FDA's Framework for Regulatory Oversight of LDTs

Abstract

The Food and Drug Administration (FDA) defines the term laboratory-developed test (LDT) as an in vitro diagnostic intended for clinical use and designed, manufactured, and used within a single laboratory. In prior years, local laboratories primarily developed LDTs. LDTs were typically used and interpreted directly by physicians and pathologists working within a single institution that was responsible for the patient. In addition, historically, LDTs were manufactured by using components that were generally marketed for clinical use.

Although some laboratories today still manufacture LDTs in this “traditional” manner, the method for laboratory development and manufacturing of LDTs has changed greatly. Some modern LDTs are:

• Manufactured with components that are not generally marketed for clinical use

• Offered beyond local populations and in high volume

• Used to screen for common diseases rather than rare diseases

• Used to direct critical treatment decisions

• Highly complex (e.g., automated interpretation, multisignal devices, use of nontransparent algorithms and/or complex software to generate device results)

The Centers for Medicare & Medicaid Services has regulated laboratories, including those that develop LDTs, under the Clinical Laboratory Improvement Amendments (CLIA) (42 U.S.C. 263a) since 1988. CLIA is responsible for ensuring that laboratory testing is done in an accurate and reliable manner, but it does not address test validation before marketing or assess the clinical validity of an LDT.

The FDA believes that it should modify its policy of enforcement discretion in a risk-based manner to ensure FDA oversight and provide appropriate assurances regarding safety and effectiveness. Hence, on July 31, 2014, the FDA provided Congress with the 60-day notice required by Food and Drug Administration Safety and Innovation Act that it intended to issue draft guidance regarding the oversight of LDTs. The “LDT Packet” that was released contained two draft guidance documents. The primary FDA guidance document, titled “Framework for Oversight of Laboratory Developed Tests (LDTs),” (FDA 2014) provides the bolus of FDA's intentions regarding the proposed regulation of LDTs. The second, titled “FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs),” provides a tutorial on the modified registration and listing requirements (Title 21 CFR Part 807), medical device reporting requirements (Title 21 CFR Part 803), and reports of corrections and removals (Title 21 CFR Part 806) already familiar to in vitro diagnostic manufacturers (Thornton 2014).

Following this 60-day notice, on September 30, 2014, the FDA posted both draft guidances on its website. On October 3, 2014, the FDA published notices in the Federal Register formally announcing their release and the beginning of a 120-day public comment period. This comment period will last until February 2, 2015.

Risk-Based Regulatory Framework

The FDA believes that this risk-based, phased-in approach is appropriate for several reasons.

• Health risks associated with LDTs, as with all in vitro diagnostics, vary with each type of device, and the FDA's regulatory activities should be implemented according to the risk associated with the device.

• A phased-in implementation period is necessary to reduce or remove any unintended and unpredictable consequences immediately, by imposing all applicable requirements.

• Some clinical laboratories may be unfamiliar with FDA regulations, and so a phased-in implementation approach will provide some time for those facilities to learn about the requirements and develop programs to comply with them.

Continued Enforcement Discretion in Full for Certain Categories of LDTs

For the following categories of devices, the FDA does not intend to enforce applicable registration and listing, adverse event reporting, premarket review, or quality system requirements:

• LDTs used solely for forensic (law enforcement) purposes

• LDTs used in CLIA-certified, high-complexity histocompatibility laboratories for transplantation

Notification to FDA of LDTs Manufactured by a Laboratory or Registration and Listing

For laboratories that manufacture, prepare, propagate, compound, assemble, or process LDTs that are an exception to the categories mentioned above and are used with organ, stem cell, and tissue transplantation, the FDA intends to continue enforcement discretion with respect to registration and listing requirements. Laboratories should notify the FDA once for each LDT. If an LDT changes substantially, the laboratory should provide additional notification.

Medical Device Reporting Requirements

Except for the categories of LDTs identified above and certain LDTs used with organ, stem cell, and tissue transplantation, the FDA intends to implement the manufacturer reporting requirements of the Medical Device Reporting (MDR) regulation (21 CFR Part 803, Subpart E) for laboratories manufacturing LDTs. The MDR regulation requires the manufacturer of a medical device to submit reports to the FDA whenever it becomes aware of an incident suggesting that a device they market may have caused or contributed to a death or serious injury or has malfunctioned in a way that would be likely to cause or contribute to a reportable death or serious injury should it recur.

Premarket Review Requirements

The FDA also aims to apply enforcement discretion for applicable premarket review requirements and quality system regulation requirements but enforce other applicable regulatory requirements, including registration and listing and adverse event reporting, for the following (Ropes & Gray, 2014):

• Low-risk LDTs

• LDTs used for rare diseases

• Traditional LDTs

• LDTs for unmet needs (when no FDA-approved or cleared equivalent device is available)

Premarket Review of High-Risk Devices (Class III devices)

The FDA plans to initially focus its enforcement priorities by generally enforcing the premarket review requirements beginning 12 months after this guidance is finalized for the following LDTs (high-risk devices):

• LDTs with the same intended use as a cleared or approved companion diagnostic

• LDTs with the same intended use as an FDA-approved class III medical device

• LDTs for determining the safety or efficacy of blood or blood products

Premarket Review of Moderate-Risk Devices (Class II Devices)

After the review of high-risk (class III) LDTs, premarket review requirements of moderate-risk (class II) LDTs will begin. This means that requirements will begin 5 years after the guidance is finalized and will be phased in over 4 years. Laboratories will have 12 months to submit a premarket application for their LDT if the FDA clears a test in that category.

Quality System Regulation Requirements

The Quality System Regulation (21 CFR Part 820) was developed to set the minimum quality system requirements that medical device manufacturers must implement to ensure that the finished device will be safe and effective and will pose no hazard to patients. Under this enforcement policy, the clinical laboratory manufacturing and using the LDT will be responsible for having in place a quality system that meets the minimum requirements codified in 21 CFR Part 820, either at premarket approval submission (the facility that makes the device must pass an inspection as a condition of premarket approval as a matter of law [21 CFR 814.45(a) (3)]) or before market launch for cleared devices, as applicable.

Conclusion

This article describes the FDA's risk-based framework for LDTs. It is intended to guide clinical laboratories that manufacture LDTs about how the FDA aims to enforce regulations, specifically premarket and postmarket requirements that apply to such laboratories as medical device manufacturers. It is important that those involved in developing, using, and needing the tests all weigh in on these important issues. A few pertinent questions include the following: Are these changes significant enough to warrant a notice of proposed rule-making? Do the guidances clearly define the terms they use? Are LDTs devices, or do they require a new unique category? Do the guidances encourage the innovation patients need while still protecting them?

There is opportunity to comment in both writing and in person. Instructions for comment can be found in the Federal Register at https://www.federalregister.gov/articles/2014/10/03/2014-23596/framework-for-regulatory-oversight-of-laboratory-developed-tests-draft-guidance-for-industry-food.

Note: This is a two-part article. Genetic Alliance's thoughts on the “Framework for Oversight of Laboratory Developed Tests (LDTs)” guidance will be published next month.

References

Thornton

(2014). A brief summary of the regulatory framework proposed by FDA for LDTs. Precision for Medicine. Available at http://www.precisionformedicine.com/wp-content/uploads/2014/08/A-Brief-Summary-of-the-Regulatory-Framework.pdf, accessed August 18, 2014.

Ropes & Gray LLP's FDA Regulatory Practice (2014). United States: FDA releases long-awaited LDT regulatory framework and finalizes companion diagnostics guidance. Available at http://www.mondaq.com/unitedstates/x/333776/Life+Sciences+Biotechnology/FDA+Releases+LongAwaited+LDT+Regulatory+Framework+and+Finalizes+Companion+Diagnostics+Guidance, accessed August 19, 2014.

US Food and Drug Administration (2014). Framework for oversight of laboratory developed tests (LDTs). Available at http://www.fda.gov/downloads/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/UCM407409.pdf, accessed August 18, 2014.