Header: It's a commonplace to see RUO-labeled kits that are clinically validated within a CLIA lab for use in clinical tests. It turns heads when FDA issues a warning letter to an RUO kit producer.
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On the FDA website, see letters dated March 15, 2024 (to Beckman Coulter), and March 12, 2024 (To Agena) citing alleged cases of "misbranding" of non-approved kits as "intended for use in the diagnosis of disease."
Beckman letter here:
Agenda letter here:
See subscription coverage at Genomeweb and at BioWorld. See also a detailed April 3 essay by the Mintz law firm, here.
Extracts from the public FDA letter to Agena include the following;
- Verbal statements made to the FDA investigator during the inspection on behalf of your firm by your firm’s Director of Regulatory and Quality indicating that your firm no longer sells the Impact Dx™ Factor V Leiden and Factor II Genotyping Test on the IMPACT Dx™ System (K132978) and has instead replaced it with a new system, the MA4, and admitting that your firm sells the MA4 and reagent panels to companies who analyze patient samples that are used for clinical diagnosis.
- Distribution records and a customer list obtained during inspection that indicates your firm shipped MA4 Systems and iPLEX HS Colon Panels to clinical testing laboratories.
- A customer notification your firm sent to customers dated June 1, 2021, regarding distributed iPLEX HS Colon Panels that alerted customers of an increase in false negative results of certain reagent lots and stated that Agena was taking steps “to not impact your laboratory workflow.” This customer notification was sent to a clinical hospital in Texas and there is no evidence that these reagents were intended for research use only.
- A copy of the iPLEX HS Panels User Guide obtained during inspection that included instructions for preparing and testing samples as well as instructions for interpreting iPLEX HS Reports including the iPLEX HS Colon Panel intended for use with the MA4.
- ...iPLEX HS Colon Panel “enables tumor profiling studies of colorectal cancer specimens”, and that, with the iPLEX HS Colon Panel, users can “Detect more than 80 clinically relevant variants across BRAF, EGFR, KRAS, NRAS, and PIK3CA”
- Your firm’s website also includes the statement that these devices are “For Research Use Only. Not for use in diagnostic procedures.” But, as discussed in this letter, on numerous occasions your iPLEX HS Colon Panel and your MA4 were not being shipped or delivered for an investigation (21 CFR 809.10(c)). And these devices were not for use in the laboratory research phase of development but rather were represented as effective IVDs (21 CFR 809.10(c)(2)(i)). Your disclaimers that the MA4 and your iPLEX HS Colon Panel are intended for research use only (RUO) are inconsistent with the evidence obtained...
Historical Note
In policymaking regarding RUO materials in 2013, FDA referred to its option to investigate manufacturers principally on the basis of selling to clinical labs or clinical centers (link, PDF page 9). At least to my memory, FDA has pretty rarely used shipping invoices as primary evidence of FDA violations.
Intended Use of Anything
In addition to the 2013 website guidance about RUO test kits, the FDA's actions are related to 2017 and 2021 Federal Register rulemaking about intended use and manufacturer relationships to off label use. (Of course, to have an "intended use" you have to be FDA approved in the first place).
So tangential to the FDA's news warning letters and their underlying 2013 guidance, see also a 2021 regulation on when manufacturers are responsible or implicated in any type of off label use. Essay from Hogan Lovells - here. Hogan writes,
The 2020 proposed rule expressed FDA’s intention to eliminate longstanding confusion created by the view that, in their then-current form, the regulations indicated that a manufacturer’s mere knowledge of an unapproved use triggers a requirement to update a product’s labeling. The final rule similarly clarifies that a manufacturer will not be deemed to have intended an off-label use based solely on knowledge that its approved product is being used or prescribed off-label. This also reflects the longstanding “practice of medicine exemption,” whereby FDA will not regulate off-label use of a lawfully marketed drug/device by a licensed health care practitioner in the context of caring for an individual patient.The final rule language also addresses [?]another highly contested issue by preserving the ability of laboratories to develop laboratory-developed tests (LDTs) using either in vitro diagnostic (IVD) or research use only (RUO) components, as long as such LDTs comply with Clinical Laboratory Improvement Amendments (CLIA) regulations in their development and are offered on the order of a health care provider...
I can't find [?] the IVD CLIA section that is "also addressed," per Hogan (discussing 86 FR 41383, 8/2/2021), neither in the 2021 rule or its 2017 predecessor. There is a lot of discussion of first amendment and case law from the courts.
There is a short discussion of oft-perplexing difference between intended use and indication for use (p 41395), with a comment that "indication for use" will not be defined in this rule.
