In the regulatory arena, a few words can make a world of difference. Back in April, the US Food and Drug Administration (FDA) released its much anticipated final rule on laboratory-developed tests (LDTs), adding a single sentence to the existing regulations. The rules now state that so-called ‘in vitro diagnostic products’ (IVDs) are medical devices – “including when the manufacturer… is a laboratory”.
Those words ignited a furious backlash and prompted the American Clinical Laboratory Association (ACLA) to file a lawsuit to challenge the rule. Why, then, does the FDA’s tweak have such power?
By explicitly defining LDTs, including IVDs, as devices under the Federal Food, Drug, and Cosmetic Act (FDCA), the FDA now requires many of them to undergo extensive pre-market review – and postmarket compliance processes – over a four-year phasein period. No wonder many insiders feel the rule change could have an enormous impact on the future of how diagnostics are manufactured. “This could get very serious, but the real effect will not be felt for three or four years,” says Dr Jonathan Genzen, the chief medical officer at ARUP Laboratories. “It will harm innovation. Is it worth going forward with a new test that might not justify the cost when development is becoming more expensive and reimbursement is getting lower?”
The FDA clearly thinks the pain is worth it. Though it declined to be interviewed by Medical Device Developments, the regulator has previously stated that patients and healthcare providers require assurances that any tests they use are safe and effective, but that it currently cannot give these assurances for IVDs without more active oversight. To quote Robert Califf, the FDA commissioner, “a growing number of clinical diagnostic tests are being offered as laboratory-developed tests without assurance that they work. The stakes are getting higher as these tests are increasingly being used to drive treatment decisions.”
External experts make a similar point. “The FDA is concerned that the public health risks associated with LDTs are greater today than they were when the agency initially adopted its enforcement discretion policy for such tests,” says Greg Levine, partner at law firm Ropes and Gray and chair of its global FDA regulatory group. “It claims that, compared to past use of LDTs, today’s LDTs are used more widely, by a more diverse patient population, with an increasing reliance on high-tech instrumentation and software, and more frequently for the purpose of guiding critical healthcare decisions.”
Amid the furore, though, are there signs that the FDA’s rule tweak may ultimately not amount to that much? After all, that headline sentence masks a detailed discussion in the preamble – over 500 pages in its pre-publication form – explaining how the FDA expects laboratories to come to terms with the new requirements. Strikingly, some LDTs are already expected to be in compliance, while others are expected to become so over the next four years. Even stragglers are only likely to come under “enforcement discretion” – implying that there will probably be no great pressure to achieve compliance under the current FDA leadership.
A war of words
To unravel these regulatory complexities, perhaps the best place to start is understanding why the new rules were introduced. Beyond worries around the reliability of LDTs, the FDA’s statements on the issue suggest they were prodded into action by the rising importance of tests in driving treatment decisions. Citing the Centers for Disease Control and Prevention, for instance, the FDA has stated that 70% of medical decisions now depend on laboratory test results.
At the same time, the rules are not dissimilar to the In Vitro Diagnostic Regulation (IVDR), which came into force in the EU in 2022. Importantly, the IVDR also considers LDTs a category of IVD, and provides an overarching regulatory framework that includes tests made and used by healthcare institutions, as well as conventional device manufacturers. Both the US and EU rules emphasise increased regulatory oversight of laboratories. Yet right from the off, opponents of the new rule, including ARUP, believe the FDA is overstepping its bounds.
“The FDA asserts that it has unambiguous authority,” says Genzen. “It claims it was authorised to regulate LDTs under a 1976 act, but actually only in 1992 did it even acknowledge that they knew about LDTs. The new rule does not align well with how people seek medical care.”
Under the so-called ‘unmet needs’ provision, a healthcare system other than the patient’s own might treat that patient, or can test that patient’s specimens. In other words, a cancer patient may need specimens tested by a different hospital.
The new rule could have a big impact on this process if, for instance, a patient is in desperate need of fast results. There is concern that a lack of financial incentives to develop LDTs for unmet needs, coupled with the cost of compliance with pre-market review, might impede the development and delivery of LDTs for unmet needs. Genzen and others believe that the new rule will affect how care can be delivered at the most crucial times. A public statement from ARUP suggests that the FDA simply does not have the staff to support a hundred or thousand-fold increase in regulatory submissions, nor is it likely that such professional expertise could be reasonably hired. The implication is that – contrary to the FDA’s intentions – the rule would lead directly to a reduction of existing and future safe and essential testing.
2.33%
The expected annual growth rate that the US market for IVDs is estimated to experience from 2024 to 2029, resulting in a market volume of US$33.78bn by 2029.
Statista
“The FDA believes that it has the authority to regulate LDTs, and that is the first point of controversy,” Genzen explains. “Many believe that it does not have such a mandate from Congress. The FDA takes its mission of ensuring protection of public health very seriously, but laboratories are already regulated by the Centers for Medicare and Medicaid Services (CMS) under CLIA [Clinical Laboratory Improvement Amendments].”
No less important, Genzen suggests that the Department of Health and Human Services (HHS) could improve transparency itself, with many in the laboratory community arguing for CLIA moderation to improve visibility of LDTs. But the HHS – for reasons that Genzen and others do not understand – has directed for such issues to be handled by the FDA.
Beyond what the FDA legally has the right to demand, meanwhile, there are also questions around that 500- page pre-publication document. “The rule itself is only ten words,” Genzen says, “but the preamble is all about exceptions, and a lot will be subject to FDA discretion. So, the laboratory community faces uncertainty. The final rule shows a lack of understanding of the clinical laboratory community and what it needs, as well as a lack of understanding of how LDTs are offered and how such services work.”
Critics say that the FDA’s apparent lack of understanding of what laboratories need to sustain testing, plus a lack of detail about modifications and changes to automation, mean that labs do not really understand what they can and cannot do.
“If you swap out a piece of equipment, do you need clearance for that modification?” wonders Genzen by way of example. “You need a decision on such things quickly – you can’t wait two years. The FDA must recognise a need to be flexible.”
See you in court?
ARUP is among many in the laboratory community supporting the ACLA’s federal lawsuit, which rests on the assertion that the FDA does not have legal authority from Congress over medical testing services – and that regulating these services is therefore unreasonable.
“The lawsuit raises serious issues under the so-called ‘major questions’ doctrine,” adds Levine. “The FDA’s position will not be helped by the recent Supreme Court decision in Loper Bright, which says that courts no longer need to give deference to agency interpretations of their own legal authorities.”
80,000
The number of LDTs that the FDA estimates are currently in use, with roughly 8,000 new LDTs introduced each year.
FDA
There’s a financial angle here too. Not all laboratories will be able to afford the cost of compliance with FDA regulations. Some labs will therefore stop offering some or all LDTs, and others could go out of business. The concern is that this will limit the availability of testing, particularly for rare diseases.
The FDA, for its part, acknowledges these outcomes, but believes it has struck the right balance by adopting several broader exceptions – especially compared to its originally proposed enforcement discretion phase-out policy.
“The FDA’s view is that it has always had the legal authority to regulate LDTs as IVDs and laboratories that offer LDTs as IVD manufacturers, but is only now choosing to exercise that authority,” says Levine. “This is the key legal question that will have to be worked out in the courts unless Congress steps in and passes legislation clarifying the issue.”
So what happens next? The phase out of enforcement discretion will undoubtedly be highly disruptive and resource-intensive for both laboratories and the FDA. The regulators may well be underestimating the degree of disruption, and overestimating its ability to handle the influx of product applications. Much depends, however, on the upcoming election.
“If the White House changes hands, we may well see the FDA reverse course,” says Levine. “Interestingly, the Supreme Court said one reason that the courts shouldn’t owe deference to administrative agencies is that administrative agencies frequently change their legal interpretations when political control of the executive branch changes hands.”
Currently, there is a strong likelihood that’s exactly what happens if Donald Trump prevails in November.
Whatever the electoral outcome, at any rate, it seems clear that a proper public conversation about the US’s ideal regulatory framework still needs to happen. For Genzen and others, a mix of the best of FDA and CLIA-oriented rules would be the right outcome, but the nature of the debate has not fostered much collaboration.
For now, the FDA seems to have gone as far as it is willing to go voluntarily, and is unlikely to back off from its position unless forced to in court. As so often in the US, then, all eyes are on the judiciary.
