On July 31, 2014, in accordance with Section 1143 of the Food and Drug Administration Safety and Innovation Act (FDASIA), FDA notified Congress of its intent to issue two draft guidance documents regarding oversight of laboratory developed tests (LDTs). FDA, Notification to Congress, July 31, 2014. The two draft guidance documents are entitled “Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)” (the Framework Guidance) and “FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs)” (the Notification Guidance) – the guidances are available via the same link as the notice to Congress. On the same day, FDA rejected the Washington Legal Foundation’s citizen petition challenging FDA’s authority to regulate LDTs. Brushing aside WLF’s arguments, FDA unequivocally stated it could regulate LDTs as devices and do so through guidance documents, not rulemaking.
At long last, we now know how FDA intends to regulate LDTs – and it’s not pretty. Of course we will have a much more detailed analysis of the draft guidance documents once we have had time to fully digest these documents, but for now we wanted to share a high-level summary.
The Framework Guidance
The Framework Guidance defines an LDT as “an IVD that is intended for clinical use and designed, manufactured and used within a single lab.” Framework Guidance at 4. FDA also identifies a number of laboratory tests that have been considered by industry to be LDTs in the past, but FDA believes are in fact IVDs. Thus, FDA simultaneously answers the question of what it considers to be an LDT and then rendered the answer moot by saying that it will handle all of these tests the same way.
According to the Framework Guidance, FDA plans to take a risk-based approach to regulating LDTs. This means that there will be three groups of LDTs: LDTs subject to full enforcement discretion; LDTs subject to partial enforcement discretion; and LDTs subject to full FDA regulation.
FDA plans to continue to exercise enforcement discretion with respect to LDTs that are used solely for forensic (law enforcement) purposes, and certain LDTs for transplantation when used in CLIA-certified, high-complexity histocompatibility laboratories.
FDA plans to exercise enforcement discretion with respect to compliance with premarket submission and quality system requirements for the second group of LDTs, but these LDTs will be required to register and list with FDA (or provide Notification – discussed below) and report adverse events. The LDTs falling into this second category are:
- Low-risk LDTs, class I devices;
- LDTs for rare diseases\“Traditional LDTs”; and
- LDTs for Unmet Needs.
Low-risk LDTs are those that are classified as a class I medical device.
An LDT for a rare disease will follow the definition of a Humanitarian Use Device (HUD) in 21 C.F.R. § 814.3(n). To qualify under this definition, the laboratory will have to perform less than 4,000 tests per year, which seems unrealistic. A therapeutic device can qualify as a HUD if it is intended for a disease or condition that “affects or is manifested in fewer than 4,000 individuals in the United States per year”. However, a diagnostic test qualifies only if fewer than 4,000 patients a year would be tested with the device. Thus, the exemption is not truly for “rare diseases,” but for “rarely performed tests.” For example, a recent study published in the New England Journal of Medicine just recommended testing for the “bubble boy” disease because if treated within 3.5 months of birth, it could save the child’s life. This disease affects only 1 in 100,000 newborns (although recent reports suggest it may be slightly higher at 1 in 50,000 newborns), making it very rare. But because testing is recommended at birth to identify the genetic mutation (rather than waiting until an individual is symptomatic) over 4,000 tests will be performed, this test would not be deemed to be “rare” for the Framework Guidance.
Traditional LDTs are “IVD devices that reflect the types of LDT[s] available when FDA began its policy of generally exercising enforcement discretion over LDTs in 1976” – essentially the preamendment device equivalent. The Framework Guidance identifies a number of factors that FDA will consider when determining if an LDT qualifies as a “Traditional LDT,” including, whether the LDT meets the definition of an LDT set out in the Framework Guidance, whether the LDT is manufactured and used at a single health care facility for a patient that is being treated in the same healthcare facility or healthcare system, whether the LDT is comprised of only legally marketed components (e.g., no RUO or IUO components), and whether the LDT is interpreted by a qualified healthcare professional, without use of software or automated instrumentation. These factors will limit the vitality of this category for many novel tests. It is not clear how or if FDA will make the determination as to what constitutes a “Traditional LDT,” or if FDA will rely on laboratories to self identify.
Finally, “LDTs for Unmet Needs” are LDTs for which there is no FDA-approved or cleared equivalent device available. Similarly to “Traditional LDTs,” the guidance lists several factors FDA will consider when determining whether an LDT qualifies as being for an unmet medical need. One such factor is “whether there is [a] FDA cleared or approved IVD available for that specific intended use.” Clarity regarding how FDA will define “specific intended use” will certainly be needed before this guidance becomes final. For example, is a sequencing test for a specific mutation the same intended use as a test system that is cleared for genetic sequencing generally, or if the LDT can identify additional mutations?
The last group of LDTs includes those high and moderate-risk tests for which FDA intends to fully regulate. The highest risk LDTs are defined in the draft guidance as: (1) LDTs with the same intended use as a cleared or approved companion diagnostic; (2) LDTs with the same intended use as an FDA-approved class III device; and (3) certain LDTs for determining safety and effectiveness of blood or blood products. Other high-risk LDTs will include those test classified as class III devices. Moderate-risk LDTs are those that are classified as class II devices. These LDTs will be required to submit and gain clearance or approval, as applicable.
The timing of these new regulatory requirements will be phased in, according to the Framework Guidance. All LDTs in the second and third groups, will be required to register and list with (or notify) FDA within 6 months of the guidance being finalized. Also, 6 months after the guidance is finalized, laboratories will need to begin reporting adverse events for these same LDTs. Thus, labs will need to develop SOPs for evaluating potential Medical Device Reports. With regard to premarket review, the high-risk LDTs will be required to start submitting premarket submissions 12 months after the guidance is finalized and will be phased-in over the following four years. Then, beginning in year 5, moderate-risk LDTs will be required to submit premarket submissions. Laboratories will be required to comply with the applicable sections of the Quality System Regulation at the time their PMA is submitted or 510(k) cleared. Interestingly, the Framework Guidance indicates that “[high-risk] devices would remain on the market during review and FDA’s consideration of applications,” but there is no corresponding statement with respect to moderate-risk devices – we fully expect that this omission is an oversight, and will need to be clarified before issuance of the final guidance. Id. at 12. While the Framework Guidance focuses on the initial premarket approval or clearance that a test will require, the concept of changes to cleared or approved LDTs gets very little attention.
It is also worth noting that the Framework Guidance does not just discuss evaluating the safety and effectiveness of LDTs as part of the new regulatory framework, but also clinical validity. Clarification regarding how clinical validity will be demonstrated as part of the PMA and 510(k) process will be needed before this guidance is finalized. Further, the Framework Guidance indicates that when the clinical validity of an LDT has been established in published literature, such literature may be used in the premarket submission for the test. However, FDA’s current standards for IVDs do not often allow for the use of literature alone to demonstrate safety and effectiveness or substantial equivalence. Thus, although the Framework Guidance states that literature may be used in a premarket submission, it is not clear whether literature alone will be sufficient to obtain clearance or approval.
FDA intends to issue guidance to describe what the Agency considers to be class I, II and III devices with respect to LDTs within twenty-four months following finalization of the guidance. In addition, during a briefing with industry regarding the draft guidances, Dr. Jeffrey Shuren, Director of CDRH, stated that CDRH will provide additional clarification regarding Quality System compliance for laboratories and the intersection between FDA regulatory requirements and CLIA.
In order to accomplish these lofty goals for regulation of LDTs, CDRH intends to employ the third-party review program to aid in reviewing new LDT 510(k) submissions. We question the practicality of this plan given the low adoption rate for the current third-party review program. More generally, it is not clear where the resources will come from for an enormous bolus of additional work. Based on Dr. Shuren’s comments during a media briefing on the guidances, we understand that the third-party review program may expand to include CLIA accrediting entities.
The intent of the Notification Guidance is to explain to laboratories how they go about notifying FDA that they “manufacture, prepare, propagate, compound, or process” LDTs and how to comply with the MDR reporting requirements.
FDA plans to exercise enforcement discretion with regard to establishment registration and listing for all LDTs, provided that laboratories notify FDA of their LDTs within six months after FDA finalizes the Framework Guidance. According to the Notification Guidance, such a notification must include: laboratory name, laboratory contact email address, test name, monthly test volume, intended use, clinical use of test, what is measured or detected (i.e., analyte, measurand, etc.), disease/condition for which the diagnostic device is indicated, patient population, whether the patient population includes pediatrics, sample type, test method, whether the test is a modification of an FDA cleared/approved test, and if so, what modifications were made. There will be no user fee associated with notification. Laboratories will not be required to register their establishment and list their LDT with FDA, until the laboratory submits a premarket submission to FDA for the LDT. In sum, it appears to us that the notification to FDA is the first step in FDA’s process to determine what LDTs exist and what level of risk each may pose. It is unclear what FDA will do with the information provided through the notification process, and whether FDA will communicate back to the laboratory what type of LDT it is running (e.g., a Traditional LDT, an LDT for an Unmet Need, etc.), or if FDA will rely on laboratories to self identify their tests.
After a laboratory notifies FDA of its LDT, as described above, FDA will issue the laboratory a notification confirmation number, which the laboratory will use in lieu of an establishment registration number when filing MDRs. In short, the Notification Guidance restates the MDR reporting requirements for medical device manufacturers (or user facilities, as applicable) as being applicable to laboratories with LDTs. Laboratories will also need to develop SOPs to decide what reports are reportable. Based on the experience of IVD manufacturers, making these determinations will often not be easy.
Finally, the Notification Guide indicates that laboratories will be required to comply with the requirements for reporting corrections and removals pursuant to 21 C.F.R. Part 806 just like any other medical device manufacturer.
In conclusion, we believe that these guidances present unsettling questions for the approximately 2,000 laboratories estimated to be affected by these guidance documents, not only with respect to their current LDTs, but to future innovation as well. In addition, the documents do not address the costs that will be incurred. And while FDA talks about the perceived risks associated with LDTs, it essentially ignores the benefits. Thus, the new documents present questions not just for laboratories, but for the entire health care system. These issues, as well as the legality of FDA’s proposed actions, are sure to be the subject of intense debate in the upcoming months.