FDA Position of LDT Guidance Still Unclear

On Friday, November 18th, the Food and Drug Administration (FDA) announced that it would not seek to finalize its guidance on laboratory developed tests (LDTs) prior to the Trump Administration taking office. Since then, the agency has elaborated on some of the details of this announcement, claiming:

While excessive oversight can discourage innovation, inadequate and inconsistent oversight in which different test developers are treated differently can also discourage innovation by making it difficult for high-quality test developers to compete with poorer performing counterparts.

Among the concerns addressed in the statement, a level playing field for traditional device manufacturers and independent laboratories referenced in the announcement.
While this news brings a little more clarity for the direction of lab-developed tests regulation by the FDA, the lack of a finalized guidance leaves the developers of LDTs, including In Vitro Diagnostic Multivariate Index Assays (IVDMIAs) in limbo.

FDA Will Now Require Electronic MDR submissions as of August 2015

In February 2014, the FDA submitted its final rule regarding updates to 21 CFR 803, Mandatory Reporting Requirements: Manufacturers, Importers and Device User Facilities.  Up until now, manufactures and importers were able to submit a paper form, known as 3500A form, or an electronic equivalent.  Effective August 1 2015, electronic submissions will be the only acceptable format.  These submissions must be in HL7 format and sent to the FDA’s Electronic Submissions Gateway.  This will be a drastic change in the way MDR submissions occur for many organizations.  Luckily, the Administration has created a free desktop application that manufactures and importers can use to generate the HL7 files.  In addition, the FDA has created an API for organizations to use to turn their existing complaints management solutions into the HL7 format.  For more information, read on the FDA’s website here and here.


A Perspective on the FDA’s IVDMIA Draft Guidance


The completion of Human Genome Project marks a defining moment in the history of medical science. New technologies in molecular diagnostics and computational biology have furthered understanding of the transcriptome and proteome at a rate previously unimaginable. Since then, a flood of gene expression profile tests and other biomarker panels have been introduced to the clinical diagnostics market. These tests were all developed in a similar manner—by measuring and comparing the abundance of a group of specific gene transcripts, proteins, or other biomarkers in populations of patients or tissues with a known pathology or prognosis state. This comparative analysis results in the development of a predictive algorithm that can determine the probability of disease or prognosis in unknown samples.

On July 26 2007, the Food and Drug Administration (FDA) published a draft guidance to address this emerging field of In Vitro Diagnostics for Multivariate Index Assays (IVDMA). An IVDMIA is defined by the FDA as a device that:

  1. Combines the values of multiple variables using an interpretation function to yield a single, patient-specific result (e.g., a “classification,” “score,” “index,” etc.), that is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment or prevention of disease, and
  2. Provides a result whose derivation is non-transparent and cannot be independently derived or verified by the end user.As a result, several organizations filed their products for de novo 510(k) clearance, while most waited for a final guidance. The topic has since been shelved by the FDA as they now consider broadening the guidance to govern complex Laboratory Developed Tests (LDTs) currently governed under CLIA. Although the final guidance has been postponed, the final version will most likely still contain most of the items identified in the draft.


The purpose of this document is to summarize the draft guidance as it pertains to Laboratory Developed Tests and discuss its implications at an independent clinical laboratory.


The scope of this document is limited to studying the draft guidance as it was written in 2007. It does not contain any commentary regarding any potential changes to the guidance as a response to industry comments or a changing regulatory climate.



The FDA continues its efforts at administrating a “least burdensome approach” for IVDMIA. The guidance states that, although there is a potential for complicated and emerging technologies to be included in IVDMIA submissions, the classification of devices will be based on risks associated with intended use. (The guidance includes an example of a test that indicates the likely prognosis of a cancer will most likely be considered Class II, versus a test that indicates the therapy regimen would be considered Class III.) The FDA acknowledges the fact the nature of the types of disease states analyzed by these new tests will most likely require a classification of II or III.

The guidance states that safety and effectiveness determination should include “review of the performance of the entire system, including the accurate measurement of the input variables, directions for use, and expected analytical or clinical performance, rather than a review of only certain subcomponents of the test” (i.e. just the algorithm). This approach is consistent with classification determination of other devices, like clinical chemistry and clinical toxicology test systems.

Premarket Regulation

In the spirit of using a “least burdensome approach”, the FDA proposes a flexible approach to safety and effectiveness determination. Although a prospective study is preferred, the administration will also consider archived samples and/or retrospective studies, as long as the study design, sample composition, sample selection and sample storage processes reflect the intended use and intended population for use of the device.

In lieu of properly designed retrospective studies, IVDMIA manufacturers may also file for “Investigational Use Only” labeling as defined by 21 CFR 809.10 and apply for an investigational device exemption (IDE). Other labeling requirements are to be consistent with those regarding other devices.

Postmarket Regulation

Consistent with other devices, the FDA states that IVDMIAs are subject to Quality System regulation as described in 21 CFR Part 820, however, the FDA intends to continue to exercise enforcement discretion for CLIA-regulated laboratories until a final guidance is approved for laboratory developed tests.

The Administration states that all IVDIAs must comply with 21 CFR 803 – Medical Device

Reporting standards. Also, laboratories that run IVDMIA test systems are considered “user facilities”, and must submit serious injury/device malfunction reports as such (CFR 21 830.50).


In an effort to reduce the effect on innovation costs in the market, FDA intends to exercise enforcement discretion with respect to all regulatory requirements for currently marketed, laboratory-developed IVDMIAs for 12 months following publication of the final guidance document. In an effort to encourage early adoption to the new standards, FDA intends to exercise enforcement discretion for an additional 6 months for any currently marketed, laboratory-developed IVDMIAs if the manufacturer submits a 510(k) or PMA within the initial 12 month period following publication of the final guidance.


While the debate on whether Laboratory Developed Tests are medical services (and should be regulated by CMS under CLIA) or medical devices (and should be regulated by the FDA as IVDs) seems to be coming to a head, LDT developers and IVD manufactures brace for a dramatic shift in regulatory environment. FDA has used “enforcement discretion” in exerting what it sees as its legal authority to regulate medical devices, but many analysts believe that the time will soon come when enforcement will be applied to some areas currently left up to CLIA. In particular, multivariate index assays have come under particular attention in recent years; enough to spur publication of draft guidance by the FDA.

This emerging development may provide some interesting opportunites for device manufacturers. Since they many systems already in place to govern compliance to FDA device manufacturing requirements for new and existing products, these systems can and should be leveraged in order to bring their own CLIA laboratory into compliance for a potential 510(k) or PMA submission when/if the time comes. Other leaders in IVDMIA laboratory testing have already begun to retrofit their current processes and build their new products with the FDA in mind, but without the institutional regulatory architecture, they will be at a disadvantage. Life Technologies has the opportunity to create IVDMIA products with competitive compliance that surpasses the expectations of regulators and their customers while controlling costs.


  1. 2007. Food and Drug administration. Draft Guidance for Industry, Clinical Laboratories, and FDA Staff. In Vitro Diagnostic Multivariate Index Assays. http://www.fda.gov
  2. 2011. Smith, Katie M. Exploring FDA-Approved IVDMIAs. http://www.ivdtechnology.com/article/exploring-fda-approved-ivdmias
  3. 2012. Wiess, Ronald L. The Long and Winding Regulatory Road for Laboratory-Developed Tests. American Journal of Clinical Pathology, 138, 20-26.


Lab-Developed Tests and the FDA: A road forward

Printable Version: Lab-Developed Tests and the FDA


Advancements in personalized medicine have the potential to revolutionize health care. Genomics and molecular biology technologies are vital in the development of theranostics and other predictive and preventative areas of personalized medicine. However, few of these laboratory-developed-tests are currently regulated by the Food and Drug Administration (FDA) for analytical and clinical efficacy. Currently, the only oversight requirements governing LDTs are the laboratory requirements prescribed in the Clinical Laboratory Improvement Amendments of 1988 (CLIA).

While the FDA assumes authority for regulating LDTs, and is currently exercising enforcement discretion, it has indicated it will be increasing oversight of LDTs in the near future. FDA Commissioner Margaret A. Hamburg is now renewing FDA’s call for more active FDA regulation of LDTs and touting the Agency’s risk-based framework for regulating LDTs that is “under development.”

On July 9, 2012, President Obama signed into law the bipartisan FDA user-fee bill, the Food and Drug Administration Safety and Innovation Act (FDASIA). For the next five years, the Act prohibits the FDA from issuing guidance on LDT regulation unless the Agency provides a 60-day advance notice to the House Energy and Commerce Committee and the Senate Health, Education, Labor, and Pension Committee of its intent to take such action. This law all but places a time clock on the impending shift in the regulation of these tests.

Several stakeholders have submitted proposals to the FDA on risk-based strategies to facilitate tighter regulation on LDTs, among these are the College of American Pathologists (CAP) and the Advanced Medical Technology Association (AdvaMed). We have selected these proposals as highest likelihood of adoption.


This article is a comparative study of the proposals by CAP and AdvaMed. It will analyze the proposed risk management strategies and comment on their likely impact on the clinical diagnostics industry should the FDA choose to accept their proposals. In addition, this article will propose a best-of-breed strategy to use as a template for any high-complexity CLIA laboratory in their assessment of the pending regulatory changes.


Only the proposals presented by the College of American Pathologists and AdvaMed as referenced below were considered when designing the best-of-breed strategy.



The CAP Proposal Summary

The CAP proposes a risk-based model employing a public-private partnership to address oversight of LDTs. In their proposal, third-party accreditors and inspectors would oversee and monitor standards for low- and moderate-risk LDTs; high-risk LDTs would be reviewed directly by the FDA. We recognize that the CAP has a biased stake in these recommendations because they are the best-equipped accrediting agency to thrive from public/private partnership; however, it is a risk-balanced approach that also addresses the lack of currently-available resources by the FDA to regulate the LDT industry. The regulatory flexibility proposed by the CAP would encourage innovation of new diagnostic and predictive tests to promote and protect public health. Each laboratory would self-assess their LDT classification based on the FDA’s criteria for low-, moderate-, and high-risk tests. The determination would be verified by the laboratory’s certifier and/or accreditor (e.g. CAP, COLA, AABB, etc). Appendix A is a summary of the proposed tiers.

The proposal also states that there should be a harmonization between CMS’s CLIA standards and the FDA when it comes to quality systems management. Since the Quality Systems Management Standards of the FDA are more robust than those of CLIA, our opinion is that CLIA would most likely adopt the FDA standards, where applicable. In addition, the CAP proposes that certain direct-to-consumer tests which are currently unregulated would now fall under CLIA and have to follow the same guidance as other CLIA laboratories.

The AdvaMed Proposal Summary

Like the CAP proposal, AdvaMed suggests a harmonization of CLIA and FDA, and that all clinical laboratories should be subject to CLIA regulations. But unlike CAP, AdvaMed proposes that the FDA should oversee the safety and effectiveness of all diagnostic tests, whether that are made in a laboratory or by a manufacturer, because they all have the same risk/benefit profile for patients. Similarly to the CAP proposal, AdvaMed suggests a risk-based tiered approach for oversight focus. While well-standardized and low-risk tests could be exempted from and FDA premarket review, novel biomarkers using new technology could face the scrutiny of a Tier III FDA review. In between these two extremes, AdvaMed proposes using the existing three-tiered FDA definitions to categorize tests, where risk assessment and mitigation ability are used to further stratify classification. Appendix B is a summary of their approach.

The AdvaMed proposal also contains a risk decision tree to aid in the determination of tier classification, risk assessment points of concentration and possible mitigating factors for these risk points.


While no one can accurately predict the political climate in the next 5 years, we can say that there is and will continue to be a significant push back from the nation’s largest clinical diagnostics companies for dramatic reforms in the CLIA/FDA regulatory areas such as those proposed by AdvaMed. It will cost these companies millions, maybe hundreds of millions of dollars to validate their systems to these new standards. It has the potential to stifle innovation and patient access to cutting-edge technology. Also, from a logistics point of view, the FDA does not currently have the resources to regulate the entire LDT industry.

The risk-based private/public partnership proposed by the CAP addresses both the logistics and the economic concerns of this issue while keeping patient safety in mind. Once considered high risk (as defined by the CAP proposal), it would then seem appropriate to classify an LDT as described in the AdvaMed proposal.

At Lab Insights, LLC, our current focus in the clinical diagnostics area is in the development of high-complexity, moderate to high risk tests run on established and new technologies. Many tests in our focus utilize multivariate algorithms, which disqualifies the tests from any FDA tier but Tiers II and III. It is most likely that when/if the FDA utilizes a risked-based approach to examine Laboratory-Developed Tests, the tests developed here will undergo a rigorous level of review.

To assess the level of regulation anticipated for FDA submission, we propose the adoption of a modified AdvaMed decision tree shown in Appendix C.
Under CAP, the following characteristics must be determined and approved by a Certified Lab Director for high-complexity testing as defined by CLIA (42 CFR 493.1443):

  • Analytic Accuracy and Precision
  • Analytic Sensitivity
  • Analytic Specificity
  • Analytic Interfering Substances
  • Reportable Range

CAP Guidelines should be followed to comply with this regulation.

Also, under CAP, computer systems must be evaluated for:

  • Computer Facility
  • LIS/Computer Manual documentation
  • Hardware and Software testing and documentation
  • Training
  • System Maintenance
  • System Security
  • Patient Result verification


  1. 2012. College of American Pathologists. 2012 CAP Checklists. http://www.cap.org
  2. 2010. College of American Pathologists. Proposed Approach to Oversight of Laboratory Developed Tests. http://www.cap.org
  3. 2012. Advanced Medical Technology Association. Risk-based Regulation of Diagnostics. www.advamed.org
  4. 2013. 42 CFR 493 – Laboratory Requirements. http://www.gpo.gov/fdsys/pkg/CFR-2003-title42-vol3/xml/CFR-2003-title42-vol3-part493.xml
  5. 2007. FDA Draft Guidance for Industry, Clinical Laboratories, and FDA Staff – In Vitro Diagnostic Multivariate Index Assays




Summary table of the AdvaMed Proposal Triage decision matrix

Classification Determining Factors Oversight
Low Risk:
the consequence of an incorrect result or incorrect interpretation is unlikely to lead to serious morbidity/mortality.
The test result is typically used in conjunction with other clinical findings to establish or confirm diagnosis. No claim that the test result alone determines prognosis or direction of therapy. The laboratory internally performs analytical validation and determines adequacy of clinical validation prior to offering for clinical testing. The accreditor during the normally scheduled inspections will verify that the laboratory performed appropriate validation studies.
Moderate Risk:
the consequence of an incorrect result or incorrect interpretation may lead to serious morbidity/mortality
AND the test methodology is well understood and independently verifiable.
The test result is often used for predicting disease progression or identifying whether a patient is eligible for a specific therapy. The laboratory may make claims about clinical accuracy. The laboratory must submit validation studies to the CMS-deemed accreditor for review and the accreditor must make a determination that there is adequate evidence of analytical and clinical validity before the laboratory may offer the test clinically.
High Risk:
the consequence of an incorrect result or incorrect interpretation cCaould lead to serious morbidity/mortality
AND the test methodology is not well understood or is not independently verifiable.
The test is used to predict risk of, progression of, or patient eligibility for a specific therapy to treat a disease associated with significant morbidity or mortality, AND;
The test methodology uses proprietary algorithms or computations such that the test result cannot be tied to the methods used or inter-laboratory comparisons cannot be performed.
The laboratory must submit test to FDA for review prior to offering the test clinically. CMS and accreditor determine compliance.

Summary table of the AdvaMed Proposal Tiered decision matrix

Category New (use of) Biomarker Established (use of) Biomarker
New Technology No Predicate devices (i.e. novel or high risk)
Little of no clinical literature
Requires analytical and clinical validation
Manufacturers and laboratories subject to premarket review
Tier III: PMA or de novo 510(k)
Sufficient Clinical evidence to assess safety and effectiveness of biomarker
Requires analytical validation of new method on clinical specimens
Review level separated by FDA experience with technology
Tier II: traditional or de novo 510(k)
Tier I: traditional or streamlined 510(k), possible labeling review
Established Technology Could have predicate device
Little/no literature on biomarker, but literature and/or FDA experience with technology platform; moderate risk products
Manufacturers and laboratories subject to premarket review
Tier III: PMA or de novo 510(k)
Tier II: traditional or de novo 510(k)
Sufficient Clinical evidence to assess safety and effectiveness of biomarker
Submission of labeling or data summarizing performance characteristics
Self certification/declaration of conformity with standards
Tier II: if moderate risk associated with use (traditional 510(k))
Tier I: if low risk associated with use (labeling review or streamlined 510(k))
Tier O: if risk low and managed, labeling review and/or consider exempt

Proposed “Triage-then-Tier” decision tree by Lab Insights, LLC

Decision Tree