Health care practitioners are more frequently using laboratory developed tests (LDTs) to diagnose and predict the risk of developing a disease, as well as to inform decisions on disease state management such as for cancer, heart disease and diabetes. As practitioners become increasingly reliant on diagnostic tests to guide important treatment decisions, concerns about the efficacy and safety of new LDTs have simultaneously arisen. As a result, regulatory safeguards that can ensure LDTs’ accuracy are warranted in order to protect patients from seeking improper treatments or delaying or forgoing necessary ones. The following includes a description of the FDA’s increased activism towards LDTs, along with a summary on the FDA’s proposed regulatory framework of LDTs.

LDTs in FDA History

The FDA has historically exercised enforcement discretion over LDTs because they were never sold to other laboratories or hospitals. LDTs have typically accounted for a small volume of tests developed by local laboratories that were relatively simple and were intended to diagnose rare diseases or meet the needs of a local patient population. However, modern LDTs are:

• More complex

• Widely used to screen for common high-risk diseases

• Manufactured in high volume by large corporations (who have international reach and offer the test beyond the local patient population)

• Made with components often not legally marketed for clinical usage

• Presenting higher risks similar to other in vitro diagnostics that have been subject to premarket review

In light of the significant shifts in the technology and business practices associated with LDTs, the FDA believes its traditional policy of enforcement discretion towards LDTs is no longer appropriate.

Several working groups have been wary about the quality and performance of contemporary LDTs for almost two decades. For example, the Task Force on Genetic Testing (convened jointly by the National Institutes of Health and the U.S. Department of Energy) issued a report in 1997 stating that “sometimes, genetic tests are introduced before they have been demonstrated to be safe, effective, and useful” and “there is no assurance that every laboratory performing genetic tests for clinical purposes meet high standards.” Further, the FDA has, in fact, highlighted quality control problems with several high-risk LDTs, purporting that some test results were erroneous due to a lack of proper controls and the falsification of data, which could have potentially led to adverse patient outcomes. The FDA has also concluded that regulatory oversight of LDTs under the Clinical Laboratory Improvement Amendments (CLIA) does not address patient safety concerns because CLIA accreditors neither validate these tests prior to marketing nor assess the clinical validity of an LDT.

FDA’s Proposed Regulation of LDTs

In October 2014, the FDA issued a draft guidance proposing a regulatory framework for oversight of LDTs based on the risks to patients if the device were to fail rather than whether the LDTs were created by a conventional manufacturer or a single laboratory. The FDA would rely upon the existing medical device classification system to gauge the risk of an LDT category, evaluating the potential for severe therapeutic consequences brought on by the initiation of unnecessary treatments or a decision to delay or forego treatment altogether for a condition.

Under the FDA’s proposed framework, low-risk LDTs (defined as class I medical devices) and LDTs for rare diseases or unmet medical needs will continue to experience enforcement discretion for applicable premarket review and quality systems requirements. However, the applicants for these devices will be required to comply with registration and listing and adverse event reporting within six months after issuance of the FDA’s final guidance on LDTs. In addition to satisfying the registration, listing, and reporting requirements for low-risk LDTs, moderate-risk (class II) and high-risk (class III) LDTs will also be subject to stricter regulatory oversight than low-risk LDTs. Moderate-risk LDTs will be subject to premarket review requirements (i.e., premarket notification, or 510(k) submissions) within 5-9 years after final guidance is implemented, whereas high-risk LDTs would be subject to premarket review beginning one year after the FDA’s guidance on LDTs is finalized.

The FDA will focus its initial efforts on reviewing LDTs that have identical intended uses as FDA-approved or -cleared companion diagnostics or class III medical devices, as well as LDTs that determine the safety or efficacy of blood or blood products. Instituting the FDA’s proposed guidelines on regulating moderate- and high-risk LDTs will likely have a significant impact on the market for personalized medicine because approximately 11,000 tests developed by 2000 different laboratories are estimated to fall under the FDA’s proposed framework. It is therefore becoming clear that providers of moderate-risk and high-risk LDTs that were once spared from FDA’s scrutiny must now seek FDA approval or clearance.