August 19, 2015 — Late last week the FDA “warned” FujiFilm, Olympus and Pentax — the manufacturers of virtually every gastrointestinal endoscope used in the U.S. — for failing to comply with federally mandated regulations.

Large Blog ImageIn letters it sent to these manufacturers, the FDA questions the safety and legal status of some of their marketed duodenoscopes.

A specialized type of GI endoscope, duodenoscopes are used to perform endoscopic retrograde cholangiopancreatography — or ERCP — more than 650,000 times per year in the U.S.

These three warning letters, dated August 12, 2015, mark the FDA’s strongest reproof of these companies since the Agency first notified the public, in early 2015, that duodenoscopes could infect patients with deadly ‘superbugs.’

The most concerning of these superbugs is CRE, or carbapenem-resistant Enterobacteriaceae, which the FDA has concluded can be too easily transmitted by duodenoscopes.

USA TODAY reports that these warning letters are a first step toward formal legal action, noting that failure by the manufacturers to correct the cited safety lapses could lead to administrative orders, fines and federal lawsuits.

Among other findings, the FDA’s warning letters assert that these three manufacturers’ devices are “adulterated” or “misbranded.”

An adulterated device lacks a pre-market approval, or PMA, whereas a misbranded device lacks a regulatory clearance, also known as a 510(k) clearance. Either is required to market a medical device legally in the U.S.

Update:  Almost a month after this article was originally published, its findings were corroborated in a USA TODAY article, dated September 15, 2015. For more details, read my related article, “FDA Investigation of ‘Superbug’ Outbreaks Now Includes Automated Endoscope Reprocessors, USA TODAY Reports” (Discussions in Infection Control; September 16, 2015)

The FDA’s finding that certain duodenoscope models lack a legal clearance has many public health implications, some obvious, others not.

One potentially significant implication impacts informed patient consent, which to date has not been discussed by the FDA in the context of the recent spate of superbug infections linked by several U.S. hospitals to these now-censured duodenoscopes.

For example, federal laws and regulations ordinarily require that patients be formally notified whenever an adulterated or misbranded device may be used to treat them.

I discuss the informed consent process as it applies to ERCP in my related article, “Another Potentially Deadly ‘Superbug’ Outbreak Suspected at a Pasadena Hospital.”

I also discuss more details about the FDA’s warning letters in my related article, “FDA Warns Three Endoscope Manufacturers for Safety Violations Following Deadly ‘Superbug’ Outbreaks.”

A second FDA letter to two manufacturers

Like these three warning letters, the FDA sent a second letter to FujiFilm and Pentax, also dated August 12, 2015, further questioning the regulatory status of certain duodenoscope models.

The FujiFilm ED-530XT and, possibly, the Pentax ED-3490TK are examples of FujiFilm and Pentax duodenoscope models that, according to the FDA, might not have a legal clearance.

This is not the first time the FDA has doubted the regulatory status of a duodenoscope sold in the U.S.

Although used today by as many as 85% of U.S. hospitals performing ERCP, the Olympus TJF-Q180V duodenoscope, which costs about $40,000, does not have a legal clearance or FDA approval as federal regulations require.

Olympus first introduced this duodenoscope model in the U.S. in 2010. But it was not until earlier this year that the FDA first began publicly questioning this device’s safety and effectiveness.

Olympus submitted an application to market this device legally in October, 2014. The FDA’s is still reviewing this application.

A revised risk assessment?

The FDA’s warning letters sent to the three duodenoscope manufacturers last week might suggest the risk of superbug infections during ERCP is higher than the Agency had originally thought.

In March, the FDA had said that it would not take action against Olympus for marketing its unapproved TJF-Q180V duodenoscope during the Agency’s review of the company’s regulatory application, which is still on-going.

Also in March, the FDA stated that this model can continue to be used by hospitals, adding that removing this device from the market could lead to an insufficient number of available duodenoscopes to meet current demand.

According to the FDA, “while the risk of infection transmission cannot be completely eliminated, the benefits of these devices continue to outweigh the risks in appropriately selected patients.”

Quality Services for Hospitals, Manufacturers, Patients:  Click here to read about Dr. Muscarella’s quality services committed to reducing the risk of healthcare-associated infections, including CRE outbreaks linked to contaminated endoscopes and other reusable medical equipment.

Automated endoscope reprocessors (AERs)

Automated endoscope reprocessors, or AERs, are typically used in U.S. hospitals to clean and disinfect — also known as “reprocess” — GI endoscopes, which include duodenoscopes. No longer is manual disinfecting commonplace.

In fact, according to USA TODAY, each of the U.S. hospitals that linked an outbreak of CRE (or a related deadly superbug) to ERCP, since 2012, used an AER to reprocess the suspect duodenoscopes between uses.

Reported now for the first time, the FDA’s concerns about the duodenoscope’s regulatory status and safety necessarily raise questions, too, about the legal clearance and effectiveness of AERs.

For background, an FDA guidance document, published earlier in 2015, instructs manufacturers to ensure that their reprocessing instructions “include only devices and accessories that are legally marketed.”

Moreover, in February 2010, the FDA wrote a letter to rigid endoscope manufacturers underscoring the importance of devices being labeled with proper instructions for use. (GI endoscopes are a type of flexible endoscope, whereas laparoscopes, for examples, are a type of rigid endoscope.)

In this 2010 letter, the FDA asserts that a rigid endoscope is “misbranded” under federal law if it is labeled to be reprocessed by an AER that lacks a legal approval or clearance. According to the FDA, such an endoscope bears inadequate directions for use.

Applied to duodenoscopes and their association with a number of recent superbug outbreaks, the FDA might therefore conclude that AERs marketed in the U.S. are also misbranded, primarily because these automated devices are labeled to reprocess specific duodenoscope models, including the Olympus TJF-Q180V model, that the FDA’s warning letters conclude are misbranded or adulterated.

According to the FDA, the safety and effectiveness of misbranded or adulterated medical devices are unknown and cannot be assured.

Whether the FDA might soon write warning letters to the manufacturers of AERs citing them for having labeled their devices to reprocess unapproved duodenoscope models — as it similarly did in 2010 to the manufacturers of rigid endoscopes — is unclear, but seems possible.

This possibility notwithstanding, the FDA has not, to date, publicly announced whether these misbranded or adulterated duodenoscopes adversely impact the regulatory status of AERs.

One corrective action that the FDA would likely advise a manufacturer to consider to obviate these potential regulatory concerns would be to remove from the labeling of its AER the claim that it can be used to reprocess any duodenoscope model that the FDA has concluded is misbranded or adulterated.

(Note: It is not, per se, my opinion that most AERs sold in the U.S. are misbranded. Rather, this would seemingly be the FDA’s conclusions, based on its previous actions.)

The effectiveness of AERs

USA TODAY reported last March that — in the wake of the CRE outbreak at UCLA’s Ronald Reagan Medical Center, which became public in mid-February — the FDA began requesting additional validation test data from AER manufacturers to evaluate whether their automated machines marketed in the U.S. perform as labeled and can successfully reprocess duodenoscopes with a closed elevator wire channel.

This channel houses a wire that the physician uses to raise and lower a lever — known as a forceps elevator mechanism, which is  located at the duodenoscope’s distal tip — to manipulate and control the direction of inserted accessories, such as cannulae and needles.

Older models of duodenoscopes sold by FujiFilm, Olympus and Pentax generally featured an exposed, or open, elevator wire channel that requires flushing with a detergent and disinfection after each procedure, to prevent disease transmissions.

Newer duodenoscopes, however, manufactured by these three companies feature a sealed elevator wire channel, and it is these newer models whose designs and safety the FDA began publicly questioning earlier this year.

A Form 483 inspection report

Reported now for the first time, an FDA’s on-site inspection of at least one AER manufacturer, in April 2015, found that this company had not validated the performance of its AER for reprocessing duodenoscopes with sealed elevator wire channels, such as the Olympus TJF-Q180V model.

Listing its observations in what’s called a “Form 483” inspection report, the FDA found that this testing had not been performed, despite, according to this report, the manufacturer having received complaints from hospitals that its AER may not be properly reprocessing these newer, harder-to-reprocess sealed duodenoscope models, posing a risk of CRE infections.

This inspection report’s observations and concerns — which may also apply to all of the other AERs marketed in the U.S. (although I am unaware of any other AER manufacturer having been similarly cited in a Form 483 report, save this one) — raise reasonable questions about whether the AERs currently in use in the U.S. can adequately reprocess duodenoscopes, especially those newer models featuring a sealed elevator wire channel.

As it notes in this manufacturer’s Form 483 inspection report, the FDA has concluded that test data and results a manufacturer has submitted to the FDA validating the effectiveness of its AER for reprocessing older duodenoscope models featuring an exposed forceps elevator channel cannot be applied to newer duodenoscope models featuring a sealed forceps elevator channel.  Instead, according to the FDA, the manufacturer would have to perform additional validation tests if its AER is labeled to reprocess these newer sealed duodenoscopes models.

While it is notable that, to date, the safety and regulatory status of AERs currently used in the U.S. have not been a focus of the FDA,validation that AER can effectively reprocess duodenoscopes is crucial to public health, since some reports have estimated that as many as 90% of U.S. hospitals reprocess duodenoscopes using an AER.

As noted previously, USA TODAY reports that every duodenoscope linked to an outbreak of CRE (or a related deadly superbug) in the U.S. since 2012 was reprocessed by an AER.

Whether the FDA might soon issue a health alert advising the public that one or more AERs may not have been properly validated for the safe and effective reprocessing of duodenoscopes featuring a sealed elevator wire channel, despite each of these AERs being labeled for reprocessing these endoscope models, is unclear, but possible.

The FDA’s advisory panel meeting in May, 2015

One month after the date of this Form 483 inspection report, the FDA hosted a two-day advisory panel meeting, on May 14-15, 2015. A summary of this meeting discussions may be read in the FDA’s 3-page letter entitled, “Brief Summary of the Gastroenterology and Urology Devices Panel Meeting May 14-15, 2015.”

The primary focus of this advisory panel’s May meeting was to discuss recent reports and investigations of ‘superbug’ outbreaks linked to contaminated duodenoscopes.

During this meeting, the FDA’s panel also discussed AERs. The FDA provides an overview of these devices in an earlier report it wrote in preparation for this panel meeting, in May. This report’s Table 3 identifies AERs that, according to the FDA, have received a legal clearance and are currently marketed in the U.S.

Below Table 3 the FDA writes in this report that: “When AER firms submit pre-market notifications for review, FDA requests validation data of currently identified worst case endoscopes, including closed (italics added) channel duodenoscopes.”

When the FDA first began enforcing this policy is unclear, however, and would have to be very recent. According to its aforementioned Form 483 report, the FDA found that validation testing demonstrating the effectiveness of an AER for reprocessing sealed duodenoscopes had not been performed, despite both the AER and some sealed duodenoscope models being sold in the U.S for more than a decade.

Understanding that a focus of this advisory panel meeting was the safety of AERs, it is further unclear why not discussed during this meeting was that the FDA — at least since April, one month earlier — was questioning the performance of at least one, and possibly all AER models sold in the U.S. — as revealed in the FDA’s aforementioned Form 483 inspection report — for lacking the necessary validation data confirming the AER’s safe reprocessing of duodenoscopes with a sealed elevator channel.

Medical device reports, or MDRs

Reaffirming the misbranding of the company’s TJF-Q180V model, the FDA’s warning letter to Olympus (dated August 12, 2015) cites the company for not filing medical device reports, or MDRs, with the Agency within 30 calendar days, as federal regulations require.

This lapse appears not to be limited to endoscope manufacturers, however, as some manufacturers of AERs also may not have always complied with the FDA’s 30-day requirement for filing a MDR, a review of the FDA’s MAUDE database suggests.

In one instance, Olympus filed an MDR in January 2015 that documents an outbreak following ERCP. This report appears to describe the aforementioned CRE outbreak at UCLA’s Ronald Reagan Medical Center that occurred between October 2014 and January 2015. In total, eight of this hospital’s patients were infected by a contaminated duodenoscope, three of whom died.

USA TODAY reported last March that this Los Angeles hospital was using an AER to reprocess duodenoscopes at the time of its CRE outbreak. Last May, The Los Angeles Times reported that UCLA officials informed the AER’s manufacturer of the outbreak in early 2015, as part of the hospital’s investigation.

Yet, a corresponding MDR filed by an AER manufacturer documenting this adverse event could not be identified in the FDA’s MAUDE database.  For their part, UCLA officials reported that during the outbreak’s investigation, they found “no functional issue” with this AER, according to the Times‘ article from last May.

In a second instance, a bronchoscope manufacturer filed a MDR in July 2015 reporting that six patients had tested “positive” for an atypical mycobacterium — Mycobacterium fortuitum conceptionese — following bronchoscopy. All six patients were examined using the same bronchoscope.

According to this manufacturer’s filed report, an AER (whose manufacturer is named in the report) was used to reprocess the bronchoscope. Yet, a corresponding MDR filed by the AER’s manufacturer documenting that the bronchoscope was inadequately reprocessed could not be identified in the FDA’s MAUDE database during a routine search.

These omissions may not be unique to one AER manufacturer. Whether the FDA might clarify that an adverse event associated with the inadequate reprocessing of an endoscope by an AER requires both of these device manufacturers to file an MDR — or whether one report filed only by the endoscope’s manufacturer is sufficient to comply with federal regulations — is unclear.

An FDA safety communication, with a twist

Reported for the first time, an interesting twist might arise if the FDA were to warn the manufacturers of AERs for labeling their devices to reprocess certain misbranded or adulterated duodenoscope models, including the Olympus TJF-Q180V model.

In it safety communication entitled, “Supplemental Measures to Enhance Duodenoscope Reprocessing (issued: August 4, 2015), the FDA recommends that healthcare facilities consider the following four supplemental measures to help reduce further the risk of superbug infections associated with the use of duodenoscopes:

  • microbiological culturing
  • ethylene oxide sterilization
  • use of a liquid chemical sterilant processing system
  • repeat high-level disinfection (typically using an AER)

Yet, experts may question the soundness of the FDA’s third and forth recommended measures.

Their merit may be questioned because both of these measures refer to the use of AERs that are labeled to reprocess misbranded endoscopes, including the Olympus TJF-Q180V duodenoscope. Pursuant to FDA regulations, an AER labeled to reprocess a misbranded endoscope would, too, be misbranded.

Whether the FDA appreciates that two of these four “supplemental measures” promote the use of automated devices — whether a system labeled to achieve liquid chemical sterilization or an AER labeled to achieve high-level disinfection — that, according to the FDA’s regulations and previous actions, is misbranded is unclear.

Article by: Lawrence F Muscarella, PhD; posted 8/19/2015; updated: 9/17/2015, Rev A. (This article is owned and copyrighted by LFM Healthcare Solutions, LLC.  All rights reserved, 2015.)

E: Twitter: @MuskiePhD

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