On July 31, 2014, the Food and Drug Administration provided Congress a 60-day notice of the agency’s intent to issue guidance on the regulation of laboratory developed tests (LDTs), previously unregulated by FDA. On October 3, 2014, FDA published a notice in the Federal Register announcing the release of the draft guidance, “Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs).” The draft guidance outlines FDA’s priorities for enforcing premarket and postmarket requirements for LDTs and the process by which the agency intends to phase in enforcement of FDA regulatory requirements. The draft also provides appendices that summarize the LDT oversight framework and offers a user-friendly question and answer discussion.

This Bulletin highlights some of the key points of the draft guidance, focusing on the proposed regulatory framework. To focus our discussion on the new developments, we will not describe the regulatory history of LTDs, previously referred to as “home brew” or “in-house devices.” In addition, we will not summarize the draft’s review of the evolution of LDT technology or the gap in regulatory oversight of LDTs. 

I. What is an LDT?

As background, an LDT is a subset of an in vitro diagnostic device (IVD). Specifically, an LDT is intended for clinical use and is designed, manufactured, and used within a single laboratory. A single laboratory refers to a facility with a single CLIA certificate. FDA offers the following example of an LTD:

A laboratory uses peer reviewed articles to guide development of a new diagnostic device. The laboratory uses general purpose reagents and analyte specific reagents combined with general laboratory instruments and develops a testing protocol, that together constitute a test system which is then verified and validated within the laboratory. Once validated this device is used by the laboratory to provide clinical diagnostic results.

II. Overview of Draft Guidance 

  • The draft guidance addresses the following topics: 
  1. FDA no longer intends to exercise enforcement discretion towards all LDTs, but it will take a risk-based, phased-in approach
  2. Notification to FDA of LDTs manufactured by a laboratory
  3. Establishment Registration and Product Listing
  4. Medical Device Reporting Requirements for LDTs
  5. Continued enforcement discretion with respect to premarket review requirements for low-risk LDTs, “Traditional LDTs,” LDTs used for rare diseases, and “LDTs for Unmet Needs”
  6. Risk-based, phased-in approach to enforcing the premarket review requirements for other high-risk and moderate risk LDTs
  7. Use of clinical literature to support a demonstration of clinical validity, which FDA expects would reduce the need for additional clinical studies to show clinical validity for LDTs
  8. Facilitation of third-party review for many moderate-risk LDTs
  9. Phased-in approach to enforcing the Quality System Regulations
  • The draft guidance also clarifies that: 
  1. Devices that are designed or manufactured completely, or partly, outside of a laboratory which offers and uses them are not considered LDTs 
  2. FDA recognizes that a wide range of risks associated with the large variety of LDTs exist and, therefore, a risk-based approach to regulatory oversight of LDTs is appropriate and necessary to protect patient safety

III. Risk-Based Classification

  • As noted, FDA will take a risk-based approach to regulatory oversight of LTDs.
  • FDA finds of particular concern the following attributes of modern LDTs: 1) manufactured with components that are not legally marketed for clinical use; 2) offered beyond local populations and manufactured in high volume; 3) used widely to screen for common diseases rather than rare diseases; 4) used to direct critical treatment decisions; and 5) highly complex. 
  • Using the existing Class I-III regulatory system for medical devices, FDA will evaluate the risk of an LDT by considering several factors, such as: 1) whether the device is intended for use in high-risk disease/conditions or patient populations; 2) whether the device is used for screening or diagnosis; 3) the nature of the clinical decision that will be made based on the test result; 4) whether a physician/pathologist would have other information (in addition to the LDT result) about the patient to assist in making a clinical decision; 5) alternative diagnostic and treatment options available to the patient; 6) the potential consequences/impact of erroneous results; and 7) the number and type of adverse events associated with the device. FDA plans to issue additional draft guidance to describe the classifications within 18 months of the guidance’s finalization.

IV. LDT Framework 

  • FDA will continue to exercise enforcement discretion for all applicable regulatory requirements for LDTs used solely for forensic (law enforcement) purposes and certain LDTs for transplantation when used in CLIA-certified, high-complexity histocompatibility laboratories for transplantation.
  • For the following types of LDTs, FDA will continue to exercise enforcement discretion for applicable premarket review requirements (i.e., 510(k) premarket notification) and quality systems requirements: 1) low-risk Class I devices; 2) LDTs for rare diseases and “traditional LDTs”; and 3) LDTs for unmet needs when no FDA-approved or cleared equivalent device is available. However, FDA will enforce (i.e., no application of enforcement discretion) other applicable regulatory requirements, including establishment registration, device listing, and adverse event reporting. 
  • For Class II or III LDTs, FDA will enforce applicable regulatory requirements, including establishment registration and product listing (with the option instead for an LDT manufacturer to provide notification), adverse event reporting, premarket review, and quality system requirements. The marketing submission deadlines will depend on whether the LDT is Class II (moderate-risk) or Class III (high-risk). FDA notes that, for many moderate risk LDTs a third-party review might be possible. For Class III LDTs, a Premarket Approval Application will likely be required.

V. Timeline

  • LDT manufacturers should notify FDA six months after the guidance becomes final if they are developing LDTs. In addition, firms must begin to report significant adverse events to the agency. 
  • FDA plans to implement a phase-in enforcement of premarket review requirements for relevant LDTs over an extended period of time based on risk and agency resources. This approach will begin twelve months after the guidance becomes final, focusing on the highest-risk LDTs.

VI. Medical Device Reporting

  • With limited exception, for certain LDTs (such as those in the forensic area), FDA intends to require MDR compliance for laboratories manufacturing LDTs. The agency noted that, because “many of these devices have not undergone premarket review,” such reporting is “particularly important.”
  • As a result, FDA reserves the right to take enforcement action against LDT companies for failure to comply with MDR requirements beginning six months following the publication of the guidance’s finalization. 
  • The agency discusses the notification and MDR requirements in more detail in a companion guidance document, “FDA Notification and Medical Device Reporting for Laboratory Developed Tests.”

VII. Notice

  • With some exceptions, FDA will continue to exercise enforcement discretion with respect to establishment registration and product listing requirements for LDTs currently on the market, as well as new LDTs on the market within six months after publication of the final LDT framework guidance document, provided that laboratories notify FDA that they are manufacturing LDTs, only manufacture or produce LDTs, and provide basic information regarding each of these LDTs.
  • Notification is expected to occur once for each LDT, although if significant changes are made to an LDT, additional notification should be provided.