Comparing Laboratory Developed Tests and FDA-Approved Companion Diagnostics

Introduction: Two Diagnostic Pathways in Precision Medicine

In the realm of personalized medicine, companion diagnostics (CDx) are essential tools that identify patients likely to benefit from specific therapies. These diagnostics can be developed as Laboratory Developed Tests (LDTs), performed in CLIA-certified laboratories, or as FDA-approved commercial test kits, regulated under the FDA’s Premarket Approval (PMA) process. Each approach carries unique advantages, regulatory obligations, and clinical implications.

This article provides a detailed comparison between LDTs and FDA-approved CDx, addressing their respective validation requirements, oversight frameworks, and implications for clinical trial design and patient care. Understanding these differences is vital for diagnostic developers, regulatory teams, and clinical researchers who must choose the optimal path for market access and compliance.

Defining LDTs and FDA-Approved CDx

Laboratory Developed Tests (LDTs) are diagnostic tests that are developed, validated, and used within a single laboratory—typically under the Clinical Laboratory Improvement Amendments (CLIA) program in the U.S. These tests are not distributed commercially as kits and, until recently, have operated under FDA’s “enforcement discretion.”

FDA-Approved CDx are in vitro diagnostic (IVD) products that undergo full FDA review through the PMA or 510(k) pathway. These diagnostics are intended for widespread use across clinical sites and are co-developed with a specific therapeutic product.

This distinction is especially relevant in oncology, where tests like PD-L1 or BRCA1/2 guide treatment eligibility and must meet stringent validation thresholds.

Regulatory Pathways and FDA’s Evolving Role

The FDA has historically exercised enforcement discretion over LDTs, meaning it has not actively regulated them. However, as the complexity and clinical impact of LDTs have grown, so has scrutiny. In 2023, FDA issued updated draft guidance indicating intent to bring LDTs under more consistent oversight.

Key documents:

• FDA Draft Guidance: Regulation of LDTs (2023)
• 21 CFR Part 809 – Labeling requirements for IVDs
• FDA’s Risk-Based Framework for LDT Oversight

Meanwhile, FDA-approved CDx must undergo rigorous analytical and clinical validation and are subject to post-market surveillance and quality system regulation (QSR).

Learn about IVD QSR compliance frameworks at PharmaValidation.in.

Validation and Performance Requirements

Validation is a cornerstone of both LDT and FDA-approved CDx development, but standards and transparency differ:

• LDTs: Validate for accuracy, precision, and reportable range using internally defined protocols; no requirement to publish data
• CDx: Must demonstrate sensitivity, specificity, reproducibility, LOD, LOQ, and robustness across multiple sites

Dummy Validation Table – Example Metrics for CDx:

Clinical Trial and Companion Diagnostic Use

In clinical trials, the choice between using an LDT or FDA-approved CDx depends on the trial phase and regulatory goals:

• Early-phase trials (Phase I/II): LDTs may be used for exploratory biomarker analysis within a CLIA-certified central lab
• Pivotal trials (Phase III): FDA prefers use of investigational device exemption (IDE)-approved CDx assays to ensure data is suitable for PMA submission

Bridging studies are required if the assay used in trials is later converted into a commercial CDx with a different format or methodology.

Case Example: A NGS-based LDT for EGFR mutation detection was later transitioned into a PMA-approved kit. Bridging required retesting archived specimens from 400 patients to demonstrate analytical equivalence.

Advantages and Limitations

Each pathway has operational and regulatory trade-offs:

For high-impact biomarkers linked to FDA-approved drugs, CDx approval is the preferred route, particularly for drugs requiring labeling stating “must be used with an FDA-approved test.”

Global Regulatory Considerations

In the European Union, the In Vitro Diagnostic Regulation (IVDR) has reduced the scope of LDT exemptions. Most tests with clinical decision impact now require conformity assessment via a Notified Body (Class C or D).

Key references:

• IVDR Article 5(5): LDT exemption conditions
• Annex XIII: Performance evaluation of IVDs

Globally, countries such as Canada, Japan, and Australia also differentiate between LDTs and commercial diagnostics, each with unique premarket review pathways.

Explore international submission guidelines at EMA.

Transitioning from LDT to FDA-Approved CDx

Many developers start with an LDT to support early clinical research, then transition to an FDA-approved CDx. This process includes:

1. Locking down assay protocol and format
2. Performing bridging studies
3. Engaging in Q-sub meetings with FDA
4. Preparing PMA submission (Modules, labeling, manufacturing data)

It’s critical to begin planning the transition during early Phase II trials to ensure alignment with drug development timelines.

Conclusion

LDTs and FDA-approved companion diagnostics serve different roles in the diagnostic development lifecycle. While LDTs offer speed and flexibility, especially in early research, FDA-approved CDx provide regulatory robustness and scalability for commercial deployment. As FDA moves toward stricter oversight of LDTs, stakeholders must evaluate the long-term strategy of their diagnostic approach to ensure regulatory compliance, data credibility, and patient safety.