Jeffrey N. N. Gibbs

The FDA has opened up the documents to comments from the public—and plenty of comments are expected.

On July 31, the Food and Drug Administration (FDA) notified Congress that it intended to issue two draft guidances regulating laboratory-developed tests (LDTs). While the Energy & Commerce Committee House Subcommittee on Health did hold a hearing on September 9, Congress took no steps to block the issuance of the documents. On October 3, 67 days after notifying Congress, FDA published the proposal in the Federal Register.

The documents released on October 3 differed in only two minor respects from the proposals provided to Congress. Reflecting the significance of these documents (and also to avoid conflicts with the holidays), FDA did provide a 120-day comment period, which is longer than usual for guidance documents.

In releasing the draft guidance documents, FDA asked commenters to specifically address certain topics. Even before releasing the documents for comments, FDA had received initial feedback from various parties. Presumably, the areas that FDA highlighted will be ones for which the agency is particularly receptive to modifying its proposal.


The Topics under Discussion

For example, although FDA said that it would exercise “enforcement discretion” (regulatory-speak for not regulate) LDTs for “rare diseases,” the draft guidances invoked the statutory definition, which limits the exception to 4,000 tests per year. (In comparison, the threshold for orphan drugs is 200,000 patients per year in the United States.) This low threshold means that tests qualifying for rare disease status will themselves be rare. FDA therefore asked whether some other criteria should be applied.

FDA also said it would apply enforcement discretion to “traditional LDTs.” FDA is soliciting comments as to whether the test needs to be conducted in the same healthcare system as the one where the patient is treated, which is what the proposal states. Applying this limitation would greatly restrict this category. 

FDA did not propose modifying another limitation on this category, that the test is “comprised only of components and instruments that are legally marketed for clinical use.” Many LDTs use instruments and reagents that are labeled “Research Use Only (RUO).” Strictly construed, this provision would appear to promote a long-desired FDA goal: restricting the purchases of RUO products by labs, since RUO products are not “marketed for clinical use.”

Another topic singled out relates to the phase-in of the Quality System regulation (QSR). FDA has proposed that the labs would need to have QSR-compliant facilities when they submit their premarket application or receive 510(k) clearance. Implementing changes to comply with QSR will be complex and costly. Even traditional IVD manufacturers that have years of experience with the QSRs often struggle in complying. FDA’s question is narrowly framed, focusing on the phase-in time allowed for the highest-risk LDTs. The issue of QSR phase-in—and minimizing conflicts with existing lab requirements under the Clinical Laboratory Improvement Amendments (CLIA)—is a broader issue than the one highlighted by FDA’s question. In a webinar on November 6, FDA noted that some educational period may be needed for labs.


The Lines Are Drawn

Although the official comment period has just begun, some of the battle lines are now clear, as exemplified by the testimony at the September 9 House hearing.

On the one hand, FDA and some groups, such as AdvaMed, the largest organization representing device manufacturers, believe that LDT regulation is essential. They argue that having two parallel systems makes no sense, and that from a patient’s perspective, it does not matter whether the test was sold by a manufacturer or developed by a laboratory. Proponents, including some patient groups, also argue that FDA regulation promotes innovation because competition by LDTs inhibits companies from pursuing FDA approval or clearance for new distributed tests. Put another way, allowing LDTs to go unregulated by FDA results in an uneven playing field that discourages traditional manufacturers. At the House hearing, Jeffrey Shuren, Director of the Center for Devices and Radiological Health, cited an example of a companion diagnostic that faced nine competing LDTs the day it was approved.

Opponents of LDT regulation make precisely that opposite argument: that FDA regulation will stifle innovation. They also argue that concurrent regulation by FDA as device manufacturers and under CLIA as laboratories will result in wasteful, duplicative regulation. They further question the ability of the FDA regulatory regime to accommodate the rapid pace of technological and scientific change. LDTs can be readily modified; cleared and approved tests cannot be substantially changed without a new approval or clearance. Proponents of LDTs assert that the long FDA approval process requires designs to be frozen in place for years, and that LDTs can reflect newer scientific insights, e.g., variants discovered in the years after the commercial test was locked down. Opponents worry about FDA resources, a concern shared by manufacturers.

FDA has also strongly argued that LDTs have been associated with safety problems, and agency oversight is essential to protect patients. During the hearing, FDA was asked to provide to Congress specific examples of harm, and promised to do so. At an October 23 webinar, FDA said it was preparing a formal response to the congressional request for specific examples of public harm. However, the details may be limited; FDA also stated that some of the examples cannot be shared publicly.

Underscoring the radically different narratives, FDA testified at the hearing that LDT regulation would potentially affect a maximum of 6,000 laboratories.  The laboratory representatives disagreed, saying it was 11,000. Dueling numbers mean dueling perspectives over the financial impact of the guidances. By using the guidance document route, instead of going through formal notice and comment rulemaking, FDA bypasses the need to conduct an economic impact assessment. Rulemaking requires economic impact assessments; guidance documents do not. Nevertheless, opponents of the guidance documents are likely to make economic arguments, including that FDA regulation will increase costs in a healthcare system already struggling with high costs. These arguments will likely be advanced not only to FDA, but also to Congress, the Department of Health and Human Services (HHS), and the Office of Management and Budget.

FDA and the laboratories also have radically divergent views on the legality of FDA’s proposal. FDA says it has the statutory authority to regulate laboratories and can proceed via guidance document rather than rulemaking because it has always had the authority to regulate laboratories. The laboratories disagree, saying the FDA’s authorizing statute does not confer power over laboratories and that regulating LDTs is a major substantive change that must go through rulemaking. These legal disputes may well be resolved in court.


The Middle Ground

There is also a middle-ground perspective: FDA regulation is appropriate, but many details need to be resolved. These operational details are hardly trivial, including how to avoid duplication with CLIA and providing much greater clarity over which tests fall into which regulatory category. Laboratories will also want clarification on FDA’s statement that revising FDA-cleared or approved tests in a manner that requires revalidation subjects them to FDA regulation. Laboratories often make modifications to kits bought from vendors. Still, early feedback suggests FDA may garner some qualified support for LDT regulation, contingent upon satisfactorily addressing multiple thorny issues. These include, for example, much greater clarity on how devices will be classified under this multi-tier scheme and when companies will find out which tier they are in, and hence when they need to submit.

FDA, HHS, and other parts of the Administration will need to sift through these competing perspectives. While guidance documents, unlike regulations, do not need to respond to comments, FDA has said it will weigh and evaluate the various views that are expressed. At the September 9 hearing, Dr. Shuren repeatedly emphasized that the agency wants to hear from interested parties on how the program can be improved. He stated, “The issue should not be do we regulate, but rather how we should regulate.” This request for comments recommending improvements in the framework notwithstanding, FDA is likely to receive comments urging no regulation whatsoever.

The concept of LDT regulation has sparked controversy for years. With the release of the draft guidance document, FDA has taken a step toward regulation. Whether FDA’s goal of regulating LDTs will be achieved—or precisely what form that regulation will take—will probably remain unsettled for several years more. The effect of the new Republican Congress remains to be seen as well.

Furthermore, whatever emerges will leave some people unhappy. Dr. Shuren forecast, “[w]hatever we get at the end of the day, someone is not going to be happy because there are so many different perspectives.” Given the contentious history of LDT regulation, Dr. Shuren’s prophecy is very likely to be fulfilled.







































Jeffrey N. Gibbs (jgibbs@hpm.com) is director of Hyman, Phelps & McNamara, P.C.