Is read-across for chemicals comparable to medical device equivalence and where to use it for conformity assessment?

Novel medical devices must conform to medical device regulation (MDR) for European market entry. Likewise, chemicals must comply with the Registration, Evaluation, Authorization and Restriction of Chemicals (REACh) regulation. Both pose regulatory challenges for manufacturers, but concordantly provide an approach for transferring data from an already registered device or compound to the one undergoing accreditation. This is called equivalence for medical devices and read-across for chemicals. Although read-across is not explicitly prohibited in the process of medical device accreditation, it is usually not performed due to a lack of guidance and acceptance criteria from the authorities. Nonetheless, a scientifically justified read-across of material-based endpoints, as well as toxicological assessment of chemical aspects, such as extractables and leachables, can prevent failure of MDR device equivalence if data is lacking. Further, read-across, if applied correctly can facilitate the standard MDR conformity assessment. The need for read-across within medical device registration should let authorities to reconsider device accreditation and the formulation of respective guidance documents. Acceptance criteria like in the European Chemicals Agency (ECHA) read-across assessment framework (RAAF) are needed. This can reduce the impact of the MDR and help with keeping high European innovation device rate, beneficial for medical device patients.

Aligning US Agency Policies for Cardiovascular Devices Through the Breakthrough Devices Program.

Importance: The US Food and Drug Administration (FDA) and Centers for Medicare & Medicaid Services (CMS) have different statutory authorities; FDA evaluates safety and effectiveness for market authorization of medical devices while CMS determines whether coverage is "reasonable and necessary" for its beneficiaries. CMS has recently enacted policies automatically providing supplemental reimbursement for new, costly devices authorized after designation in FDA's Breakthrough Devices Program (BDP) and in June 2023 issued notice for a new Transitional Coverage for Emerging Technologies pathway, accelerating coverage for Breakthrough devices. Observations: Aiming to incentivize innovation, FDA awards Breakthrough designations early in device development to expedite market authorization and can accept greater uncertainty in benefit and risk, contingent on postmarket evidence generation. Since 2020, Breakthrough designation has effectively automatically qualified devices to receive supplemental Medicare reimbursement after CMS waived a long-standing requirement that devices demonstrate "substantial clinical improvement" for beneficiaries. Using publicly available information, 3 examples of cardiovascular devices illustrate that the BDP may allow for FDA authorization based on less rigorous evidence, such as single-arm trials focused on surrogate end points with short-term follow-up whose participants are often not representative of Medicare beneficiaries. In 1 case, Breakthrough designation allowed a 30% decrease in enrollment of a trial used to support approval. Initial positive findings for some devices have remained unverified, and in 1 case even partially nullified, by postmarket studies. Manufacturers have also used Breakthrough designations to set the price of devices to facilitate additional pass-through payments, leading to higher short-term and long-term costs to CMS and health care systems. Conclusions and Relevance: The BDP may qualify new, costly devices for higher and automatic Medicare reimbursement despite evidence not being representative of CMS beneficiaries and persistent uncertainty of benefit and risk. To ensure the best evidence is generated to inform clinical care, FDA could apply more selectivity to BDP eligibility, specify objective criteria for revoking Breakthrough designation when appropriate, and ensure timely postmarket evidence generation, whereas CMS could independently review clinical evidence, advise manufacturers about standards for coverage review, and make supplemental payments and long-term device reimbursement contingent on clinical outcome benefit and postmarket evidence generation.

Assessment of US Food and Drug Administration-Approved Digital Medical Devices for Just-in-Time Interventions: A Systematic Review.

Importance: Just-in-time interventions (JITIs) are a type of digital therapeutic intervention that combines remote monitoring tools and algorithms to personalize the delivery of specific interventions at the right time. The US Food and Drug Administration (FDA) regulatory approval documents are often the only available source of information on the effectiveness of therapeutic interventions based on these devices. Objective: To systematically review the publicly available information from the FDA on all recently approved medical devices used in JITIs to (1) assess how they operate to deliver JITIs and (2) appraise the evidence supporting their performance and clinical effectiveness. Evidence Review: Two reviewers systematically searched the Premarket Notifications (510(k)), Premarket Approvals, De Novo, and Humanitarian Device Exemption databases from January 2019 to December 2021 for all entries associated with devices that monitored patients' data over time to personalize the delivery of interventions to treat, prevent, or mitigate health conditions or events. They assessed whether the product summaries (1) enabled an understanding of how the device operated to deliver a JITI (eg, the nature, type, and frequency of the monitoring, the nature of the decision algorithm, and the nature and intended receiver of the intervention); (2) informed about the performance and effectiveness of the JITI; and (3) included information on data security and ownership. Findings: In total, 38 devices were included in this review. These were mainly intended for cardiac conditions (12 [31.6%]), diabetes (10 [26.3%]), and neurological diseases (4 [10.5%]). Monitoring devices ranged from wearable (18 of 28 [64.4%]; eg, smartwatches) to implanted sensors (6 of 28 [21.4%]; eg, inserted electrocardiographic sensors). Only 10 of 38 product summaries (26.3%) allowed a full understanding of how the device operated to deliver a JITI. Similarly, only 12 of 28 (42.9%), 12 of 36 (33.3%), and 5 of 38 (13.2%) reported the assessment of the performance of the monitoring device, assessment of the decision algorithm, and results of clinical studies assessing the effectiveness of the JITI, respectively. Finally, 14 of 36 product summaries (38.9%) included some information on data security, but none included information on data ownership. Conclusion and Relevance: The results of this systematic review suggest that the information publicly available in the FDA databases on the performance and effectiveness of digital medical devices used in JITIs is heterogeneous.

Time to publication of cost-effectiveness analyses for medical devices.

OBJECTIVES: Academic researchers and physicians have called for greater use of cost-effectiveness analyses in informing treatment and reimbursement decisions. This study examines the availability of cost-effectiveness analyses for medical devices, in terms of both the number of studies and when studies are published. STUDY DESIGN: Analysis of the number of years between FDA approval/clearance and publication for cost-effectiveness analyses of medical devices in the United States published between 2002 and 2020 (n = 86). METHODS: Cost-effectiveness analyses of medical devices were identified using the Tufts University Cost-Effectiveness Analysis Registry. Studies in which the model and manufacturer of the medical device used in the intervention were identifiable were linked to FDA databases. Years between FDA approval/clearance and publication of cost-effectiveness analyses were calculated. RESULTS: A total of 218 cost-effectiveness analyses of medical devices in the United States published between 2002 and 2020 were identified. Of these studies, 86 (39.4%) were linked to FDA databases. Studies examining devices approved via premarket approval were published a mean of 6.0 years after the device received FDA approval (median, 4 years), whereas studies examining devices that were cleared via the 510(k) process were published a mean of 6.5 years after the device received FDA clearance (median, 5 years). CONCLUSIONS: There are few studies describing the cost-effectiveness of medical devices. Most of these studies' findings are not published until several years after the studied devices received FDA approval/clearance, meaning that decision makers will likely not have evidence of cost-effectiveness when making initial decisions related to newly available medical devices.

Summary of the FDA virtual public workshop on spinal device clinical review held on September 17, 2021.

The mission of Food and Drug Administration (FDA)'s Center for Devices and Radiological Health is to protect and promote public health. It assures that patients and providers have timely and continued access to safe, effective, and high-quality medical devices and safe radiation-emitting products by providing meaningful and timely information about the products we regulate and the decisions we make. On September 17, 2021, an FDA workshop was held to provide information to stakeholders, including members of the spine community, device manufacturers, regulatory affairs professionals, clinicians, patients, and the general public regarding FDA regulations, guidance and regulatory pathways related to spinal device clinical review. It was not intended to communicate any new policies, processes, or interpretations regarding medical device marketing authorizations. This workshop consisted of individual presentations, group discussions, question and answer sessions, and audience surveys. Information-sharing included discussions related to patient-reported outcomes, clinician-reported outcomes, observer-reported outcomes, and performance outcomes. Discussions involving external subject matter experts covered topics related to spinal device clinical studies including definition of a target population, enrollment criteria, strategies for inclusion of under-represented patient groups, reporting of adverse event and secondary surgical procedures, clinical study endpoints, and clinical outcome assessments. A meeting transcript and webcast workshop link are currently posted on the FDA website. Important related issues and challenges were discussed, and an exciting range of new ideas and concepts were shared which hold promise to advance regulatory science, patient care and future innovation related to spinal devices.

Use of Real-World Evidence for Regulatory Approval and Coverage of Medical Devices: A Landscape Assessment.

OBJECTIVES: To enhance the generalizability of the evidence it reviews, the US Food and Drug Administration (FDA) has encouraged manufacturers to expand the submission of real-world evidence (RWE). The extent to which this evidence, which is generated outside of research settings, can support decision making remains unclear. We described the current use of RWE for medical devices, assessed manufacturers' challenges in generating and using it for regulatory and coverage decisions, and identified opportunities to expand its use. METHODS: We conducted 27 solo and group interviews with FDA officials and representatives of device manufacturers, payers, and health technology assessment organizations. All interviews used a semistructured protocol and were transcribed to allow thematic analysis. RESULTS: Accessing and linking real-world data sources, identifying unique devices, capturing longitudinal data, limited staff expertise, and uncertain return on investment have hampered efforts to use real-world data. Many companies in our sample were conducting research using real-world data, but none had submitted RWE as the primary evidence supporting a premarket approval. FDA guidance was helpful, but regulatory requirements remained ambiguous and examples of successful regulatory decisions based on RWE were limited. Payers mainly used RWE to supplement experimental evidence in coverage decisions, evaluated both types of evidence in similar ways, and had concerns about the rigor of RWE. CONCLUSIONS: Technical challenges may slow efforts to generate and use RWE in the near term. Additional regulatory guidance and examples, greater use of rigorous study designs and analytic methods, and continued stakeholder engagement could accelerate the use of RWE.

Mulheres na gestão de tecnologias e engenharia clínica: o caso dos ventiladores pulmonares na Covid-19 / Women in technology management and clinical engineering: the case of pulmonary ventilators at Covid-19

RESUMO O risco iminente de desabastecimento de ventiladores pulmonares nos serviços de saúde acarretou diversas frentes de trabalho para disponibilizar o maior número possível desses equipamentos para o tratamento dos pacientes acometidos. O agravamento da crise sanitária colapsou serviços de saúde com busca isocrônica por leitos. Em meio ao colapso, foi detectada nova variante da linhagem Sars-CoV-2 e confirmado o primeiro caso de reinfecção. Entre os pontos críticos, foi destaque a escassez caótica de oxigênio e taxas de ocupação de leitos acima de 90%. Pretende-se relatar a participação das autoras nas iniciativas para o enfrentamento da pandemia de relevância internacional. Destacar a participação de mulheres em atividades que são cruciais para responder, em tempo oportuno, às demandas oriundas de emergências sanitárias. Por meio de método de pesquisa de abordagem descritiva e exploratória, buscou-se verificar o perfil das mulheres atuantes na gestão de tecnologias no enfrentamento da pandemia. Destaca-se a pesquisa recente da Associação Brasileira de Engenharia Clínica que verificou que apenas 19% dos associados respondentes eram mulheres, enquanto 81% eram do sexo masculino. Assim, divulgar e dar amplo conhecimento das ações de mulheres nessa área pode colaborar para o alcance da igualdade de gênero e empoderar todas as mulheres e meninas.

ABSTRACT The imminent risk of shortage of pulmonary ventilators in health services has resulted in several work fronts to maintain and make available the largest possible number of equipment available for the treatment of patients. The worsening of the health crisis has collapsed health services with an isochronic search for beds. Amid the collapse, a new variant of the Sars-CoV-2 strain was detected and the first case of reinfection was confirmed. Among the critical points was the chaotic oxygen scarcity and bed occupancy rates above 90%. We intend to report the participation of the authors in the initiatives to face the pandemic; highlight the participation of women in activities that are crucial to respond, in a timely manner, to the demands arising from health emergencies. Through a research method with a descriptive and exploratory approach, we sought to verify the profile of women working in the management of technologies in facing the pandemic. The recent survey by the Brazilian Association of Clinical Engineering stands out, which found that only 19% of the respondent associates were women. Thus, disseminating and giving broad knowledge of women´s actions in this area can collaborate in achieving gender equality and empower all women and girls.

Measuring Patient Preferences at the FDA Center for Devices and Radiological Health: Reflections and Projections.

OBJECTIVES: Patient preference information (PPI) is a way to incorporate the patient voice in the evaluation of medical devices. The US Food and Drug Administration (FDA) Center for Devices and Radiological Health (CDRH) has been working to encourage the voluntary inclusion of PPI throughout the medical device lifecycle for nearly a decade. This article reflects CDRH's efforts to encourage collection of PPI and offers perspectives on the future of PPI in the evaluation of medical devices. METHODS: CDRH regulatory guidance, public meetings, and collaborations relating to PPI were explored. RESULTS: Since 2012 when CDRH issued guidance on how PPI can be used as scientific evidence in the benefit-risk regulatory submission, CDRH has issued 5 subsequent guidance documents expanding on the use of PPI in medical device evaluations. CDRH remains committed to advancing the science and application of PPI in the medical device ecosystem through many collaborations with professional organizations, patient advocacy groups, and academic institutions. By hosting and actively participating in multiple scientific and regulatory public meetings and conferences, CDRH fosters a continuous learning environment where the experience of using PPI in regulatory submissions can be shared. A September 2020 meeting cosponsored by FDA and International Society for Pharmacoeconomics and Outcomes Research (ISPOR) discussed the state of PPI in regulatory applications and beyond. CONCLUSION: This article describes these pivotal events that have helped to increase the use of PPI in medical device evaluation as well as discusses future applications of PPI.

Scientific research and product development in the United States to address injuries from a radiation public health emergency.

The USA has experienced one large-scale nuclear incident in its history. Lessons learned during the Three-Mile Island nuclear accident provided government planners with insight into property damage resulting from a low-level release of radiation, and an awareness concerning how to prepare for future occurrences. However, if there is an incident resulting from detonation of an improvised nuclear device or state-sponsored device/weapon, resulting casualties and the need for medical treatment could overwhelm the nation's public health system. After the Cold War ended, government investments in radiation preparedness declined; however, the attacks on 9/11 led to re-establishment of research programs to plan for the possibility of a nuclear incident. Funding began in earnest in 2004, to address unmet research needs for radiation biomarkers, devices and products to triage and treat potentially large numbers of injured civilians. There are many biodosimetry approaches and medical countermeasures (MCMs) under study and in advanced development, including those to address radiation-induced injuries to organ systems including bone marrow, the gastrointestinal (GI) tract, lungs, skin, vasculature and kidneys. Biomarkers of interest in determining level of radiation exposure and susceptibility of injury include cytogenetic changes, 'omics' technologies and other approaches. Four drugs have been approved by the US Food and Drug Administration (FDA) for the treatment of acute radiation syndrome (ARS), with other licensures being sought; however, there are still no cleared devices to identify radiation-exposed individuals in need of treatment. Although many breakthroughs have been made in the efforts to expand availability of medical products, there is still work to be done.

Key Principles of Clinical Validation, Device Approval, and Insurance Coverage Decisions of Artificial Intelligence.

Artificial intelligence (AI) will likely affect various fields of medicine. This article aims to explain the fundamental principles of clinical validation, device approval, and insurance coverage decisions of AI algorithms for medical diagnosis and prediction. Discrimination accuracy of AI algorithms is often evaluated with the Dice similarity coefficient, sensitivity, specificity, and traditional or free-response receiver operating characteristic curves. Calibration accuracy should also be assessed, especially for algorithms that provide probabilities to users. As current AI algorithms have limited generalizability to real-world practice, clinical validation of AI should put it to proper external testing and assisting roles. External testing could adopt diagnostic case-control or diagnostic cohort designs. A diagnostic case-control study evaluates the technical validity/accuracy of AI while the latter tests the clinical validity/accuracy of AI in samples representing target patients in real-world clinical scenarios. Ultimate clinical validation of AI requires evaluations of its impact on patient outcomes, referred to as clinical utility, and for which randomized clinical trials are ideal. Device approval of AI is typically granted with proof of technical validity/accuracy and thus does not intend to directly indicate if AI is beneficial for patient care or if it improves patient outcomes. Neither can it categorically address the issue of limited generalizability of AI. After achieving device approval, it is up to medical professionals to determine if the approved AI algorithms are beneficial for real-world patient care. Insurance coverage decisions generally require a demonstration of clinical utility that the use of AI has improved patient outcomes.

Regulatory Agilities in the Time of COVID-19: Overview, Trends, and Opportunities.

PURPOSE: Crucial steps have been adopted by health and regulatory authorities around the world to respond to the COVID-19 pandemic. This review aims to highlight these steps by providing an overview of the regulatory approaches adopted during the onset of the pandemic, provide an assessment of observed trends, and offer some reflections and proposals to leverage learnings and opportunities from this current pandemic. METHODS: Documents and informational materials on regulating the development and management of medical products during the COVID-19 pandemic were collected and classified. These materials were sourced from official websites and press releases from health authorities and international bodies from selected markets across the globe, and covered the period between January and July 2020. Additional information to support this study was gathered through a literature review and analysis of related data available from the public domain, and was complemented with the authors' personal experience. FINDINGS: Communication has been vital in addressing the impact of COVID-19. A total of 1705 documents and informational materials related to health or regulatory response to the COVID-19 pandemic were gathered. Of these, 343 (around 20%) were identified as regulatory agilities. These agile approaches were classified into 3 categories, namely, where health and regulatory authorities had: (1) facilitated product management across the entire lifecycle, notably in expediting medical product use for COVID-19, ensuring the continuity of clinical trials, and addressing supply chain issues; (2) strengthened international cooperation; and (3) addressed regulatory burden with the adoption of electronic and digital tools. IMPLICATIONS: While many regulatory measures have been introduced temporarily as a response to the COVID-19 crisis, there are opportunities for leveraging an understanding from these approaches in order to collectively achieve more efficient regulatory systems and to mitigate and address the impact of COVID-19 and further future-proof the regulatory environment.

Efficacy of a conversion from filgrastim to filgrastim-sndz in stem cell transplant patients undergoing mobilization.

During autologous stem cell transplant, granulocyte colony-stimulating factors (G-CSF) serve the integral role of mobilizing hematopoietic cells into the peripheral blood for subsequent collection by leukapheresis. Filgrastim (Neupogen®) is a G-CSF and affects hematopoietic cells by stimulating growth and differentiation of neutrophils. Filgrastim-sndz (Zarxio®), a biosimilar of filgrastim, received landmark approval as the first biosimilar product approved by the FDA in the United States. As a result of the recent FDA approval, our medical center made the conversion in August 2016 from using filgrastim to filgrastim-sndz to provide patients the same benefits of the filgrastim injection at a reduced cost. This retrospective, observational cohort study evaluated the comparative efficacy of the filgrastim-sndz biosimilar in 147 patients who underwent mobilization prior to stem cell transplant with filgrastim between 1 August 2015 and 31 July 2016 or filgrastim-sndz between 1 September 2016 and 30 November 2017. The mean number of CD34 cells collected during apheresis was 7.38 × 106 in the filgrastim group and 8.86 × 106 in the filgrastim-sndz group. Filgrastim-sndz was significantly non-inferior, as the difference between filgrastim and filgrastim-sndz was -1.48 × 106 with an upper 95% confidence bound equal to -0.24 × 106 that did not include the non-inferiority margin of 1 × 106 (p = 0.0006). The median number of days of apheresis was 2 in both groups (p= 0.3273). In conclusion, the biosimilar product was non-inferior for mobilization and the conversion from filgrastim to filgrastim-sndz afforded patients similar efficacy for mobilization in stem cell transplant at a reduced cost.

Device profile of the LithoVue single-use digital flexible ureteroscope in the removal of kidney stones: overview of safety and efficacy.

Introduction: Flexible ureteroscopy is a commonly performed urologic procedure for visualization and treatment of the upper urinary tracts. Traditionally, ureteroscopy has been performed with reusable scopes, which have large initial purchasing costs. LithoVue was the first widely adopted single-use flexible ureteroscope clinically available in 2016 and has caused reevaluation of this paradigm. Areas covered: This review is an objective assessment of the LithoVue single-use ureteroscope based on available studies at the time of publication. The authors searched major databases for papers that included the term 'LithoVue' and included relevant papers. The state of the market, technical specifications, results from clinical studies and cost analyses, and competitors are discussed. Expert opinion: The LithoVue single-use flexible ureteroscope has comparable clinical performance to existing reusable ureteroscopes based on available data. Direct clinical comparisons to competing single-use ureteroscopes, many of which are relatively new, are limited. In numerous pre-clinical studies LithoVue performed favorably compared to available competitors. Cost analyses suggest that benefit of single-use ureteroscopes is institution-specific, and will likely be favorable at a low volume of cases and with high local costs for repairs of reusable scopes.

Assessment of Data Sources That Support US Food and Drug Administration Medical Devices Safety Communications.

Importance: Medical Device Safety Communications (MDSCs) are used by the US Food and Drug Administration (FDA) to convey important new safety information to patients and health care professionals. The sources of initial safety signals that trigger MDSCs have not been described previously. Objective: To assess the sources of initial safety signals that trigger publication of MDSCs and the potential associations among MDSC data source, type of safety issue, and subsequent FDA action. Design, Setting, and Participants: In this cross-sectional study, all MDSCs published on the FDA website between January 1, 2011, and December 31, 2019, were assessed. The MDSC characteristics, sources of initiating safety signals, regulatory approval or clearance pathways of the related medical devices, and subsequent FDA actions were collected from the FDA website. Main Outcomes and Measures: The main outcome was the distribution of sources of initial safety signals that led to publication of MDSCs. Secondary aims included exploration of potential associations among safety signal sources (direct reporting vs other), type of safety issue (death vs other), and FDA action (withdrawal vs other). Results: A total of 93 MDSCs were evaluated. Median time from device approval to MDSC posting was 10 years (interquartile range, 6-16 years). The most common data sources that triggered MDSCs were direct reports to the FDA through the Medical Device Reporting (MDR) program (44 of 93 [47%]) followed by regulator-initiated assessments (32 [34%]). Common safety issues included patient injury (25 [27%]), potential wrong diagnoses (19 [20%]), and death (18 [19%]). Frequent FDA action after MDSC posting included recommendation for increased vigilance and caution (47 [51%]), complete device withdrawal (12 [13%]), and warnings of specific lots or clinics (12 [13%]). There was a statistically significant correlation between direct reports of adverse events to the FDA through the MDR program and risk of death as a safety issue (14 of 44 [32%] for direct reporting vs 4 of 49 [8%] for any other data sources, P = .007). Conclusions and Relevance: In this cross-sectional study, the most common source of initial safety signals that triggered MDSCs was direct reports of real-world adverse events to the FDA through the MDR program. The delayed detection of postmarketing adverse events highlights the importance of proactive identification of emerging device-related safety issues.