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A House Subcommittee plans to take up draft legislation at a hearing next month that brings together test kits and lab-developed tests into a new regulatory category. The proposal offers many ways for tests to avoid a “high-risk” classification. “The Gray Sheet” compares the provisions to recent proposals vetted in the Senate.


The House Energy and Commerce Health Subcommittee will consider a legislative discussion draft to establish new regulated medical product category of in vitro clinical tests to counter FDA’s proposed laboratory developed test (LDT) framework at a Nov. 17 hearing.


The draft contains provisions intended to limit the number of tests, including test kits, that are labeled as “high risk." It also proposes that FDA establish a separate center to regulate IVCTs.


The draft looks like a more fully-developed proposal set out by a coalition of test kit makers and laboratories called the Diagnostic Test Working Group earlier this year. The IVCT proposal is intended to address the concerns of laboratories, which say FDA’s proposed LDT framework is an overreach, while also responding to calls by diagnostic test-kit manufacturers for a level regulatory playing field for all assays sold to and developed by labs.


Although legislation is being considered, Senate and House staffers signaled last month that Congress is willing to wait for FDA’s final guidance on LDTs, before making any changes. (See (Also see "Congress Will Not Tinker With FDA LDT Guidance Before Final, Staffers Indicate" - Medtech Insight, 10 Sep, 2015.).) FDA officials affirmed this week at the Regulatory Affairs Professionals Society annual meeting in Baltimore that the agency plans to finalize its guidance documents establishing an oversight framework for LDTs in 2016. (See (Also see "FDA Plan To Regulate LDTs Includes Long Phase-In, Unmet-Need Exceptions" - Medtech Insight, 31 Jul, 2014.).)


It's not yet clear if diagnostics reform legislation as proposed in the latest discussion draft, might be included in some version of the previously passed House 21st Century Cures legislation after it is aligned with a Senate medical innovation bill that could come out by next year.


Draft legislative language providing alternative plans for regulation of diagnostics and laboratory operations, with shared roles for FDA, the Centers for Medicare and Medicaid Services, and state governments, are also being vetted by the Senate’s Health, Education, Labor and Pensions Committee in. One proposal circulating is the draft developed by the Diagnostic Test Working Group that would cover rules for both in vitro diagnostic kits and LDTs. (see (Also see "Senators Circulate Plan For Standalone FDA Diagnostics Center, ‘In Vitro Clinical Test’ Rules" - Medtech Insight, 16 Jun, 2015.)). A separate proposal is backed by the Association for Molecular Pathology. (See (Also see "Molecular Pathologists Propose Third-Party Review Of High-Risk Dx In Alternative To FDA LDT Plan" - Medtech Insight, 21 Aug, 2015.).)

Burden Of Proof On FDA For "High-Risk" Classification


The proposed House legislation provides several options for existing and new laboratory tests to avoid being classified as high risk products that would require tougher regulations than moderate-risk or low-risk tests. Under the proposal, moderate-risk tests could be cleared for marketing by an accredited third-party reviewer that the lab selects and pays for, rather than undergoing direct agency scrutiny. To gain moderate-risk status, a lab or test manufacturer could employ or point to risk-mitigation measures for its diagnostic, submit a request for reclassification into a lower class, or appeal a high-risk classification decision to an advisory panel, and the onus would be on FDA to prove that a high risk classification is warranted.


If, for example, a laboratory can provide a risk mitigation factor for what might otherwise be considered a “high-risk test”, such as that clinical use of the test is well characterized, or other tests are available to diagnose the target disease, it could be called a moderate-risk test.


If the IVCT has never been classified by FDA previously, a laboratory could submit a classification request to place it in a moderate- or low-risk class, and the agency would only have 60 days to make up its mind on classification. If the agency does not make a swift-enough decision to place it in a high-risk class, than it must publish an order rejecting, modifying or accepting the classification.


The draft sets a lower bar for FDA to accept a laboratory or lab-test manufacturer’s proposed low- or moderate-risk classification than if it wanted to modify or reject a reclassification request. If FDA wants to reject or modify a laboratory’s proposed moderate- or low-risk-classification, it would have to explain the reason for its objections, and say why the explanations provided by the laboratory do not support a lower classification.


Further, a laboratory would be able to request review of a recommended classification by an advisory panel within 180 days of FDA’s decision to reject or modify the lab’s proposed moderate- or low-risk classification request. Such advisory panels would have to include “a balanced representation of interested persons representing physicians, consumers and the in vitro clinical test manufacturing and laboratory industries.”


Also, if FDA failed to make a final determination about a test’s classification 90 days after the advisory panel’s recommendation, “it shall be presumed that the classification recommended by the advisory panel is the final classification” and the agency would have to post that decision as final, or “rebut such presumption using scientific evidence,” according to the draft. Such rebuttals would have to include “a public health justification demonstrating the need for upclassification,” the discussion draft says.


A section in the House discussion draft on “prevention of upclassification” instructs FDA how to add mitigation measures to a test to avoid a “high-risk” classification.


In separate sections of the discussion draft, labeled “prevention of upclassification” and “upclassification”, respectively, the draft lays out a process for FDA to add mitigation measures during a review to prevent an IVCT’s upclassification, and prevents any FDA employee or official except the chief scientific officer or other FDA IVCT Center senior manager from generating an upclassification order.


If FDA proposed a high-risk classification for an IVCT, the laboratory or manufacturer sponsoring it would rarely or never have to perform a clinical trial to provide valid scientific evidence to support its clearance or approval. Sponsors can claim that an FDA requirement for additional data collection would provide a negative “impact on innovation” – or use any other of 15 factors the discussion draft lists and sponsors can draw upon to limit their collection of data in support of a test approval application.


Comparison Shows Diagnostic Proposal Differences


Several legislative drafts are circulating to reform regulations of diagnostic in lieu of FDA's LDT proposal. In addition to the latest House discussion draft, two other proposals have been vetted by the Senate Health, Education and Labor Committee. Those include the Diagnostic Test Working Group (DTWG) IVCT proposal, detailed in a March 5 white paper endorsed by test kit makers Becton Dickinson & Co. and Roche, and laboratories including Mayo Clinic, Laboratory Corp. of America Holdings and ARUP Laboratories, and a proposal backed by the Association for Molecular Pathology (AMP).



Diagnostic Regulatory Reform: Comparison Of Legislative Proposals 
 Provision House Discussion Draft  DTWG Proposal  AMP Proposal 

Covered Tests

 In Vitro Clinical Tests (IVCTs) are lab test protocols or finished products for collection, preparation, analysis of human specimens. They are NOT drugs, devices or biologics; not for identifying blood used in transfusion or identifying infectious diseases.

 IVCTs are lab test protocols or finished products for collection, preparation, analysis of human specimens. They are NOT drugs or devices under Federal Food, Drug and Cosmetic Act or biological products under Public Health Service Act.

Lab-Developed Test Procedures (LDPs) are procedures or services provided by a CLIA certified laboratory. They are NOT medical devices or test kits.

 Automatically Exempt

 Non-clinical use tests, including: forensic tests, drugs-of-abuse tests, and genetic tests for non-clinical purposes.


Forensic tests,
Drugs-of-Abuse tests;
Genetic tests for non-clinical purposes;
Investigational Use Only tests;
Research Use Only Tests.


LDPs intended to be used solely for public health surveillance.



 A new FDA Center for In Vitro Chemical Tests would regulate IVCTs. Proposal also addresses CMS jurisdiction, certification of laboratories under the Clinical Laboratory Improvements Act.

 A new FDA Center for In Vitro Chemical Tests would have control over IVCT and reagent design, development and validation; CMS would control lab apparatus, preparation of reagents; states supervise practice of medicine using tests.

 Primarily, CMS would have jurisdiction, except that LDPs with proprietary algorithms would go to FDA for review.

 Risk Classification


High Risk: IVCTs for which a clinically significant inaccurate result would cause serious irreversible harm or death by disease, based on failure to treat, incorrect treatment, invasive procedures or prolonged disability; and there are no risk mitigating factors, such as substitutes for the test.

Moderate Risk: Same as for high risk, except risk mitigation factors exist, such as test is well characterized, clinical presentation, other confirmatory tests available, or other mitigating measures.

Low Risk: Same as for moderate risk, but risk mitigating factors AND a clinically significant inaccurate result would cause minimal or no harm.


Must demonstrate (to FDA) a reasonable assurance of analytical validity and clinical validity for intended use. Analytical validity: Must demonstrate test measures an analyte or substances showing sensitivity, specificity, accuracy and precision.

Clinical validity: Must demonstrate with reliability and accuracy that an IVCT can identify, predict, monitor or can select treatment for a patient.

CMS will develop and review a minimum level of standards for analytical and clinical validity, with the help of public advisory boards. Clinically validity means the association of a biomarker or analyte with the presence, absence, predisposition to, or risk of a specific clinical condition and is NOT established by lab itself, but by scientific/medical community via peer-reviewed scientific literature OR data is collected or documented. Health care professionals, patients and regulatory agencies must have access to accuracy, precision and known clinical significance of an LDP, and that data should be publicly displayed in a searchable, standardized format.

Evidence for clinical validity

 May include, alone or in combination: peer reviewed literature, clinical guidelines, reports of significant human experience with an offered IVCT, bench studies, case studies, clinical data, consensus standards, reference standards, data registries, postmarket data, and clinical trials. The need to supply ANY of this data to FDA, including clinical trials, can vary, depending on the impact on innovation, or 14 other factors outlined in the proposal.

 May include: peer reviewed literature, clinical guidelines, expert opinion, bench studies, past experience, case studies, clinical data, consensus standards, reference standards, data registries, post-market data and clinical trials. Clinical trials not needed, unless the FDA center in writing says that other evidence is insufficient.

 May include, but not limited to: peer reviewed literature, clinical practice guidelines, subject matter expert opinion, bench studies, past experience, case studies, clinical data, consensus standards, reference standards, data registries, such as ClinGen, ClinVar, etc., postmarket data, or clinical trials, including those outside the U.S. Labs would only need a clinical trial if CMS, in writing, explains to the lab why such a trial is needed.

 Third-Party Reviews

 Allowed for moderate-risk tests only. For purposes of reviewing and approving moderate-risk tests, FDA shall establish a process by which third parties may conduct reviews and approvals.

 An improved third-party review process will be developed and made available for moderate-risk submissions.

 No third-party reviews of high-risk LDPs. CMS will establish a transparent process in which non-governmental organizations may be approved as third-party reviewers; and CMS-approved accrediting organizations may be third-party reviewers.

Adverse Events Reporting

 Developer of an IVCT must submit a report of an adverse event associated with a test to FDA no later than five days after if it involves a death and no later than 15 days after if it presents an imminent threat to human health. Quarterly reports on all adverse events involving the test are required. The developer of an IVCT shall not be required to maintain records or report on laboratory errors.

Developer of an IVCT must report to FDA: deaths or serious injuries caused by an IVCT error; or any IVCT errors that could result in a reasonable probability of death or serious injury. 

Requires labs to have a mechanism for ordering physicians to report possible laboratory or LDP errors, any investigations of a lab revealing errors posing jeopardy to a lab’s patients must be reported to CMS immediately, CMS has to provide information to the public on errors through a publicly-available database. Also, CMS must ask FDA to investigate an FDA cleared or approved test when there is sufficient concern. 

Quality System Regulations

 Quality requirements for development and production of IVCTs shall be established, and may include elements such as management responsibility, design controls, production and processing controls, corrective and preventive actions, etc. Finished IVCT products require a unique identifier. The rules apply only to design, development, validation, manufacture, or processing of the test, and may not apply to laboratory operations. Separate national standards for quality assurance in cytology services, and performance of laboratory operations, shall be established.

 A line is drawn between quality rules for lab operations and test development. FDA quality requirements are needed for test development activities; modernized CLIA obligations would apply to laboratory operations.

 CMS sets minimum requirements for CMS-approved lab inspectors and the inspection process to reduce variability in oversight among the various accrediting organizations. Proficiency testing of analytes required to ensure performance and validity of all LDPs meet accepted standards.

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