Current guidelines use an “all or nothing” approach to modifying in vitro diagnostic (IVD) devices, which fails to reflect real-world situations in laboratories. No agreed-upon mechanisms exist to deem a modification as minor or insignificant or to verify its impact on accuracy, safety, or effectiveness, an opinion paper in Clinical Chemistry concludes. The authors—Jenna Rychert, Julio C. Delgado, and Jonathan R. Genzen—suggest that CLIA quality system regulations (QSR) in conjunction with federal guidance would offer more flexibility to IVD modifications while adequately addressing test safety and effectiveness.
The U.S. Food and Drug Administration (FDA) regulates IVDs; CLIA allows for modifications to FDA approved/cleared tests used for clinical purposes. “Any modification of an FDA test re-categorizes it as high complexity, which requires the laboratory to meet the personnel, proficiency testing, and quality requirements of high complexity testing,” wrote the editorialists, who all work at ARUP Laboratories in Salt Lake City.
Premarket notifications are necessary if changes affect safety or effectiveness in a “major” or “significant” way. FDA, however, has acknowledged the subjectivity of these terms, clarifying in further guidance that not all modifications require premarket submission. CLIA QSR allows manufacturers to evaluate minor or nonsignificant modifications without FDA involvement. “These regulations require the manufacturer to review, approve, and document any changes to device design and production and obligate that manufacturer to validate any process modification that results in a change to the device specifications,” explained the editorialists.
The U.S. Centers for Medicare and Medicaid Services (CMS) in the meantime advises that any change to an FDA-approved or cleared assay is considered a modification, regardless of whether it is major or minor, significant or nonsignificant, Rychert, the paper’s lead author, told CLN Stat.
Though similarities exist among quality system regulations, no mutually agreed upon mechanisms exist for labs to verify and document that a modification does not alter an assay’s performance characteristics or intended use. “If there were, the lab could continue to treat the assay as FDA cleared/approved,” Rychert said.
What constitutes a “modification” is also subject to debate, the editorialists noted, citing examples that address specimen handling, packaging, and materials. What should labs do when manufacturer instructions on instruments, computer hardware, software, or firmware become outdated? If a newer technology is needed to conduct a fluorescent antibody test, for example, would switching out a 100-watt mercury lamp for a microscope with an LED light source constitute a “significant” change?
“Examples such as this of incremental improvements in technology that a manufacturer would be unlikely to go back to the FDA to obtain a new premarket notification are particularly problematic as it puts the clinical laboratory in a very difficult position,” according to Rychert, Delgado, and Genzen.
Clinical tests may gain additional uses as care advances quicker than FDA’s approval process. The U.S. Centers for Disease Control and Prevention (CDC), for example, advises that labs use FDA-approved HIV nucleic acid tests to confirm acute infection. Currently, FDA has only approved qualitative RNA tests for this purpose. “This is despite the fact that there are multiple quantitative HIV RNA tests on the market with sensitivity and specificity as good or better than the qualitative alternatives,” some of which have been approved outside of the United States for HIV diagnosis, the editorialists pointed out.
Many labs only offer quantitative HIV tests, despite CDC’s recommendations. Clinicians in turn, end up using the quantitative test instead of the qualitative test. In the editorialists’ view, this represents a modification of a quantitative HIV viral load test from its approved intended use, raising questions about labs’ regulatory risk in using these tests.
For minor changes, CLIA QSR would suffice in maintaining a test’s safety and efficacy. “This more nuanced approach, in addition to more robust guidance from CMS, would be a great benefit to the clinical laboratory community, since it would reduce the regulatory uncertainty that comes with modifying an FDA cleared/approved test,” suggested Rychert, Delgado, and Genzen.