform
Curetis De novo clearance of multiplex lower respiratory tract infections detection test, the first such test to be cleared by FDA
DarioHealth Clearance of iPhone-compatible blood glucose monitoring system, enabling users to access firm’s Dario app on iPhone 7, 8 and X mobile devices
Ortho Clinical Diagnostics Clearance of Ortho Connect V2.0 integrated and customizable middleware system
DiaSorin Clearance of Simplexa HSV 1 & 2 Direct assay for running on Liaison MDx instrument for detection and differentiation of herpes simplex virus DNA in lesion swabs
Cepheid Clearance for Xpert CT/NG Assay running on GeneXpert instrument for automated detection and differentiation of genomic DNA from Chlamydia trachomatis and/or Neisseria gonorrhoeae
Siemens Healthineers Clearance for received clearance for Atellica IM Total hCG human chorionic gonadotropin assay for early pregnancy detection run on Siemen’s Atellica IM Analyzer
Runbio BioTech Clearance for David Home Pregnancy Test Cassette, over-the-counter lateral flow immunoassay for early pregnancy detection
Guangzhou Wondfo Biotech Clearance for Preview Digital Pregnancy Test used to detect human chorionic gonadotropin in urine for early pregnancy detection
Phadia Clearance for Elia PR3s immunoassay for measuring IgG antibodies targeting proteinase 3 in human serum and plasma
Phadia Clearance for Elia MPOs immunoassay for measuring IgG antibodies targeting myeloperoxidase in human serum and plasma
Phadia Clearance for Elia GBM assay for measuring IgG antibodies to α3 chain of collagen IV in human serum and plasma
Diazyme Clearance for latex particle enhanced immunoturbidimetric assay for determination of lipoprotein(a)
Becton Dickinson Clearance for BD Veritor System rapid chromatographic immunoassay for influenza A and B viral nucleoprotein antigens
Immco Diagnostics Clearance for ImmuLisa Enhanced RNA POL III Antibody ELISA to detect anti-RNA POL III IgG antibodies in human serum
Hardy Diagnostics Clearance for Granada Medium agar to detect Group B streptococcus after18 to 24 hours of incubation of Lim broth
Liofilchem Clearance for MIC Test Strip, a quantitative method that determines antimicrobial susceptibility of bacteria

During the period, the following FDA CLIA waiver was announced:


Manufacturer(s) Product(s)
EKF Diagnostics Holdings DiaSpect Tm hand-held reagent-free hemoglobin analyzer for use in point-of-care settings

New CE Marks & Global Certifications
Notable European CE certifications:


Manufacturer(s) Product(s)
Curetis CE/IVD marking for Unyvero UTI test cartridge diagnosing severe urinary tract infections run on company’s Unyvero platform
Mobidiag CE/IVD marking for Amplidiag CarbaR+MCR single test to detect main carbapenemase-producing organisms and colistin resistance markers
Mobidiag CE/IVD marking for Novidiag Bacterial GE+ molecular diagnostic test concurrently identifying common enteric pathogens from stool samples
Beckman Coulter Diagnostics CE marking for DxH 520 hematology analyzer
CareDx CE marking for Olerup QType real time human leukocyte antigen typing test
Now Diagnostics EC Design Examination Certificate authorizing over the counter sale of AdexusDx hCG pregnancy test
Novosanis CE marking for Colli-Pee self-sampling urine collection device
Emosis CE marking for HIT Confirm cytometry-based heparin-induced thrombocytopenia test
Seventh Sense Biosystems CE marking for Tap, one-step push-button TAP blood collection device
Siemens Fast Track Diagnostics CE marking for real-time PCR assay detecting 14 human papillomavirus subtypes in high-risk patients

Other international clearances announced in the past month:

Manufacturer(s) Country(ies) Product(s)
Curetis (via its Southeast Asian partner, Acumen Research Laboratories) Singapore Clearance to market Unyvero blood culture cartridge to detect more than 103 diagnostic targets associated with sepsis
Myriad Genetics Japan Approval to market and manufacture its BRACAnalysis Diagnostic System

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