In vitro diagnostics, or IVDs, have a somewhat unique position among the gamut of products that the Food and Drug Administration (FDA) oversees and regulates on behalf of the U.S. public. IVDs are classified as medical devices and include “reagents, instruments, and systems intended for use in diagnosis, including determining the state of health, through the collection, preparation, and examination of specimens taken from the human body.” Unlike human drug and non-IVD device products, which generally must be authorized for a specific medical use prior to commercialization, IVD products may be sold for certain scientific research studies without FDA authorization, but such IVD products may not be sold for clinical diagnostic use. 

FDA’s 2013 guidance document on the Distribution of In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only – also known as RUO/IUO labeling – emphasizes that “mere placement of an RUO or IUO label on an IVD product does not render the device exempt from otherwise applicable…requirements. FDA may determine that the device is intended for use in clinical diagnosis based on other evidence, including how the device is marketed.” The guidance then provides a high-level summary of what constitutes appropriate labeling and distribution practices for RUO/IUO IVD products, as well as examples of practices that would be considered “inconsistent with” RUO/IUO designations for such products. Inconsistent practices include things like soliciting business from clinical laboratories engaged in diagnostic testing; disseminating instructional or promotional labeling that incorporates clinical performance claims; and offering specialized technical support relating to clinical applications of the IVD product. Such practices are “inconsistent” with RUO/IUO labeling because they are evidence of the manufacturer’s intent to have the product used in one or more non-research, clinical uses to diagnose patient diseases or conditions.

Notwithstanding that the RUO/IUO guidance document is over a decade old, there are few agency actions in this space to give further clarity to IVD developer stakeholders. A new FDA warning letter – issued on March 21, 2024 and posted publicly in the agency’s database on April 2, 2024 – provides a deep dive into many of the issues discussed in the RUO that/IUO guidance, as well as additional examples of objective evidence FDA used to determine that the manufacturer intended that its unauthorized IVD be used for clinical diagnostic purposes. Evidence collected and cited by the agency in this recent warning letter included:

• “Distribution records and a customer list” collected during FDA’s inspection of the company’s manufacturing facility indicating that the products were sold and shipped to clinical laboratories that perform diagnostic testing.
• A company-issued “customer notification” in 2021 to a Texas hospital stating, among other things, that the company was taking steps “to not impact your laboratory workflow.” 
• Product descriptions on the company’s website that, among other things, claimed the IVD “enables tumor profiling studies of colorectal cancer specimens” and that users could “[d]etect more than 80 clinically relevant variants across BRAF, EGFR, KRAS, NRAS, and PIK3CA.”
• Customer testimonials on the company’s website that indicated the IVD was being used for clinical diagnostic use, as well as the following statement from the CEO: “We are proud to have the [IVD] chosen to be an integral part of one of the top newborn screening programs in the country…” 

Critically, these and other pieces of evidence that FDA gathered regarding the company’s unauthorized IVD belied the company’s disclaimer that the product was not intended for diagnostic uses. The agency clearly points out in the warning letter that although the test was labeled with the statement “For Research Use Only. Not for use in diagnostic procedures” – and similar language also appeared on the company’s website – such disclaimers were ineffective to override the totality of the objective evidence collected about the test and its intended use.

As FDA takes a greater interest in the clinical laboratory industry as a whole, which includes the vendors and service providers that do business in this space, companies offering RUO/IUO tests for research or investigational use should be secure in their compliance with the agency’s laws and regulatory requirements. The recently issued warning letter should serve as a reminder to ensure your product labeling, marketing materials, digital advertising, and contractual relationships do not suggest that an unauthorized IVD is actually intended for clinical diagnostic uses. 

In particular, firms offering RUO/IUO IVDs should not:

• Use product descriptions or claims that relate to clinical or diagnostic uses
• Discuss how the product supports the identification, diagnosis, or monitoring of specific diseases or conditions
• Make claims relating to accuracy or performance in a clinical setting or practice
• Compare utility to diagnostic tests or to cleared or approved medical devices
• Claim that the product may be used as part of an LDT or offer services relating to the development or validation of an LDT

We suspect that FDA’s March 21st warning letter may be the tip of the iceberg and that similar agency actions are likely to follow. If your company is active in this space, now would be a great time to mitigate risks and ensure your regulatory house is in order.