Using Biosensor Devices and Ecological Momentary Assessment to Measure Emotion Regulation Processes: Pilot Observational Study With Dialectical Behavior Therapy.

Background: Novel technologies, such as ecological momentary assessment (EMA) and wearable biosensor wristwatches, are increasingly being used to assess outcomes and mechanisms of change in psychological treatments. However, there is still a dearth of information on the feasibility and acceptability of these technologies and whether they can be reliably used to measure variables of interest. Objective: Our objectives were to assess the feasibility and acceptability of incorporating these technologies into dialectical behavior therapy and conduct a pilot evaluation of whether these technologies can be used to assess emotion regulation processes and associated problems over the course of treatment. Methods: A total of 20 adults with borderline personality disorder were enrolled in a 6-month course of dialectical behavior therapy. For 1 week out of every treatment month, participants were asked to complete EMA 6 times a day and to wear a biosensor watch. Each EMA assessment included measures of several negative affect and suicidal thinking, among other items. We used multilevel correlations to assess the contemporaneous association between electrodermal activity and 11 negative emotional states reported via EMA. A multilevel regression was conducted in which changes in composite ratings of suicidal thinking were regressed onto changes in negative affect. Results: On average, participants completed 54.39% (SD 33.1%) of all EMA (range 4.7%-92.4%). They also wore the device for an average of 9.52 (SD 6.47) hours per day and for 92.6% of all days. Importantly, no associations were found between emotional state and electrodermal activity, whether examining a composite of all high-arousal negative emotions or individual emotional states (within-person r ranged from -0.026 to -0.109). Smaller changes in negative affect composite scores were associated with greater suicidal thinking ratings at the subsequent timepoint, beyond the effect of suicidal thinking at the initial timepoint. Conclusions: Results indicated moderate overall compliance with EMA and wearing the watch; however, there was no concurrence between EMA and wristwatch data on emotions. This pilot study raises questions about the reliability and validity of these technologies incorporated into treatment studies to evaluate emotion regulation mechanisms.

Bridging the Gap: Quality by Design as a Catalyst for Enhanced Quality Management Systems in Biopharmaceutical Manufacturing.

The document emphasizes the importance of addressing key issues in Quality Management Systems (QMS) to stay competitive and provide high-quality goods and services in a dynamic market. It highlights the need to adopt novel quality management techniques for long-term success. The fundamentals of Quality by Design (QbD) are discussed, tracing back to pioneers like Joseph M. Juran and the Six Sigma concept for effective implementation. QbD is described as a systematic approach focusing on risk management, Quality Target Product Profile (QTPP), and Critical Quality Attributes (CQAs) to create products meeting predetermined quality standards. QbD incorporates quality concepts into the development and production processes. Its goal is to guarantee the quality of the product by determining and managing important factors. Manufacturers can be flexible with it while still adhering to strict quality standards. It signifies a change in the industry's paradigm.

Comparing supplemental indications for cancer drugs approved in the US and EU.

IMPORTANCE: Cancer drugs initially granted regulatory approval for one disease may also prove useful in treating other diseases. In these cases, manufacturers may seek to add supplemental indications to their drug labels. The extent to which manufacturers seek supplemental indications for cancer drugs may differ in the US and EU. OBJECTIVE: To investigate how manufacturers have pursued supplemental indications for cancer drugs approved in the US vs. EU. METHODS: We performed a retrospective observational cohort study of cancer drugs first approved in the US and EU from 2005-2022 to compare the rate at which supplemental indications are added to drug labels and the times to first, second, and third supplemental indications. RESULTS: Among 129 cancer drugs approved in both the US and EU from 2005-2022, approval occurred an average of 0.79 years earlier in the US. These drugs had a total of 145 indications at the time of approval in the US and 144 indications in the EU. Supplemental indications were granted at a rate of 0.22 per drug-year in the US, compared to 0.17 per drug-year in the EU (incidence rate ratio=1.30, 95 % confidence interval [CI]: 1.06-1.60, p = 0.01). This resulted in a total of 221 approved supplemental indications in the US and 152 approved supplemental indications in the EU through October 1, 2023. The times to the first and second supplemental indications were similar across the two jurisdictions, while the time to the third supplemental indication was shorter in the US (hazard ratio: 2.06, 95 % CI: 1.03-4.14, p = 0.04). CONCLUSIONS AND RELEVANCE: Manufacturers obtained supplemental indications for cancer drugs in the US at a higher rate than in the EU, which could be due to variable regulatory requirements and/or different market forces.

The feasibility and acceptability of using EMA and physiological data to measure day-to-day occupational stress, musculoskeletal pain and mental health.

OBJECTIVES: This study aimed to assess the feasibility and acceptability of using EMA questionnaires and physiological data via wristbands to measure day-to-day occupational stress, musculoskeletal pain, and mental health among university employees (N = 23), across 10 work days. Adherence to the study protocol as well as participant experiences (via semi-structured interviews) with the protocol were used to assess feasibility and acceptability of the method. RESULTS: Adherence to the study protocol was excellent. Participants wore the wristband for a mean of 9.7 days. Participants completed a mean of 24.5 EMAs (out of 30). Semi-structured interviews with participants revealed that a small number of participants had difficulties uploading data from the wristband. The timing of EMAs was challenging for some participants, resulting in missed EMAs, raising questions about whether EMA frequency and timing could be changed to improve adherence. Some EMA items were difficult to answer due to the nature of participants' roles and the work undertaken. Overall, the protocol was feasible and acceptable but highlighted future potential changes including using a different physiological data collection tool, reducing the number of EMAs, adjusting EMA timings, and reviewing EMA items.

Integrating Real-Time Air Quality Monitoring, Ecological Momentary Assessment, and Spirometry to Evaluate Asthma Symptoms: Usability Study.

BACKGROUND: Individuals are exposed to a variety of indoor residential toxins including volatile organic compounds and particulates. In adults with asthma, such exposures are associated with asthma symptoms, asthma exacerbations, and decreased lung function. However, data on these exposures and asthma-related outcomes are generally collected at different times and not in real time. The integration of multiple platforms to collect real-time data on environmental exposure, asthma symptoms, and lung function has rarely been explored. OBJECTIVE: This paper describes how adults with asthma perceive the acceptability and usability of three integrated devices: (1) residential indoor air quality monitor, (2) ecological momentary assessment (EMA) surveys delivered via a smartphone app, and (3) home spirometry, over 14 days. METHODS: Participants (N=40) with uncontrolled asthma were mailed the Awair Omni indoor air quality monitor, ZEPHYRx home spirometer, and detailed instructions required for the in-home monitoring. The air quality monitor, spirometer, and EMA app were set up and tested during a videoconference or phone orientation with a research team member. Midway through the 14-day data collection period, participants completed an interview about the acceptability of the study devices or apps, instructional materials provided, and the setup process. At the end of the 14-day data collection period, participants completed a modified System Usability Scale. A random sample of 20 participants also completed a phone interview regarding the acceptability of the study and the impact of the study on their asthma. RESULTS: Participants ranged in age from 26 to 77 (mean 45, SD 13.5) years and were primarily female (n=36, 90%), White (n=26, 67%), college graduates (n=25, 66%), and residing in a single-family home (n=30, 75%). Most indicated that the air quality monitor (n=23, 58%), the EMA (n=20, 50%), and the spirometer (n=17, 43%) were easy to set up and use. Challenges with the EMA included repetitive surveys, surveys arriving during the night, and technical issues. While the home spirometer was identified as a plausible means to evaluate lung function in real time, the interpretation of the readings was unclear, and several participants reported side effects from home spirometer use. Overall, the acceptability of the study and the System Usability Scale scores were high. CONCLUSIONS: The study devices were highly acceptable and usable. Participant feedback was instrumental in identifying technical challenges that should be addressed in future studies.

Evaluating the role of binge planning and binge inevitability within affect regulation models of binge eating.

Affect regulation models posit that aversive affective states drive binge-eating behavior, which then regulates negative emotions. However, recent findings among individuals with binge-eating disorder (BED) suggest that food-related anticipatory processes may precede and potentially explain the negative affect thought to drive binge eating. Specifically, studies using ecological momentary assessment (EMA) demonstrate that the negative affective state of "Guilt" (from the Positive and Negative Affect Schedule) most strongly predicts later binge eating in the natural environment, and it has been hypothesized that planning a binge or feeling that a binge-eating episode is inventible may account for the increases in Guilt observed prior to binge episodes. In the present study, we tested the hypothesis that binge planning or inevitability may contribute to feelings of shame (a key facet of the broader Guilt construct), which then predict binge-eating episodes, using EMA in 43 individuals with BED. Consistent with hypotheses, feelings of binge inevitability and planning prospectively predicted binge-eating episodes. Further, binge planning predicted subsequent increases in shame. However, shame did not predict subsequent increases in binge planning. Finally, a mediation model revealed that binge planning (Time 1) predicted future binge eating (Time 3) directly and indirectly through increases in shame (Time 2). The results provide novel evidence that individuals with BED anticipate and actively plan for binge-eating episodes, and that binge planning may explain the increased shame/guilt typically observed before binge eating. Overall, accruing evidence suggests that negative affect, although predictive of binge eating, may be better conceptualized as a consequence of the anticipatory processes that lead to binge eating, rather than the starting point, at least among some individuals with BED. Future experimental research is needed to more conclusively test this hypothesis.

Functional Principal Component Analysis for Continuous Non-Gaussian, Truncated, and Discrete Functional Data.

Mobile health studies often collect multiple within-day self-reported assessments of participants' behavior and well-being on different scales such as physical activity (continuous scale), pain levels (truncated scale), mood states (ordinal scale), and the occurrence of daily life events (binary scale). These assessments, when indexed by time of day, can be treated and analyzed as functional data corresponding to their respective types: continuous, truncated, ordinal, and binary. Motivated by these examples, we develop a functional principal component analysis that deals with all four types of functional data in a unified manner. It employs a semiparametric Gaussian copula model, assuming a generalized latent non-paranormal process as the underlying generating mechanism for these four types of functional data. We specify latent temporal dependence using a covariance estimated through Kendall's τ $$ \tau $$ bridging method, incorporating smoothness in the bridging process. The approach is then extended with methods for handling both dense and sparse sampling designs, calculating subject-specific latent representations of observed data, latent principal components and principal component scores. Simulation studies demonstrate the method's competitive performance under both dense and sparse sampling designs. The method is applied to data from 497 participants in the National Institute of Mental Health Family Study of Mood Spectrum Disorders to characterize differences in within-day temporal patterns of mood in individuals with the major mood disorder subtypes, including Major Depressive Disorder and Type 1 and 2 Bipolar Disorder. Software implementation of the proposed method is provided in an R-package.

Cognitive Health Benefits of Everyday Physical Activity in a Diverse Sample of Middle-Aged Adults.

BACKGROUND: Physical activity has been associated with a wide range of health benefits including long-term benefits for cognitive and brain health. Whether episodes of everyday physical activity are associated with immediate cognitive benefits remains unknown. PURPOSE: The purpose of the current study was to examine whether episodes of physical activity, occurring over the course of participants' daily lives, are associated with short-term improvements in cognitive health. METHODS: Participants completed a 9-day ecological momentary assessment protocol involving 5 daily assessments of self-reported physical activity and ambulatory cognitive assessments of processing speed and visuospatial working memory. Data were analyzed in a multilevel modeling framework to explore changes in performance on each task associated with physical activity during the period leading up to the assessment as well as individual differences in average frequency of physical activity. RESULTS: Results of MLMs indicated that engaging in physical activity during the period (~3.5 hr) leading up to an assessment was associated with improvements in processing speed equivalent to 4 years of cognitive aging. Such improvements were observed for both light and moderate-to-vigorous physical activity levels. No association was observed for visuospatial working memory accuracy; however, response time during the working memory task reliably mirrored the association observed for processing speed. The short-term benefits were observed, particularly, for individuals with an overall higher frequency of reported physical activity. CONCLUSIONS: Our findings suggest that engaging in everyday physical activity of any intensity level may have short-term, acute benefits for cognitive health and point to new potential targets for intervention. CLINICAL TRIAL INFORMATION: NCT03240406.

Exercise may help improve brain health and prevent brain disease (e.g., Alzheimer's disease). But, what are the possible brain health benefits of "everyday" types of physical activities like playing with our kids or walking the dog? The challenge is designing a study that can see these benefits in action. Recent advances in smartphones allow us to interact with research participants continuously as they go about their daily lives. We asked our participants to check in with us 6 times per day (every ~3.5 hrs) for 7 days and report whether they had been physically active in the past few hours. Every time they checked in, we also asked them to play a few "brain games" (brief cognitive assessments) to measure their cognitive functioning throughout each day. When participants reported being physically active sometime in the previous 3.5 hrs, they showed improvements in mental speed equivalent to being 4 years younger. This benefit was observed regardless of whether the activities they reported were higher intensity (e.g., running/jogging) or lower intensity (e.g., walking, chores). These findings suggest that everyday physical activity may promote cognitive health in midlife and that the benefits may be enjoyed immediately.

Comparing regulatory guidance on risk minimization/mitigation and the Reporting recommendation Intended for pharmaceutical Risk Minimization Evaluation Studies checklist.

The latest country-specific regulatory guidance for assessing effectiveness of risk minimization measures (RMM) strategies was identified across five continents-Africa (Egypt, South Africa), Asia (Australia, China, Japan, South Korea, Singapore), Europe (EU-27, United Kingdom), North America (Unites States, Canada) and South America (Brazil)-and compared to the Reporting recommendation Intended for pharmaceutical Risk Minimization Evaluation Studies (RIMES) checklist, developed to assess the quality of effectiveness evaluations and endorsed by the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). RIMES checklist items address study hypothesis, participants, measures, statistical analysis and results. European Medical Agency (EMA) and Food and Drug Administration (FDA) guidance only partially aligned with RIMES, primarily for measures and results. In the absence of country-specific guidance, most countries recommended following EMA or FDA guidelines; Japan and South Africa mentioned the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH E2E) guideline; Brazil and China had no guidance/recommendations. Worldwide, there was a lack of RMM-specific guidance and, when guidance existed, they were not harmonized, and alignment with the RIMES checklist was limited.

First Molecular Evidence of Babesia caballi and Theileria equi in Imported Donkeys from Kyrgyzstan.

Equine piroplasmosis (EP) is an important tick-borne disease of equids, caused by Theileria equi, Theileria haneyi, and Babesia caballi. Nonetheless, there has been a scarcity of systematic reports on EP parasites in donkeys in Kyrgyzstan, Central Asia. In this study, piroplasms were screened in 1900 blood samples from imported donkeys from the Osh Oblast (southwestern Kyrgyzstan) by targeting partial 18S ribosomal RNA using the polymerase chain reaction (PCR). Through molecular and phylogenetic analyses, all positive samples were sequenced to identify the species and genotypes. The results indicated the presence of both B. caballi and T. equi, with prevalence rates of 8.4% (160/1900) and 12.2% (232/1900), respectively. By amplifying part of the Erythrocyte Merozoite Antigen 1 (EMA-1) and Rhoptry-Associated Protein (RAP-1) genes, B. caballi genotype B and T. equi genotype A were identified. To the best of our knowledge, this is the first report on piroplasm infection among donkeys from Kyrgyzstan.

ModFOLD9: A Web Server for Independent Estimates of 3D Protein Model Quality.

Accurate models of protein tertiary structures are now available from numerous advanced prediction methods, although the accuracy of each method often varies depending on the specific protein target. Additionally, many models may still contain significant local errors. Therefore, reliable, independent model quality estimates are essential both for identifying errors and selecting the very best models for further biological investigations. ModFOLD9 is a leading independent server for detecting the local errors in models produced by any method, and it can accurately discriminate between high-quality models from multiple alternative approaches. ModFOLD9 incorporates several new scores from deep learning-based approaches, leading to greatly improved prediction accuracy compared with earlier versions of the server. ModFOLD9 is continuously independently benchmarked, and it is shown to be highly competitive with other public servers. ModFOLD9 is freely available at https://www.reading.ac.uk/bioinf/ModFOLD/.

From willpower to strategies: Existing insights and outstanding issues in self-control strategy use in daily life.

This paper focuses on recent advances in research on strategies that support self-control in everyday life. No one strategy or set of strategies appears to be effective at all times and in all situations. To understand effective self-control, we must expand our understanding of how strategies fit the situation and the person. To this end, we propose researching unexplored aspects of situations, how self-control strategies develop in the first place, and the role of emotion regulation in self-control strategy effectiveness. We also highlight methodological blind spots and offer ways to correct them and introduce new methodological approaches to best capture self-control strategies in everyday life.

An Improved YOLOv8 OBB Model for Ship Detection through Stable Diffusion Data Augmentation.

Unmanned aerial vehicles (UAVs) with cameras offer extensive monitoring capabilities and exceptional maneuverability, making them ideal for real-time ship detection and effective ship management. However, ship detection by camera-equipped UAVs faces challenges when it comes to multi-viewpoints, multi-scales, environmental variability, and dataset scarcity. To overcome these challenges, we proposed a data augmentation method based on stable diffusion to generate new images for expanding the dataset. Additionally, we improve the YOLOv8n OBB model by incorporating the BiFPN structure and EMA module, enhancing its ability to detect multi-viewpoint and multi-scale ship instances. Through multiple comparative experiments, we evaluated the effectiveness of our proposed data augmentation method and the improved model. The results indicated that our proposed data augmentation method is effective for low-volume datasets with complex object features. The YOLOv8n-BiFPN-EMA OBB model we proposed performed well in detecting multi-viewpoint and multi-scale ship instances, achieving the mAP (@0.5) of 92.3%, the mAP (@0.5:0.95) of 77.5%, a reduction of 0.8 million in model parameters, and a detection speed that satisfies real-time ship detection requirements.

Radiopharmaceutical small-scale preparation in Europe: will we be able to harmonize the situation?

BACKGROUND: Radiopharmaceuticals have been considered a special group of medicines in Europe since 1989. The use of radiopharmaceuticals that have marketing authorization should always be the first option in clinical use, however due to their special properties the availability of approved radiopharmaceuticals is limited. For this reason, they can be produced on a small scale outside the marketing authorization process. MAIN BODY: The in-house radiopharmaceutical preparations represent an important source of these special medicines for routine nuclear medicine practice. However, a lack of harmonization in Member States' regulations leads to extreme differences in the use and availability of radiopharmaceuticals across Europe. The aim of this work is to provide an overview of the different national regulatory frameworks in which Directive 2001/83/UE is adopted on the preparation of radiopharmaceuticals outside the marketing authorization track in Europe. Nine different national regulations have been studied to describe how unlicensed radiopharmaceuticals are prepared. Special attention is paid to reflect the minimum standards that these preparations should meet as well as the educational requirements to be a radiopharmacist in charge of them. CONCLUSION: The rapid development of new radiopharmaceuticals used in radiometabolic therapy requires a common regulation that allows balance between the use and preparation of licensed and unlicensed radiopharmaceuticals. The absence of a harmonized regulation for the radiopharmaceutical small-scale preparation and the implementation of Good Manufacture Practices, leads to extreme differences in the use, quality assurance and availability of radiopharmaceuticals in Europe.

A machine learning based EMA-DCPM algorithm for production scheduling.

Some special manufacturing fields such as aerospace may encounter mixed production of multiple research and development projects and multiple batch production projects. Under these special production conditions resource conflicts are more severe, resulting in uncertain operating times that are difficult to predict. In addition, a single project may have tens of thousands of supporting products, making it difficult to effectively control the total construction process. To address these challenges this paper proposes new methods. A model, EMA-DCPM (dynamic critical path method) incorporating attention mechanisms in Enterprise Resource Planning and Mechanical Engineering Society) has been proposed. This model predicts product job time through machine learning methods and discovers the predictive advantage of the attention mechanism through data comparison. The CPM control algorithm was improved to enhance its robustness and an efficient modeling method, "5+X" was proposed. This new method is suitable for mixed line planning management in sophisticated manufacturing projects and has value for practical applications.

Insights into Early Interactions on Innovative Developments with European Regulators.

INTRODUCTION: The European Medicines Agency Innovation Task Force (ITF) acts as early point of contact for medicine and technology developers to enable innovation during early drug development stages through ITF briefing meetings. AIM: To reflect on the current pace of innovation and to assess the potential of ITF stakeholder interactions, a comprehensive analysis of the ITF briefing meetings held between 2021 and 2022 was conducted with a focus on individual questions raised by the developers and the related feedback provided by the European regulators. METHODS: Questions raised during ITF briefing meetings were extracted and categorised into main and sub-categories, revealing different themes across the whole medicine development process such as manufacturing technologies, pre-clinical developments, and clinically relevant questions. RESULTS: There was positive feedback from regulators who gave initial guidance in 85% of the answers, provided concrete examples in 20% of the answers and recommended to continue discussions through additional regulatory procedures in 22% of the answers. CONCLUSION: This analysis frames the content and the type of topics discussed during ITF briefing meetings. Moreover, it describes the type of regulatory feedback provided to medicine developers and identified potential for improvement of these early interactions. Therefore, this analysis emphasises the role of ITF briefing meetings in fostering innovation in medicine.

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.

Estimation of withdrawal interval recommendations following administration of fenbendazole medicated feed to ring-necked pheasants (Phasianus colchicus).

Introduction: Prescribing fenbendazole medicated feed for pheasants in the USA is considered extra-label drug use under CPG Sec 615.115, and a safe estimated withdrawal interval (WDI) must be applied following administration to this minor food-producing species. This study sought to determine the pharmacokinetic and residue depletion profile for fenbendazole and its major metabolites to estimate a WDI for pheasants following fenbendazole administration as an oral medicated feed. Method: Pheasants (n = 32) were administered fenbendazole as an oral medicated feed (100 ppm) for 7 days. Fenbendazole, fenbendazole sulfoxide, and fenbendazole sulfone (FBZ-SO2) in liver and muscle samples were analyzed using HPLC-UV. Tissue WDIs were estimated using FDA, European Medicines Agency (EMA), and half-life multiplication methods for US poultry tolerances, EMA maximum residue limits, and the analytical limit of detection (LOD; 0.004 ppm). Terminal tissue elimination half-lives (T1/2) were estimated by non-compartmental analysis using a naïve pooled data approach. Results: The tissue T1/2 was 14.4 h for liver, 13.2 h for thigh muscle, and 14.1 h for pectoral muscle. The maximum estimated withdrawal interval was 153 h (7 days) for FBZ-SO2 in pectoral muscle using the FDA tolerance method (95% confidence interval for the 99th percentile of the population), and the LOD as the residue limit. Discussion: The results from this study support the use of FBZ-SO2 as the marker residue in the liver of pheasants and the provision of evidence based WDIs following the extra-label administration of fenbendazole medicated feed (100 ppm) for 7 days.

New Oncologic Drugs from 2008 to 2023-Differences in Approval and Access between the United States, Europe and Brazil.

INTRODUCTION: Advancements in oncology have revolutionized cancer treatment, with new drugs being approved at different rates worldwide. Our objective was to evaluate the approval of new oncological drugs for solid tumors by the Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Brazilian Health Regulatory Agency (ANVISA) since 2008. METHODS: Data were collected from public and online databases by searching for the date of submission, the date of the procedure, the date of approval, clinical indication, and drug characteristics. The distribution was tested using the Shapiro-Wilk, test and comparisons were made using the Mann-Whitney U test; the data are reported using median days and interquartile range (IQR1-IQR3). RESULTS: In total, 104 new oncologic drugs for the treatment of solid tumors were approved by the three agencies: 98 by the FDA, 90 by the EMA, and 68 by ANVISA. The cancer types with the highest number of first indications were lung cancer (n = 24), breast cancer (n = 15), and melanoma (n = 15). Most approvals were for oral medications (n = 63) and tyrosine-kinase inhibitors or other small-molecule inhibitors (n = 54). Time to approval after submission was as follows: the FDA-224 days (167-285); the EMA-364 days (330-418); and ANVISA-403 days (276-636) (p < 0.00001 for the FDA to the EMA and the FDA to ANVISA). The difference between submission dates among the agencies was as follows: EMA-FDA: 24 days (0-85); ANVISA-FDA: 255 (114-632); and ANVISA-EMA: 260 (109-645). The difference in approval dates between the agencies was as follows: EMA-FDA: 185 days (59-319); ANVISA-FDA: 558 (278-957); and ANVISA-EMA: 435 days (158-918). CONCLUSIONS: New oncologic drugs are submitted to the FDA and EMA for approval on similar dates; however, the longer appraisal period by the EMA pushes the approval date for Europe to approximately 6 months later. The same steps at ANVISA delay the approval by 1.5 years. Such procedures cause a significant difference in available medications between these regions.