By Kelly M. Pyrek

As part of its dialogue around EtO sterilization of medical devices in November hearings, the General Hospital and Personal Use Devices Panel of the FDA’s Medical Device Advisory Committee addressed the challenges around processing of complex medical devices such as duodenoscopes. The panel examined data in the Medical Device Reports (MDR) and post-market surveillance studies, as well as reviewed the challenges with implementing new reprocessing methods and adoption of new technologies.

Overall, 1,115 duodenoscope reports related to a patient infection, exposure, or device contamination for devices marketed inside and outside the U.S. were received from January 2015 to mid-2019, according to the FDA. The number of reports related to patient infection was 553; patient exposure to an infectious agent numbered 54, and contamination without the mention of patient exposure or infection totaled 508. The MDR data indicate a decrease in the number of reported infections from 247 MDRs in 2015 to 55 MDRs reported in the first half of 2019.

Of these 1,115 duodenoscope reports, 858 were associated with duodenoscope models marketed in the U.S., including the Olympus TJF‐Q180V, TJF‐160VF/F, JF‐140F, PJF‐160, the Pentax ED-3490TK, ED34-i10T, and the Fujifilm ED-530XT (no MDRs have been submitted for the Fujifilm ED-580XT cleared in March 2019). There were reports of patient infection (378), patient exposure to an infectious agent (49), and contamination without the mention of patient exposure or infection (431). These reports are related to adverse events received inside and outside the U.S. Of the 378 reports received of patient infection associated with duodenoscope models cleared in the U.S., 270 of these reports occurred in the U.S.
The panel was asked to comment on FDA’s previous actions and whether the trajectory that FDA had taken to reduce the risk of infections continued to be appropriate.

To review the actions taken by FDA, following the agency being alerted in 2013 by the Centers for Disease Control and Prevention (CDC) about potential association between multidrug-resistant bacteria and duodenoscopes, the FDA stepped up its oversight and discovered that the reported cases of infection were occurring despite confirmation that the users were following proper manufacturer cleaning and disinfection or sterilization instructions.

In 2015, the FDA solicited expert scientific and clinical opinion from healthcare, consumer and industry representatives related to reprocessing of duodenoscopes based on available scientific information. Following two days of presentations, testimony and other input, panel participants were asked to answer questions focused on duodenoscope and AER safety and effectiveness, notably strategies to promote adherence to reprocessing instructions, the CDC's Interim Duodenoscope Surveillance Protocol, and risk communication. Potential strategies emerged in the following areas:

1. Manual Cleaning and Human Factors
Manual cleaning prior to disinfection or sterilization is critical to effective reprocessing. To ensure that manual cleaning is performed consistently and accurately, the panel recommended strengthening competency training for reprocessing staff in healthcare facility reprocessing departments and incorporating human-factors testing when developing reprocessing instructions. It is important to consider the device, end user and use environment when developing reprocessing instructions. Thus, human-factors testing ensures that end users will be able to understand and correctly follow the reprocessing instructions in the labeling.

2. Device Design
Duodenoscopes should be designed to enable meticulous cleaning and disinfection or sterilization; manufacturers were urged to design duodenoscopes that enable thorough cleaning and effective reprocessing through device disassembly or disposable parts.

3. Microbiological Culturing of Duodenoscopes
Healthcare facilities may perform microbiologic culturing, which involves sampling duodenoscope channels and the distal end of the scope and culturing those samples to identify any bacterial contamination that may be present on the scope after reprocessing. The FDA recommended additional data and validation testing to demonstrate the methodology is robust and demonstrates consistent and reliable culturing results before health care facilities can incorporate as a best practice.

4. Supplemental Measures to Enhance Duodenoscope Reprocessing
Additional strategies can reduce the risk of infection transmission, such as: microbiological culturing, sterilization, use of a liquid chemical sterilant processing system and repeat high-level disinfection as part of strict adherence to the manufacturer's reprocessing instructions.

In October 2015, the FDA ordered U.S. duodenoscope manufacturers Olympus, Fujifilm and Pentax to conduct post-market surveillance studies to better understand how these devices are reprocessed in real-world settings and their impact on duodenoscope-transmitted infections. In February 2018, the FDA, CDC and American Society for Microbiology (ASM) released voluntary standardized protocols for duodenoscope surveillance sampling and culturing. In March 2018, the FDA issued warning letters to all three manufacturers for failure to provide sufficient data; the manufacturers then submitted plans outlining how study milestones would be achieved.

In December 2018, the FDA issued interim results from the ongoing mandated post-market surveillance studies of duodenoscope reprocessing. Interim results indicated higher-than-expected contamination rates after duodenoscope reprocessing. Facilities and staff that reprocess duodenoscopes are reminded of the importance of manual cleaning prior to disinfection or sterilization and proper servicing of duodenoscopes.

In April 2019, the FDA updated the post-market surveillance study results for duodenoscopes used in ERCP and reminded healthcare facilities about the importance of strictly adhering to the manufacturer's reprocessing and maintenance instructions, following best practices, and reporting adverse event information to the FDA.

In August 2019, the FDA updated the post-market surveillance study results for duodenoscopes used in ERCP and provided additional recommendations and updates:
- Hospitals and endoscopy facilities should begin transitioning to duodenoscopes with innovative designs that facilitate or eliminate the need for reprocessing.
- Issuing new mandated post-market surveillance study orders to manufacturers of duodenoscopes with disposable endcaps to gather more data and verify that the new designs reduce the contamination rate. (Upon completion of these studies, the FDA expects the labeling on duodenoscopes with disposable endcaps to be updated with contamination rate data.)
- Warning healthcare facilities that adenosine triphosphate (ATP) test strips should not be used to assess duodenoscope cleaning. To date, the FDA has not evaluated them for effectiveness for assessing duodenoscope reprocessing. Manufacturers of ATP test strips are advised to submit data to support the legal marketing of these strips for this use.

At the November FDA hearings, IAHCSMM clinical educator, Susan Klacik, emphasized that exacerbating the problem was the design of medical devices, particularly that of scopes. Citing their complex design, Klacik said they are difficult, if not impossible to clean, and that the materials used in the manufacturing of the scopes can be difficult to thoroughly clean if heavily soiled post-procedure. She explained that internal channels become scratched during use, creating optimal conditions for microbial growth, and added that it can be difficult to visualize debris and defects. Compounding these issues are complex IFUs that require numerous processing steps.

Klacik further detailed additional challenges, including:
- Lengthy processing time, with the labor time needed to clean medical devices as being more than an hour
- The technology needed for processing may not be available in all facilities, including the availability of borescopes and the use of other cleaning verification testing methods
- Education and training of sterile processing personnel is an imperative, yet barriers include the competency levels of sterile processing techs ranging from entry to expert
- Repeated motions required in sterile processing may result in occupational injuries
- Turn-around demands for medical devices are high and often unrealistic

The consensus of the November panel was that training of reprocessing personnel was of utmost importance. The panel recognized that such training falls outside of FDA’s purview; nonetheless, FDA was encouraged to collaborate with manufacturers, accrediting organizations, and other stakeholders to promote correct reprocessing of duodenoscopes in healthcare settings. Some panel members commented that the magnitude of the problem did not raise concerns, and that FDA mandates on strategies to reduce the risk of infection for duodenoscopes would not be helpful. The panel recommended that FDA carefully consider next steps and make deliberate decisions.

The panel discussed FDA’s proposal to standardize duodenoscope durability testing. Shani Haugen, PhD, a microbiologist with FDA’s Center for Devices and Radiological Health, noted, “The FDA is considering an additional durability test required for reusable duodenoscopes, as there are no standardized methods currently -- different scope manufacturers will use different methods for testing if their device is durable enough for multiple uses. Labeling recommends functional tests such as leak testing, and an optical performance check, as well as visual inspection of the device to determine whether the scope should continue to be used. The labelling will request annual inspection to identify any damage the scope may have sustained. Studies from manufacturers attribute some damage to the duodenosocopes from cleaning and high-level disinfection.” Haugen said the FDA proposal includes the requirement of 250 cycles of simulated use of cleaning, high-level disinfection and sterilization.

Duodenoscope pre-market submissions have included different types of mechanical testing, according to the FDA. Because initial analyses from duodenoscope manufacturers and reports from the literature have indicated that device damage may lead to continued contamination of duodenoscopes after reprocessing, the FDA is seeking to standardize the types of mechanical and durability tests that are conducted prior to marketing reusable duodenoscopes, and is requesting feedback from the committee on the testing to demonstrate that duodenoscopes can withstand reprocessing cycles, including sterilization.

Since 2015, FDA has requested that duodenoscope manufacturers recommend at least annual maintenance of duodenoscopes. During the maintenance visit, duodenoscope manufacturers will inspect components of the device and replace damaged or worn parts, as well as those components that require periodic replacement. Because duodenoscopes should undergo at least annual maintenance, durability testing should include a worst-case simulation of duodenoscope use in a healthcare facility within a single year. That simulation should include simulated clinical use and simulated reprocessing.

To identify the number of times a single duodenoscope may be clinically used in a single year, FDA considered reports from the literature, conducted informal surveys of healthcare, and assessed the number of simulated use cycles conducted by duodenoscope manufacturers in their premarket submissions. Based on these estimates, the FDA says a minimum of 250 cycles to simulate uses in a single year appears reasonable for durability testing.

Current durability testing includes simulated clinical use of the device (repeated insertion of worst-case accessory instruments, angulation of the bending section of the duodenoscope while worst-case accessory instruments are within the instrument channel, and angulation of worst-case accessory instruments by the elevator) and simulated reprocessing (e.g., cleaning and high level disinfection in accordance with the duodenoscope manufacturer’s reprocessing instructions).

According to the FDA, duodenoscope durability testing typically has not included a worst-case number of terminal sterilization cycles, and this may have been a reasonable approach when duodenoscope sterilization was uncommon. However, given the need to provide an adequate margin of safety to mitigate the risk of infection for patients, the FDA says it is considering a recommendation that durability testing include a worst-case number of terminal sterilization cycles (i.e., the same number of sterilization cycles as cleaning/high-level disinfection). Alternatively, duodenoscope manufacturers may identify the number of sterilization cycles that the device is compatible with and use the labeled number of sterilization cycles in the durability testing.

The November panel’s consensus was that standardized durability testing was appropriate, because damage to the duodenoscopes was not often recognized by healthcare personnel. The panel noted that the details of the durability testing should be further discussed and refined with industry.
The panel discussed the potential of new designs to reduce duodenoscope contamination rates and the urgency with which the transition should be made.

Haugen emphasized that the distal end of scopes poses a significant challenge to cleaning and high-disinfection, and explained that since 2017, two scopes with disposable components have been cleared by the FDA.

“The disposable cap improves access for cleaning,” Haugen said at the November hearings. “From media reports, we’ve learned that manufacturers are considering more disposable components and developing completely disposable duodenoscopes. Device design is a key factor that contributes to reprocessing challenges. In agreement with conclusions from the 2015 panel convened by the FDA, the best solution to reduce the risk of infection by duodenoscopes is through innovative device designs that make reprocessing easier more effective or unnecessary. In August, the FDA recommended the transition to disposable components and asked duodenoscope manufacturers to transition from fixed caps to reduce or eliminate the need for reprocessing. FDA recognizes that a transition away from conventional duodenoscopes to the newer, innovative models will take time, due to costs and market availability. We encourage healthcare facilities purchasing new duodenoscopes to begin developing a transition plan and work to replace conventional duodenoscopes with newer models.”

The panel’s consensus was that there is a potential that the new designs could reduce contamination, but there is insufficient data to demonstrate that reduction. The panel commented that additional modifications to the device design and reprocessing instructions, education, and practices could be made.

“New designs are predicted to improve reprocessing outcomes,” Haugen said at the November hearings. “Upon completion of manufacturers’ new post-market surveillance studies of duodenscopes with disposable end caps to verify that the new designs reduce the contamination rate, we expect the labeling to be updated with contamination rate data.”

The panel also was asked to comment on the appropriate balance between obtaining data premarket versus post-market for devices that are intended to reduce the risk of infection from duodenoscopes. The panel noted that there is a need to demonstrate effectiveness of designs intended to reduce the risk of contamination prior to those devices being available for use, however the challenges associated with generating such data prior to marketing were also noted.

In late August, the FDA recommended that duodenoscope manufacturers and healthcare facilities transition to different types of duodenoscopes that may pose less risk to patient safety. Specifically, because of challenges with cleaning these devices for reuse (reprocessing) and persistent high levels of contamination, the agency is recommending moving away from using duodenoscopes with fixed endcaps to those with disposable components that include disposable endcaps—or to fully disposable duodenoscopes when they become available. Disposable designs simplify or eliminate the need for reprocessing, which may reduce between-patient duodenoscope contamination as compared to reusable, or fixed endcaps.

“We recognize that a full transition away from conventional duodenoscopes to innovative models will take time and immediate transition is not possible for all healthcare facilities due to cost and market availability,” said Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health, in a recent statement. “This is why we’re communicating with healthcare facilities now—so they can begin developing a transition plan to replace conventional duodenoscopes—and those facilities that are purchasing duodenoscopes with fixed endcaps can invest in the newer, innovative models. We are also encouraging the manufacturers of these duodenoscope models to assist health care facilities with their transition plans. We continue to work with manufacturers to increase the supply of disposable cap duodenoscopes and the development of other new and innovative device designs that will further minimize or eliminate the risk of patient infection. Duodenoscopes remain critical to life-saving care for many patients in the U.S. While the risk of infection from inadequate reprocessing is relatively low, we are taking action because of continuing elevated levels of contamination in duodenoscopes.”

Also in late August, the FDA announced additional steps it is taking, including ordering new post-market surveillance studies on duodenoscopes with disposable endcaps, requesting the inclusion of real-world contamination rates in duodenoscope labeling, and issuing letters to manufacturers of certain test strips used to assess duodenoscope cleanliness that have not been through proper FDA premarket review.

Reprocessing of duodenoscopes involves cleaning outside surfaces, interior channels and the elevator recess to remove tissue and fluids, followed by high-level disinfection to reduce harmful microbes so that the device is reasonably assured to be free of the risk of disease transmission. Failure to correctly reprocess a duodenoscope could result in tissue or fluid from one patient remaining in a duodenoscope and potential for disease transmission. Information from post-market surveillance human factors studies indicate that many steps in the reprocessing instructions cannot be reliably followed by healthcare facilities.

The FDA says it is concerned about the results of post-market human factors studies it required of each U.S. duodenoscope manufacturer (Fujifilm, Olympus and Pentax) to evaluate whether healthcare facility staff could understand and follow the manufacturer’s reprocessing instructions in real-world healthcare settings.

In December 2018, the agency released an alert about rates of duodenoscope contamination from scope manufacturers’ preliminary post-market data. At the time, the FDA’s Shuren reported on the U.S. duodenoscope manufacturers’ study examining the sampling and culturing of reprocessed duodenoscopes that are in clinical use to characterize contamination rates and to learn more about issues that contribute to contamination, as well as another study to assess how effectively hospital staff follow the manufacturers’ reprocessing instructions.

As Shuren stated last year, “Interim results from the sampling studies indicate higher-than-expected contamination rates after reprocessing, with up to 3 percent of properly collected samples testing positive for more than 100 colony forming units of low concern organisms that are unlikely to cause serious infections (but an indication of a reprocessing failure) and an additional 3 percent of properly collected samples testing positive for ‘high-concern’ organisms. These are bacteria more often associated with disease, such as E. coli or Staphylococcus aureus.”

Some factors that may have contributed to device contamination include device damage and errors in reprocessing. Shuren said that healthcare facilities that use duodenoscopes should meticulously follow manufacturers’ reprocessing instructions. In addition, healthcare facilities should consider implementing supplemental reprocessing measures to reduce the risk of infection transmission, such as microbiological culturing, sterilization, use of a liquid chemical sterilant processing system and repeat high-level disinfection.

At the November hearings, the FDA’s Haugen reported that a recent survey found widespread implementation of supplemental measures to enhance duodenoscope reprocessing. Thaker (2018) reported that of 249 healthcare facilities, 90 percent implement one or more supplemental measures:
- Repeat manual cleaning and HLD: 63%
- Surveillance microbiological culturing: 53%
- Liquid chemical sterilization: 35%
- EtO gas sterilization: 12%

Haugen noted that results of the sampling/culturing post-market surveillance study are consistent with published reports (Bartles 2018, Rauwers 2018, Ross 2015, Rex 2018, Snyder 2017, Visrodia 2017) that found some percentage of duodenoscopes remain contaminated after use. Additionally, repeat HLD does not significantly impact the contamination rate compared to single HLD (Bartles 2018, Snyder 2017).

Further, Haugen explained the literature shows that:
- Contamination rates after EO sterilization are variable (Naryzhny 2016, Snyder 2017)
- Ethylene oxide sterilization of duodenoscopes led to cessation of outbreaks (Epstein 2015, Smith 2015, Humphries 2017)
- Additional sterilization technologies are in development for duodenoscopes (Molloy-Simard 2019)

The FDA also recommended that hospital staff carefully inspect a component of the duodenoscope that is difficult to clean, called the elevator recess, and to repeat cleaning if any soil or debris is visible. We are also emphasizing that users follow the manufacturer’s recommendations for inspection, leak testing and maintenance of the duodenoscope and return the duodenoscope to the manufacturer, at least once a year, for inspection, servicing and maintenance. The FDA also encouraged healthcare providers to participate in the manufacturers’ sampling and culturing studies and consider initiating their own duodenoscope surveillance sampling and culturing to reduce the risks of infection.

However, Shuren added, “It has become clear that following the manufacturer’s reprocessing and maintenance instructions, while critical, is not sufficient to avoid all infections associated with the use of duodenoscopes. That is why the FDA has also been working with developers on new product designs, including disposable components. Technological advances in product design hold promise to reduce the risk of contamination and enhance patient safety.”

The results of these manufacturers post-market surveillance studies suggest that users frequently had difficulty understanding and following manufacturers’ instructions for use (IFUs) and were not able to successfully complete reprocessing, which may leave the duodenoscopes contaminated. The FDA says it continues to work with manufacturers to conduct additional testing and revise reprocessing instruction manuals, as appropriate.

At the November hearings, Shani Haugen, PhD, a microbiologist with FDA’s Center for Devices and Radiological Health, noted, “A contaminated duodenoscope indicates a failure somewhere in the reprocessing procedure and raises the risk of infection for patients, but it is unknown how the percentage of contaminated duodenoscopes relates to patient infections.”

Haugen pointed to the fact that the manufacturers, in their post-market surveillance studies, found that between 4 percent and 6 percent of duodenoscopes were contaminated.

“While not every exposure leads to infection, these rates are concerning to the FDA,” she emphasized at the November hearings. “These rates tell us that improvements are necessary. The FDA is committed to taking additional steps to reduce contamination and infections even further.”

The FDA says the best path to reducing the risk of disease transmission by duodenoscopes is through innovative device designs, such as those with disposable components, that make reprocessing easier, more effective or unnecessary.

Fixed endcap duodenoscopes have a plastic or rubber cap permanently glued to the metal edges around the distal end to prevent tissue injury from the metal edges on the scopes, but when permanently affixed, the endcaps also limit the accessibility to clean the crevices at the distal end. The FDA is recommending healthcare facilities transition away from fixed endcap models including Olympus Corporation’s TJF-Q160, TJF-Q180V, PJF-160 and JF-140F; Fujifilm Medical Systems USA’s ED-530XT; and Pentax Medical’s ED-3490TK. The FDA has cleared two duodenoscopes with disposable end caps: Fujifilm Corporation, model ED-580XT and Pentax Medical, model ED34-i10T. Additionally, other firms have publicly announced plans to develop fully disposable duodenoscopes.

As we have seen, the FDA previously required post-market surveillance studies from each U.S. duodenoscope manufacturer (Olympus, Fujifilm and Pentax) to determine the real-world contamination rates for duodenoscopes and serve as measures for the effectiveness of reprocessing. Because these studies continue to show elevated rates of contamination in fixed endcap duodenoscopes, including the presence of organisms more often associated with disease transmission, such as E. coli, the FDA believes that incorporating disposable components can simplify cleaning, reduce contamination and reduce disease transmission following reprocessing. While not every exposure to a contaminated scope leads to infection, any rate of contamination is concerning, which is why the FDA is taking multiple steps to address the issue.

The FDA is recommending a gradual transition to duodenoscopes with disposable components because full market withdrawal of conventional, fixed endcap duodenoscopes is not feasible at this time. Removing these devices from the market too quickly could create a shortage of duodenoscopes and prevent patients from accessing this beneficial and often life-saving procedure. The FDA says it believes, at this time, the continued availability of these devices is in the best interest of the public health.
In its comments submitted to the FDA for purposes of the November hearings, the Society of Gastroenterology Nurses and Associates (SGNA) says it believes that more research is needed on disposable endoscopes/endoscopes with disposable components. As the organization asks, “What are the benefits versus harms of using disposable devices? What research has been done to demonstrate the clinical effectiveness of disposable items? It is necessary for our members and the clinical community to have data on clinical acceptability and cost analysis of disposable duodenoscopes and other new technologies to determine the feasibility of integrating these into practice.”

Additionally, SGNA president Lea Anne Myers, MSN, RN, CGRN, says that the organization “believes that improvements should be made at the manufacturing level to make duodenoscopes more resistant to damage with routine use. The problem of duodenoscope processing failures cannot be solved until it is well defined. We urge the FDA and manufacturers to work together to perform analysis of duodenoscope disinfection failures. Use the results of the analysis to systematically provide improvements to both product design and reprocessing instructions. We believe that manufacturers should be supported in validating and updating processing instructions for use that keep up with the scientific literature. SGNA looks to the FDA to hold manufacturers accountable for evaluating the complexity of IFUs and considering human factors in the development of IFUs.”

Myers adds, “SGNA advocates that new recommended technologies be based on scientific evidence and not manufacturer bias or the need for a quick solution. SGNA recognizes the importance of bringing forward new ideas and solutions that will improve patient care. We are advocating for a synthesis of the scientific literature (level one evidence) be provided on the effectiveness of low temperature gas (EO, H2O2, ozone, etc.) sterilization and its effects on endoscope materials and on the occupational hazards of HLD/sterilization methods to the people who are performing endoscope processing at each step of the process.”

Brian J. Dunkin, MD, vice president of medical affairs for Boston Scientific Endoscopy, presented five perceived challenges to adoption of new duodenoscope technology:
1. A medical community that may not fully perceive a need for change due to the fact that endoscope-associated infections (EAIs) are hard to detect and the symptoms they cause are variable, resulting in underreporting. Further, endoscopists believe that modifications in reprocessing made by their units mitigate the risk of infection despite a lack of evidence. Finally, the healthcare community may have information fatigue from multiple communications over time and the perception that recommendations offered are unproven or eventually shown to be ineffective.
2. Skepticism that a single-use duodenoscope can be used as effectively as a reusable one.
3. Costs that are not accounted for in current ERCP procedural payment. To support patient access and safety while minimize costs for treating patients with EAIs, a device-specific payment for single-use duodenoscopes, in addition to the ERCP procedural payment, is needed.
4. Limited supply, as no medical device manufacturer with an effective solution will be able to serve the entire market immediately. Guidance is required on which patients benefit most from use of innovative technology so that clinicians may prioritize its use.
5. Uncertainty about the value of unproven solutions, as spending resources on unproven or ineffective solutions may not result in commensurate reduction in RAIs.

“The FDA has been diligent in investigating the cause for duodenoscope-related infections and fostering solutions to mitigate the risk,” says Dunkin. “The FDA should continue to precisely and transparently educate the healthcare community about this topic, encourage early interaction with manufacturers in development of innovative models and methods, support the value proposition of new technology in this space, work with societies, government agencies, and industry to provide guidance to clinicians making decisions about use of technology not available to all, and use data to drive endorsements of technology.”