RUO and IUO requirements and where CLIA fits in

In preparation for the LDT Rule Phase 2 - Part 1 of our series on the US Investigational Device Exemption Regulation (21 CFR 812)

In advance of the FDA’s February 25, 2025 webinar on Investigational Use Only (IUO) Requirements, we wanted to provide a summary of the distinctions between Research Use Only (RUO), Investigational Use Only (IUO), and CLIA/laboratory developed test validation requirements.

Note that this post specifically covers the US requirements around RUO and IUO products does not address the requirements under EU IVDR.

FDA guidance (https://www.fda.gov/media/87374/download) defines Research Use Only (RUO) products as those that are intended exclusively for research purposes. These products are not intended for diagnostic or clinical purposes or to inform patient management. The FDA does not require any particular Quality System or validation requirements for RUO products. RUO products may not be used for medical management of patients in a clinical trial.

Investigational Use Only (IUO) products are intended for use in clinical investigations to gather safety and effectiveness data for FDA approval. The quality system and validation requirements for IUO products are governed by 21 CFR 812. There are three risk levels of investigational device studies described in the regulation:

• Exempt

• Non-significant risk (NSR)

• Significant risk (SR)

Depending on the risk level of the study, some or all of the requirements of 21 CFR 812 need to be followed. For example, for SR studies, the study sponsor needs to submit an Investigational Device Exemption (IDE) application to FDA. FDA needs to approve the IDE before the study can be started. In a future blog post, we will lay out the methodology for determining the risk level of a study.

The Design Control regulations spelled out in 21 CFR 820 are applicable to IUO tests.

The Clinical Laboratory Improvements Amendments (CLIA) do not specify requirements for validation of laboratory developed tests. These requirements can typically be found in College of American Pathology guidelines, through the New York State Department of Health Clinical Laboratory Evaluation Program (NYSDOH CLEP), or through standards from the Clinical Laboratory Standards Institute (CLSI). Importantly, validation of a test through the CLIA, CAP, NYSDOH or CLSI standards is insufficient for the use of the test as an IUO test. 21 CFR 812 requirements must be followed as described above..

This is a complex topic and we intend to have additional blog posts on this topic.