In vitro permeation testing for the evaluation of drug delivery to the skin.

This review considers the role of in vitro permeation testing (IVPT) for the evaluation of drug delivery from topical formulations applied to the skin. The technique was pioneered by Franz in the 1970's and today remains an important tool in the development, testing and optimization of such topical formulations. An overview of IVPT as well as selection of skin for the experiment, integrity testing of the membrane, and required number of replicate skin samples is discussed. In the literature many researchers have focused solely on permeation and have not reported amounts of the active remaining on and in the skin at the end of the IVPT. Therefore, a particular focus of this article is determination of the complete mass balance of the drug. It is noteworthy that for the evaluation of bioequivalence of topical formulations the draft guideline issued by the European Medicines Agency (EMA) requires the IVPT method to report on both the skin deposition and distribution of the active in the skin as well as amount permeated. Other aspects of current guidance from the EMA and United States Food and Drug Agency for IVPT are also compared and contrasted. Ultimately, harmonisation of IVPT protocols across the regulatory agencies will expedite the development process for novel topical formulations as well as the availability of generic products.

On-Demand Vaccine Production via Dock-and-Display of Biotinylated Antigens on Bacterial Extracellular Vesicles.

Engineered outer membrane vesicles (OMVs) derived from Gram-negative bacteria are a promising vaccine technology for developing immunity against diverse pathogens. However, antigen display on OMVs can be challenging to control and highly variable due to bottlenecks in protein expression and localization to the bacterial host cell's outer membrane, especially for bulky and complex antigens. Here, we describe methods related to a universal vaccine technology called AvidVax (avidin-based vaccine antigen crosslinking) for rapid and simplified assembly of antigens on the exterior of OMVs during vaccine development. The AvidVax platform involves remodeling the OMV surface with multiple copies of a synthetic antigen-binding protein (SNAP), which is an engineered fusion protein comprised of an outer membrane scaffold protein linked to a biotin-binding protein. The resulting SNAPs enable efficient decoration of OMVs with a molecularly diverse array of biotinylated subunit antigens, including globular and membrane proteins, glycans and glycoconjugates, haptens, lipids, nucleic acids, and short peptides. We detail the key steps in the AvidVax vaccine production pipeline including preparation and isolation of SNAP-OMVs, biotinylation and enrichment of vaccine antigens, and formulation and characterization of antigen-loaded SNAP-OMVs.

Discussion of EMA Draft Guideline on Quality and Equivalence of Topical Products Based on Comparison of Approved Mometasone Furoate Drugs.

INTRODUCTION: Today, the approval for a generic topical product includes the presentation of therapeutic equivalence to the originator based on clinical trials. To facilitate this procedure, in 2018 the European Medicines Agency (EMA) published a draft guideline on quality and equivalence of topical products, which includes request parameters regarding the quality of the newly developed generic product and test protocols for the implementation of equivalence tests regarding efficacy. METHODS: To date, no data are available on the quality and evidence of the proposed test conditions. In this study, we performed an in vitro penetration test (IVPT) following the terms of the EMA draft guideline on two authorized topical products for which therapeutic equivalence was already proven during the approval process. RESULTS: The complex biometric data processing revealed that in vitro equivalence could not be observed for all skin sections for either originator or generic product. Moreover, the necessity of the negative control proposed in the draft guideline is more than questionable. From the results presented, there were indications that a reduced number of skin donors would be sufficient to achieve statistically significant equivalence in the comparison of all applied formulations. Here, n = 7 donors was proposed instead of n ≥ 12 as the EMA draft guideline demands, decreasing the degree of biodiversity simultaneously. Moreover, a higher number of independent replicates (n > 2) was proposed for proper statistics. CONCLUSION: This bioequivalence study shows insufficient parameters, which should be discussed together with the EMA draft guideline.

Developing a transdiagnostic Ecological Momentary Assessment protocol for psychopathology.

OBJECTIVES: The network approach to psychopathology posits that mental disorders emerge from dynamic interactions among psychopathology-relevant variables. Ecological Momentary Assessment (EMA) is frequently used to assess these variables in daily life. Considering the transdiagnostic nature of the network approach to psychopathology, this study describes the development of a transdiagnostic EMA protocol for psychopathology. METHODS: First, 96 clinicians completed an online survey, providing three EMA constructs for up to three disorders they specialize in, and three EMA constructs relevant across disorders (transdiagnostic constructs). Second, 12 focus groups were conducted with clinical experts for specific types of diagnoses (e.g., mood disorders, anxiety disorders). Finally, a selection of items was reached by consensus. Two raters independently coded the online survey responses with an inter-rater agreement of 87.3%. RESULTS: Jaccard indices showed up to 52.6% overlap in EMA items across types of diagnoses. The most frequently reported transdiagnostic constructs were mood, sleep quality, and stress. A final set of EMA items is created based on items' frequency and informativeness, ensuring completeness across diagnoses and minimizing burden. CONCLUSIONS: The described procedure resulted in a feasible EMA protocol to examine psychopathology transdiagnostically. Feasibility was helped by the overlap in mentioned symptoms across disorders. Such overlap raises questions about the validity of DSM categories.

The MoodWheel app: validation and factor structure of a new tool for the assessment of mood based on the experience sampling method.

BACKGROUND: The MoodWheel app is a newly developed tool that uses experience sampling method (ESM) for assessing negative and positive emotions, based on the circumplex model of emotions and the binary model of distress, and including behavioral and heart rate (HR) measurement via photoplethysmography and the possibility to personalize the application with additional measures. Aims: This study was designed to assess the factorial structure, reliability and validity of the MoodWheel (MW) application for evaluating emotions in children, adolescents. METHODS: A sample of 490 children and adolescents were recruited from the schools. Internal consistency was assessed via Cronbach's alpha test. Concurrent validity was assessed by evaluating the correlations between MW and Profile of Emotional Distress scale (PED) scores, in terms of functional/dysfunctional negative and positive emotions. RESULTS: Results obtained show that MW has good to excellent internal consistency and test-retest reliability, while the convergent validity was also adequate. Moreover, we found support for the organization of the MW based on the binary model of distress, given the predictive value found for the irrational and rational beliefs. CONCLUSIONS: The MW application is a useful and easy to use tool that can be used for the accurate measurement of emotions, which will be complimented in future with additional behavioral parameters to provide a comprehensive and dynamic assessment.

Biosimilars in the Era of Artificial Intelligence-International Regulations and the Use in Oncological Treatments.

This research is based on three fundamental aspects of successful biosimilar development in the challenging biopharmaceutical market. First, biosimilar regulations in eight selected countries: Japan, South Korea, the United States, Canada, Brazil, Argentina, Australia, and South Africa, represent the four continents. The regulatory aspects of the countries studied are analyzed, highlighting the challenges facing biosimilars, including their complex approval processes and the need for standardized regulatory guidelines. There is an inconsistency depending on whether the biosimilar is used in a developed or developing country. In the countries observed, biosimilars are considered excellent alternatives to patent-protected biological products for the treatment of chronic diseases. In the second aspect addressed, various analytical AI modeling methods (such as machine learning tools, reinforcement learning, supervised, unsupervised, and deep learning tools) were analyzed to observe patterns that lead to the prevalence of biosimilars used in cancer to model the behaviors of the most prominent active compounds with spectroscopy. Finally, an analysis of the use of active compounds of biosimilars used in cancer and approved by the FDA and EMA was proposed.

Ecological momentary assessment and cue-elicited drug craving as primary endpoints: study protocol for a randomized, double-blind, placebo-controlled clinical trial testing the efficacy of a GLP-1 receptor agonist in opioid use disorder.

BACKGROUND: Despite continuing advancements in treatments for opioid use disorder (OUD), continued high rates of relapse indicate the need for more effective approaches, including novel pharmacological interventions. Glucagon-like peptide 1 receptor agonists (GLP-1RA) provide a promising avenue as a non-opioid medication for the treatment of OUD. Whereas GLP-1RAs have shown promise as a treatment for alcohol and nicotine use disorders, to date, no controlled clinical trials have been conducted to determine if a GLP-1RA can reduce craving in individuals with OUD. The purpose of the current protocol was to evaluate the potential for a GLP-1RA, liraglutide, to safely and effectively reduce craving in an OUD population in residential treatment. METHOD: This preliminary study was a randomized, double-blinded, placebo-controlled clinical trial designed to test the safety and efficacy of the GLP-1RA, liraglutide, in 40 participants in residential treatment for OUD. Along with taking a range of safety measures, efficacy for cue-induced craving was evaluated prior to (Day 1) and following (Day 19) treatment using a Visual Analogue Scale (VAS) in response to a cue reactivity task during functional near-infrared spectroscopy (fNIRS) and for craving. Efficacy of treatment for ambient craving was assessed using Ecological Momentary Assessment (EMA) prior to (Study Day 1), across (Study Days 2-19), and following (Study Days 20-21) residential treatment. DISCUSSION: This manuscript describes a protocol to collect clinical data on the safety and efficacy of a GLP-1RA, liraglutide, during residential treatment of persons with OUD, laying the groundwork for further evaluation in a larger, outpatient OUD population. Improved understanding of innovative, non-opioid based treatments for OUD will have the potential to inform community-based interventions and health policy, assist physicians and health care professionals in the treatment of persons with OUD, and to support individuals with OUD in their effort to live a healthy life. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04199728. Registered 16 December 2019, https://clinicaltrials.gov/study/NCT04199728?term=NCT04199728 . PROTOCOL VERSION: 10 May 2023.

Industry perspective on regulatory authority (RA) quality reviews of biosimilar applications - an evaluation of RA guidance and expectations for chemical, manufacturing, and controls information through in-depth query analysis.

PURPOSE: Evaluate the type and quantity of quality information (i.e. Chemistry, Manufacturing, and Control) requested by the US FDA and EMA in queries pertaining to biosimilar applications. METHODS: Numbers/types of queries received following regulatory submissions (FDA/EMA, n = 7/n = 5) for seven biosimilars (PF-filgrastim [Nivestym], PF-rituximab [Ruxience®], PF-trastuzumab [Trazimera®], PF-bevacizumab [Zirabev®], PF-pegfilgrastim [Nyvepria®], PF-adalimumab [Abrilada™/Amsparity®], PF-infliximab [Ixifi]) from a single product portfolio were analyzed considering published regulatory authority (RA) guidance and in relation to sections/subsections of Module 3: Quality from the Common Technical Document regulatory dossier and topics based on keyword assignment. RESULTS: Queries were most frequently assigned (FDA/EMA %, range) to Drug Substance Manufacture (subsection 3.2.S.2; 21-35%/13-50%), Control of Drug Substance (3.2.S.4; 3-11%/5-17%), Drug Product Pharmaceutical Development (3.2.P.2; 1-12%/1-15%) and Manufacture (3.2.P.3; 17-41%/2-13%), and Analytical Similarity (3.2.R; 4-21%/4-20%). The proportion of Drug Substance and Drug Product queries was significantly different between RAs (n1 = 952, n2 = 468, p-value <0.001; two-sample proportion z-test). Topic assignments included: Control (12-27%/12-28%), Manufacturing (56-72%/34-66%), Stability (1-12%/2-24%), Biosimilarity (5-16%/5-25%), and Container Closure (0-3%/0-9%). CONCLUSION: The focus of both RAs on topics related to manufacturing and controls is valuable in understanding expectations for scientific and technical content related to gaining biosimilar approval.

The underrepresentation of racial/ethnic minorities in research on co-use of nicotine, alcohol, and/or cannabis via ecological momentary assessment methods: A narrative review.

BACKGROUND: Co-use of nicotine, alcohol and/or cannabis is common among adults in the United States. Co-use may represent greater addiction severity than single substance use. Recent studies have examined the extent to which the frequency, order, simultaneity, motivations, and contextual factors associated with co-use differ from that of single use. Co-use has become prevalent among racial/ethnic minority individuals who exhibit distinct co-use patterns and related outcomes; however, most of these studies rely on cross-sectional or sparse longitudinal observations. Ecological momentary assessment (EMA) can illuminate such patterns and associations with time-varying contexts. This review summarizes EMA studies on co-use published from 2008 to 2023 involving racial/ethnic minority individuals and point to gaps. Our review addresses: 1) whether use of one substance leads to substitution or complementary use of another, 2) whether antecedents/contexts differ by co-use patterns and minority status, and 3) what consequences of co-use have been documented across co-use patterns or minority status. METHODS: Search results yielded 465 articles, with 33 meeting inclusion criteria. We extracted study-level characteristics and synthesized the findings. RESULTS: The findings largely focused on co-use patterns, categories of co-use, proximal antecedents and contexts, and consequences. Variations by minority status were rarely examined; few examined acute effects of unique experiences that may contribute to co-use among racial/ethnic minority adults. CONCLUSIONS: The EMA literature on co-use is burgeoning in recent years and supports complementary hypothesis. More research to capture time-intensive data on experiences to contextualize the co-use among racial/ethnic minority groups with greater diversity in race/ethnicity is warranted.

The ReCoDe addiction research consortium: Losing and regaining control over drug intake-Findings and future perspectives.

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy.

From anticipation to action: A RCT on mental imagery exercises in daily life as a motivational amplifier for individuals with depressive symptoms.

Encouraging engagement in rewarding or pleasant activities is one of the most important treatment goals for depression. Mental imagery exercises have been shown to increase the motivation for planned behaviour in the lab but it is unclear whether this is also the case in daily life. Therefore, we aimed to investigate the effect of mental imagery exercises on motivation and behaviour in daily life. Participants with depressive symptoms (N = 59) were randomly assigned to a group receiving mental imagery (MI) exercises or a control group receiving relaxation (RE) exercises via study phones. We employed an experience sampling design with 10 assessments per day for 10 days (three days baseline, four days with two exercises per day and three days post-intervention). Data was analysed using t-tests and multilevel linear regression analyses. As predicted, MI exercises enhanced motivation and reward anticipation during the intervention phase compared to RE. However, MI did not enhance active behaviour or strengthen the temporal association from reward anticipation (t-1) to active behaviour (t). Mental imagery exercises can act as a motivational amplifier but its effects on behaviour and real-life reward processes remain to be elucidated.

Bis-EMA/Bis-GMA ratio effects on resin-properties and impregnated fiber-bundles.

OBJECTIVES: To evaluate the effect of different ratios of Bis-EMA/Bis-GMA resin mixtures on the inherent viscosity and curing-related properties: including degree of cure (DC%), shrinkage strain, Knoop micro-hardness (KH) and flexural strength of resin-impregnated fiber-bundles. METHODS: Bis-EMA/Bis-GMA monomers were mixed (by weight) in the following ratios: M1 = 30 %/70 %, M2 = 50 %/50 %, M3 = 70 %/30 %, and M4 = 100 %/0 %. Standard measurements were made of refractive index, viscosity, degree of conversion, shrinkage strain and Knoop hardness (KHN). For 60 % glass fiber-bundles impregnated with 40 % resin, three-point bending test for flexural strength and shrinkage strain were measured. Data were analyzed by One-way ANOVA and Bonferroni post-hoc tests (α = 0.05). RESULTS: For resin mixtures, increasing Bis-EMA proportion decreased refractive index (p < 0.05), and viscosity (p < 0.05), and increased monomer conversion (DC%), shrinkage strain and KHN (p < 0.05). DC% increased after 1 h for all resin mixtures. The shrinkage strain and flexural strength of resin-impregnated fiber-bundles reduced with increased Bis-EMA. SIGNIFICANCE: Monomeric mixtures with highest amounts of Bis-EMA showed enhancement in several clinically-relevant properties and polymerization of respective resin-impregnated glass fibers. This makes them potential candidates for impregnating glass fibers in fiber-reinforced restorations.

Patterns of Skin Picking in Skin Picking Disorder: Ecological Momentary Assessment Study.

BACKGROUND: Skin picking disorder (SPD) is an understudied mental illness that is classified as a body-focused repetitive behavior disorder. Literature suggests that pathological skin picking is strongly integrated into the daily lives of affected individuals and may involve a high degree of variability in terms of episode characteristics, frequency, and intensity. However, existing data on the phenomenology of SPD are limited and typically involve retrospective assessments, which may fail to accurately capture the behavior's variability. OBJECTIVE: This study aimed to investigate skin picking in the daily lives of individuals with SPD by using ecological momentary assessment (EMA). The first aim focused on the description of skin picking patterns (eg, characteristics, intensity, and distribution of episodes and urges), and the second aim explored differences in characteristics and patterns between automatic and focused skin picking. METHODS: Participants were recruited online and underwent a web-based screening, a diagnostic telephone interview, and a comprehensive online self-report questionnaire before participating in an EMA protocol. The latter included 10 consecutive days with 7 pseudorandom, time-contingent assessments per day between 8 AM and 10 PM. The EMA questionnaire assessed the current skin picking urge, the occurrence of the behavior, and a detailed assessment of the episodes' characteristics (eg, length, intensity, and consciousness) if applicable. RESULTS: The final sample consisted of 57 participants, who completed at least 70% of the scheduled assessments (n=54, 94.7% female: mean age 29.3, SD 6.77 years). They completed 3758 EMAs and reported 1467 skin picking episodes. Skin picking occurred frequently (mean 2.57, SD 1.12 episodes per day and person) in relatively short episodes (10-30 min; 10 min: nepisodes=642, 43.8%; 20 min: nepisodes=312, 21.3%; 30 min: nepisodes=217, 14.8%), and it was distributed quite evenly throughout the day and across different days of the week. Focused and automatic episodes were relatively balanced across all reported episodes (focused: nepisodes=806, 54.9%) and over the course of the day. The analyses showed statistically significant differences between self-reported triggers for the different styles. Visual or tactile cues and the desire to pick the skin were more important for the focused style (visual or tactile cues: mean focused style [Mf]=4.01, SD 0.69 vs mean automatic style [Ma]=3.47, SD 0.99; P<.001; SMD=0.64; desire to pick: Mf=2.61, SD 1.06 vs Ma=1.94, SD 1.03; P<.001; SMD=0.82), while boredom and concentration problems were more prominent in automatic skin picking (boredom: Mf=1.69, SD 0.89 vs Ma=1.84, SD 0.89; P=.03; SMD=-0.31; concentration problems: Mf=2.06, SD 0.87 vs Ma=2.31, SD 1.06; P=.006; SMD=-0.41). CONCLUSIONS: These results contribute to an enhanced understanding of the phenomenology of SPD using a more rigorous assessment methodology. Our findings underscore that picking can impact affected persons multiple times throughout their daily lives. TRIAL REGISTRATION: German Clinical Trials Register DRKS00025168; https://tinyurl.com/mr35pdwh.

Towards a coordinated approach for managing accelerated patient access to potentially beneficial medicines: reporting the perspectives of a multi-stakeholder, international workshop.

Accelerated and conditional regulatory pathways for drug approvals are intended to enable earlier patient access to potentially life-saving treatments, or treatments that provide benefits in addressing a significant unmet need. However, there are questions about how well such pathways work, how appropriately they are applied, and how the work of regulators can be better coordinated with that of health technology assessment (HTA) and payer bodies, providers and health systems, and other stakeholders. In June 2023, a multi-stakeholder, international workshop was convened in Adelaide, Australia, to deliberate the challenges, goals, and opportunities to improve accelerated access pathways. Workshop attendees included representatives from patient organizations, regulators, HTA/payer bodies, universities (ethicists, health economists), and companies developing and marketing new medicines from Australia, Asia, Europe, and North America. We reviewed the contents of this workshop to identify areas of agreement and disagreement, report the key themes of the discussion, and delineate next steps for improving accelerated access pathways. We found that there was general agreement among workshop attendees that accelerated access could be improved significantly by strengthening processes for stakeholder coordination, and that coordinated efforts will be required to implement meaningful change moving forward.

SEMA3: A free smartphone platform for daily life surveys.

Traditionally, behavioral, social, and health science researchers have relied on global/retrospective survey methods administered cross-sectionally (i.e., on a single occasion) or longitudinally (i.e., on several occasions separated by weeks, months, or years). More recently, social and health scientists have added daily life survey methods (also known as intensive longitudinal methods or ambulatory assessment) to their toolkit. These methods (e.g., daily diaries, experience sampling, ecological momentary assessment) involve dense repeated assessments in everyday settings. To facilitate research using daily life survey methods, we present SEMA3 ( http://www.SEMA3.com ), a platform for designing and administering intensive longitudinal daily life surveys via Android and iOS smartphones. SEMA3 fills an important gap by providing researchers with a free, intuitive, and flexible platform with basic and advanced functionality. In this article, we describe SEMA3's development history and system architecture, provide an overview of how to design a study using SEMA3 and outline its key features, and discuss the platform's limitations and propose directions for future development of SEMA3.

Ecological momentary assessment of physical activity and sedentary behaviour in shift workers and non-shift workers: Validation study.

This study examined the criterion validity of an ecological momentary assessment (EMA)-reported physical activity and sedentary time compared with accelerometry in shift workers and non-shift workers. Australian workers (n = 102) received prompts through a mobile EMA app and wore the Actigraph accelerometer on the right hip for 7-10 days. Participants received five EMA prompts per day at 3-hour intervals on their mobile phones. EMA prompts sent to shift workers (SW-T) were tailored according to their work schedule. Non-shift workers (NSW-S) received prompts at standardised times. To assess criterion validity, the association of EMA-reported activities and the Actigraph accelerometer activity counts and number of steps were used. Participants were 36 ± 11 years and 58% were female. On occasions where participants reported physical activity, acceleration counts per minute (CPM) and steps were significantly higher (ß = 1184 CPM, CI 95%: 1034, 1334; ß = 20.9 steps, CI 95%: 18.2, 23.6) than each of the other EMA activities. Acceleration counts and steps were lower when sitting was reported than when no sitting was reported by EMA. Our study showed that EMA-reported physical activity and sedentary time was significantly associated with accelerometer-derived data. Therefore, EMA can be considered to assess shift workers' movement-related behaviours with accelerometers to provide rich contextual data.

RSDNet: A New Multiscale Rail Surface Defect Detection Model.

The rapid and accurate identification of rail surface defects is critical to the maintenance and operational safety of the rail. For the problems of large-scale differences in rail surface defects and many small-scale defects, this paper proposes a rail surface defect detection algorithm, RSDNet (Rail Surface Defect Detection Net), with YOLOv8n as the baseline model. Firstly, the CDConv (Cascade Dilated Convolution) module is designed to realize multi-scale convolution by cascading the cavity convolution with different cavity rates. The CDConv is embedded into the backbone network to gather earlier defect local characteristics and contextual data. Secondly, the feature fusion method of Head is optimized based on BiFPN (Bi-directional Feature Pyramids Network) to fuse more layers of feature information and improve the utilization of original information. Finally, the EMA (Efficient Multi-Scale Attention) attention module is introduced to enhance the network's attention to defect information. The experiments are conducted on the RSDDs dataset, and the experimental results show that the RSDNet algorithm achieves a mAP of 95.4% for rail surface defect detection, which is 4.6% higher than the original YOLOv8n. This study provides an effective technical means for rail surface defect detection that has certain engineering applications.

Fitbit's accuracy to measure short bouts of stepping and sedentary behaviour: validation, sensitivity and specificity study.

Objective: This study aims to assess the suitability of Fitbit devices for real-time physical activity (PA) and sedentary behaviour (SB) monitoring in the context of just-in-time adaptive interventions (JITAIs) and event-based ecological momentary assessment (EMA) studies. Methods: Thirty-seven adults (18-65 years) and 32 older adults (65+) from Belgium and the Czech Republic wore four devices simultaneously for 3 days: two Fitbit models on the wrist, an ActiGraph GT3X+ at the hip and an ActivPAL at the thigh. Accuracy measures included mean (absolute) error and mean (absolute) percentage error. Concurrent validity was assessed using Lin's concordance correlation coefficient and Bland-Altman analyses. Fitbit's sensitivity and specificity for detecting stepping events across different thresholds and durations were calculated compared to ActiGraph, while ROC curve analyses identified optimal Fitbit thresholds for detecting sedentary events according to ActivPAL. Results: Fitbits demonstrated validity in measuring steps on a short time scale compared to ActiGraph. Except for stepping above 120 steps/min in older adults, both Fitbit models detected stepping bouts in adults and older adults with sensitivities and specificities exceeding 87% and 97%, respectively. Optimal cut-off values for identifying prolonged sitting bouts achieved sensitivities and specificities greater than 93% and 89%, respectively. Conclusions: This study provides practical insights into using Fitbit devices in JITAIs and event-based EMA studies among adults and older adults. Fitbits' reasonable accuracy in detecting short bouts of stepping and SB makes them suitable for triggering JITAI prompts or EMA questionnaires following a PA or SB event of interest.

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.

Clinical development and marketing application review times for novel orphan-designated drugs.

Development of an orphan-designated drug has been more challenging and financially less attractive than that of other drugs due to low prevalence of the condition, poorly defined biomarkers and lack of experience of healthcare providers in diagnosing and treating the condition. Guidance and incentives in some countries support the sponsors in developing orphan-designated drugs despite the challenges. Expedited regulatory programs as offered by the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMA) support the development of drugs, provide shorter marketing application review times or provide preliminary approval. In this study, we analyze marketing application review times in the US and in the European Union (EU) and clinical development times for novel, i.e., containing new molecular entity, orphan-designated drugs that were approved in the US between 1 June 2020 and 31 May 2023, and their correlation with expedited regulatory programs. Seventy-three marketing applications for novel orphan-designated drugs were approved by the FDA, and 39 also received a positive opinion from the EMA. The marketing application review time by the FDA for the 73 novel orphan-designated drugs approved in the US was 244 days (n = 73, median), and the marketing application review time by the EMA for the 39 drugs that were also approved in the EU was 353 days (n = 39, median). The typical clinical development time for a novel orphan-designated drug was 7.2 years (n = 72).