Introduction

Recently, the U.S. Food and Drug Administration (FDA) issued a warning letter to Luminex Corporation. Luminex "manufactures microsphere-based and [polymerase chain reaction] PCR-based multiplexing systems for in-vitro diagnostic or life science research use." The indication for in-vitro diagnostic use makes these products medical devices because they are "intended for use in the diagnosis of disease or other conditions …"

Device Failure and Patient Death

The facts leading to the FDA's assertion of regulatory violations, as outlined in the warning letter, are as follows (in part): device malfunction, at least in part, led to a failure to diagnose a patient with a multi-drug (antibiotic) resistant bacterial (Pseudomonas) infection. Antibiotic therapy was delayed for several days until the patient was subsequently correctly diagnosed. The patient then died about two days later.

The FDA noted that the "false negative device result may have led to a missed opportunity to initiate effective treatment earlier" and that the "risk of false negative results could be the inappropriate de-escalation or lack of escalation of antibiotic therapy until subculture sensitivity testing was completed."

Implication

Violations like those alleged in the warning letter, when associated with a significant adverse event (for example, patient death), can create tort claims liability for the company. This is an especially important consideration for diagnostic companies whose tests and products diagnose serious medical conditions.

The Alleged Violations

The warning letter cited Luminex for several regulatory violations, including failure to report to the FDA a correction and removal to prevent a serious injury or death, product adulteration-based quality systems regulations violations, and product misbranding. We briefly highlight some of these violations.

Failure to Report a Correction and Removal to Prevent a Serious Injury or Death

The warning letter recites, among other things, that a field service engineer found a failed verification and recalibrated the instrument. Repairs were made, the instrument passed all verification testing. But shortly after this, another false negative result was reported on a quality control sample and the instrument was returned to the company. After investigation of the returned instrument, the company confirmed the malfunction and determined that the device could not detect Pseudomonas aeruginosa in three separate positive samples.

The FDA found that "removal of this instrument was initiated to reduce a risk to health [because continued use of the instrument could continue to produce false negative bacterial test results], and that this was not reported to the FDA." Federal regulations require, in part, that each "device manufacturer … shall submit a written report to FDA of any correction or removal of a device … if the correction or removal was initiated … to reduce a risk to health posed by the device." The FDA maintains that the company violated these federal regulations.

Quality System Violation

In addition to the violation described above, the FDA also cited the company for several alleged violations of quality systems regulations (QSRs). A quality system is a system that helps to ensure that quality is manufactured into a medical device, and that manufacturing activities (from design to production to testing) are planned and systematic. Thus, quality system violations can lead to device performance failures such as those as alleged in the FDA's warning letter.

For example, the first alleged QSR violation included a failure to validate a process when changes or process deviations occurred. The warning letter asserted that the company began using heater fixtures produced by a different component manufacturer and the new heater fixture was not adequately validated, reviewed, or approved.

It is worth remembering that heating to a precise temperature and for a precise duration of time is an integral part (for double stranded polynucleotide de-annealing) of any polymerase chain reaction (PCR) cycle. While it is unclear from the warning letter exactly why the bacterial test resulted in false negative results, an unvalidated heater fixture could cause deficiencies in PCR cycles, leading, at least in part, to a paucity of amplicons and resulting test failure.

Failure to Report a Correction and Removal Also Cited as a Misbranding Violation

The FDA alleged a misbranding violation because the agency said the company "failed or refused to furnish material or information respecting the device." "Violations include failure to submit a written report of a correction or removal of a device initiated to reduce a risk to health posed by the device, or to remedy a violation of the [Federal Food, Drug, and Cosmetic] Act caused by the device, which may present a risk to health."

Conclusion

Medical device manufacturers, including diagnostic test providers, can be liable to (at least) patients if their devices or tests malfunction and return erroneous test results which lead to significant adverse events (e.g., death). Getting a warning letter like the one described above can make a finding of liability more likely. Further, receipt of a warning letter can significantly impact a company's financial performance, make it more difficult to raise further equity rounds and create adverse publicity. For public companies, receipt of a warning letter is generally disclosable in SEC filings and can negatively impact stock performance. As such, failure to take broad based corrective action to ensure public safety and on-going compliance with regulatory requirements can result in significant legal exposure.