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.

Analysis of Devices Authorized by the FDA for Clinical Decision Support in Critical Care.

This case series study examines the clinical evidence cited for US Food and Drug Administration­approved clinical decision support devices for use in the critical care setting.

Use of Recalled Devices in New Device Authorizations Under the US Food and Drug Administration's 510(k) Pathway and Risk of Subsequent Recalls.

Importance: In the US, nearly all medical devices progress to market under the 510(k) pathway, which uses previously authorized devices (predicates) to support new authorizations. Current regulations permit manufacturers to use devices subject to a Class I recall-the FDA's most serious designation indicating a high probability of adverse health consequences or death-as predicates for new devices. The consequences for patient safety are not known. Objective: To determine the risk of a future Class I recall associated with using a recalled device as a predicate device in the 510(k) pathway. Design and Setting: In this cross-sectional study, all 510(k) devices subject to Class I recalls from January 2017 through December 2021 (index devices) were identified from the FDA's annual recall listings. Information about predicate devices was extracted from the Devices@FDA database. Devices authorized using index devices as predicates (descendants) were identified using a regulatory intelligence platform. A matched cohort of predicates was constructed to assess the future recall risk from using a predicate device with a Class I recall. Main Outcomes and Measures: Devices were characterized by their regulatory history and recall history. Risk ratios (RRs) were calculated to compare the risk of future Class I recalls between devices descended from predicates with matched controls. Results: Of 156 index devices subject to Class I recall from 2017 through 2021, 44 (28.2%) had prior Class I recalls. Predicates were identified for 127 index devices, with 56 (44.1%) using predicates with a Class I recall. One hundred four index devices were also used as predicates to support the authorization of 265 descendant devices, with 50 index devices (48.1%) authorizing a descendant with a Class I recall. Compared with matched controls, devices authorized using predicates with Class I recalls had a higher risk of subsequent Class I recall (6.40 [95% CI, 3.59-11.40]; P<.001). Conclusions and Relevance: Many 510(k) devices subjected to Class I recalls in the US use predicates with a known history of Class I recalls. These devices have substantially higher risk of a subsequent Class I recall. Safeguards for the 510(k) pathway are needed to prevent problematic predicate selection and ensure patient safety.

Association Between Regulatory Submission Characteristics and Recalls of Medical Devices Receiving 510(k) Clearance.

Importance: Most regulated medical devices enter the US market via the 510(k) regulatory submission pathway, wherein manufacturers demonstrate that applicant devices are "substantially equivalent" to 1 or more "predicate" devices (legally marketed medical devices with similar intended use). Most recalled medical devices are 510(k) devices. Objective: To examine the association between characteristics of predicate medical devices and recall probability for 510(k) devices. Design, Setting, and Participants: In this exploratory cross-sectional analysis of medical devices cleared by the US Food and Drug Administration (FDA) between 2003 and 2018 via the 510(k) regulatory submission pathway, linear probability models were used to examine associations between a 510(k) device's recall status and characteristics of its predicate medical devices. Public documents for the 510(k) medical devices were collected using FDA databases. A text extraction algorithm was applied to identify predicate medical devices cited in 510(k) regulatory submissions. Algorithm-derived metadata were combined with 2003-2020 FDA recall data. Exposures: Citation of predicate medical devices with certain characteristics in 510(k) regulatory submissions, including the total number of predicate medical devices cited by the applicant device, the age of the predicate medical devices, the lack of similarity of the predicate medical devices to the applicant device, and the recall status of the predicate medical devices. Main Outcomes and Measures: Class I or class II recall of a 510(k) medical device between its FDA regulatory clearance date and December 31, 2020. Results: The sample included 35 176 medical devices, of which 4007 (11.4%) were recalled. The applicant devices cited a mean of 2.6 predicate medical devices, with mean ages of 3.6 years and 7.4 years for the newest and oldest, respectively, predicate medical devices. Of the applicant devices, 93.9% cited predicate medical devices with no ongoing recalls, 4.3% cited predicate medical devices with 1 ongoing class I or class II recall, 1.0% cited predicate medical devices with 2 ongoing recalls, and 0.8% cited predicate medical devices with 3 or more ongoing recalls. Applicant devices citing predicate medical devices with 3 or more ongoing recalls were significantly associated with a 9.31-percentage-point increase (95% CI, 2.84-15.77 percentage points) in recall probability compared with devices without ongoing recalls of predicate medical devices, or an 81.2% increase in recall probability relative to the mean recall probability. A 1-SD increase in the total number of predicate medical devices cited by the applicant device was significantly associated with a 1.25-percentage-point increase (95% CI, 0.62-1.87 percentage points) in recall probability, or an 11.0% increase in recall probability relative to the mean recall probability. A 1-SD increase in the newest age of a predicate medical device was significantly associated with a 0.78-percentage-point decrease (95% CI, 1.29-0.30 percentage points) in recall probability, or a 6.8% decrease in recall probability relative to the mean recall probability. Conclusions and Relevance: This exploratory cross-sectional study of 510(k) medical devices cleared by the FDA between 2003 and 2018 demonstrated significant associations between 510(k) submission characteristics and recalls of medical devices. Further research is needed to understand the implications of these associations.

Effect of the FDA Safety and Innovation Act on racial and gender diversity in neurosurgical device trials.

OBJECTIVE: The US FDA uses evidence from clinical trials in its determination of safety and utility. However, these trials have often suffered from limited external validity and generalizability due to unrepresentative study populations with respect to clinical patient demographics. Section 907 of the FDA Safety and Innovation Act (FDASIA) of 2012 attempted to address this issue by mandating the reporting of certain study demographics in new device applications. However, no study has been performed on its effectiveness in the participant diversity of neurosurgical device trials. METHODS: The FDA premarket approval (PMA) online database was queried for all original neurosurgical device submissions from January 1, 2006, to December 31, 2019. Endpoints of the study included racial and gender demographics of reported effectiveness trials, which were summated for each submission. Chi-square tests were performed on both endpoints for before and after years of FDASIA passage and implementation. RESULTS: A total of 33 device approvals were analyzed, with 14 occurring before SIA implementation and 19 after. Most trials (96.97%) reported gender to the FDA, while 66.67% reported race and 63.64% reported ethnicity. Gender breakdown did not change significantly post-SIA (53.30% female, p = 0.884). Racial breakdown was significantly different from the 2010 US Census for all races (p < 0.001) both pre- and post-SIA. Only Native American race was significantly different in terms of representation post-SIA, increasing from 0% to 0.63% (p = 0.0187). There was no significant change in ethnicity. CONCLUSIONS: The FDASIA, as currently written, does not appear to have had a significant impact on the racial or gender diversity of neurosurgical device clinical trial populations. This may be due to the noncompulsory nature of its guidance, or a lack of more stringent regulation on the composition of clinical trials themselves.

FDA Regulation and Approval of Medical Devices: 1976-2020.

Importance: US law generally requires testing of high-risk medical devices prior to approval, as well as premarket evaluation of moderate-risk medical devices, with the goal of ensuring that the benefits of these products exceed their risks. The US Food and Drug Administration (FDA) attempts to balance the need for evidence generation with an approval process that facilitates access and encourages innovation. Objective: To review the development of laws and standards affecting the evaluation and oversight of medical devices by the US regulatory system and the outcomes of this system from 1976 to 2020. Evidence Review: Laws enacted by US Congress and regulations promulgated by the FDA through 2020; databases maintained by the FDA of device authorizations from 1976 to 2020; and annual reports of user fees paid to the FDA by industry. Findings: Since Congress and the FDA initiated premarket review of medical devices in 1976, some fundamental innovations in the device regulation system have included special pathways to accelerate availability of investigational devices, more flexible evidence and review requirements, and increased funding to the FDA through industry-paid user fees. From 1987 to 2020, the annual number of novel devices granted premarket approval (which excludes supplements) ranged from 8 to 56 (median, 32), and the number of clearances for 510(k) devices (those that are "substantially equivalent" to marketed devices) ranged from 2804 to 5762 (median, 3404). User fee funding for devices was established in 2002 and annual fees collected increased from $30 million in 2003 (in 2019 dollars) to more than $208 million in 2019; this represented 43% of FDA funding related to the review of medical devices. Although many new devices have led to considerable patient benefit, such as hypodermic needles and magnetic resonance imaging machines, important adverse events caused by some devices, such as an implanted device for birth control and a surgical mesh implant for pelvic organ prolapse, have led to calls to reexamine the regulatory system for such products. Conclusions and Relevance: Over the last 45 years, medical device regulation has become more complex, with more regulatory pathways and greater variations in the evidence and controls required for authorization. Increased FDA support from industry and concern about flexible authorization requirements reflect the tension between efficient access and the need for assurances that products will safely benefit patients.

Easing Medical Device Regulatory Oversight: The FDA and Testing Amidst the COVID-19 Pandemic.

The FDA already subjects most medical devices to much less stringent approval requirements than drugs and biologics, and attempts to speed up rollout during the COVID crisis have been problematic. Agency decisions, including to allow antibody test marketing without emergency use authorization or review, and the back-and-forth guidance on laboratory-developed tests, have met harsh criticism and unreliable results. Though the long-term results of these decisions are unclear, the FDA's credibility, reliability, and commitment to safety are threatened by even further lessening medical device regulatory oversight during the coronavirus pandemic. The relaxed and fix-it-later approach to many of the FDA's public health emergency decisions regarding medical devices reflect the ongoing criticisms of medical device regulation in general, specifically the 510(k) process and laboratory developed test regulation, offering a point of reflection towards reform. Adaptive legislation and a risk-based and evidentiary approach to premarket and postmarket review can begin to address these issues both generally and in an emergency context.

Quantification of US Food and Drug Administration Premarket Approval Statements for High-Risk Medical Devices With Pediatric Age Indications.

Importance: Medical device companies submit premarket approval (PMA) statements to the US Food and Drug Administration (FDA) for approval of the highest-risk class of devices. Devices indicated for the pediatric population that use the PMA pathway have not been well characterized or analyzed. Objective: To identify and characterize high-risk devices with pediatric age indications derived from PMA statements. Design, Setting, and Participants: In this cross-sectional study of PMA statements, those statements containing the words indicated or intended for medical devices listed in the FDA PMA database as of February 2020 were retrieved. Age indications were manually annotated in these approval statements via PubAnnotation. Based on the PMA identification from the PMA statements, device metadata including product codes, regulation numbers, advisory panels, and approval dates were queried. Main Outcomes and Measures: The main outcome was discernment of the distribution of devices indicated for the pediatric population (neonate, infant, child, and adolescent). Secondary measures included outlining the clinical specialties, device types, and lag time between the initial approval date and the first date of an approval statement with a pediatric indication for generic device categories. Results: A total of 297 documents for 149 unique devices were analyzed. Based on the manual age annotations, 102 devices with a pediatric indication, 10 with a neonate age indication, 32 with an infant age indication, 60 with a child age indication, and 94 with an adolescent age indication were identified. For indications for patients from age 17 to 18 years, the number of devices available nearly doubled from 42 devices to 81 devices. Although more than half of the surveyed devices had a pediatric age indication, many were available only for a limited range of the pediatric population (age 18-21 years). For indications for patients from age 0 to 17 years, the mean (SD) number of clinical specialties at each age was 7.27 (1.4), and 12 clinical specialties were represented from ages 18 to 21 years. Conclusions and Relevance: In this cross-sectional study on device PMA statements, a gap was identified in both quantity and diversity of high-risk devices indicated for the pediatric population. Because the current scarcity of pediatric devices may limit therapeutic possibilities for children, this study represents a step toward quantifying this scarcity and identifying clinical specialties with the greatest need for pediatric device innovation and may help inform future device development efforts.

Risk of Recall Among Medical Devices Undergoing US Food and Drug Administration 510(k) Clearance and Premarket Approval, 2008-2017.

Importance: The US Food and Drug Administration (FDA) uses 510(k) clearance and premarket approval (PMA) pathways to ensure device safety before marketing. Premarket approval evaluates high-risk medical devices and requires clinical trials, whereas 510(k) clearance evaluates moderate-risk devices and relies on benchtop (nonclinical and biomechanical) and descriptive data. Existing literature suggests that the clinical trials required by PMA are associated with reduced risk of recall compared with devices granted 510(k) clearance. Several investigators have found weaknesses in pivotal PMA trials, raising safety concerns. Furthermore, methodological factors may have led to a previous underestimation of recall risk for devices with PMA. Objectives: To compare risk of recall and high-risk recall between devices that received 510(k) clearance and those that received PMA and to compare the risk of recall between devices for medical specialties. Design, Setting, and Participants: This cohort study compared devices with 510(k) clearance vs those with PMA that reached the market between January 1, 2008, and December 31, 2017. Two- to 12-year follow-up was obtained from the FDA's 510(k) and PMA medical device database. Orthopedic surgery was chosen arbitrarily as the reference category for analysis between specialties because no baseline exists. Statistical analysis was performed from February 1 to November 1, 2020. Main Outcomes and Measures: The FDA issues recalls for safety concerns. These recalls are stratified into class I, II, and III, with class I representing high-risk issues for serious harm or death. The main outcome was the hazard ratio of any recall and class I recall between devices with PMA and those with 510(k) clearance. The secondary outcome was the recall hazard ratio between specialties with respect to the reference category. A single Cox proportional hazards regression model evaluating the association of medical specialty and FDA approval pathway with the risk of recall was performed. Results: During the study period, 28 246 devices received 510(k) clearance and 310 devices (10.7%) received PMA; 3012 devices (10.7%) with 510(k) clearance and 84 devices (27.1%) with PMA were recalled. A total of 216 devices (0.8%) with 510(k) clearance and 16 devices (5.2%) with PMA had class I recalls. Devices with PMA compared with those with 510(k) clearance had a hazard ratio for recall of 2.74 (95% CI, 2.19-3.44; P < .001) and a hazard ratio for high-risk recall of 7.30 (95% CI, 4.39-12.13; P < .001). Only radiologic devices were associated with an increased risk of recall (hazard ratio, 1.57; 95% CI, 1.32-1.87; P < .001), whereas 6 specialties were assocated with a decreased risk compared with the orthopedic reference category: general and plastic surgery, otolaryngology, obstetrics and gynecology, physical medicine, hematology, and general hospital. Conclusions and Relevance: This study suggests that high-risk medical devices approved via PMA are associated with a greater risk of recall than previously reported. Most recalls are for devices with 510(k) clearance, also raising safety concerns. Strengthening postmarketing surveillance strategies and pivotal trials may improve device safety.

The U.S. Food and Drug Administration's role in improving radiation dose management for medical X-ray imaging devices.

The U.S. Food and Drug Administration (FDA) has been concerned with minimizing the unnecessary radiation exposure of people for half a century. Manufacturers of medical X-ray imaging devices are important partners in this effort. Medical X-ray imaging devices are regulated by FDA under both its electronic product regulations andits medical device regulations. FDA also publishes guidance documents that represent FDA's current thinking on a topic and provide a suggested or recommended approach to meet the requirements of a regulation or statute. FDA encourages manufacturers to develop medical devices that conform to voluntary consensus standards. Use of these standards is a central element of FDA's system to ensure that all medical devices marketed in the U.S. meet safety and effectiveness requirements. FDA staff participate actively in the development and maintenance of these standards, often advancing or introducing new safety and dose management requirements. Use of voluntary consensus standards reduces the amount of time necessary to evaluate a premarket submission and reduces the burden on manufacturers. FDA interacts with industry and other stakeholders through meetings with industry groups, public meetings, public communications, and through the development of voluntary consensus standards. In these interactions, FDA staff introduce new concepts for improving the safety of these devices and provide support for similar initiatives from professional organizations. FDA works with all stakeholders to achieve its mission of protecting and promoting the public health.

Comparison of supportive regulatory measures for pediatric medical device development in Japan and the United States.

Further development of medical devices for children is required in Japan, but the development of such devices is delayed compared to that of medical devices for adults. Herein, we investigated policies for advancing the development of pediatric medical devices in Japan and the United States. Considering the achievements of each policy, we proposed a strategy to promote further development of pediatric medical devices in Japan. We investigated policies for supporting the development of pediatric medical devices and approved cases in Japan and the United States by searching contents of websites of regulatory bodies and other related administrations, and scientific papers. We found the main six policies in Japan and nine main policies in the United States for the development of pediatric medical devices. In the United States, various measures have initiated mainly in the 2000s, while in Japan, the main measures have been in place since 2013. Similarities were found in both countries, such as subsidies for application fees and research and development expenses, exemption of requirements for regulatory approval, and priority review and consultation by the regulatory body. Our study revealed that there are similarities in initiatives by both countries. To promote further development of pediatric medical devices in the future, improvements to expediting the review process to approval by the regulatory body, global development, and implementation of alternative measures to ensure the efficacy and safety of the device instead of large-scale clinical trials should be anticipated through cooperation among industry, government, and academia.