EU's Medical Device Expert Panels: Analysis of Membership and Published Clinical Evaluation Consultation Procedure (CECP) Results.

BACKGROUND: The new EU Medical Device Regulation (MDR) places greater importance on the role of clinical evidence to establish safety and performance. Article 54 of the MDR calls for expert committees to independently review the scientific, technical, and clinical evidence supporting the market authorization of certain novel devices independently from the established process of Notified Body reviews. These experts provide a review and opinion that ultimately is taken into consideration alongside the information reviewed by the Notified Body during the review process. Four expert committees (General and Plastic Surgery and Dentistry; Orthopaedics, Traumatology, Rehabilitation, Rheumatology; Circulatory System; and Neurology) have published at least one Scientific Opinion (SO) under the Clinical Evaluation Consultation Procedure (CECP) in 2021-2022. METHODS: The four expert committees with published CECP opinions were reviewed to assess the academic backgrounds and professional expertise of each member with respect to clinical, technical, and biological domains on a 0-2 scale for each domain. A content review was conducted on the 10 CECP opinions published by these committees to assess their consistency with the goals and outcome expectations set by the MDR. The extent of content related to each of the clinical, technical, and biological domains was also assessed on a 0-2 scale. RESULTS: All committees were composed primarily by members with strong clinical expertise, but only a few had strong technical and biological expertise. Across committees, the average scores of members related to academic background and professional expertise both ranged from 1.64 to 2.00 in the clinical domain, but only 0-0.15 and 0.15-0.69, respectively, in the biological domain, and 0.12-0.55 and 0.23-0.73, respectively, in the technical domain. A content review for the 10 SOs showed that all opinions focused exclusively or primarily on the clinical evidence. Three contained a modest amount of additional text directed at technical/engineering issues and five at biological issues. CONCLUSION: Expert committees are composed predominantly of expert clinical reviewers but have many fewer members with significant technical or biological expertise. This may limit the ability of the committees to evaluate the significant technical and biological risks that are often best understood by preclinical testing. Broadening the expertise across the committees may improve the depth of their benefit/risk critiques.

Use of patent term extensions to restore regulatory time for medical devices in the United States.

BACKGROUND: Medical devices can seek patent term extensions (PTEs), which extend market exclusivity to compensate for delays related to clinical trials and regulatory review. Pharmaceutical companies commonly use PTEs, but their use by medical device companies has not been clear. RESEARCH DESIGN AND METHODS: We examined the use of PTEs by medical device companies between 1984 and 2024 using a database published in the Federal Register and a list published by the Patent and Trademark Office. RESULTS: Only 178 medical device submissions were linked to a PTE application. They were mostly concentrated in 116 product codes associated with 15 medical specialties; nearly half were associated with cardiovascular devices. Numbers increased significantly in the past decade. Successful applications restored 987 days on average. CONCLUSIONS: The patent restoration opportunity appears underutilized. It is unclear whether some companies do not recognize the opportunity it promises, or whether it does not meet their needs. Different business features and marketing strategies in device versus pharmaceutical industries may decrease the usefulness of the PTE program for these types of medical products. However, the finding that a small subset of manufacturers operating in competitive markets adopted patent extension strategies more commonly suggests a significant competitive advantage when competition increases.

Standalone Regulatory Agreements for Product-Development Collaborations in the Medical Products Industry.

BACKGROUND: Medical-product companies often outsource research and manufacturing needs to contracting or partnering organizations but then must manage a challenging patchwork of regulatory activities. A standalone regulatory agreement could clarify the relationships and responsibilities between companies working jointly on a single regulated product. This study explored the need for and current use of standalone regulatory agreements. METHODS: A survey instrument was developed using an implementation framework and disseminated to mid- to senior-level employees and consultants for sponsor and vendor companies in the medical products sector. RESULTS: Of 294 respondents, about half, primarily from companies with more than 200 employees, were familiar with standalone regulatory agreements, and half of this subgroup had moved forward to implement them. Such agreements were considered beneficial to clarify regulatory roles and responsibilities, standardize regulatory expectations between the companies, and stimulate earlier discussion about joint regulatory strategies. However, the development of regulatory agreements appears challenged by the fact that such agreements are not required by regulatory agencies overseeing medical products and have no standardized templates, agency or industry guidance. Respondents whose organizations do not now use regulatory agreements either had not considered or did not see a need for a standalone agreement. CONCLUSIONS: Standalone regulatory agreements are becoming more common but are not yet implemented fully by most companies. Their usefulness and content appeared to depend upon the type of partner, the complexity of the relationship and the availability of internal expertise and support.

Trends and Challenges in Access to Essential Medicines in Ethiopia and the Contributions of Local Pharmaceutical Production.

Decades ago, the United Nations declared that access to essential medicines was a key element of universal human rights. Accordingly, member states have been striving to address this issue through strategic policies and programs. Strengthening local pharmaceutical production has been a pivotal strategy adopted by many developing countries including Ethiopia. The government of Ethiopia identified local pharmaceutical production as a key industrial sector and has been implementing a ten-years strategic plan to improve capabilities and attract investment. Such support is needed because local production could satisfy only 15 to 20% of the national demand, typically from a limited portfolio of medicines in conventional dosage forms. The increasing prevalence of chronic diseases has accentuated the need for a more sustainable supply to reduce reliance on imports and increase access to essential medicines. A full understanding of the structure, constraints and complexities of the Ethiopian pharmaceutical market structure is vital to direct effective policies, target most impactful investments and exploit opportunities for leapfrogging. Hence, the purpose of this review was to assess the trends and challenges in access to essential medicines and local pharmaceutical production in Ethiopia. Literature search through major databases and review of policy documents and performance reports from relevant sector institutions were made to extract information for the review.

A novel maturity index for assessing medical device startups.

Background: Startup companies in the healthcare sector often fail because they lack sufficient entrepreneurial, regulatory, and business development expertise. Maturity models provide useful frameworks to assess the state of business elements more systematically than heuristic assessments. However, previous models were developed primarily to characterize the business state of larger nonmedical companies. A maturity index designed specifically for startup companies in the medical product sector could help to identify areas in which targeted interventions could assist business development. Methods: A novel MedTech Startup Maturity Index (SMI) was developed by a collaborative team of academic and industry experts and refined through feedback from external stakeholders. Pediatric medical device startups associated with the West Coast Consortium for Technology & Innovation in Pediatrics (CTIP) were scored and ranked according to the SMI following semi-structured interviews. The CTIP executive team independently ranked the maturity of each company based on their extensive experiences with the same companies. Results: SMI scores for 16 companies ranged from 1.2 to 3.8 out of 4. These scores were well aligned with heuristic CTIP rankings for 14 out of 16 companies, reflected by strong correlations between the two datasets (Spearman's rho = 0.721, P = 0.002, and Kendall's tau-b = 0.526, P = 0.006). Conclusions: The SMI yields maturity scores that correlate well with expert rankings but can be assessed without prior company knowledge and can identify specific areas of concern more systematically. Further research is required to generalize and validate the SMI as a pre-/post-evaluation tool.

Pediatric Medical Device Development and Regulation: Current State, Barriers, and Opportunities.

Few medical devices are designed and marketed specifically for children. Instead, adult devices are often repurposed and used off-label in pediatrics. The innovation gap between pediatric and adult devices is complex and multifactorial. This review aims to summarize the medical device landscape, describe barriers to pediatric device development, and provide an update on current strategies to help overcome these limitations. Medical devices are regulated by the Food and Drug Administration. They are registered, cleared, or approved on the basis of a 3-tier risk classification system and a differentiated set of regulatory pathways. This includes some for products that receive special designations on the basis of specific aspects that warrant more rapid review and approval. Pediatric devices number only one-quarter of those developed for adults for multiple reasons. Clinically, innovators must adjust their products to address the smaller sizes, growth, and longer duration of use in children. Smaller sample sizes and population heterogeneity also challenge the ability to obtain sufficient safety data for regulatory submissions. Financial concerns stem from lower pediatric reimbursement rates coupled with a lack of nationally standardized coverage. There are a number of promising initiatives, including the Pediatric Device Consortia Program, Early Feasibility Studies, and the new System of Hospitals for Innovation in Pediatrics - Medical Devices. However, the gap will likely not be narrowed without broad cooperation across stakeholders from industry, academia, patient advocacy groups, health care providers, investors, payors, regulators, and Congress.

Impact of non-binding FDA guidances on primary endpoint selection in Alzheimer's disease trials.

Introduction: The U.S. Food and Drug Administration (FDA)'s guidances help describe the agency's current thinking on regulatory issues and serve as a means of informal policymaking that is non-binding. This study examines the impact of two guidance documents for Alzheimer's disease (AD) trials. The first guidance in 2013 encouraged the use of cognitive/functional endpoints, while the second in 2018 modified such recommendation. Methods: Using pivotal trial data, we applied a regression discontinuity in time (RDiT) framework to examine trialist response to these guidance documents. Results were stratified by disease-modifying therapy (DMT) status, and controlled for disease staging, FDA registration status, and trial phase. Results: Among AD DMT trials, annual use of cognitive/functional composite endpoints significantly increased after the 2013 guidance (+12.9%, P < .001), and significantly decreased after the 2018 guidance (-19.9%, P = .022). Discussion: Although guidance documents do not set new legal standards or impose binding requirements, our findings indicate they are broadly followed by AD trialists.

Turning Neural Prosthetics Into Viable Products.

Academic researchers concentrate on the scientific and technological feasibility of novel treatments. Investors and commercial partners, however, understand that success depends even more on strategies for regulatory approval, reimbursement, marketing, intellectual property protection and risk management. These considerations are critical for technologically complex and highly invasive treatments that entail substantial costs and risks in small and heterogeneous patient populations. Most implanted neural prosthetic devices for novel applications will be in FDA Device Class III, for which guidance documents have been issued recently. Less invasive devices may be eligible for the recently simplified "de novo" submission routes. We discuss typical timelines and strategies for integrating the regulatory path with approval for reimbursement, securing intellectual property and funding the enterprise, particularly as they might apply to implantable brain-computer interfaces for sensorimotor disabilities that do not yet have a track record of approved products.

Opportunities for Regulatory Changes to Promote Pediatric Device Innovation in the United States: Joint Recommendations From Pediatric Innovator Roundtables.

OBJECTIVE: The purpose of this report is to provide insight from pediatric stakeholders with a shared desire to facilitate a revision of the current United States regulatory pathways for the development of pediatric healthcare devices. METHODS: On August 5, 2020, a group of innovators, engineers, professors and clinicians met to discuss challenges and opportunities for the development of new medical devices for pediatric health and the importance of creating a regulatory environment that encourages and accelerates the research and development of such devices. On January 6, 2021, this group joined regulatory experts at a follow-up meeting. RESULTS: One of the primary issues identified was the need to present decision-makers with opportunities that change the return-on-investment balance between adult and pediatric devices to promote investment in pediatric devices. DISCUSSION/CONCLUSION: Several proposed strategies were discussed, and these strategies can be divided into two broad categories: 1. Removal of real and perceived barriers to pediatric device innovation; 2. Increasing incentives for pediatric device innovation.

Graduate Training Capacity for Regulatory Professionals at US Universities: Are We Facing a Talent Crisis?

BACKGROUND: Talent acquisition in regulatory affairs has been a continuing challenge now exaggerated by demographic shifts and expansion of regulatory requirements nationally and globally. METHODS: Survey and interview methods were used to provide information on graduation rates, graduate characteristics, and enrollment trends in the 17 US regulatory programs that could be identified to offer graduate degrees in regulatory affairs or regulatory science. RESULTS: US programs graduated approximately 522 MS and 4 doctoral students in 2018. About 70% of students attended programs in the Northeast; the remaining students were evenly split between programs in the Northwest and Southeast/Southwest. About half of the programs provided content by distance only. About 127 students were new entrants to the workforce; enrollments for this group most commonly leveled or decreased over the last 3 years. The primary challenge identified by most programs was the high tuition that discouraged participation by qualified candidates for the programs. Challenges were also reported when attracting international students because of tightening visa restrictions and consequent reluctance of industry to hire students with a temporary visa status. CONCLUSIONS: The small number of graduating regulatory professionals from US universities is alarming because it falls far short of needs estimates for positions in regulatory departments. The particularly low number of entry-level professionals seems unlikely to be adequate as unemployment rates tighten and experienced professionals become harder to attract. These shortfalls may be particularly hurtful to small companies unable to compete for experienced professionals.

Biobank Continuity Management: A Survey of Biobank Professionals.

Academic biobanks face challenges that call for continuity and disaster planning. However, current regulations do not require such planning, so it is unclear if and how biobanks have prepared themselves to deal with future crises. This exploratory study used mixed methods to understand the state of continuity planning in U.S. biobanks. It first reviewed the current state of regulatory and implementation requirements that drive and challenge continuity planning. A survey instrument was then developed and critiqued by a focus group of experienced practitioners in biobanking. The refined survey was disseminated to a targeted group of respondents employed at biobanks across the United States. Most respondents were associated with relatively mature biobanks in operation for more than 6 years and these typically had some form of continuity plan in place. More commonly, continuity planning was reported to be focused on countering natural disasters rather than organization- or personnel-related crises. Respondents identified their most common limitation to be financial resources affecting all phases of implementation. Although many respondents appeared to be aware of some guidance documents and standards for continuity planning, many reported that they did not use or reference them when constructing their biobank continuity plans. Furthermore, nearly 25% of surveyed biobanks did not have a continuity plan and 61% indicated concern in having a mandated continuity plan. Results suggested academic organizations would benefit from a continuity plan template and best practice guidelines for plan development and implementation.

Validation Master Plans: Progress of Implementation in the Pharmaceutical Industry.

BACKGROUND: Some international regulatory agencies require that companies develop a validation master plan (VMP) to govern their validation activities, but such a plan is not an explicit requirement of US regulations. This paper examines the progress that US pharmaceutical companies have made to implement VMPs for drug products manufactured and produced in accordance with the US FDA Good Manufacturing Practice for Finished Pharmaceuticals. METHODS: A survey instrument was developed using an established framework with a focus on behavior and capability and disseminated electronically to midlevel and senior regulatory and quality professionals concentrated in the US. RESULTS: Responses from 42 senior regulatory professionals showed that VMPs are incorporated into the quality systems of most companies but approaches to implementation differ. Small companies typically employ centralized VMPs whereas larger companies commonly decentralize their VMPs. Companies of all sizes most commonly use paper rather than electronic tools to organize and track validations including validations of equipment. CONCLUSION: The fact that VMPs are commonly used even when they are not mandated suggests that the VMP is becoming an industry standard and may suggest that global standards are playing a significant role in the quality approaches of US-based companies.

Assessing the Benefit-Risk Profile for Pediatric Implantable Auditory Prostheses.

BACKGROUND/AIMS: Children with congenital cochleovestibular abnormalities associated with profound hearing loss have few treatment options if cochlear implantation does not yield benefit. An alternative is the auditory brainstem implant (ABI). Regulatory authority device approvals currently include a structured benefit-risk assessment. Such an assessment, for regulatory purposes or to guide clinical decision making, has not been published, to our knowledge, for the ABI and may lead to the design of a research program that incorporates regulatory authority, family, and professional input. METHODS: Much structured benefit-risk research has been conducted in the context of drug trials; here we apply this approach to device studies. A qualitative framework organized benefit (speech recognition, parent self-report measures) and risk (surgery- and device-related) information to guide the selection of candidates thought to have potential benefit from ABI. RESULTS: Children with cochleovestibular anatomical abnormalities are challenging for appropriate assessment of candidacy for a cochlear implant or an ABI. While the research is still preliminary, children with an ABI appear to slowly obtain benefit over time. A team of professionals, including audiological, occupational, and educational therapy, affords maximum opportunity for benefit. CONCLUSIONS: Pediatric patients who have abnormal anatomy and are candidates for an implantable auditory prosthetic require an individualized, multisystems review. The qualitative benefit-risk assessment used here to characterize the condition, the medical need, potential benefits, risks, and risk management strategies has revealed the complex factors involved. After implantation, continued team support for the family during extensive postimplant therapy is needed to develop maximum auditory skill benefit.

Global Regulatory Dissonance: A Case Study of Industry Views on the Development of Drugs for Postmenopausal Osteoporosis.

BACKGROUND: The footprint of drug distribution is multinational, but the regulatory frameworks supporting drug development, review, and approval remain largely regional. As a result, industry faces regulatory standards that may be complementary, additive, or contradictory, resulting in global regulatory dissonance (GRD). METHODS: Global regulatory dissonance was explored through a case study of drug development (postmenopausal osteoporosis) using survey methodology. RESULTS: In the feedback received, respondents generally agreed that GRD increases the complexity, timelines, and size of registration studies. Dissonant regulatory feedback on proposed labeling, applications, and benefit-risk assessments was also reported. Multiple causes of GRD were identified, including dissonant drug regulatory authority advice, guidelines, benefit-risk assessments, drug approval precedents, medical standards of care, and health technology assessments. Harmonization of guidelines, scientific advice, benefit-risk procedures, and expanded use of mutual recognition agreements were identified as mechanisms thought to reduce GRD. CONCLUSIONS: The results suggest that global access to new drugs may be enhanced through a greater understanding of GRD.

Management of Clinical Trial Agreements: Current Practices of Investigators in the United States.

The clinical trial agreement (CTA) is a key but often underappreciated document governing the relationship between a study site and a sponsor. Previous anecdotal materials have suggested that investigators may not often be involved in the review or negotiation of the CTA and may attach little importance to it. To provide more systematic current information, survey methods were used to explore the level of engagement, knowledge, and perceptions of investigators in the United States. The survey was distributed to more than 700 investigators-university affiliated and nonaffiliated-and/or related study staff, of whom 167 responded. Most respondents identified that they did not manage the clinical trial agreement process but were actively engaged in its review. Most were encouraged by their institutions to participate. However, some respondents expressed concerns with regard to their satisfaction with the content of the CTA, particularly with respect to issues such as financial negotiations and payments, indemnification, and subject injury language. The majority of investigators either strongly agreed or agreed that it was important for the investigator to be actively involved in the CTA process. Data from this survey provide the first systematic look at the current practices of US investigators, possible issues, and areas for improvement from the investigator's point of view.

Incentivizing Quality in the Manufacture of Pharmaceuticals: Industry Views on Quality Metrics and Ratings.

BACKGROUND: An increasing number of industry-wide quality breaches and consequential drug shortages have fueled interest in finding better ways to improve the manufacturing quality of pharmaceuticals. Quality metrics offer a way of focusing FDA inspectional resources by using risk-based paradigms and communicating the quality status of different companies to other stakeholders. This exploratory study investigated industry views related to the use of quality metrics and ratings to help advance these discussions. METHODS: A 23-question survey engaged 2 separate populations of industry professionals: a panel of identified US industry experts (n = 110) and a broader population (n = 328) of professionals working primarily in southern California. RESULTS: FDA metrics most valued by industry were warning letters and other observations, often characterized as "lagging" metrics. Respondents were generally hesitant to share information that would establish "leading" metrics, such as process performance measures that may warn of problems earlier. Ratings were recognized to incentivize higher quality by broadening stakeholder influence. However, concerns were identified related to the equity, misuse, or misunderstanding of the rating schemes and underlying metrics. CONCLUSIONS: Industry is an important stakeholder in the development of metrics. The concerns of industry must be recognized and addressed if policies related to metrics and ratings are to be effective in building an industry-wide quality culture.

The Role of Universities in the Commercialization of Medical Products: A Survey of Industry Views.

Survey methods were used to explore the expectations and recommendations of senior business development professionals with respect to the roles, activities, and interactions with US universities in the development of new medical products. This target group was chosen because it was judged to be most likely to interact with university faculty and technology transfer services and seek and acquire university assets. The survey instrument was first reviewed by a focus group of individuals with experience both in technology transfer and in academic or industry policy, then distributed to a selected subset of 80 business development professionals, of whom 72 responded. Serious concerns were expressed over the current mechanisms for technology transfer and university support of commercialization. When asked if they believed that there is a need for a change in the way that universities interact with industry in the US, 86% of the respondents replied that they either strongly agreed or agreed that there was, indeed, a need for change. Among several areas that might be improved, the availability of proof-of-concept facilities and funds for early-stage feasibility studies were most often identified as important.

Percutaneous fiber-optic sensor for chronic glucose monitoring in vivo.

We are developing a family of fiber-optic sensors called Sencils (sensory cilia), which are disposable, minimally invasive, and can provide in vivo monitoring of various analytes for several weeks. The key element is a percutaneous optical fiber that permits reliable spectroscopic measurement of chemical reactions in a nano-engineered polymeric matrix attached to the implanted end of the fiber. This paper describes its first application to measure interstitial glucose based on changes in fluorescence resonance energy transfer (FRET) between fluorophores bound to betacyclodextrin and Concanavalin A (Con A) in a polyethylene glycol (PEG) matrix. In vitro experiments demonstrate a rapid and precise relationship between the ratio of the two fluorescent emissions and concentration of glucose in saline for the physiological range of concentrations (0-500mg/dl) over seven weeks. Chronic animal implantation studies have demonstrated good biocompatibility and durability for clinical applications.

The BION devices: injectable interfaces with peripheral nerves and muscles.

OBJECT: The purpose of this study was to describe a novel technology for implantable neuromuscular stimulation to treat complications of paralysis and disuse atrophy, including shoulder subluxation, hand contractures, drop foot, and osteoarthritis. The authors review the results so far of several pilot clinical studies of these muscle stimulation devices. METHODS: Miniature wireless stimulators received power and individually addressed command signals from an external radiofrequency transmission coil. One or more implants were injected through a 12-gauge hypodermic insertion tool into muscles or adjacent to motor nerves, where they provided the means to activate the muscles in any desired pattern of intensity and frequency. Randomized controlled studies in small numbers of patients are underway to identify efficacy, acceptability, best methods of practice, and any design changes that may be required to improve the technology. Fifty patients have been enrolled in five studies; 35 patients have undergone implantation of a total of 79 BION1 devices. Comparisons with surface stimulation in patients who have suffered a stroke with shoulder subluxation and hand contractures show similar improvements in objective measures of efficacy but higher comfort levels for stimulation by implants. CONCLUSIONS: Injected microstimulators represent a promising new class of technology for the rehabilitation of patients with upper motor neuropathies. As the technology evolves, practitioners may be able to use it to facilitate functional reanimation of paralyzed limbs.

BIONic WalkAide for correcting foot drop.

The goal of this study was to test the feasibility and efficacy of using microstimulators (BIONs) to correct foot drop, the first human application of BIONs in functional electrical stimulation (FES). A prototype BIONic foot drop stimulator was developed by modifying a WalkAide2 stimulator to control BION stimulation of the ankle dorsiflexor muscles. BION stimulation was compared with surface stimulation of the common peroneal nerve provided by a normal WalkAide2 foot drop stimulator. Compared to surface stimulation, we found that BION stimulation of the deep peroneal nerve produces a more balanced ankle flexion movement without everting the foot. A three-dimensional motion analysis was performed to measure the ankle and foot kinematics with and without stimulation. Without stimulation, the toe on the affected leg drags across the ground. The BIONic WalkAide elevates the foot such that the toe clears the ground by 3 cm, which is equivalent to the toe clearance in the unaffected leg. The physiological cost index (PCI) was used to measure effort during walking. The PCI is high without stimulation (2.29 +/- 0.37; mean +/- S.D.) and greatly reduced with surface (1.29 +/- 0.10) and BION stimulation (1.46 +/- 0.24). Also, walking speed is increased from 9.4 +/- 0.4 m/min without stimulation to 19.6 +/- 2.0 m/min with surface and 17.8 +/- 0.7 m/min with BION stimulation. We conclude that functional electrical stimulation with BIONs is a practical alternative to surface stimulation and provides more selective control of muscle activation.