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US FDA Outlines Possible New Dx Paradigm

US FDA is seriously engaging with lawmakers in an effort to revamp how diagnostics, including test kits and lab-developed tests, are regulated.

The agency sent lawmakers who are working on a comprehensive diagnostics regulatory reform bill a “technical assistance” document earlier this month that maps out a unique plan for establishing a new regulatory category for lab tests.

The document, accompanied by a two-page summary, responds to the Diagnostics Accuracy and Innovation Act discussion draft that was first circulated by Reps. Diana DeGette, a Democrat from Colorado, and Larry Bucshon, a Republican from Indiana, in March 2017. (Also see "Diagnostics Reg Overhaul Floated In US House" - Medtech Insight, 21 Mar, 2017.)  The House Energy and Commerce Committee had asked the agency for its input, but the process took longer than industry and Hill staffers had anticipated. (Also see "bioMérieux America CEO Talks Dx Reform Progress, Antibiotic Resistance" - Medtech Insight, 27 Jun, 2018.)

FDA's document supports the fundamental tenet in the DAIA bill of establishing a new regulatory category of "In Vitro Clinical Tests" (IVCTs) combiningin vitrodiagnostic(IVD) test kits that currently fall under active FDA oversight and laboratory-developed test (LDT) services that have not routinely undergone FDA review that would be subject to the same agency framework. But the document diverges on many details from the DAIA discussion draft, introducing concepts such as pre-certification, new approaches to risk classification, and different paradigms for oversight of novel and modified products. (See table below.)

Stakeholders are still reviewing the document. A coalition of test manufacturers, lab groups and patient advocates that have been lobbying Congress to move forward on legislative reforms for diagnostics say they are generally pleased with the forward progress.

Members of the coalition – including AdvaMedDx, the American Clinical Laboratory Association, the American Cancer Society Cancer Action Network, and Friends of Cancer Research, among others – have urged lawmakers to move quickly to pass a diagnostics regulatory reform bill. (Also see "Labs, Test Makers Urge Congress To Pass Diagnostic Reforms" - Medtech Insight, 11 May, 2018.) In an Aug. 8 letter to relevant House and Senate Committee leaders, the group commended FDA for contributing, though it did not comment on the substance of the agency's provisions.

“We are appreciative of the Food and Drug Administration’s detailed technical assistance on the discussion draft by Reps. Larry Bucshon and Diana DeGette, the Diagnostic Accuracy and Innovation Act, as it represents an important and necessary next step in the pursuit of comprehensive legislative reform,” the letter states.

No Mention Of Substantial Equivalence

The technical assistance document notes that it should not be "interpreted as any kind of approval or endorsement of the legislation by the Department of Health and Human Services and its agencies, or the administration." But it clearly signals FDA's willingness to consider a new direction in how it regulates IVDs, while brining LDTs into its regulatory fold.

In one major departure from current device and IVD oversight, FDA's document makes no mention of substantial equivalence or predicate devices."Those terms ‒ 510(k), substantial equivalence, and predicate device ‒ have been part of regulatory lingo for over four decades.Under FDA’s framework, they would disappear," writes Jeffrey Gibbs, a director with law firm Hyman, Phelps & McNamara, in an FDA Law Blog post.

The agency introduces the new concept of a "test group," which would define assays with common elements and would help inform how test modifications are addressed, and how to identify "first-of-a-kind" tests that are truly novel and might require more scrutiny.

According to FDA, a test group could be created based on these common elements:

  • The substance measured;

  • The type of specimen;

  • The test method;

  • The test purpose, e.g., screening or monitoring;

  • The disease or condition;

  • The patient population; and

  • The place of use, whether over the counter or in a clinical lab.

Pre-Cert As Path To IVCT Exemptions

Rather than focusing on an elaborate classification scheme outlining a regulatory process for assessing high-, moderate- and low-risk diagnostics that the original DAIA discussion draft does, FDA includes only definitions for "high risk" and "low risk" tests. It also asks Congress to consider a pre-certification process for eligible test developers that could allow them to bypass pre-market review if FDA gains trust in their process for developing new assays.

The approach of pre-vetting individual manufacturers is similar what the agency is pursuing in its Digital Health Precertification Program (Pre-Cert) for software developers. (Also see "FDA Readies Digital Health Pre-Cert Program For Lift Off" - Medtech Insight, 26 Apr, 2018.) And it has also applied the strategy for direct-to-consumer genetic screening, with the recent review of 23andMe’sPersonal Genome Service Genetic Health Risk (GHR) Report(Also see "US FDA Greenlights First Direct-To-Consumer Cancer-Risk Test" - Medtech Insight, 6 Mar, 2018.)

“FDA believes an optional pre-certification program for certain eligible test developers and categories of IVCTs can encourage innovation and quality,” the agency commented to Congress. “After an entity has been pre-certified, IVCTs within the specified pre-certification category would not be subject to pre-market review.”

The proposal lays out eligibility requirements for pre-certification. For instance, companies who have had prior significant violations of FDA regulations wouldn't be eligible, and first-of-a-kind IVCTs couldn't gain an exemption under pre-certification, according to FDA's plan.

The agency added that the pre-certification process for diagnostic developers would work for two years, after which it could be reviewed.

Need For Oversight, Ability To Remove Tests From Market If Needed

FDA also wants all IVCTs to be subject to oversight for clinical and analytical validity, it said, and added that “there should be appropriate mechanisms for grandfathering IVCTs already on the market and for assuring access to tests for small patient populations and rare diseases or conditions.”

The agency makes clear in its comments it needs to “address IVCTs of concern, including an ability, when appropriate, to remove an IVCT from the market.”

Below is a chart illustrating some key differences between the original DAIA discussion draft, and FDA’s recommendations as laid out in its technical assistance document.

FDA Technical Assistance Document Vs.DAIA Discussion Draft

Regulation Category

FDA Technical Assistance Document

DAIA Discussion Draft

Definition: IVCT

Definition includes test protocols, platforms, articles used to retrieve specimens, software, parts of testing such as reagents, calibration components

Does not include protocols, test platforms, articles used to retrieve specimens, software

Establish new FDA diagnostics center

Not Mentioned

90 days after law enactment, a Center for In Vitro Clinical Tests shall be established at FDA.

Definition: clinical validity

Ability of an IVCT to adequately achieve the purpose for which it is intended in identifying, screening, measuring, monitoring, diagnosing etc., a human disease or condition.

Reliability and accuracy by which tests, as claimed by developers, identify, screen, measure, monitor, diagnose, etc. a human disease or condition.

Definition: valid scientific evidence

Includes clinical studies, peer reviewed literature, reports of significant human experience, bench studies, clinical data, data registries,well documentedcase studies, and “data collected in countries other than USif such data are demonstrated to be adequate for purposes of making regulatory determinations in the US.”

Includes clinical studies, peer reviewed literature, reports of significant human experience, bench studies, clinical data, data registries, case studies, and “data collected in countries other than US.”

Risk classification levels

Recognizes only high-risk or low-risk tests, with most low-risk IVCTs exempted from pre-market approval and some regulatory requirements.


Recognizes high-risk, moderate-risk, and low-risk IVCTs and proposes how they should be regulated or exempted from pre-market approval, with low risk IVCTs exempted.

Pre-market review requirements

Unless specifically exempted by category or pre-certification, all IVCTs must go through pre-market review. Must provide general information on IVCTs, including description of indications for use, etc., risk assessments, the methods used to develop test. Must provide valid scientific evidence to support analytical, clinical validity.Raw data needed for high risk and first-of-a-kind tests.

Exemptions for IVCTs from pre-certified developers, low-risk tests, manual tests, rare disease tests (used for diseases afflicting 8,000 or less people annually), public health surveillance tests, forensic use and law enforcement tests, custom tests and investigational use tests.

Developer of high-risk, moderate-risk IVCTs supplies name and address, intended use of IVCT, summary description of indications for use, etc., performance standards, design controls, proposed labeling for tests, risk assessment of test, and summary of valid scientific evidence.Raw data only required if FDA chief science officer requests so in a letter to support analytical, clinical validity of test.

Exemptions for low-risk IVCTs, rare disease tests, public health surveillance tests, forensic use and law enforcement tests.

Deadlines for FDA review of IVCT

FDA must approve or deny pre-market approval application “promptly.”

Agency has 120 days to approve or deny high-risk premarket approval for IVCTs; 75 days to approve or deny approval for moderate-risk IVCTs.

Pre-certification process

FDA recommends that developers of IVCTs who are pre-certified be exempted from premarket review. They must apply for pre-certification, and submit data on their IVCT development methods, which must adhere to quality system standards, provide ‘reasonable assurance’ of analytical and clinical validity. Raw data must be provided for one or more of the developers’ IVCTs that could be introduced into interstate commerce. Developers may market their tests while pre-certification is pending.

Not mentioned

Classification process

Not mentioned

Developer must apply for a classification for IVCT, with a description of test, recommended classification, proposed mitigation options if needed. FDA has 60 days to approve or deny the recommended classification, and if it fails to do so after then, the recommended classification is automatic.

Adverse event reporting

Required for grandfathered tests, pre-certified tests, pre-enactment tests, high-risk tests, low-risk tests, rare disease tests, customized tests.

Required by CLIA (Clinical Laboratory Improvements Amendments)-certified labs where tests are developed, and by the test developer.

From the editors of The Gray Sheet

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