In our prior posting, we provided a brief overview of the notification and adverse event reporting requirements that will apply to the vast majority of a subset of in vitro diagnostic devices known as Laboratory Developed Tests (LDTs), most likely in the not so distant future. These requirements were detailed in the draft guidance documents published on October 3 of this year, outlining the agency’s proposed plan to begin actively regulating firms that produce LDTs.
The draft guidance documents may be found here: Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories: Framework for Oversight of Laboratory Developed Tests (LDTs); and here Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories: FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs).
This posting provides an overview of the remainder of the regulatory controls outlined in these guidance documents.
PREMARKET REVIEW AND QUALITY SYSTEM REGULATION
FDA will begin applying various levels of additional requirements to LDTs based on the agency’s view of the amount of risk posed by the test. These additional controls will include, among others, premarket review and compliance with manufacturing quality controls found in the Quality System Regulation (QSR). These requirements will apply to both LDTs that are currently in clinical use and to those that a laboratory intends to introduce in the future. The draft guidance indicates that the agency will establish three classes of LDTs and apply varying levels of premarket scrutiny and QSR compliance to each according to the risk they present.
- Lowest Level of Scrutiny: No Premarket Review and No QSR Requirements
The lowest level of premarket scrutiny and QSR compliance will be applied to devices considered to be of the lowest risk. These will include “Traditional LDTs.” “LDTs Used for Rare Diseases,” and “LDTs for Unmet Needs.” While notification and MDR requirements still apply, FDA intends to continue to exercise enforcement discretion regarding premarket review and QSR requirements for LDTs that fit into these categories.
- a) Traditional LDTs
Although the use of the term “Traditional LDTs” may appear promising, the agency defines the term in the guidance in a way that is likely to be far narrower than laboratories’ own definition of the term. As a consequence, many laboratories that believe they are offering traditional LDTs may not in fact be doing so under FDA’s definition and will not be eligible for this exemption from the premarket review and QSR requirements. Under FDA’s definition, only those IVDs intended for clinical use that are designed, manufactured, and used within a single laboratory and are of the type of LDTs that were available when FDA first opted to exercise enforcement discretion for LDTs in 1976 are considered to be “Traditional LDTs.” FDA indicates that it will consider several factors in determining if an LDT meets its definition of a “Traditional LDT.” These factors include:
- Whether the device meets the definition of LDT (a device designed, manufactured and used by a single laboratory);
- Whether the LDT is both manufactured and used by a health care facility laboratory (such as one located in a hospital or clinic) for a patient that is being diagnosed and/or treated at that same health care facility or within the facility’s health care system;
- Whether the LDT is comprised only of components and instruments that are legally marketed for clinical use (e.g., analyte specific reagents, general purpose reagents, and various regulated laboratory instruments); and
- Whether the LDT is interpreted by qualified laboratory professionals, without the use of automated instrumentation or software for interpretation.
When such criteria are ultimately applied, many laboratories that presently believe that they are offering a “Traditional LDT” may, in fact, learn that they are not and face more significant FDA regulatory burdens.
- b) LDTs Used for Rare Diseases
Likewise, the term “LDTs Used for Rare Diseases” is also defined in a way that makes it less inclusive than may initially appear. Rather than basing the definition on the prevalence of a disease, the category is limited to instances where the number of persons that may be tested with the device is fewer than 4,000 per year. If there are more than 4,000 persons a year who would be tested with the LDT, it would not qualify as an “LDT Used for Rare Diseases.” Perhaps a better and more descriptive name than the one chosen by the agency for this category of tests might have been “Rarely Used LDTs.”
- c) LDTs for Unmet Needs
Generally, “LDTs for Unmet Needs” are those used to meet urgent health care needs where there is not a comparable FDA-cleared or approved alternative. FDA has published a number of factors it will use to determine if an LDT should be considered one that is “for unmet needs.” These factors include:
- Whether the device meets the definition of LDT in this guidance (a device designed, manufactured and used by a single laboratory);
- Whether there is no FDA-cleared or approved IVD available for that specific intended use; and
- Whether the LDT is both manufactured and used by a health care facility laboratory (such as one located in a hospital or clinic) for a patient that is being diagnosed and/or treated at that same health care facility or within that facility’s health care system.
- Highest-Risk LDTs: Highest Level of Scrutiny
LDT’s presenting the most risk (high-risk) will be considered Class III medical devices and will be subject to the highest level of regulatory control. The premarket review requirements for these LDTs will begin twelve months after the guidance is finalized. FDA considers the highest risk LDTs to include LDTs with the same intended use as a cleared or approved companion diagnostic (i.e., those that provide essential information for the safe and effective use of a corresponding therapeutic product), LDTs with the same intended use as an FDA-approved Class III medical device; and certain LDTs for determining the safety or efficacy of blood or blood products. In most instances, these LDTs generally will require a Premarket Approval Application (PMA) and may remain on the market during the twelve month period and during the pendency of their PMA (provided it is filed within the initial twelve month period following the publication of the finalized guidance). Enforcement of the premarket review requirement for other high-risk LDTs will be phased-in over four years after finalization of the guidance.
- Moderate-Risk LDTs: Moderate Level of Scrutiny
Once FDA has addressed the highest-risk Class III LDTs, it will turn to the enforcement of regulatory controls for moderate-risk LDTs which will be considered to be Class II devices by the agency. FDA has yet to identify which types of LDTs will fit into this category. Presumably, the information gathered as laboratories begin complying with the notification requirement will assist the agency in making this determination and the agency has announced that it will issue a guidance to describe what it considers to be Class I, Class II and Class III devices within two years after the guidance is finalized. Beginning five years after the guidance is finalized and continuing over the four subsequent years, FDA intends to begin enforcing the premarket review process for these moderate-risk LDTs and, in most instances, will require premarket notification (510(k) clearance) for their continued marketing.
- QSR Compliance for High-Risk and Moderate-Risk LDTs
Compliance with the QSR will be required for both high-risk and moderate-risk LDTs. The QSR sets forth the requirements for the methods used in, and the facilities and controls used for, the design, manufacture, packaging, storage, and installation of medical devices and also includes system requirements in areas of concern to all manufacturers of finished devices. According to the draft guidance, FDA will continue to exercise its enforcement discretion with respect to QSR compliance for LDT manufacturers of moderate-risk devices until the time that the LDT is the subject of a cleared 510(k). For high-risk LDTs that require a PMA, enforcement discretion will end at the time that the PMA is submitted to the agency for review and approval.
The trigger for when FDA will begin enforcing controls is upon the publication of the final versions of these draft guidance documents. Potentially, this could occur as soon as April 2015. For some laboratories, the shift from operating under FDA’s enforcement discretion to being fully-regulated as a medical device manufacturer is sure to be a significant and difficult challenge. Making such a change will require these laboratories to consider, plan for, and dedicate resources to achieve compliance with FDA requirements. Even for established medical device companies, doing so is no small effort. The key to success for these laboratories will be to begin assessing how FDA’s proposed requirements will apply to their LDTs now, the burdens that they will assume, and to establish a plan to be in compliance before FDA’s enforcement discretion comes to an end.
Until such time, however, FDA is accepting comments regarding these proposed guidances from members of the public. Accordingly, firms have an opportunity to make their voices heard before FDA’s regulatory scheme comes into effect. If you believe that your own organization will be unduly burdened by this proposed regulatory scheme, we would very much encourage you to have your say while there is still a chance that you can make a difference.
 21 C.F.R. Part 820.