What Will Red Tape Mean for LDTs?

Let’s begin by defining laboratory-developed tests (LDTs). These are tests created because a commercial test is not currently available. Examples include urine testing for drugs of abuse by mass spectrometry, serum catecholamine testing by high performance liquid chromatography, and blood volatiles analysis by gas chromatography. Modified US Food and Drug Administration (FDA) approved tests to fill an unmet clinical need are also classed as LDTs, for example, body fluid chemistries (amylase in peritoneal fluid) are LDTs because the test’s FDA approved sample, serum/plasma, is modified to analyze a different fluid (peritoneal fluid, in this case). Also, many tests performed by clinical laboratories are LDTs, including infectious disease testing, chromatography, molecular diagnostics, and even point-of-care testing when a device is used outside manufacturer claims or off-label from the package insert. The list is seemingly endless!

Because these tests are developed in the lab, does not mean that they are immune to the scrutiny of the regulators, though, and changes to the regulatory process in the US are afoot, which some argue, could stifle innovation and even access to much needed tests.

The 1976 medical device amendments to the Federal Food, Drug, and Cosmetic Act, gives the FDA the authority to regulate all laboratory tests, regardless of whether they are commercially distributed or developed by a laboratory. According to the Act, the FDA must ensure that in vitro diagnostic devices are safe, effective, and perform as claimed for their intended use, so patients are not harmed. So far, the FDA has used enforcement discretion towards LDTs by not enforcing some or all applicable laws and regulations. LDTs are also subject to quality regulations under the US Centers for Medicare and Medicaid Services (CMS) Clinical Laboratory Improvement Amendments of 1988 (CLIA) as high complexity tests.

Recently, however, the FDA has announced that it will begin regulating LDTs much like commercially-marketed diagnostic tests (1,2). How will this work? Laboratories creating LDTs will need to submit the test performance claims to independent premarket review. They must also assure the test provides clinically meaningful results (clinical validation), adhere to quality system requirements in production, and be subject to post-market reporting and surveillance of test incidents. This won’t happen immediately, though. The FDA proposes to start with those tests presenting the greatest risk to public safety while continuing enforcement discretion for some low risk LDTs.

This change in FDA guidance poses a number of operational and practical issues for clinical laboratories. Having two regulatory oversight agencies (FDA and CMS) with overlap in their requirements will be confusing. Manufacturers have regulatory affairs departments devoted to handling the requirements of test approval. However, the rigorous processes of FDA submission, quality system regulations and medical device reporting are entirely new concepts for clinical laboratories and they will require additional staff resources and training. Laboratories will face additional expenses to conduct the studies required for clinical utility of the test as well as filing fees for review and ongoing device taxes imposed once the LDTs are approved.

Seeking FDA approval will also impose delays and disruption in clinical care. And, we’ll need longer lead times to conduct the studies required for submission. Indeed, some labs may even be unwilling to submit their LDTs for review because of the added expense and resources required to meet this change in FDA guidance. This will lead to possible discontinuation of some currently available LDTs and risk limiting patient access to tests. And, there is uncertainty over how FDA and CMS will interact once the regulations are imposed, and how private accreditation organizations will need to change their inspection process.

The FDA proposes initial enforcement for high-risk tests with a phase-in of the regulations over several years. How risk will be decided for specific tests and whether labs will have to stop conducting LDTs while going through FDA review is not clear at this time. Modifications of FDA-approved tests and whether labs will need to submit them as a new LDT is also not clear. There are currently many unanswered questions.

I believe that these proposed FDA changes, while intended to enhance LDT quality, may actually have the opposite outcome. Increased costs could prevent labs from developing new LDTs and stifle future development. Increased regulations could lead to removal of currently offered LDTs from the market. Limited FDA staff and resources could delay review of pending submissions given the flood of new submissions from clinical laboratories. Dual systems of oversight from FDA and CMS with overlapping requirements and different viewpoints could confuse the market and further discourage new test development. Most importantly, the increased oversight could interfere with current physician-laboratory director relationship that fosters LDT development and professional test result interpretations within an institution. The future impact of this change in regulatory approach feels quite overwhelming.

Recent discussion at the annual 2015 AACC meeting in Atlanta were promising, however. A working group of the FDA and CMS has been formed to streamline the LDT review process and reduce agency overlap. In addition, the FDA announced its flexibility and openness to publicly discussing these issues and working through the challenges of the proposed changes with the clinical laboratories and diagnostic manufacturers. I have no doubt that the entire clinical laboratory industry will look forward to these discussions over the next several months and it will certainly be interesting to see what the overall impact these changes will have on laboratories and, importantly, on patient care.