Characteristics of clinical trials of new oncology drugs approved in China.

BACKGROUND: Since reforms were introduced to incentivize drug innovation in 2015, the Chinese pharmaceutical market has experienced unprecedented prosperity, with more new drugs than ever before, especially anticancer treatments. In 2021, Chinese regulatory agencies issued the new guideline for clinical research and development of antitumor drugs, triggering a series of responses on the drug market. Limited research has outlined the nature of the original new drugs in China to understand the dynamic response of the market. METHODS: The objective of this article was to map the clinical development of approved new oncology drugs in China from 2015 to 2021 and differed from previous studies by focusing on original new drugs, using the United States as a benchmark, and elaborating the endogenous features of clinical trials. RESULTS: Clinical trials conducted in China have risen to a level similar to that of the United States in many aspects of trial design, but there is still distance between the implementation and operational details of clinical trials. In the meantime, China has made significant breakthroughs in drug approval. Greater than 60% of novel anticancer drugs in China received accelerated approved for their first listing. Approximately 90% of the pivotal clinical trials supporting initial drug approval used surrogate measures as end points, and one half were nonrandomized or did not have a control group. However, duplicate development without evidence of a clinical advantage compared with current therapies was widely observed. CONCLUSIONS: By presenting a multidimensional landscape of clinical trials and approvals in the real world, this review allows interested researchers, developers, and even regulators to understand what has been done and what should be done next in anticancer drug development in China.

Digital Health Applications (DiGAs) on a Fast Track: Insights From a Data-Driven Analysis of Prescribable Digital Therapeutics in Germany From 2020 to Mid-2024.

BACKGROUND: This study aimed to analyze the rapidly evolving ecosystem of digital health applications (Digitale Gesundheitsanwendung; DiGAs) in Germany, spurred by the 2019 Digital Healthcare Act. With over 73 million people in Germany now having access to DiGAs, these prescribable digital health apps and web-based applications represent a substantial stride in health care modernization, supporting both patients and health care providers with digital solutions for disease management and care improvement. OBJECTIVE: Through a data-driven approach, this research aimed to unpack the complexities of DiGA market dynamics, economic factors, and clinical evidence, offering insights into their impact over the past years. METHODS: The analysis draws from a range of public data sources, including the DiGA directory, statutory health insurance reports, app store feedback, and clinical study results. RESULTS: As of July 1, 2024, there are 56 DiGAs listed by the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte), divided into 35 permanently and 21 preliminarily listed applications. Our findings reveal that a majority of DiGAs extend beyond the intended 1-year period to achieve permanent listing, reflecting the extensive effort required to demonstrate clinical efficacy. Economic analysis uncovered a dynamic pricing landscape, with initial prices ranging from approximately €200 to €700 (€1=US $1.07), averaging at a median of €514 for a 3-month DiGA prescription. Following negotiations or arbitration board decisions, prices typically see a 50% reduction, settling at a median of €221. Prescription data offer valuable insights into DiGA acceptance, with total prescriptions jumping from around 41,000 in the first period to 209,000 in the latest reporting period. The analysis of the top 15 DiGAs, representing 82% of the total prescriptions, shows that these best-performing apps receive from a minimum of 8 to a maximum of 77 daily prescriptions, with native apps and early market entrants achieving higher rates. Clinical evidence from all 35 permanently listed DiGAs indicates a uniform preference for randomized controlled trials to validate primary end points, with no noteworthy use of alternative study designs encouraged in the Digital Healthcare Act and related regulations. Moreover, all evaluated DiGAs focused on medical benefits, with health status improvement as a key end point, suggesting an underuse of patient-relevant structural and procedural improvement in demonstrating health care impact. CONCLUSIONS: This study highlights the growth and challenges within the DiGA sector, suggesting areas for future research, such as the exploration of new study designs and the potential impact of patient-relevant structural and procedural improvements. For DiGA manufacturers, the strategic advantage of early market entry is emphasized. Overall, this paper underscores the evolving landscape of digital health, advocating for a nuanced understanding of digital health technology integration in Germany and beyond.

The health benefits of dietary polyphenols on pediatric intestinal diseases: Mechanism of action, clinical evidence and future research progress.

Pediatric intestinal development is immature, vulnerable to external influences and produce a variety of intestinal diseases. At present, breakthroughs have been made in the treatment of pediatric intestinal diseases, but there are still many challenges, such as toxic side effects, drug resistance, and the lack of more effective treatments and specific drugs. In recent years, dietary polyphenols derived from plants have become a research hotspot in the treatment of pediatric intestinal diseases due to their outstanding pharmacological activities such, as anti-inflammatory, antibacterial, antioxidant and regulation of intestinal flora. This article reviewed the mechanism of action and clinical evidence of dietary polyphenols in the treatment of pediatric intestinal diseases, and discussed the influence of physiological characteristics of children on the efficacy of polyphenols, and finally prospected the new dosage forms of polyphenols in pediatrics.

[Element relationship and extension path of clinical evidence knowledge map with Chinese patent medicine].

This study aims to construct the element relationship and extension path of clinical evidence knowledge map with Chinese patent medicine, providing basic technical support for the formation and transformation of the evidence chain of Chinese patent medicine and providing collection, induction, and summary schemes for massive and disorganized clinical data. Based on the elements of evidence-based PICOS, the conventional construction methods of knowledge graph were collected and summarized. Firstly, the data entities related to Chinese patent medicine were classified, and entity linking was performed(disambiguation). Secondly, the study associated and classified the attribute information of the data entity. Finally, the logical relationship between entities was constructed, and then the element relationship and extension path of the knowledge map conforming to the characteristics of clinical evidence of Chinese patent medicine were summarized. The construction of the clinical evidence knowledge map of Chinese patent medicine was mainly based on process design and logical structure, and the element relationship of the knowledge map was expressed according to the PICOS principle and evidence level. The extension path crossed three levels(model layer, data layer application, and new evidence application), and the study gradually explored the path from disease, core evaluation indicators, Chinese patent medicine, core prescriptions, syndrome and treatment rules, and medical case comparison(evolution law) to new drug research and development. In this study, the top-level design of the construction of the clinical evidence knowledge map of Chinese patent medicine has been clarified, but it still needs the joint efforts of interdisciplinary disciplines. With the continuous improvement of the map construction technology in line with the characteristics of TCM, the study can provide necessary basic technical support and reference for the development of the TCM discipline.

The emerging role of leptin in obesity-associated cardiac fibrosis: evidence and mechanism.

Cardiac fibrosis is a hallmark of various cardiovascular diseases, which is quite commonly found in obesity, and may contribute to the increased incidence of heart failure arrhythmias, and sudden cardiac death in obese populations. As an endogenous regulator of adiposity metabolism, body mass, and energy balance, obesity, characterized by increased circulating levels of the adipocyte-derived hormone leptin, is a critical contributor to the pathogenesis of cardiac fibrosis. Although there are some gaps in our knowledge linking leptin and cardiac fibrosis, this review will focus on the interplay between leptin and major effectors involved in the pathogenesis underlying cardiac fibrosis at both cellular and molecular levels based on the current reports. The profibrotic effect of leptin is predominantly mediated by activated cardiac fibroblasts but may also involve cardiomyocytes, endothelial cells, and immune cells. Moreover, a series of molecular signals with a known profibrotic property is closely involved in leptin-induced fibrotic events. A more comprehensive understanding of the underlying mechanisms through which leptin contributes to the pathogenesis of cardiac fibrosis may open up a new avenue for the rapid emergence of a novel therapy for preventing or even reversing obesity-associated cardiac fibrosis.

Clinical evidence requirements according to the IVDR 2017/746: practical tools and references for underpinning clinical evidence of IVD-MDs.

In May 2022, the European Regulation 2017/746 (IVDR) came into force. It changes the approach of in vitro medical devices (IVD-MDs) for industry and institutions. It reinforces the clinical evidence requirements to improve performance, safety and transparency. Despite extended transition periods and existing guides, IVDR remains difficult to interpret and bringing devices into compliance requires efforts. The generation of clinical evidence is essential to demonstrate compliance with IVDR, and encompasses scientific validity, analytical performance and clinical performance. It is required to demonstrate, per intended use in the target population and clinical care pathway, IVD-MDs clinical performance (compared to a predefined clinical performance). Thus, there is a need for IVD-manufacturers and end-users in health care institutions, to obtain guidance on how to generate this clinical evidence. This article aims industrials and clinicians to identify key steps imposed by the IVDR for bringing IVD-MDs to the EU-market. We propose a general view of performance evaluation requirements for IVD-MDs and provide key references, including how to establish study design that will enable to document clinical performance of existing, refined or emerging medical tests. Finally, we propose a roadmap to address the relevant questions and studies in relation to the documents requested in the IVDR.

Chinese patent medicines for coronary microvascular disease: clinical evidence and potential mechanisms.

Coronary microvascular disease (CMVD) is a high risk factor for many cardiovascular events. Due to the limited understanding of its pathophysiological mechanism, modern medicine still lacks therapeutic drugs for CMVD. Existing clinical studies have shown that traditional Chinese medicine (TCM) can effectively improve the clinical symptoms and quality of life of CMVD patients. As an indispensable part of TCM, Chinese patent medicines (CPMs) are widely used in clinical practice. In the face of numerous oral CPMs for treatment of CMVD, how to choose a reasonable medication regimen is one of the important issues in clinic. Based on this, this paper reviewed the clinical efficacy and recommended level of 12 CPMs in the treatment of CMVD, which are recommended by expert consensus on diagnosis and treatment of coronary microvascular disease with integrated Chinese and Western medicine (WM). In addition, this study also systematically summarized the possible mechanisms of CPMs in the treatment of CMVD by protecting coronary microvascular endothelial cells, improving vascular endothelial function, inhibiting inflammation, reducing oxidative stress, promoting angiogenesis, and improving hemorheology, aiming to provide meaningful information for its clinical application.

Clinical application of 675 nm laser therapy for dorsal hand skin hyperpigmentation.

BACKGROUND: Noninvasive skin rejuvenation treatment is growing in recognition to aesthetic medicine. AIM: The objective of the study was to assess the efficacy and the safety of the 675-nm laser source treatment of photodamaged hands. MATERIALS AND METHODS: The study included 21 patients (6 males and 15 females) with a mean age of 63 (± 9) years. Patients were treated with -two to three sessions of the 675-nm laser with a 1-month interval between sessions. Photos of each patient were collected at baseline, and 3 months after the last laser session. The 5-point Global Aesthetic Improvement Scale (GAIS) was recorded with their final assessment session (3 months). RESULTS: The total GAIS scores showed satisfactory results: 15 patients (71%) experienced 4 score (excellent improvement) changes and 6 patients (29%) experienced 3 score (good improvement) changes. Clinical images showed good efficacy and visible aesthetic results for the management of photodamaged skin. No serious adverse effects were recorded. CONCLUSION: This study demonstrates the safety and efficacy of for the aesthetic improvement of skin pigmentation and texture for photodamaged hands.

The Value of Scientific Publications in Surgical Device Innovation.

BACKGROUND: Clinical trials represent a significant risk in the commercialization of surgical technologies. There is incentive for companies to mitigate their regulatory risk by targeting 510K over Premarket Approval (PMA) pathways in order to limit the scope, complexity and cost of clinical trials. As such, not all companies will publish clinical data in the scientific literature. PURPOSE: We set out to investigate the relationship between scientific publication by surgical device companies and the impact it has on company valuation. We hypothesize that publishing in the scientific literature correlates with success of the surgical device companies as measured by funding. RESEARCH DESIGN: We first obtained a list of surgical device startup companies and their financial deals using the Pitchbook database. Those companies were then cross referenced with the FDA database and the Dimensions database for product registrations and peer reviewed publications, respectively. Analysis was then performed using these query results. STUDY SAMPLE AND DATA COLLECTION: We obtained a list of US surgical device startups financing deals closed between 2010 and 2020 from the Pitchbook database. We queried the Pitchbook for deal dates from January 1, 2010 to January 1, 2020 for deal types spanning early stage investment to IPO. Deals were limited to those conducted in the United States and to the surgical device industry. We queried the FDA database for product registration information associated with each of the companies involved in the deals. We tabulated the number of journal articles associated with surgical device companies using the Dimensions Search API as well as a manual confirmation. RESULTS: Five hundred thirty five (535) deals from 222 companies were found in Pitchbook that met our criteria. Querying the FDA database resulted in 578 registrations associated with these companies. Publications per company ranged widely. CONCLUSIONS: Companies that are able to generate a more numerous publications had correspondingly higher valuations during funding rounds. A subset of outstanding companies were analyzed and at least four factors affect: direct value of publications, indirect valve of publications, survivorship bias, and adoption share; each of which will be discussed in this manuscript.

Therapeutic Effect of Curcumin on Metabolic Diseases: Evidence from Clinical Studies.

Metabolic diseases have become a serious threat to human health worldwide. It is crucial to look for effective drugs from natural products to treat metabolic diseases. Curcumin, a natural polyphenolic compound, is mainly obtained from the rhizomes of the genus Curcuma. In recent years, clinical trials using curcumin for the treatment of metabolic diseases have been increasing. In this review, we provide a timely and comprehensive summary of the clinical progress of curcumin in the treatment of three metabolic diseases, namely type 2 diabetes mellitus (T2DM), obesity and non-alcoholic fatty liver disease (NAFLD). The therapeutic effects and underlying mechanisms of curcumin on these three diseases are presented categorically. Accumulating clinical evidence demonstrates that curcumin has good therapeutic potential and a low number of side effects for the three metabolic diseases. It can lower blood glucose and lipid levels, improve insulin resistance and reduce inflammation and oxidative stress. Overall, curcumin may be an effective drug for the treatment of T2DM, obesity and NAFLD. However, more high-quality clinical trials are still required in the future to verify its efficacy and determine its molecular mechanisms and targets.

Halving the usage of rigid-soled postoperative shoes does not affect outcomes in forefoot reconstruction surgery.

BACKGROUND: Postoperative shoes are commonly used after forefoot surgery. This study's aim was to demonstrate that reducing rigid-soled shoe time to 3 weeks neither compromises functional outcomes nor does it produce complications. METHODS: Prospective cohort study: 6 weeks versus 3 weeks of rigid postoperative shoe (100 and 96 patients respectively), after forefoot surgery with stable osteotomies. Manchester-Oxford Foot Questionnaire (MOXFQ) and pain Visual Analog Scale (VAS) were studied preoperative and one year postoperative. Radiological angles were also assessed after removing the rigid shoe and at 6 months. RESULTS: The MOXFQ index and pain VAS depicted similar results in each group (group A: 29.8 and 25.7; group B: 32.7 and 23.7) with no differences between them (p = .43 Vs. p = .58). Moreover, no differences were reported in their differential angles (HV differential-angle p = .44, IM differential-angle p = .18) or in their complication rate. CONCLUSION: In forefoot surgery with stable osteotomies, shortening the postoperative shoe time to 3 weeks, neither impairs clinical results nor the initial correction angle.

Second-line treatments in advanced biliary tract cancer: systematic literature review of efficacy, effectiveness and safety.

Background: A systematic review was conducted to understand clinical, economic and health-related quality-of-life outcomes in second-line biliary tract cancer. Materials & methods: The review followed established recommendations. The feasibility of network meta-analysis revealed limited networks, thus synthesis was limited to a summary of reported ranges, percentiles and medians. Results: The review included 62 trials and observational studies highly variable with respect to key baseline characteristics. Commonly evaluated second-line treatments included fluoropyrimidine-, gemcitabine- and S-1-based regimens. Across active treatment arms, median overall survival ranged from 3.5 to 15.0 months (median: 6.9), median progression-free survival from 1.4 to 6.5 months (median: 2.9) and objective response from 0 to 36.4%. Outcomes were similar between study types, with a few notable outliers. Treatment-related/emergent adverse events were infrequently reported; no studies reported economic or health-related quality-of-life outcomes. Conclusions: Biliary tract cancer is a difficult-to-treat disease with poor prognosis. Despite evolving treatment landscapes, more recent studies did not show clinical outcome improvement, highlighting an unmet need among advanced/metastatic patients.

A systematic review of published literature was undertaken to understand the clinical, economic and health-related quality-of-life impact of second-line biliary tract cancer (BTC). A total of 62 relevant studies were identified. The patient populations included across these studies were highly variable with respect to key patient characteristics (i.e., age, sex, physical functioning and tumor type). Commonly evaluated treatments included fluoropyrimidine-, gemcitabine- and S-1-based regimens. Reported values for key outcomes varied substantially, somewhat explained by a few outlier studies. Median overall survival ranged from 3.5 to 15.0 months, median progression-free survival from 1.4 to 6.5 months and objective response from 0 to 36.4%. Treatment-related/emergent adverse events were infrequently reported; no studies reported economic or health-related quality-of-life outcomes. The results demonstrate that BTC is a difficult-to-treat disease with poor prognosis. Despite evolving treatment landscapes, more recent studies did not show clinical outcome improvement, highlighting an unmet need among advanced/metastatic second-line BTC patients.

Statins in depression: a repurposed medical treatment can provide novel insights in mental health.

Depression has a large burden, but the development of new drugs for its treatment has proved difficult. Progresses in neuroscience have highlighted several physiopathological pathways, notably inflammatory and metabolic ones, likely involved in the genesis of depressive symptoms. A novel strategy proposes to repurpose established medical treatments of known safety and to investigate their potential antidepressant activity. Among numerous candidates, growing evidence suggests that statins may have a positive role in the treatment of depressive disorders, although some have raised concerns about possible depressogenic effects of these widely prescribed medications. This narrative review summarises relevant findings from translational studies implicating many interconnected neurobiological and neuropsychological, cardiovascular, endocrine-metabolic, and immunological mechanisms by which statins could influence mood. Also, the most recent clinical investigations on the effects of statins in depression are presented. Overall, the use of statins for the treatment of depressive symptoms cannot be recommended based on the available literature, though this might change as several larger, methodologically robust studies are being conducted. Nevertheless, statins can already be acknowledged as a driver of innovation in mental health, as they provide a novel perspective to the physical health of people with depression and for the development of more precise antidepressant treatments.

Cognitive impairment caused by hypoxia: from clinical evidences to molecular mechanisms.

Hypoxia is a state of reduced oxygen supply and excessive oxygen consumption. According to the duration of hypoxic period, it can be classified as acute and chronic hypoxia. Both acute and chronic hypoxia could induce abundant neurological deficits. Although there have been significant advances in the pathophysiological injuries, few studies have focused on the cognitive dysfunction. In this review, we focused on the clinical evidences and molecular mechanisms of cognitive impairment under acute and chronic hypoxia. Hypoxia can impair several cognitive domains such as attention, learning and memory, procession speed and executive function, which are similar in acute and chronic hypoxia. The severity of cognitive deficit correlates with the duration and degree of hypoxia. Recovery can be achieved after acute hypoxia, while sequelae or even dementia can be observed after chronic hypoxia, perhaps due to the different molecular mechanisms. Cardiopulmonary compensatory response, glycolysis, oxidative stress, calcium overload, adenosine, mitochondrial disruption, inflammation and excitotoxicity contribute to the molecular mechanisms of cognitive deficit after acute hypoxia. During the chronic stage of hypoxia, different adaptive responses, impaired neurovascular coupling, apoptosis, transcription factors-mediated inflammation, as well as Aß accumulation and tau phosphorylation account for the neurocognitive deficit. Moreover, brain structural changes with hippocampus and cortex atrophy, ventricle enlargement, senile plaque and neurofibrillary tangle deposition can be observed under chronic hypoxia rather than acute hypoxia.

[Scoping review of clinical evidence of Chinese patent medicines for digestive system diseases in children].

This study analyzed and reported the basic information and clinical evidence of Chinese patent medicines for digestive system diseases in children in a scoping review manner. Based on the drug instructions, the basic information of Chinese patent medicines for digestive system diseases in children was obtained by searching the three lists of national medicines. At the same time, the relevant clinical literatures from the first day of establishment to March 7, 2022 were obtained from Chinese and English databases. According to the screening criteria, 39 Chinese patent medicines were included, involving 8 dosage forms. Eight Chinese medicines including Crataegi Fructus, Poria, Citri Reticulatae Pericarpium, Hordei Fructus Germinatus, Arecae Semen, Massa Medicata Fermentata, Dioscoreae Rhizoma, and Atractylodis Macrocephalae Rhizoma were frequently used, and the main effects were invigorating spleen, checking diarrhea, promoting digestion, clearing heat, and harmonizing stomach. The indications for Chinese patent medicines were mainly diarrhea, anorexia, food accumulation, dyspepsia, and rotavirus enteritis in children. Among all drug instructions, only 4 mentioned adverse reactions and 6 mentioned contraindications. Ninety-two clinical studies were included ultimately, including 84 randomized controlled studies, 2 systematic reviews/Meta-analysis, 1 retrospective study, and 5 case series. The literatures only covered 21 kinds of Chinese patent medicines, with the most studies related to Xingpi Yanger Granules, accounting for 32.6% of the total literature volume. The sample size in the literatures was mainly focused on 51-200 cases, and 51-100 cases were selected by the most literatures, accounting for 34.45%. The interventions of the experimental group were mainly Chinese patent medicines or Chinese patent medicines combined with western medicines. The literatures with treatment course of 0-7 d accounted for the largest proportion(51.10%). The effective rate and symptom improvement time were used as the indexes to evaluate the results. The main adverse reactions were vomiting, constipation, nausea, rash, cold, diarrhea, redness of the skin around the umbilicus, or red itchy skin. The analysis of this study found that Chinese patent medicines have good curative effect and research prospects in the treatment of digestive system diseases in children. However, most clinical evidence has problems, such as limited indexes to evaluate the results, lack of traditional Chinese medicine characteristics, uneven quantity and low quality of Chinese patent medicine literatures, and insufficient specification of instructions. In the future, high-quality clinical studies on this field should be actively carried out, and economic studies and clinical comprehensive evaluation of Chinese patent medicines should be strengthened to explore the characteristics and advantages of its treatment, so as to provide decision-making basis for finding the accurate clinical positioning and promoting the rational clinical application of Chinese patent medicines for treating digestive system diseases in children.

[Clinical comprehensive evaluation of Ginkgolide Injection in treatment of cerebral infarction].

This clinical value-oriented comprehensive evaluation of drugs was carried out in accordance with Guidelines for Management of Comprehensive Clinical Evaluation of Drugs(trial version 2021), with the qualitative and quantitative evaluation methods adopted. Based on the evidence-based medicine, epidemiology, clinical medicine, pharmacoeconomics, mathematical statistics, and health technology evaluation(HTA), the clinical value of Ginkgolide Injection was evaluated from the "6+1" dimension by giving weight to the criterion level and index level and calculating with multi-criteria decision analysis(MCDA) model and CSC v2.0. After entering the market, Ginkgolide Injection has been subjected to phase Ⅳ clinical trial, spontaneous reporting system(SRS)-based data monitoring, systematic review and Meta-analysis, acute toxicity and long-term toxicity assays, active monitoring, and RCTs, and the evidence of safety was sufficient. The results of active monitoring showed that the incidence of adverse reactions was 0.09%(rare), mainly manifested as flushing, dizziness, rash, nausea, and vomiting. According to the nested case-control study, the adverse reactions of this drug had nothing to do with the product batch, implying that the drug quality was controllable. The adverse reactions mainly resulted from the pharmacodynamic reactions. Because the drug was effective in resisting platelet aggregation, the resulting adverse reactions such as flushing, dizziness, headache, and phlebitis were caused by vasodilation. Skin rash and gastrointestinal symptoms were mainly attributed to the patients' sensitivity to drugs and their own allergic constitution. According to the sufficiency of evidence and the incidence of adverse reactions in the safety research, the safety of Ginkgolide Injection was grade A. The results of Meta-analysis showed that Ginkgolide Injection combined with conventional western medicine was superior to conventional western medicine in improving the clinical effective rate, neurological function score, and activity of daily living score of patients with cerebral infarction. The validity evidence was evaluated according to the PICO principle to be high. According to the GREAD evaluation principle, the quality of such evidence as clinical effective rate, National Institute of Health stroke scale(NIHSS), and Barthel Index(BI) was evaluated, and the results demonstrated that the evidence quality of clinical effective rate and activity of daily living score was medium. The effectiveness of Ginkgolide Injection was grade A. According to the economic report of Ginkgolide Injection, it had short-term and long-term pharmacoeconomic advantages in the treatment of ischemic stroke, and the economic evidence value was good. According to the CASP economic evaluation checklist, the overall quality evaluation results of the economic report are basically clear. To be specific, the economic evidence quality was high. Based on the comprehensive economic evidence quality and economic value, the economy of this drug was grade A. The innovation of this product was evaluated from three aspects: clinical innovation, enterprise service system innovation, and industrial innovation. Ginkgolide Injection could be used 24 h after intravenous thrombolysis for improving patients' neurological function without increasing bleeding, indicating its important clinical innovation. There were many innovations in ensuring drug supply, especially at the grass roots, drug safety, effectiveness, and reasonable price, which has provided reference for establishing enterprise philosophy, managing drug resources, developing process and technology, and determining enterprise management and marketing. Therefore, its innovation was grade A. The drug had no special medication plan in use, exhibiting good suitability for doctors, nurses, and patients. The suitability was grade B. Compared with similar drugs, its price was at a medium level, meaning good affordability, sufficient production capacity, and easy accessibility. Its accessibility was therefore grade B. This drug belonged to Chinese medicinal injection. The large-sample real-world research revealed rich human use experience, so it was grade C for the traditional Chinese medicine characteristic. According to the comprehensive evaluation, the clinical value of Ginkgolide Injection in the treatment of cerebral infarction fell into class A. It is suggested that it can be transformed into the relevant policy results of basic clinical medication management according to the procedure.

Clinical recommendations: The role of mechanisms in the GRADE framework.

The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework has become one of the most influential frameworks for assessing quality of research and developing clinical recommendations. The GRADE framework has been presented as an evolution in the Evidence-Based Medicine (EBM) movement. Both GRADE and EBM emphasize effect estimates derived from population-level clinical trials and, as a consequence, devalue the role of mechanisms as the basis for clinical decisions. Although mechanisms do not hold the epistemic privilege of rigorous clinical trials in EBM reasoning, this paper will argue that mechanisms appear to be important in the use and application of GRADE, as described in the literature. The seemingly necessary role of mechanisms in the development of clinical recommendations has, so far, received little attention and is not explicitly featured in the literature describing GRADE. The analysis of the GRADE framework presented in this paper reveals an apparent tension between EBM's willingness to downplay mechanisms and what seems their inevitable use in GRADE. In this paper, we take the position that if mechanistic reasoning is inevitable in the use of GRADE, then the instructional literature on the framework would benefit from more explicit discussion of how to consider and integrate mechanisms.

Development of a Treatment-decision Algorithm for Human Immunodeficiency Virus-uninfected Children Evaluated for Pulmonary Tuberculosis.

BACKGROUND: Limitations in the sensitivity and accessibility of diagnostic tools for childhood tuberculosis contribute to the substantial gap between estimated cases and cases notified to national tuberculosis programs. Thus, tools to make accurate and rapid clinical diagnoses are necessary to initiate antituberculosis treatment in more children. METHODS: We analyzed data from a prospective cohort of children <13 years old being routinely evaluated for pulmonary tuberculosis in Cape Town, South Africa, from March 2012 to November 2017. We developed a regression model to describe the contributions of baseline clinical evaluation to the diagnosis of tuberculosis using standardized, retrospective case definitions. We included baseline chest radiographic and Xpert MTB/RIF assay results to the model to develop an algorithm with ≥90% sensitivity in predicting tuberculosis. RESULTS: Data from 478 children being evaluated for pulmonary tuberculosis were analyzed (median age, 16.2 months; interquartile range, 9.8-30.9 months); 242 (50.6%) were retrospectively classified with tuberculosis, bacteriologically confirmed in 104 (43.0%). The area under the receiver operating characteristic curve for the final model was 0.87. Clinical evidence identified 71.4% of all tuberculosis cases in this cohort, and inclusion of baseline chest radiographic results increased the proportion to 89.3%. The algorithm was 90.1% sensitive and 52.1% specific, and maintained a sensitivity of >90% among children <2 years old or with low weight for age. CONCLUSIONS: Clinical evidence alone was sufficient to make most clinical antituberculosis treatment decisions. The use of evidence-based algorithms may improve decentralized, rapid treatment initiation, reducing the global burden of childhood mortality.

Evidence-Based Guidelines and Secondary Meta-Analysis for the Use of Transcranial Direct Current Stimulation in Neurological and Psychiatric Disorders.

BACKGROUND: Transcranial direct current stimulation has shown promising clinical results, leading to increased demand for an evidence-based review on its clinical effects. OBJECTIVE: We convened a team of transcranial direct current stimulation experts to conduct a systematic review of clinical trials with more than 1 session of stimulation testing: pain, Parkinson's disease motor function and cognition, stroke motor function and language, epilepsy, major depressive disorder, obsessive compulsive disorder, Tourette syndrome, schizophrenia, and drug addiction. METHODS: Experts were asked to conduct this systematic review according to the search methodology from PRISMA guidelines. Recommendations on efficacy were categorized into Levels A (definitely effective), B (probably effective), C (possibly effective), or no recommendation. We assessed risk of bias for all included studies to confirm whether results were driven by potentially biased studies. RESULTS: Although most of the clinical trials have been designed as proof-of-concept trials, some of the indications analyzed in this review can be considered as definitely effective (Level A), such as depression, and probably effective (Level B), such as neuropathic pain, fibromyalgia, migraine, post-operative patient-controlled analgesia and pain, Parkinson's disease (motor and cognition), stroke (motor), epilepsy, schizophrenia, and alcohol addiction. Assessment of bias showed that most of the studies had low risk of biases, and sensitivity analysis for bias did not change these results. Effect sizes vary from 0.01 to 0.70 and were significant in about 8 conditions, with the largest effect size being in postoperative acute pain and smaller in stroke motor recovery (nonsignificant when combined with robotic therapy). CONCLUSION: All recommendations listed here are based on current published PubMed-indexed data. Despite high levels of evidence in some conditions, it must be underscored that effect sizes and duration of effects are often limited; thus, real clinical impact needs to be further determined with different study designs.

US Food and Drug Administration utilization of postmarketing requirements and postmarketing commitments, 2009-2018.

BACKGROUND/AIMS: The US Food and Drug Administration outlines clinical studies as postmarketing requirements and commitments to be fulfilled following approval of new drugs and biologics ("therapeutics"). Regulators have increasingly emphasized lifecycle evaluation of approved therapeutics, and postmarketing studies are intended to advance our understanding of therapeutic safety and efficacy. However, little is known about the indications that clinical studies outlined in postmarketing requirements and commitments investigate, including whether they are intended to generate evidence for approved or other clinical indications. Therefore, we characterized US Food and Drug Administration postmarketing requirements and commitments for new therapeutics approved from 2009 to 2018. METHODS: We conducted a cross-sectional study of all novel therapeutics, including small-molecule drugs and biologics, receiving original US Food and Drug Administration approval from 2009 to 2018, using approval letters accessed through the Drug@FDA database. Outcomes included the number and characteristics of US Food and Drug Administration postmarketing requirements and commitments for new therapeutics at original approval, including the types of studies outlined, the indications to be investigated, and the clinical evidence to be generated. RESULTS: From 2009 to 2018, the US Food and Drug Administration approved 343 new therapeutics with 1978 postmarketing requirements and commitments. Overall, 750 (37.9%) postmarketing requirements and commitments outlined clinical studies. For 71 of 343 (20.7%) therapeutics, no postmarketing requirements or commitments for clinical studies were outlined, while at least 1 was outlined for 272 (79.3%; median 2 (interquartile range: 1-4)). Among these 272 therapeutics, the number of postmarketing requirements and commitments for clinical studies per therapeutic did not change from 2009 (median: 2 (interquartile range: 1-4)) to 2018 (median: 2 (interquartile range: 1-3)). Among the 750 postmarketing requirements and commitments for clinical studies, 448 (59.7%) outlined new prospective cohort studies, registries, or clinical trials, while the remainder outlined retrospective studies, secondary analyses, or completion of ongoing studies. Although 455 (60.7%) clinical studies investigated only original approved therapeutic indications, 123 (16.4%) enrolled from an expansion of the approved disease population and 61 (8.1%) investigated diseases unrelated to approved indications. CONCLUSIONS: The US Food and Drug Administration approves most new therapeutics with at least 1 postmarketing requirement or commitment for a clinical study, and outlines investigations of safety or efficacy for both approved and unapproved indications. The median number of 2 clinical studies outlined has remained relatively constant over the last decade. Given increasing emphasis by the US Food and Drug Administration on faster approval and lifecycle evaluation of therapeutics, these findings suggest that more postmarketing requirements and commitments may be necessary to address gaps in the clinical evidence available for therapeutics at approval.