Will the Industry be satisfied with FDA’s First LDT Webinar?

On October 31st, the FDA held its first LDT webinar, following the publication of the controversial proposed LDT rule on September 29th, to explain the definition and scope of LDTs, as well as the details of its jurisdiction. The webinar was highly anticipated because the FDA plans to regulate LDTs and gradually implement the new rule in the near future.

The FDA’s interest in regulating LDTs can be dated back to thirteen years ago, when it noticed that LDTs were developed and manufactured by more and more commercial corporations, rather than hospitals or public health laboratories. These LDTs are often used to assess high-risk but relatively common diseases and conditions, and to inform critical treatment decisions. However, these tests are not performed in the patient’s health care center under the supervision of physicians and pathologists, but in remote commercial laboratories.

All the signs have become such a concern that even thirteen years later, the FDA still spends half of its draft focusing on the explanation of the commercialization trend of LDTs.

The rule may have good intentions, but the reality is alarming. Steve Rusckowski, the CEO of Quest Diagnostics, argued that the FDA’s regulation“will impede innovation, increase costs, delay diagnostics, threaten jobs, and ultimately harm patients.”The American Society of Clinical Laboratories also issued a statement on the same day the FDA proposed its rule, claiming that the FDA’s actions were not in the best interests of U.S. patients or the U.S. healthcare system, and the proposed rule exceeded FDA’s existing authority. The ACLA planned to submit comments urging the FDA to withdraw the rule.

The industry’s opposition is not the only challenge for the FDA. The policy itself has many vague concepts and doubts, so the meeting is more of an occasion for the FDA to clarify the ambiguous aspects and contents of the policy, and to try to address the industry’s concerns through clarifying the scope, manufacturers, phaseout, resources, CLIA, and implementation of the rule.

Moreover, in order to justify its takeover of LDT, the FDA kept emphasizing that LDT is an IVD during the meeting, showing its determination to change the industry.

The FDA’s proposed rule consists of five phases, which will gradually phase out the general enforcement discretion approach to LDTs. This approach is a historical legacy that means the FDA does not currently require LDT laboratories to comply with the FDA’s regulatory requirements for medical devices, such as premarket review, medical device reporting, and device registration and listing. This approach also creates a“back door”for LDTs since the 1976 Medical Device Amendments signed by the President in 1976.

In the next four years, the FDA will enforce the same regulations for LDTs as for all other IVD products. These regulations include medical device reporting, quality system requirements, and premarket review by the FDA. The timeline and content of the phaseout are as follows:

What “goodwill” did the FDA offer to ease the industry’s concerns?

Let’s take a look at the “good intentions” that the FDA showed this time.

First, since the FDA has been claiming the LDT industry has changed since 1976 and that the Medical Device Amendments of 1976 are no longer applicable, the FDA proposed that a general enforcement discretion approach can still be applied to “1976-Type LDTs”, which share some of the following common characteristics: they are manually operated, without automation, and performed by laboratory personnel with specialized expertise; using components legally marketed for clinical use; and designed, manufactured, and used within a single CLIA-certified laboratory that meets the requirements under CLIA for high complexity testing.

Some examples of“1976-Type LDTs”are cytology, hematology, and bacterial infection tests that are done manually without using automation. There are also some tests based on immunobiochemistry, karyotyping, and FISH that could possibly qualify as“1976-Type LDTs”.

Second, regarding clinical trials, the FDA has indicated that it has used the least burdensome approach to evaluate a product’s compliance with premarket requirements. The FDA stated at this webinar that literature evidence is adequate to demonstrate the clinical validity of a device, and that laboratories are not expected to generate additional clinical data. The FDA also suggested the use of available and appropriate literature information. Moreover, the FDA has established a human genetic variant databases for manufacturers to leverage the information in the database and FDA-recognized databases to support the clinical validity of their tests.

Furthermore, the FDA supports the use of Predetermined Change Control Plans (PCCP) on LDTs, which is a process that allows manufacturers to specify in the product’s premarket submission document that how the device will change its functionality in the future through a predetermined plan to maintain its safety and effectiveness, eliminating the need for the manufacturer to spend a great deal of time and effort on submitting a new 510(k) application to the FDA.

Of course, to make this phaseout process smoother, the FDA has also indicated that it will provide additional resources for specific topics, such as guidance on labeling requirements and validation.

What else did the FDA clarify to address concerns?

First, the FDA clarified the use of components and kits that are “Research Use Only” (RUO). This issue is a common concern for many LDT labs, as most of them use RUO reagents at present. Since RUO components and kits can be incorporated into IVD products, the FDA believes that if an IVD product contains RUO components or kits, the IVD product will be treated the same as a test manufactured by a conventional manufacturer. The manufacturer thus needs to ensure that the RUO components meet all proposed LDT rules and quality management requirements. This means that laboratories cannot avoid FDA regulatory requirements by using RUO components and must ensure the overall quality and compliance of their LDTs.

Second, many U.S. laboratories modify FDA-approved products and then commercialize them as LDTs. The FDA made it clear that the definition of manufacturer includes a remanufacturer, which is a person who does any act to a finished device that significantly changes the performance, safety specifications, or intended use. Therefore, even if a laboratory does not manufacture the IVD itself, it will be considered a remanufacturer if it modifies the IVD product to the extent that it significantly alters the product’s performance or safety specifications or intended use. Laboratories can no longer manufacture LDTs by modifying FDA-approved products, but must follow FDA’s proposed rule of submitting premarket review of their modified products.

Third, regarding submission, the FDA estimates that only 5% of LDTs will require a PMA, while the majority will go through De Novo or 510(k). The FDA also has the Breakthrough Device Designation program, which is an accelerated approval pathway.

Some in the industry are worried that LDT approvals will be delayed because the FDA is understaffed. The FDA said it would enhance its third party review program, and seek comment on leveraging existing programs, such as the New York State Department of Health and the Veterans Health Administration.

What is the industry reaction after the meeting?

After the webinar, the FDA’s open comments section is “full” of industry opposition, and several examples were cited in the comments to show the impracticality of the FDA taking over LDTs.

For example, when a lab develops a new test and there is not a single journal article using the lab’s equipment or test, FDA regulation would deprive patients of the opportunity of accurate testing.

Another example is a lab that uses the LDT for substance abuse and prescription drug adherence confirmation. The lab stated that without the LDT method, physicians would not be able to identify the specific drug/compound that a patient tested positive (or negative) for. The FDA only approves immunoassays, which are not specific enough for accurate diagnosis.

Additionally, while the FDA explained many concepts at this meeting, we found that there are still some outstanding issues, such as fees to be paid by manufacturers, investigational devices, labeling requirements for products, and design controls.

Overall, the FDA held this meeting to clarify some of the ambiguities and emphasize the legitimacy of its takeover of LDTs, hoping to gain congressional approval to move forward with strict regulation of LDTs. However, the clinical laboratory industry is still strongly opposed to the FDA’s rule, as it affects their profit. So even if the FDA explains the concept of gradual implementation, the industry will not accept it. Unless the FDA can address the main reason for opposition, which is “proposed rule is curbing innovation in the testing industry,” the clinical laboratory industry will continue to oppose the FDA’s regulation of LDTs.