14.1 Introduction
Multiple outbreaks of antibiotic-resistant bacteria in recent years have been traced to contaminated duodenoscopes in health care facilities in the United States and Europe.Footnote 1 These events prompted intensive postmarket surveillance of three large duodenoscope manufacturers, the creation of voluntary hospital-based culturing programs,Footnote 2 and US Food and Drug Administration (FDA) safety warnings emphasizing the importance of following manufacturers’ instructions for use (IFUs) for performing high-level disinfection (HLD) or sterilization of equipment, also known as reprocessing.Footnote 3 However, as outbreaks continued, the US Joint Commission made high-level disinfection or sterilization of all reusable scopes and probes a central component of its 2018 hospital accreditation programming.Footnote 4 This chapter highlights the regulations governing medical devices, the etiology of the duodenoscope outbreaks, and the policy measures implemented and regulatory challenges persisting in the wake of the outbreaks. Given the proliferation of scopes and probes in medical care – including outbreak settings of highly infectious diseases such as the Ebola virus diseaseFootnote 5 and carbapenem-resistant Enterobacteriaceae (CRE)Footnote 6 – reprocessing cannot and should not remain an abstract part of device regulation. Amplifying the perspective of infection prevention and control in the medical device regulatory landscape is critical to achieve optimal and sustainable reforms.
14.2 Regulatory History and Duodenoscope Outbreaks
Under FDA regulations, devices fall into three classes. Duodenoscopes are categorized as Class II devices, which confer moderate risk and require regulatory controls such as the establishment of performance standards, postmarket surveillance, patient registries, and/or labeling requirements.Footnote 7 Class II devices require only premarket notification through the FDA’s 510(k) pathway.Footnote 8 By contrast, Class III devices such as implantable pacemakers, which “support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury,”Footnote 9 require premarket approval (PMA), the most stringent type of device market application required by the FDA.
Yet despite its classification as a Class II device, duodenoscopes were linked to at least twenty-five outbreaks of CRE between 2012 and 2015.Footnote 10 The actual toll was likely far higher, but unknown given gaps in reporting and surveillance.Footnote 11 By early 2013, the manufacturer Olympus knew of two independent lab reports, which found that one of their duodenoscope models featuring a difficult-to-access elevator channel could harbor bacteria even after cleaning according to the manufacturer’s instructions.Footnote 12 Even though the FDA began investigating elevator channels in 2013 in collaboration with the Centers for Disease Control and Prevention (CDC), Olympus did not forward the laboratory reports to the FDA or alert US hospitals, physicians, or patients to the risk of infection until February 2015.Footnote 13 Further investigation revealed that two major duodenoscope manufacturers failed to pursue a new 510(k) premarket notification prior to bringing their devices with elevator channels to market. Custom Ultrasonics, the manufacturer of an automated reprocessor that was implicated in some outbreaks, also failed to report critical updates to their device to FDA as required by law.Footnote 14 Finally, the FDA was also unaware of manufacturer warnings to European regulators that had occurred as early as 2013.Footnote 15
These events highlighted various inadequacies in manufacturer reporting, hospital investigation, and regulator action, which prompted the CDC and FDA to reexamine reprocessing IFUs. In March 2015, the CDC released an interim duodenoscope surveillance protocol for health care facilities in cooperation with the FDA and the American Society for Microbiology (ASM).Footnote 16 In October of the same year, the FDA ordered three major duodenoscope manufacturers to conduct postmarket surveillance studies to better understand duodenoscope-transmitted infections.Footnote 17
However, it was not until June 2017 that the FDA promulgated regulations to require manufacturers of certain high-risk reusable Class II medical devices to include validated IFUs regarding cleaning, disinfection, and sterilization in their premarket notification 510(k).Footnote 18 These regulations acknowledged that the design of some devices, such as those with lumens or crevices, were higher risk than others.Footnote 19 Additionally, the regulations emphasized the importance of the validated instructions not only for automated reprocessors and washing devices, but also for such high-risk devices.Footnote 20
Over the next four years, the FDA released six general updates of reprocessing instructions, twelve general communications on duodenoscopes, and sixteen public correspondences to duodenoscope manufacturers.Footnote 21 In November 2015, there was a mandatory recall of Custom Ultrasonics reprocessors and in February 2018, the FDA, CDC, and ASM released voluntary standardized protocols for duodenoscope surveillance culturing.Footnote 22 Yet in an August 2019 safety communication, the FDA’s postmarket surveillance report noted a continued “elevated rates of contamination, including the presence of high concern organisms” such as E. Coli and Pseudomonas aeruginosa, highlighting persisting concerns of HLD and complex endoscope design.Footnote 23
These concerns have helped fuel a growing market for single-use equipment, with manufacturers of varying scopes and probes developing completely disposable designs. In November 2019, the FDA recommended transitioning to duodenoscopes with disposable components and one month later, gave market clearance for the first fully disposable duodenoscope.Footnote 24
14.3 Challenges
Amid this backdrop, several practical difficulties and regulatory challenges remain. First, although IFUs for reprocessing higher-risk medical devices must now be validated in accordance with FDA regulation, processes for validation are not standardized and are often unclear. Current FDA guidance refers manufacturers to technical information reports (TIRs) developed by the Association for the Advancement of Medical Instrumentation (AAMI), specifically AAMI TIR 2 (“labeling instructions for reusable medical device”) and TIR 30 (“compendium of processes, materials, test methods, and acceptance criteria for cleaning reusable medical devices”).Footnote 25 However, most AAMI TIRs were last published in 2010 and are in critical need of updating.
In 2015, AAMI published the more rigorous “Standard 91: Flexible and semi-rigid endoscope processing in healthcare facilities,” which outlines facility-level quality control practices, addresses human factors issues related to reprocessing, and comments on the design and flow of reprocessing departments.Footnote 26 Yet full implementation of this standard, including cleaning verification processes, schedules, and tracking and tracing of all related endoscope equipment, remains challenging.Footnote 27 Additionally, given rapid advances in disinfection and sterilization science and changes in regulation, this guidance also requires updating.Footnote 28 Work on this has been ongoing since early 2019, but a new draft document had not yet been released as of December 2020.Footnote 29
Thus, over the past decade, manufacturers have largely been left to author IFUs without clear guidance as to what is an acceptable or standard cleaning protocol,Footnote 30 resulting in widespread variation in how IFUs are structured and written, the methods used to demonstrate that effective disinfection has occurred, and storage and handling practices.Footnote 31 For example, there are no agreed-upon standards to assess if proper cleaning (e.g., detection of protein versus blood versus microbial DNA) has occurred,Footnote 32 when older equipment should be sent for maintenance, repair, or replacement, or whether borescopes – an optical device – should be used to detect microscopic rips or tears, particularly in otherwise inaccessible cavities.Footnote 33
Particularly critical to the disinfection process are manual precleaning steps. Although the FDA requires that reprocessing instructions “should be understandable,”Footnote 34 many IFUs are dense and difficult to follow (some IFUs exceed 100 pages). In mandated human factors postmarketing surveillance studies conducted by Fujifilm and Olympus, “most participants expressed some difficulty adhering to the reprocessing manual,” with one study concluding that the materials “are not sufficient to consistently ensure user adherence in these core reprocessing areas: precleaning, manual cleaning, manual high-level disinfection, rinsing, and storage and disposal.”Footnote 35
IFUs can also contradict guidance from professional societies, which can be in conflict with each other. For example, the Society of Gastroenterology Nurses, the Association for Professionals in Infection Control and Epidemiology, and the Association of Perioperative Registered Nurses all have different recommendations on storage and “hang time” – the maximum duration of storage time before the endoscope is processed for next use.Footnote 36 Recognizing such variability, the Joint Commission recently released its own clarification for hospitals, outlining that the IFU remains paramount to professional society guidance and consensus documents. Yet, gaps remain when IFUs are nonspecific or do not address key concerns, leaving hospitals in the position of having to reach out to manufacturers directly.Footnote 37
The interplay between IFUs can also be a challenge. While device manufacturers create their own IFUs, they typically do so separately from the manufacturers of automated reprocessors and high-level disinfectants.Footnote 38 This creates another layer of complexity for end users in health care facilities, particularly those that use manual methods of disinfection. In reconciling IFUs, a hospital’s ability to swiftly recognize concerns and call attention to appropriate leadership can be hampered.Footnote 39 Some device manufacturers of scopes create their own reprocessing equipment exclusively for their own devices,Footnote 40 which can mitigate the burden of IFU coordination but can also result in undue contractual leverage, limiting the ability of hospitals to diversify their inventories.
More broadly, concern exists that HLD may be insufficient for scopes.Footnote 41 The decades-old Spaulding criteria outlines the use of HLD for semi-critical devices such as scopes and sterilization for critical devices such as surgical instruments.Footnote 42 Performing HLD typically results in a 6-log10 reduction of micro-organisms, whereas sterilization results in at least a 12-log10 reduction.Footnote 43 However, flexible endoscopes acquire high levels of microbial contamination or bioburden during each use, and may contain tenFootnote 44 enteric micro-organisms after use, with buildup around closed channels.Footnote 45 Accordingly, some infection prevention experts refer to HLD as creating a “nonexistent margin of safety” that is unable to achieve disinfection consistently.Footnote 46
Challenges also exist with sterilization. Typical scope materials cannot handle the high temperatures required for the most commonly available and robust methods of sterilization (i.e., steam).Footnote 47 Additionally, existing sterilants have notable drawbacks. For example, ethylene oxide, a sterilant for rigid scopes, requires lengthy processing and aeration time.Footnote 48 In high quantities, it also poses health hazards, including carcinogen risk.Footnote 49 Because of this risk, ethylene oxide is unavailable in many US hospitals. In 2019, two large device facilities were closed by state environmental protection agencies in response to higher than acceptable levels of ethylene oxide in the air, creating abrupt shortages of sterilized devices.Footnote 50
Finally, while the market for single-use equipment may be viewed as a clear path forward, inadequate attention has been given to associated waste streams. Use of disposable duodenoscopesFootnote 51 would contribute to the market growth of disposable designs for other scopes and probes, but the environmental footprint of single-use equipment has yet to be modeled nationally and internationally.Footnote 52 In one study, single-use laryngoscope handles generated an estimated sixteen to eighteen times more lifecycle carbon dioxide equivalents (CO2-eq) than traditional low-level disinfection of the reusable steel handle, and single-use plastic tongue blades generated an estimated five to six times more CO2-eq than the reusable steel blade treated with high-level disinfection.Footnote 53 However, some studies suggest higher emissions of C02-eq may be offset by the cost of personal protective equipment (PPE), and that the energy consumption of reprocessing equipment also needs to be considered.Footnote 54 These comments underscore the need for further data points to build comprehensive models.
14.4 Solutions and Future Discussion
Addressing the above challenges requires engagement between manufacturers, clinicians, regulators, central processing departments, infection prevention and control leadership, and health care administrators. Inconsistencies between IFUs and the lack of transparency and standardization around validation in all domains – precleaning, disinfection, storage, maintenance, and repair – should be key priorities for the FDA and AAMI. Encouragingly, updates to key TIRs are in progress.Footnote 55 While working groups developing these documents include diverse stakeholders, including key manufacturers, regulators, and infection prevention experts, TIRs are not made available for public comment.Footnote 56 The AAMI standards are made available for public comment, but are solicited by notice in “appropriate AAMI publications or on the AAMI website.”Footnote 57 Making drafts of TIRs under review publicly available for comment, and making AAMI standards more widely available for review may present opportunities for improvement and promote swifter uptake by manufacturers and health care facilities.Footnote 58 Additionally, ensuring timely and concordant adoption of TIRs by the CMS could help ensure that health care facilities and manufacturers keep up to date.
Even with updated AAMI standards, however, implementation will remain a challenge. To facilitate optimal execution, health care administrators should seek to invest in competency and training programs for reprocessing staff and consider including them in contracted services with manufacturers and vendors.Footnote 59 Coordination of IFUs across vendors requires close coordination of health care facility infection prevention and control, biomedical/clinical engineering, supply chain, and contracting departments. While committees comprised of representatives from these groups may be found at many large acute care inpatient centers, they may not exist in ambulatory settings or surgical centers, where procedures are common.Footnote 60 The absence of such committees should be considered in a facility’s gap analysis and should be examined as part of regulatory and reaccreditation requirements.Footnote 61
Since the outbreaks began in 2012, the FDA has expanded its ability to examine the regulatory controls for medical device regulation. The Medical Device Innovation Consortium (MDIC) is a 501(c)(3) public-private partnership with the objective of advancing approaches that “promote patient access to innovative medical technologies and the use of real world evidence in guiding the needs for all stakeholders.”36 As part of the MDIC, the National Evaluation System for Health Technology coordinating center (NESTcc) aims to conduct “efficient and real-world evidence studies throughout the total product life cycle,” to “develop, verify, and operationalize methods of evidence generation” and data use in both the pre and postmarket space, and to bring together stakeholders, including the voice and preferences of the patient.Footnote 62 The MDIC patient-centered benefit-risk framework creates decision analysis models that evaluate tradeoffs such as risk of infection or associated length of stay associated with a device that a patient may consider.Footnote 63 However, the MDIC and NESTcc should ensure the completeness of data to inform such metrics. For example, the risks of device-associated infection cannot be properly quantified without understanding real-world gaps in IFUs related to disinfection and sterilization.
The NESTcc could also elevate its voice in the postmarket space. In partnership with the FDA, the MDIC should continue to support and use evidence from medical device safety reporting by hospitals and device manufacturers through portals like the MedWatch and MedSun.Footnote 64 The MDIC and the NESTcc could also offer support in the design and development of postmarket surveillance studies. Though small, the human factors studies mandated by the FDA for Fujifilm and Olympus manufacturers in postmarket surveillance were revealing.Footnote 65 In particular, they plainly demonstrated the difficulty in adhering to complex IFUs.Footnote 66 If these studies were part of active surveillance in the postmarket period, they could offer critical and earlier insight for manufacturers, health care personnel, and the FDA.
In appreciating the pitfalls of complex IFUs, many infection prevention and control experts have called for the reclassification of scopes as critical devices that require sterilization.Footnote 67 There is regulatory precedent for such action. In 1992, the FDA mandated a shift from disinfection to sterilization for dental handpieces, even though there were no documented cases of disease transmission associated with dental hand pieces.Footnote 68 Professional societies should support this transition, and accreditation agencies should start developing standards to facilitate institutional accountability.Footnote 69
Incentives will likely be needed to encourage further development of sterilization options, including low temperature sterilization technologies (LTSTs). The FDA recently started this process, announcing in November 2019 four participants in an “innovation challenge” to identify disinfection and sterilization alternatives that can be implemented at a large scale and maintain high throughput.Footnote 70 Two of these participants will focus on the use of vaporized hydrogen peroxide technology that is currently being used on a large scale to disinfect respirators during the COVID-19 pandemic.Footnote 71 While participation does not constitute “regulatory acceptance,” manufacturers should expect that the FDA remains committed to expeditiously clearing LTSTs as they are developed if safety and effectiveness standards are met.38 In turn, manufacturers should commit to the FDA’s endorsement of creating scopes with innovative designs, including manufacturing scopes with materials that are compatible with LTSTs.Footnote 72
More recently, the FDA announced a second innovation challenge to decrease ethylene oxide emissions.Footnote 73 In parallel and in light of closures of sterilization facilities due to high ethylene oxide emissions, the US Environmental Protection Agency (EPA) issued a notice of proposed rulemaking to solicit information from industry and the public on strategies for further reducing ethylene oxide emissions from commercial sterilization and fumigation operations. This includes reviewing and updating regulations for sources that emit ethylene oxide and to better understand and address ethylene oxide emissions at facilities.Footnote 74 Such interagency coordination will be needed to more identify the optimal role of ethylene oxide in medical device sterilization, the effects of endoscope sterilization, and the impact on the supply chain and transportation operations.Footnote 75
Finally, hospitals and clinics will need to consider the far-reaching impacts of incorporating disposable equipment, especially as pathogens of high consequence such as CRE, take hold.Footnote 76 Hospitals and clinics will need to partner and engage early with major biomedical waste companies and recycling vendors both in the United States and globally to create a regulated, functional waste stream.Footnote 77 These groups will need to understand large throughput hospital- and clinic-based workflows, calculate new labor costs, and consider implications for their supply chains. Corporate social responsibility platforms should expand to account for the impact of such activities and integrate this work into ongoing sustainability efforts, including tracking fleet and incinerator emissions.Footnote 78 To more fully weigh complete environmental impact, cradle-to-grave lifecycle assessment and lifecycle costing methods should be used.Footnote 79 For example, the EPA’s Tool for the Reduction and Assessment of Chemical and other Environmental Impacts can be used to model environmental impacts of greenhouse gases and other pollutant emissions.Footnote 80 As is required to examine ethylene oxide impacts, a sustained FDA and EPA partnership can help, facilitating detailed data gathering to inform national and international economic and environmental analyses. This effort should discuss how to weigh energy consumption of reprocessing departments and facilities, human labor costs, and PPE usage.
While the NESTcc represent the FDA’s efforts to modernize the 510(k) process, the FDA will need to embed both the perspectives of infection control and environmental sustainability to transform its approach.Footnote 81 In particular, understanding the tradeoffs associated with sustainable production and consumptions practices can shift the FDA approach from reactive to proactive.Footnote 82
14.5 Conclusions
High-level disinfection and sterilization of medical equipment has slowly evolved over the past three decades. The outbreaks of drug-resistant bacteria traced to contaminated duodenoscopes offer a case study in understanding the gaps in medical device regulation. Although the FDA has made strides in closing these gaps, important and critical problems persist; the concerns exposed in the duodenoscope outbreaks expand beyond scopes and spans larger concerns around device design, cleaning, disinfection, management, uptake and care. Together, these experiences call for a greater voice for infection prevention and control in the medical device ecosystem. The NESTcc and the FDA’s ongoing private-public partnership consolidate national efforts for medical device safety: minimizing disease transmission and considering environmental harms should be part of that mission.
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