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A Product Development Plan For My Laboratory Developed Test

It has been a long time coming, but the FDA’s enforcement discretion of Laboratory Developed Tests (LDTs) may phase out. Clinical Laboratory Improvement Amendments (CLIA) won’t cut it and the FDA will oversee LDTs within an in vitro diagnostic (IVD) medical device regulatory paradigm. The rule traveled express through the White House – Office of Information and Regulatory Affairs (OIRA) and the FDA formally published the rule (528 pages) May 6, 2024, with an expectation it has no major changes from the original proposed legislation.

The Food and Drug Administration (FDA, the Agency, or we) is proposing to amend its regulations to make explicit that in vitro diagnostic products (IVDs) are devices under the Federal Food, Drug, and Cosmetic Act (FD&C Act) including when the manufacturer of the IVD is a laboratory. In conjunction with this amendment, FDA is proposing a policy under which FDA intends to phase out its general enforcement discretion approach for laboratory developed tests (LDTs) so that IVDs manufactured by a laboratory would generally fall under the same enforcement approach as other IVDs.[i]

A widely held opinion is while the rule has gotten this far, it could stall in the controversy of FDA legal authority to regulate laboratory testing as medical devices. Whether the rule reaches the final implementation destination or not, it is prudent to at least understand some of the gaps between an LDT offered by a CLIA certified lab, and an FDA cleared/approved IVD.

Device manufacturers have been assessing their market and potential return on IVD investment, building tests using supplier and design controls, tailoring Intended Use for the most favorable regulatory path through the FDA, and baking the costs into their product development plans (PDP) for the sake of an FDA clearance or approval of medical devices. On the other hand, a single CLIA certified laboratory that designs, manufactures, and offers a laboratory developed test may need a robust gap assessment to inform their IVD/assay business plan and regulatory compliance strategy. Some laboratories may have resources and funding to move their products from LDT to cleared or approved medical devices, but others may need to re-examine their products, pipeline, and capabilities to prioritize business goals.

Definition of an LDT

IVDs function with samples removed from the body and usually include supplies (most often available off the shelf) and instructions for collecting, preparing, and testing a biospecimen. IVDs designed, developed, and manufactured out of a single CLIA-certified laboratory are called laboratory-developed tests or LDTs. At the time of the 1976 device amendments, the FDA considered LDTs to be simple, single-analyte tests using legally marketed components and standard techniques by local laboratory personnel. Enforcement discretion at the time seemed reasonable because these kinds of tests were low risk. With the evolution of LDTs from simple,

relatively low-risk tests to complex technology with software and algorithms used to guide treatment, over the last 10+ years the FDA has attempted to reconsider enforcement discretion with proposed guidance and now rule-making. Whether the rule goes all the way or not, it is a good time to understand that even in the current enforcement discretion environment, the following are NOT considered LDTs:

  • A network of clinical laboratories using a device design transferred from a single lab entity within that network
  • An academic institution that licenses a CLIA-certified lab to perform the test the institution designed and developed
  • Any test that requires parts or components from a third-party manufacturer
  • Any test developed by a contracted developer and transferred to a clinical laboratory for final validation and clinical diagnostic testing
  • Any test that has more than a low to moderate risk associated with a false test result (case in point: Inova Genomics Laboratory – 577422 – 04/04/2019 | FDA)

What does an IVD PDP look like?

Laboratory leaders who cringe in response to any one of these bullet points may consider the value of a PDP for their LDT – if just to assess the test/assay claims against the current FDA definitions of an LDT while waiting to see what happens next with the rule. In addition, a PDP template is a good start to assess the impact of the LDT rule on the commercial viability of an LDT once the rule is published. An IVD medical device PDP is a strategic map of the activities required to take the device from the initial concept through market release and post-market monitoring. It could also be a template for a gap analysis of the current state of LDT business and the impact of the LDT rule on the market viability and opportunity under the new regulations. It includes key functional or focal areas such as marketing, regulatory, clinical, reimbursement, etc., and each of these has key activities or project requirements.

IVD product development includes device design verification and validation. CLIA regulations require clinical laboratory directors to establish performance characteristics for laboratory-developed tests. Laboratories determine the type of experiments that are required, include the acceptable number and type of specimens, and choose the statistical methods to evaluate the data. Laboratories may refer to Clinical and Laboratory Standards Institute (CLSI) standards for test protocols and specific assay performance characteristics. So, there is likely valuable test validation data documented in CLIA laboratories, though it may not be enough. For example, CLIA test validation may not check all the FDA product development boxes–such as interference studies–or may not test enough samples or replicates over enough days with enough users for the FDA to evaluate safety and effectiveness.

How does an IVD PDP work as an LDT gap analysis?

In the process of moving an LDT to a fully regulated product, a PDP puts strategy into structure and the structure can be leveraged as a tool to compare the LDT compliance obligations within the CLIA regulations to the new FDA rule. There are significant costs associated with medical device product development from idea to commercialization. Knowing what the assay portfolio is worth as an LDT is critical to an assessment of the cost associated with the LDT as a fully regulated medical device and how the new requirements impact the business in terms of assay sales volume, cost/revenue opportunity, clinical utility, and patient care. An assessment of the LDT product strategy in the context of the LDT rule includes:

  • Understanding business objectives and inventory of current technology and assay portfolio
  • Comparison of the technology and assay portfolio to the new LDT rule to determine how the rule applies to the products in that portfolio
  • Where the technology and assays require FDA medical device class II clearance or class III approval, a determination of what requirements are achieved within the CLIA regulations and what new requirements are necessary to comply with the new rule

What are the potential gaps for an LDT under the proposed new LDT rule?

In addition to test accuracy, the new rule is likely to impose many of the 1976 Medical Device Amendment requirements on all tests including device classification based on the risks of false test results on patient safety, and a regulatory clearance –510(k) or approval (PMA)–pathway consistent with the level of risk.

The Clinical Laboratory Improvement Amendments (CLIA) are regulated by the Centers for Medicare & Medicaid (CMS). Laboratories are CLIA certified by inspection to have adequate quality and process controls around specimen procurement and processing, reagents, supplies, equipment storage and maintenance, testing procedures, and records and data (test methodologies, staff qualifications, education, training, etc.). CLIA regulations require laboratory parameters for test accuracy and precision, but do not require an assessment of the clinical impact of the test on decision making (clinical accuracy).

The FDA regulates IVDs as medical devices according to the level of control necessary to assure safety and effectiveness of the device. The intended use, indications for use and the risks of a false test result determine the device risk classification (Class I, II, III), and the type of premarketing submission/application required for FDA clearance/approval to market. The FDA also requires compliance with 21 CFR 820, the Quality Management System Regulation (final rule published January 31, 2024 to align the current good manufacturing practice (GMP) with international consensus standards for Quality Systems).

The potential gaps between these two oversight regulations may inform the LDT compliance and requirements of the new LDT rule:

  • FDA requirements for Design Controls (21 CFR 820.30) including specific Intended Use, Indications for Use, claims, analytical design verification, and clinical validation
  • FDA requirements for supplier qualification
  • FDA requirement for risk management and compliant quality systems
  • New applicable regulatory standards including registration, listing, and adverse event reporting
  • Predicate assessment, best FDA regulatory pathway
  • Clinical evidence requirements for test validation
  • Clinical validation sample requirements to support clinical utility data
  • Requirements for Adverse Event Reporting
  • Pricing return on investment (ROI) for cost to fill the gaps

How can NAMSA help?

We can help today with an LDT compliance assessment, regulatory gap assessment, and strategic planning. We are able to support LDT transition to an FDA cleared/approved IVD and have a multi-disciplinary team of IVD subject matter experts for all the phases of IVD product development including biocompatibility, quality and regulatory, and clinical trials.



Phases and Activities for IVD Product Development

Phase 0 – Concept
Business and Concept Review
Coding, Coverage and Payment
Phase I – Design Planning and Development
User Needs, Design Inputs, Performance Requirements, Risk Management Plan
Product Description, Intended Use, Indications for Use
Risk Classification
Proof of Concept testing
Regulatory Plan
Regulatory Pathway
Small Business Certification for FDA User Fees
513(g) Regulatory Submission
Q-Submission focused on _______________________
Quality System Initiation
Phase II – Design Verification
Quality System development – ISO 13485 Certification
Analytical Sensitivity (LOD)
Analytical Specificity
Analytical Reactivity
Interfering Substances
Carry Over
Sample Characterization (stability, processing, storage, shipping, fixative, transport media)
Verification/Clinical Readiness
IDE Application
IFU, User Manual, QRI, Installation, Technical Support
Special Controls (Patient Education, Genetic Counseling, “Patient Support”)
Sterilization, Packaging, Shipping Validation
IEC 60601 (Electrical Standards) Plan, Testing, and Report
IEC 62304 Medical Device Software (SoMD) Risk Management, Change Control, etc.
SaMD Testing Requirements
Risk Assessment / Hazard Analysis (Document tasks, identify “critical” tasks)
Human Factor Engineering / Usability (formative summary in Hazard Analysis)
Initiate Technical Documentation
Phase III – Design Validation
Human Factor Engineering / Usability (Summative if “critical” tasks)
Clinical Investigations (Feasibility)
Clinical Investigations (Pivotal) (Study Design, Sample Size Calculation (Prevalence),
Objectives, Scientific Endpoints)
Clinical Evaluation Report (EU)
Phase IV – Process Validation  and Commercialization
Process and Equipment Validation Finalization
Quality System Certification Audit then Maintenance
Development and Finalization of Technical Documentation
Authority Review (FDA, NB, else)
Phase V – Post Market Activities

[i] 2023-21662.pdf (govinfo.gov)

Wendy Schroeder, RN, BSN, CCRC/PM, CRCP

Wendy Schroeder has been involved with research and clinical trials for more than 20 years, and has a deep understanding of in vitro diagnostics (IVDs) and companion diagnostics (CDx). She has served as a key company stakeholder in the implementation of an in-house contract research organization (CRO) infrastructure for a commercial laboratory moving bench IVD science into clinical validation studies and launching a biorepository of blood samples with annotated clinical data. Wendy has provided research operations oversight for commercial laboratories (Caris Life Sciences, Ashion Analytics) and IVD manufacturers (VisionGate, Inc.) as well as at hospital and clinical sites. Wendy holds a Bachelor of Science in nursing degree from Arizona State University (Tempe, AZ). She is a certified Research Coordinator and Project Manager (ACRP) and a certified Research Contracts Professional (MAGI). She has been an invited speaker and author of peer-reviewed journal publications on molecular diagnostics (MDx), clinical trial billing and IVD/Laboratory Developed Test (LDT) regulatory matters.