Special Analysis: Addressing Key Concerns Around the FDA’s Final LDTs Rule

The U.S. Food and Drug Administration’s (FDA’s) new final rule on laboratory-developed tests (LDTs) continues to create more questions than provide answers to clinical labs.

Formally published on May 6, 2024, the rule regulates LDTs as medical devices, akin to in vitro diagnostics (IVDs). The rule carves out some grandfathering provisions for LDTs, including exempting LDTs from premarket submission and records requirements if those tests were created prior to May 6, 2024.

The rule also sets the following five transition phases for labs as they move toward FDA review of LDTs:

• Stage 1 (takes effect May 6, 2025): Requires LDTs to comply with medical device reporting requirements, including correction and removal of tests, and quality system requirements regarding complaint files.
• Stage 2 (takes effect May 6, 2026): Implementation of other IVD requirements not covered in Stage 3, e.g., registration.
• Stage 3 (takes effect May 6, 2027): Compliance with quality system requirements other than for complaints.
• Stage 4 (takes effect November 6, 2027): Premarket review requirements for high-risk LDTs, unless a premarket submission has been received.
• Stage 5 (takes effect May 6, 2028): Expands premarket review requirement compliance to low- and moderate-risk LDTs for which a premarket submission has not been received.

G2 Intelligence and its sibling brand, Today’s Clinical Lab, hosted a webinar on May 30 that addressed the requirements of the rules and offered a Q&A session for the hundreds of attendees. The webinar, “Key Things Labs Need to Know about the FDA’s Final LDTs Rule,” is available on demand at https://www.g2intelligence.com/category/webinars/.

Below are some of the key questions from that session that will apply to many hospital labs, along with the answers provided by our webinar’s expert speakers:

• Julie Ballard, principal at Carrot Clinical, an independent clinical lab consulting firm
• Shannon Bennett, director of regulatory affairs for the Department of Laboratory Medicine and Pathology at Mayo Clinic

These answers are current as of June 21, 2024.

Q: What does a lab do if it wants to implement a new LDT today?

Bennett: Basically, if you had to introduce an LDT today, you would not qualify for the grandfathering enforcement discretion. One thing you’ll need to determine: Is there another enforcement discretion category that your test would qualify for? And then as the phasing milestones come up, you would need to be compliant with the relevant milestones. For example, if you are a laboratory integrated with a healthcare system, and your LDT addressed an unmet need, you would need to meet the year-one milestone and the year-two milestone—so, medical device reporting, registration and listing, etcetera. If the test falls into New York state enforcement discretion, you need to meet year one, two, and three milestones. And if you don’t fall into enforcement discretion, you need to meet year one, two and three, and then submit your test to the FDA through the 510(k), De Novo, or premarket approval application process.

Q: Is a clinical lab now considered a “manufacturer” by the FDA?

Bennett: Yes. That’s the short answer. That comes from the 10 key words that FDA added to the actual regulation. A clinical diagnostic is overseen by the FDA, whether it’s made in a factory or in a laboratory.

Q: How should labs that are used to following CLIA and College of American Pathologists [CAP] governance think about this new FDA rule? Is one side going to take precedence over the others, or are they going to have to work together?

Ballard: I think all three have to work together because whatever happens to this FDA rule, the CLIA regulations and CAP requirements are still going to apply. Assuming that the FDA rule stays in place, labs will now need to comply with FDA requirements. Over time, if we run into conflicting requirements, we’ll have to figure out how to resolve those. But all three entities are definitely going to have to work together. Otherwise, it’s just going to become too chaotic for the labs.

Q: Who will end up inspecting labs regarding LDTs? Will it be the FDA or another group, like CAP?

Bennett: FDA is going to inspect your tests. CAP, Joint Commission, and other organizations that inspect for CLIA will continue to inspect laboratory operations. It is entirely possible that you will be inspected by multiple entities looking at slightly different things.

Q: Will labs be expected to purchase multiple platforms potentially from different vendors because an FDA-approved IVD may be available on certain platforms, as opposed to creating its own LDT to address an unmet need?

Bennett: One of the reasons that laboratories create an LDT is there isn’t an FDA-authorized version of that test on the market. But another reason historically that labs create an LDT is that lab has a particular instrument, there’s an FDA-authorized test, but it would require the lab to purchase another really expensive instrument. So instead, the lab develops an LDT on the instrument it already has that staff is familiar with. With this final rule, having [a certain] instrument within the laboratory will not be a legitimate reason to fall into the unmet needs category. FDA also says things like cost and efficiency are also not legitimate reasons to qualify as unmet need. So, a new LDT would truly need to have some specific medical, scientific, or technical advantage over anything that’s available on the market right now.

Ballard: Based on my understanding of how FDA is defining unmet need, I get the impression that there aren’t going to be very many tests that fall into that category. If a patient and a health system doesn’t have access to a test, there may be some circumstances where they can get it from another lab that’s offering a test for an unmet need, but they have to jump through all these hoops that are not realistic. So realistically, I think the number of tests that fall into the unmet need category will be very small.

Q: Complaints handling is new in the rule. Can you elaborate on what a complaint would be? Does it need to be formal, or could it be a casual conversation?

Bennett: FDA’s expectation is a complaint could be formal or informal. An example I heard is if you know one of your salespeople sits down for dinner with a client, and the client offhandedly mentioned a concern about one of your tests, technically, that’s a complaint. It should be investigated and potentially reported to the FDA. The bottom line is if you receive a complaint through any mechanism, it needs to be investigated. So that is certainly something that you’ll need to be training your staff to be on the lookout for.

Ballard: If you get anything that could be perceived as a complaint, the important thing is to document it. Address the ones that are serious complaints—do an investigation and document any action taken to resolve the complaint. On the other hand, it may be that what you document as a complaint can be resolved easily, but it’s important to have the documentation to show what the resolution is.

Q: Could you provide some clarity regarding the differences between a modified test and a lab-developed test?

Bennett: Strictly speaking, they’re all laboratory-developed tests because the laboratory has either created a test from scratch or taken someone else’s test, tweaked it, and made it their own. In some ways, LDTs don’t exist anymore. There are just IVDs, and the question is whether your IVD falls under enforcement discretion, which includes a test that’s manufactured in a laboratory that addresses an unmet need.

Q: Do LDT laboratories now need to meet ISO 13485 standards since LDTs are going to be considered medical devices?

Bennett: ISO 13485 is basically good manufacturing practices—or GMP—requirements. So, if you are an IVD manufacturer or a kit manufacturer, you need to meet all those requirements. However, if you’re a laboratory developing LDTs, FDA says you only need to meet a subset of those requirements. Those requirements are design controls, purchasing controls, acceptance activities, and corrective and preventative actions. So yes, labs need to meet ISO 13485 requirements, but only a portion of them.

Ballard: Related to this is FDA updated the Quality System Regulation, or QSR, recently. QSR is going to be replaced by QMSR, which stands for Quality Management System Regulation. QMSR references ISO 13485. The new QMSR is supposed to become effective in February 2026. FDA expects a lab to comply with whichever policy is in effect at the time.

Q: The rule says “1976-type tests” are exempt from FDA submission. What are examples of 1976-type LDTs? And who determines whether a test gets the label?

Bennett: The criteria are straightforward. Essentially, it’s a manual LDT that does not use any automation and does not leverage any sort of software. There are limited examples.

Q: Will our lab need to submit to the FDA for approval of an LDT if we alter the reference range as provided in the manufacturer’s published documentation?

Bennett: I’ve fielded several questions along these lines. A similar one was: What if I add a new specimen type, like a body fluid, for example? No one’s going to like this answer: It depends. Some instructions for use in kits are very loosely written, so there might be more latitude to make changes. Some instructions might be very restrictive. And so, if you make changes, you stumble into one of four types of changes that would require FDA submission. Those types include changing the intended use, changing a major reagent, changing methodology or technology, or adversely impacting test performance. If you make a modification that falls in one of those categories, it will require submission to FDA. In any case, if you modify the LDT, it becomes your laboratory’s LDT at that point regardless of whether you [are the original developer of the test]. The question is simply whether that LDT falls within modification enforcement discretion or whether the modification moved the test out of that enforcement discretion.

Q: Do the FDA rules apply to Veterans Affairs labs?

Bennett: No. Any clinical laboratories within the Veterans Health Administration and the Department of Defense are exempted from these LDT regulations.

Q: Is there any indication yet of what this rule means to reagent manufacturers?

Bennett: That’s an interesting question. I don’t think there are direct impacts in the regulation, but I think there could be indirect impacts. So, year three has purchasing control and supplier qualification requirements. It’s possible that a manufacturer has clients who may be pushing for a higher level of quality and consistency from reagents because the related tests are now more highly regulated. So, I think there could be some indirect impacts.

Q: Has New York state’s Clinical Laboratory Evaluation Program [CLEP] made any statement about how they will handle the influx of LDT submissions?

Bennett: I’m not aware of anything. The only thing I know they do have is a disclaimer on their website stating essentially that they will not do à la carte LDT reviews. I wouldn’t be surprised if we get some additional statements from New York about their plan or how this will work. But there’s nothing as of yet. FDA has indicated that they are in close communication with the New York state CLEP program. They are talking, so that’s important.