Regulatory challenges in innovation and evaluation of extracorporeal membrane oxygenation: Database analysis and future perspectives

To the Editor: During the coronavirus disease 2019 (COVID-19) pandemic, patients with severe respiratory failure required ventilators or even higher levels of life support, bringing extracorporeal membrane oxygenation (ECMO) into the spotlight.[1] ECMO is commonly used for the rescue and treatment of patients with severe cardiopulmonary failure; its core components are the membrane lung (oxygenator) and blood pump with two fundamental support modes: venovenous (V-V) and venoarterial (V-A) ECMO. COVID-19 patients may require V-V ECMO for acute respiratory distress syndrome and when combined cardio-circulatory support is needed; the support mode could be V-A ECMO. Due to its high cost and heavy reliance on imported equipment in China, the rapid growth in patient demand during the pandemic has highlighted the “shortcomings” and “bottlenecks” in the development of high-end medical devices.[2] The Chinese government and the medical field have begun to pay attention to the establishment and capacity building of intensive care units (ICUs). Led by ECMO, they promote the research, development, and manufacturing of high-end medical devices. Considerable room still exists for improvements in the development and clinical research of ECMO for critically ill patients. We reviewed data on medical quality control for extracorporeal life support in China, including data from the National Center for Cardiovascular Quality Improvement (NCCQI), the Chinese Society of Extracorporeal Circulation (ChSECC), and the Chinese Society of Extracorporeal Life Support (CSECLS). Postmarketing reports of ECMO devices from regulatory authorities in the United States, Canada, Japan, Australia, the United Kingdom, and Germany were also collected. Commonly reported circuit- and device-related adverse events were analyzed. Recently, approved domestic ECMO systems and their characteristics, as well as key points of the review of the premarket approval of ECMO, are further described. In 2021, a total of 2042 tertiary hospitals and 3309 secondary hospitals were included in the Hospital Quality Monitoring System (HQMS) for cardiovascular disease diagnosis and treatment. Among these, 592 centers have submitted ECMO data to CSECLS, comprising a total of 10,656 cases [Table 1]. This marks the first year in which the reporting system has documented over 10,000 ECMO cases. There has been a noticeable rise in cases of extracorporeal cardiopulmonary resuscitation (ECPR) in the past 3 years. It is noteworthy that centers handling a case volume exceeding 50 cases annually account for over 50% of the total number of cases. Table 1 - ECMO cases and performance during 2019–2023 in China, from CSECLS. Items 2019 2020 2021 2022 2023 Report center, n 365 500 592 675 814 Reported ECMO case, n 6526 6937 10,656 13,491 18,486 Center with case volume >50 case/year, n (%) 29 (8) 31 (6) 53 (9) 60 (9) 98 (12) Respiratory support case, n (%) 2090 (32) 1822 (26) 2566 (24) 3407 (25) 5362 (29) Cardiac support case, n (%) 3483 (53) 3761 (54) 5951 (56) 7189 (53) 9076 (49) ECPR case, n (%) 953 (15) 1354 (20) 2139 (20) 2895 (22) 4048 (22) CSECLS: Chinese Society of Extracorporeal Life Support; ECMO: Extracorporeal Membrane Oxygenation; ECPR: Extracorporeal cardiopulmonary resuscitation. According to HQMS data, the in-hospital mortality rate for ECMO-supported patients in 2021 was 28.7% compared with 29.1% in 2020. The median length of hospital stay for patients gradually decreased, and the in-hospital mortality rate showed a declining trend. In 2021, the average total cost for hospitalized patients receiving ECMO support was RMB 258,575.7 Yuan, decreasing compared with RMB 288,501.7 Yuan in 2020. In 2021, the interprovincial out-of-town treatment rate for ECMO technology was 10.3%, indicating a smaller difference in ECMO technology between different regions. Moreover, given the development of cardiac surgery, potential exists for an increase in the use of ventricular assist devices, which affects the number of patients receiving heart transplants. Prior to 2019, the number of ECMO patients receiving cardiovascular surgery support rapidly increased by 30–60%, closely related to the acceptance of doctors and the promotion and training of academic organizations. Following the COVID-19 pandemic, the increase in the number of patients supported by ECMO became more pronounced, reflecting the continuous expansion of indications and the treatment timing as China’s ECMO treatment technology gradually matured. According to reports of COVID-19-related acute respiratory distress syndrome patients who were evaluated for lung transplantation, all patients were supported by ECMO during the perioperative period.[3] For non-transplanted COVID-19 patients, ECMO could be used in up to 8% of COVID-19 patients in 2020.[4] The most commonly reported adverse event from our analysis of the database was blood/fluid leakage. The main modes of mechanical pump failure included mechanical failure, clot development inside the pump, or cracks/leaks in the pump assembly. For the membrane oxygenator, the main failure modes included membrane rupture or cracking. Issues related to access cannulae include structural damage leading to cracking and leakage of cannulae, resulting in blood loss. Other failure modes included the malfunction and alarm of the ECMO pump console or control unit, drive, and in-line monitors. Patient-related adverse events are outlined in Supplementary Table 1, https://links.lww.com/CM9/C200. In recent years, the licensed manufacturers of ECMO products in the Chinese market, from the United States and Europe, account for more than 70% of the global market. Since early 2023, three domestic ECMO systems from Shenzhen city, Jiangsu Province, and Beijing have been approved by the National Medical Products Administration (NMPA), China. These devices have been marketed since approval and have demonstrated their efficiency and safety in clinical use. According to the regulatory review, the verification of device performance and clinical research design were key focuses before device marketing and post-marketing investigations. From the point of view of regulatory authority reviews, several points need to be emphasized, and more evidence must be submitted and evaluated in premarket approval reviews [Supplementary Table 2, https://links.lww.com/CM9/C200]. The future development of ECMO primarily stems from improving the design of existing system flaws. Research directions and approaches include further improving the biocompatibility of existing membrane materials and coatings, miniaturizing and biomimicking blood pumps, and enhancing oxygenation and carbon dioxide removal efficiency. Anticoagulation coatings have been developed for use in ECMO circuits to address prolonged ECMO support. Research groups from China have devoted substantial efforts to developing more reliable and sustainable anticoagulant coatings to enhance the performance of domestic equipment.[5] ECMO-based respiratory support medical devices, which are used in critically ill patients, carry inherent risks and are classified as Class III medical devices in China. Before market approval, strict risk–benefit assessments and robust clinical trial evidence are required for the first clinical use of such devices. Regulatory agencies in the United States, Japan, and China have been promoting upgrades in extracorporeal life support and artificial organ technologies through the establishment of standards, guidelines, and principles. Currently, no established method or model for in vivo and in vitro testing of long-term device applications exists, which hinders comprehensive evaluation of the safety and effectiveness of new devices. The current reference standard is ISO 7199:2016; however, it does not fully simulate the flow, pressure, or real-time monitoring of O2/CO2 under physiological and pathological conditions in long-term application environments. The lack of consideration for changes in blood composition over time, differences between the patient’s blood environment and the test fluid, and the effects of anticoagulation all affect the consistency between in vitro testing data and animal models or human application scenarios. In addition to considering various indicators of biocompatibility for premarket product safety and efficacy evaluations, it is essential to identify the appropriate patient population for clinical application to objectively assess the therapeutic effects of the devices and the extent to which they improve the prognosis of end-stage patients. During the development of ECMO, data on critically ill patients were obtained from multiple centers, national databases, and international ECMO data registries. In the current clinical application of ECMO, the diversity of experiences from different disciplines and centers significantly increases the heterogeneity of treatment outcomes, research conclusions, and medical costs. Given the gradual increase in the standardization of ECMO practices and the emergence of domestic ECMO equipment, patients’ long-term survival and quality of life, as well as the total medical cost, will be more optimized. In 2023, there was a noticeable uptick in pediatric ECMO cases, drawing increased attention to critically ill pediatric patients. The clearance of more domestic ECMO systems led to a significant rise in reported cases since 2023. Consequently, especially in the realm of intricate treatments that encompass various influencing factors like medications or medical devices utilized in managing critical conditions such as end-stage heart failure or respiratory failure, the comprehensive adoption of a pre-ECMO management strategy is crucial. This strategy includes optimized respiratory support and hemodynamic management. Hence, the incorporation of flexible trial designs and the assessment of probabilities regarding patient benefits under diverse scenarios are imperative for a more impartial evaluation of ECMO’s availability, safety, and efficacy within patient cohorts. Currently, medical device evaluation and regulatory agencies in China are continuously promoting the establishment of a scientific evaluation guidance principle system. By intervening early in the development process, they continually discuss critical issues with enterprises, promptly share the latest insights on common problems with the industry, fully consider emergency authorizations and clinical needs, establish a scientific and efficient technical evaluation pathway, and promote public accessibility to high-end medical devices. The establishment of a medical equipment-oriented research queue can ensure timely, open, and transparent data, allowing all parties in the industry to promptly learn about clinical application progress, and adjust research and development directions or health policies. In the context of COVID-19 pandemic control, global experience in the use of ECMO systems has been accumulated, driving technological advancements in related fields. Apart from preparing for future outbreaks of infectious diseases and providing more life support options for critically ill patients, medical institutions, enterprises, and regulatory agencies need to establish new collaborative models in product development, clinical trial design, and data interpretation. Furthermore, post-market supervision to enhance strategic technological capabilities and strategic reserve capacity in epidemic prevention and control and public health fields quickly fills the gaps in high-end medical equipment and safeguards the rights of people to life and health. Funding This study was supported by grants from Noncommunicable Chronic Diseases-National Science and Technology Major Project (No. 2023YFC2507100) and National Medical Products Administration Key Laboratory for Extracorporeal Circulation Devices: Open Project (No. 2024YB01).

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