Agena Bioscience, Inc.

During an inspection of your firm located at 4755 Eastgate Mall, San Diego, CA on June 7, 2023, through June 13, 2023, an investigator from the United States Food and Drug Administration (FDA) determined that your firm is a manufacturer of the MassARRAY4 System (MA4) and the iPLEX HS chemistry panels including the iPLEX HS Colon Panel in vitro diagnostic (IVD) products. Based on the inspection and our review of your firm’s website, it appears the iPLEX HS Colon Panel intended for use with the MA4 is intended for clinical diagnostic use. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h), this product is a device because it is intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body.

The evidence reveals that the iPLEX HS Colon Panel intended for use with the MA4 is adulterated under section 501(f)(1)(B) of the Act, 21 U.S.C. § 351(f)(1)(B), because your firm does not have an approved application for premarket approval (PMA) in effect pursuant to section 515(a) of the Act, 21 U.S.C. § 360e(a), or an approved application for an investigational device exemption under section 520(g) of the Act, 21 U.S.C. § 360j(g). The device is also misbranded under section 502(o) the Act, 21 U.S.C. § 352(o), because your firm did not notify the agency of its intent to introduce the device into commercial distribution, as required by section 510(k) of the Act, 21 U.S.C. § 360(k).

You currently have clearance for the Impact Dx™ Factor V Leiden and Factor II Genotyping Test on the IMPACT Dx™ System (K132978) under 21 CFR 864.7280 for the following indications:

The IMPACT Dx™ Factor V Leiden and Factor II Genotyping Test is a qualitative in vitro diagnostic device intended for use in the detection and genotyping of a single point mutation (G1691A, referred to as the Factor V Leiden mutation or FVL) of the Factor V gene, located on Chromosome 1q23, and a single point mutation (G20210A) of the prothrombin gene (referred to as Factor II or FII), located on Chromosome 11p11-q12, from genomic DNA isolated from EDTA anti-coagulated human whole blood samples. The test is to be performed on the IMPACT Dx™ System and is indicated for use as an aid in diagnosis of patients with suspected thrombophilia.

During the inspection, your firm’s Director of Regulatory and Quality made verbal statements to the FDA investigator that your firm no longer sells the cleared Impact Dx™ Factor V Leiden and Factor II Genotyping Test on the IMPACT Dx™ System and has since only marketed and distributed the MA4.

Based on evidence obtained during the inspection and a review of your firm’s website the iPLEX HS Colon Panel intended for use with the MA4 appears intended for clinical diagnostic use. Such evidence includes:

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.

Your firm’s website (last accessed on March 20, 2024) includes product descriptions and statements that the 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” and “Identify variants at as low as 1% variant allele frequency.” [https://www.agenabio.com/products/panel/iplex-hs-colon-panel/]

Your firm’s website (last accessed on March 20, 2024) includes customer stories from clients of Agena that indicate your MA4 System is intended for clinical diagnostic use. For instance, on the “FEATURED CUSTOMER STORIES” page, a portion of a testimonial reads, “Accurate, Cost-effective Newborn Screening for the Illinois Department of Health on the MassARRAY [MA4]…” And a statement from your CEO reads, “We are proud to have the MassARRAY System [MA4] chosen to be an integral part of one of the top newborn screening programs in the country…” [https://www.agenabio.com/stories/hgt/accurate-cost-effective-cftr-variant-detection-newborn-screening/]. Another customer story comes from a client that is identified as a hospital system that uses your MA4 and iPLEX HS chemistry panels in tumor profiling and can deliver a quick and cost-effective test for clinically informative variants with a statement that other labs should explore the MassARRAY (MA4) for rapid, low-cost tumor profiling panels with a link to a product page for the iPLEX HS Colon Panel. [https://www.agenabio.com/stories/onc/massarray-enables-sensitivity-quick-turnaround-tumor-profiling-bsw/].

Your firm’s Director of Regulatory and Quality indicated that your firm markets the MA4 as a research use only (RUO) product and that your firm sells and distributes the MA4 to both research and clinical diagnostic companies. Your firm’s Director of Regulatory and Quality also indicated that labeling distributed with your MA4 products, and the labeling obtained during the inspection for your iPLEX HS Colon Panel, included the statement that these devices are “For Research Use Only. Not for use in diagnostic procedures.” 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 during the inspection and statements identified on your firm’s website as identified above and FDA has determined that your MA4 and iPLEX HS Colon Panel are intended for clinical diagnostic use.

Your iPLEX HS Colon Panel intended for use with the MA4 appears to be a tumor profiling test intended for the diagnosis of colorectal cancer. You were required to submit to FDA a 510(k) for this device, because it either is a new device (21 CFR 807.81(a)(1)) or, if your iPLEX HS Colon Panel intended for use with the MA4 represents a change or modification from the device cleared in K132978 (which is indicated for use as an aid in diagnosis of patients with suspected thrombophilia), has been significantly changed or modified in design, components, method of manufacture, or intended use (21 CFR 807.81(a)(3)). For a device requiring premarket approval, the notification required by section 510(k) is deemed satisfied when a PMA is pending before the agency [21 CFR 807.81(b)]. The kind of information that your firm needs to submit in order to obtain approval or clearance for the device is described on the Internet at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/default.htm. The FDA will evaluate the information that your firm submits and decide whether the product may be legally marketed.

Our inspection also revealed that your firm’s iPLEX HS Colon Panel is misbranded under section 502(t)(2) of the Act, 21 U.S.C. § 352(t)(2), in that your firm failed or refused to furnish material or information respecting the device that is required by or under section 519 of the Act, 21 U.S.C. § 360i, and 21 CFR Part 806 – Medical Devices; Reports of Corrections and Removals. Significant violations include, but are not limited to, failure to submit a written report to FDA of any correction or removal of a device initiated to reduce a risk to health posed by the device, as required by 21 CFR Part 806.10. For example:

On June 1, 2021, your firm issued a Customer Notification alerting customers that certain lots of your iPLEX HS Colon v1.0 Panel did not include the A nucleotide termination in Well #8 which your firm determined could result in false negative results for three target variant alleles. Your firm instructed customers to not use the results for the impacted variants and that your firm would reformulate and verify the termination mix and provide further updates on availability. Your firm did not submit a written report of this removal to the agency, as required by 21 CFR 806.10.

We request that your firm immediately cease any activities that result in the misbranding or adulteration of your devices. Your firm should take prompt action to address any violations. Failure to adequately address the matters discussed in this letter may result in legal action being initiated by the FDA without further notice. These actions may include, but are not necessarily limited to, seizure, injunction, and civil money penalties.

Other federal agencies may take your compliance with the FD&C Act and its implementing regulations into account when considering the award of federal contracts. Additionally, should FDA determine that you have Quality System regulation violations that are reasonably related to premarket approval applications for Class III devices, such devices will not be approved until the violations have been addressed. Should FDA determine that your devices or facilities do not meet the requirements of the Act, requests for Certificates to Foreign Governments (CFG) may not be granted.

Please notify this office in writing within fifteen business days from the date you receive this letter of the specific steps your firm has taken to address the concerns noted in this letter. Include documentation of any corrections and/or corrective actions (which must address systemic problems) that your firm has taken. If your firm’s planned corrections and/or corrective actions will occur over time, please include a timetable for implementation of those activities. If corrections and/or corrective actions cannot be completed within fifteen business days, state the reason for requiring additional time and the time within which these activities will be completed. Your firm’s response should be comprehensive and address any violations. If you believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration as part of your response.

Your firm’s response should be sent to both: Jessica Mu, Director of Compliance Branch, at oradevices3firmresponse@fda.hhs.gov and to CDRHWarningLetterResponses@fda.hhs.gov. Refer to CMS # 665159 when replying. If you have any questions about the contents of this letter, please contact: Jeff R. Wooley, Compliance Officer, at 214-253-5251 or jeffrey.wooley@fda.hhs.gov.

Finally, you should know that this letter is not intended to be an all-inclusive list of any deficiencies at your firm’s facility or associated with your firm’s devices. It is your firm’s responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific concerns noted in this letter may be symptomatic of serious problems in your firm’s manufacturing and quality management systems. Your firm should investigate and determine the causes of any violations and take prompt actions to address any violations and bring the products into compliance.