Regulation of Laboratory-Developed Tests in Preventive Oncology: Emerging Needs and Opportunities

Abstract

Cancer predictive or diagnostic assays, offered as Laboratory-Developed Tests (LDTs), have been subject to regulatory authority and enforcement discretion by the US Food and Drug Administration. Many LDTs enter the market without US Food and Drug Administration or any regulatory review. The Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement Amendments focuses on analytic performance, but has limited oversight of the quality or utility of LDTs, including whether patients have been harmed as a result of their use. Increasingly, LDTs for cancer risk or early detection have been marketed directly to consumers, with many LDT developers depicting these tests, requested by patients but ordered by personal or company-associated physicians, as procedures falling under the practice of medicine. This patchwork of regulation and enforcement uncertainty regarding LDTs and public concerns about accuracy of tests given emergency authorization during the COVID-19 pandemic led to the Verifying Accurate Leading-edge IVCT (in vitro clinical test) Development Act of 2021. This pending federal legislation represents an opportunity to harmonize regulatory policies and address growing concerns over quality, utility, and safety of LDTs for cancer genomics, including tests marketed directly to consumers. We review here questions regarding the potential benefits and harms of some cancer-related LDTs for cancer risk and presymptomatic molecular diagnosis, increasingly marketed to oncologists or directly to the worried well. We offer specific proposals to strengthen oversight of the accuracy and clinical utility of cancer genetic testing to ensure public safety.

Laboratory-Developed Test Orders in an Academic Health System

“…30 NGS and genomic testing, particularly for use in oncology and prenatal screening, are often referenced as justifications in support of diagnostic regulatory reform efforts. 31 Ultimately, the potential burden and cost of regulatory reform efforts may have a disproportionate impact on the ability to develop and sustain assays that are not frequently ordered.…”

The potential clinical value of plasma biomarkers in Alzheimer's disease

“…An inherent limitation of LDTs is that they are only designed and validated in one laboratory setting or network; therefore, if used elsewhere under different test conditions, they may produce inconsistent results, meaning that patients may be misclassified. LDTs may need to be more tightly regulated as, in recent years, an increasing number of LDTs from a variety of therapeutic areas have been marketed directly to clinicians and the general public, who may not necessarily understand the limitations of the claims made about this type of test 42 . There are several examples in which incorrect LDT use has resulted in patients being misclassified and either not receiving necessary treatment such as chemotherapy, or undergoing unnecessary treatment including invasive surgery 43 .…”

Laboratory Selection in Germline Genetic Testing: Laboratory Science Matters

“…5 There are many laboratories that offer testing, making selection of an accurate and appropriate genetic test difficult. 6 Federal regulation of genetic testing is complicated and fragmented; oversight is provided by the Centers for Medicare & Medicaid Services (CMS), the FDA, and the Federal Trade Commission (FTC). 4,5 CMS regulates laboratories through the CLIA program.…”