Decisions by FDA to clear or approve medical devices, including genomic diagnostic tests, for marketing are based on the safety and effectiveness of the product. The Medical Device Amendments of 1976 implemented a three-tier system. Class I devices are common, low-risk devices that are generally exempt from premarket evaluation by the agency. Class II devices are moderate-risk devices that are subject to premarket notification (also known as the 510(k) process), in which the sponsor must demonstrate substantial equivalence of the device to an already marketed product. Class III devices are the most complex and present the highest risk; makers of Class III devices must submit a premarket approval application demonstrating safety and effectiveness and obtain FDA approval prior to marketing.
Initially, genetic tests focused on single genes. The in vitro diagnostics industry was not very interested in developing such tests because they typically constituted a small market with poor reimbursement, according to Leonard. As a result, genetic tests were developed largely by clinical laboratories using standard molecular biology methods. These laboratory-developed tests (LDTs) tended to be based on published genotype-phenotype correlations, were developed using a set of patient and control samples, and usually were produced in small volumes. They were performed by specialists with advanced training and usually required expert interpretation. LDTs generally were and still are developed under the provisions of the Clinical Laboratory Improvement Amendments (CLIA) without clearance or approval from FDA.
Today’s genomic tests are quite different. They often are based on complex testing algorithms that encompass multiple genetic variants, genes, or gene expression patterns and, most recently, whole-exome or whole-genome sequencing, said Leonard. The results are used not only for diagnosis but for the selection of therapies, dosing decisions, prognosis, and detection of residual disease. Tests are increasingly empirical and nontransparent and rely on complex statistical methods. They often require complex software, many incorporate automated interpretation, and their clinical validity is not well understood (Wright and Kroese, 2009). Novel tests are often developed by companies and “licensed” to a laboratory, the volume and types of LDTs have grown significantly, and they are often a mechanism for the market entry of novel tests. A higher proportion come from commercial laboratories and biotechnology companies, and they often do not involve a close relationship between clinicians, pathologists, and patients. Some tests are broadly advertised and aggressively marketed to clinicians. Others are marketed directly to consumers and are available over the Internet with overnight shipping (Meyers, 2011). They can have a national or even international reach.