The reimbursement decision speed for oncology new drugs in China and its determinant factors.

Introduction: China has initiated national price negotiations to improve access to innovative drugs. Learning the factors that contributed to the time gap from marketing authorization to reimbursement leads to more clarity to decision-making, which remains under-researched in China. Methods: We collected new oncology drug approvals that were marketed before 30 Jun 2022, using the Listed Drug Database of the Chinese drug agency. Major information of each approval was obtained from the published review report, including the first approval region (China or the US) and the receipt of expedited review pathways (priority review and conditional approval). The reimbursement lists issued by China National Healthcare Security Administration from 2015 to 2023 were used to determine the reimbursement status of drugs. The duration from marketing authorization to reimbursement was defined as the reimbursement decision speed, and the Cox regression was performed to explore the underlying factors. Results: A total of 186 oncology approvals were included. More than half of the approvals qualified for reimbursement (110[59.14%]), and the median reimbursement decision speed was accelerated from 540.5 days in the third-round negotiation to 448 days in the seventh-round. Domestic new drugs had a higher probability of being adopted by the Chinese payer than drugs developed by foreign companies (adjusted HR = 3.73, 95% CI 2.42 to 5.75; P < 0.001). Furthermore, new drug applications receiving the regular review pathway were more likely to be reimbursed (adjusted HR = 2.15, 95% CI 1.13 to 4.08; P = 0.020) compared to those approved under the conditional approval pathway. Discussion: These findings indicate that the Chinese government is actively working toward improving access to new oncology drugs. The faster reimbursement decision speed for domestic drugs might be attributed to their pricing advantages and the regulator's efforts to stimulate innovation in the domestic pharmaceutical industry. However, concerns about the uncertainty in drug benefits can affect the reimbursement decision-making, which suggests the delicate tradeoff between drug accessibility and risk involved in the reimbursement process.

Review time of oncology drugs and its underlying factors: an exploration in China.

Introduction: How the launch delay of drugs and other factors of interest can influence the length of the review period by drug agencies is still unknown, and understanding this can help better strike the trade-off related to review speed. Methods: We included all new oncology drug applications submitted to China's National Medical Product Administration (NMPA) between 1 January 2018 and 31 December 2021, and ultimately succeeded in achieving marketing approval. For each drug, the length of the NMPA review process and other major characteristics were collected, including the registration class, approval class, priority review designation, and launch delay relative to the United States, as well as the number of patients enrolled, comparator, and primary endpoint of the pivotal trials supporting the approval. Linear regression model was employed to analyze the effects of factors of interest on the NMPA review time. Results: From 2018 to 2021, NMPA received 137 oncology applications that were ultimately approved. Half of the approvals [76 (55.5%)] were first licensed in the US, leaving a median launch delay of 2.71 years (IQR, 1.03-5.59) in China. In the pivotal studies, the median enrollment was 361 participants (IQR, 131-682), and the use of control groups [90 (65.7%)] and surrogate endpoints [101 (73.7%)] was prevalent. The median review time was 304 days (IQR, 253-376). Multivariate analysis for log-transformed review time showed that larger enrollment (> 92) was associated with a drop of 20.55% in review time (coefficient = -0.230; 95% CI, -0.404 to -0.055; p = 0.010); and a short delay (0 < delay ≤ 1.95 years) was associated with a drop of 17.63% in review time (coefficient = -0.194; 95% CI, -0.325 to -0.062; p = 0.004). Discussion: The short launch delay relative to the US was one important driver to the review speed of NMPA, which might suggest its latent regulatory reliance on the other global regulator during the post-marketing period when new information on the drug's clinical benefit was still lacking.

Real-Time Cell Temperature Fluctuation Monitoring System Using Precision Pt Sensors Coated with Low Thermal Capacity, Low Thermal Resistance, and Self-Assembled Multilayer Films.

Real-time monitoring of cell temperature fluctuation can help researchers better understand physiological phenomena and the effects of drug treatment on cells, which is a novel and important tool for cellular informatics. The platinum (Pt) temperature sensor is widely used in temperature measurement with the advantages of strong stability, great accuracy, and high sensitivity. However, the commercially available Pt sensors have large thermal resistance and heat capacity which are difficult to be applied for cell temperature measurement because only a very small amount of heat flux is generated by live cells. In this study, we designed a system using precision Pt thin-film temperature sensors with low heat capacity and thermal resistance. The Pt thin-film sensors are covered by a silicon nitride insulation layer grafted with a self-assembled multilayer silane film for promoting cell adhesion. The temperature coefficient of resistance of the Pt temperature sensor was about 2100 ppm/°C. The four-wire lead design next to the sensor detection area ensured maximum accuracy, resulting in a system noise below 0.01 °C over a long time. HEK-293T and HeLa cells were cultured on the sensor surface, respectively. The temperature fluctuation of 293T cells was monitored in a cell culture medium, showing a temperature increase of about 0.05-0.12 °C. The temperature fluctuation of HeLa cells treated with cisplatin was also measured and recorded, indicating a temperature decrease of 0.01 °C first and then a gradual temperature increase of 0.04 °C. The Pt sensor system we developed demonstrated high sensitivity and long stability for cell temperature fluctuation monitoring, which can be widely used in cell activity and cellular informatics studies.

Bridging the new drug access gap between China and the United States and its related policies.

Introduction: The access gap for novel pharmaceuticals between China and the developed countries is a major public health issue in China. It is crucial to understand the determinants of this gap to ensure timely access to new drugs and enhance patient health. Methods: We included all new drugs approved by the US Food and Drug Administration (FDA) between 2012 and 2019, and collected their approval timings in China. Major factors of interest comprised orphan designation and expedited review pathways granted by the FDA, along with the proportion of Asian subjects in the pivotal trial supporting the FDA approval and whether the trial included study sites in China. The elapsed time from the FDA approval to the market authorization in China constituted the time-to-event outcome, and Cox proportional-hazards regression was used for multivariate analysis. Results: A total of 327 new drugs were approved by the FDA between 2012 and 2019, among which 41.3% were found to be authorized in China as of 1 November 2023. The median lag time for the mutually approved drugs was 3.5 years. The Cox model found that orphan drugs had lower likelihood of being approved in China (HR = 0.59, 95% CI 0.39-0.89; p = 0.011), while the FDA's Breakthrough-Therapy drugs (HR = 2.33, 95% CI 1.39-3.89; p = 0.001) and Fast-Track drugs (HR = 1.58, 95% CI 1.05-2.38; p = 0.028) had shorter lag times. In the pivotal trials that supported the FDA approvals, a higher proportion of Asian subjects was associated with faster drug entry into the Chinese market (HR = 1.02, 95% CI 1.01-1.03; p < 0.001), and the inclusion of study sites in China mainland was likewise conducive to reducing the drug lag (HR = 5.30, 95% CI 3.20-8.77; p < 0.001). After the trials with China-based sites supported the FDA approvals, 77.8% of the trials also supported the subsequent approvals in China. Discussion: China's involvement in global drug co-development can streamline clinical development, by reducing repeated trials solely in the Chinese population. This is primarily due to the openness of the Chinese drug agency towards overseas clinical data and is a positive sign that encourages global drug developers to include Chinese patients in their development plans as early as possible.

Phase Change Energy Storage Material with Photocuring, Photothermal Conversion, and Self-Cleaning Performance via a Two-Layer Structure.

Compared with the thermal curing process, the photocuring process has advantages such as high efficiency and less energy consumption. However, the preparation of photocurable phase change materials (PCMs) with photothermal conversion and self-cleaning properties is challenging due to the conflict between the transparency required by the photocurable resin system and the opacity deduced by the large number of fillers required by photothermal conversion and the negative effect of filler steric hindrance on the reaction rate and crystallinity. In this work, a "thiol-ene" click chemical reaction induced using UV was used to prepare photocurable PCMs, followed by spraying a carboxylated multiwalled carbon nanotube (CCNT) suspension (with ethyl acetate) onto the surface to achieve an effective two-layer composite of the PCM and CCNTs, by which the rough surface of the PCM and the interaction offered by the hydrogen bonds on the interface of the PCM and the CCNTs provide sufficient adhesion for the two phases. The "thiol-ene" cross-linked polymer network provided shape stability as a support material. 1-Octadectanethiol (ODT) and beeswax (BW) were encapsulated in the cross-linked polymer network as phase change components, providing phase change latent heat. The CCNT layer provided excellent photothermal conversion and self-cleaning properties. The experimental results show that the latent heat of the PCM can reach 124.2 J/g, the water contact angle is 144°, the photothermal conversion efficiency reaches 75%, and it has significant self-cleaning performance. To the best of our knowledge, this is the first report on a photocurable PCM with photothermal conversion and self-cleaning properties.

Bioinspired Rotation Microneedles for Accurate Transdermal Positioning and Ultraminimal-Invasive Biomarker Detection with Mechanical Robustness.

Microneedle permits transdermal biosensing and drug delivery with minor pain. However, accurate microneedle transdermal positioning with minimal skin deformation remains a significant technical challenge due to inhomogeneous skin topology and discontinuous force applied to the microneedle. Here, we introduce bioinspired rotation microneedles for in vivo accurate microneedle positioning as inspired by honeybees' stingers. We demonstrate the benefits of rotation microneedles in alleviating skin resistance through finite element analysis, full-thickness porcine validations, and mathematical derivations of microneedle-skin interaction stress fields. The max penetration force was mitigated by up to 45.7% and the force attenuation rate increased to 2.73 times in the holding stage after penetration. A decrease in max skin deflection and a faster deformation recovery introduced by rotation microneedles implied a more precise penetration depth. Furthermore, we applied the rotation microneedles in psoriasis mice, a monogenic disorder animal model, for minimally invasive biological sample extraction and proinflammatory cytokine monitoring. An ultrasensitive detection method is realized by using only one microneedle to achieve cytokine mRNA level determination compared to commonly required biopsies or blood collection. Thus, rotation microneedles permit a simple, rapid, and ultraminimal-invasive method for subcutaneous trace biological sample acquisition and subsequent point-of-care diagnostics with minimal damage to both microneedles and skins.

Wavelength-tunable deep-ultraviolet thin-film filter: design and experimental demonstration.

A deep-ultraviolet (DUV) narrowband tunable filter with a central wavelength of 225.0 nm is designed, fabricated, and demonstrated experimentally. The simulation results showed a transmittance of about 42.1% at 225.0 nm and a full width at half-maximum (FWHM) of ∼1.2nm. The experimental results for normal incidence light revealed a corresponding central wavelength of 225.0 nm, a transmittance of 27.7%, and a FWHM of 1.9 nm. By changing the incident angle, the central wavelength can be tuned from 225.0 to 224.5 nm. This DUV narrowband tunable filter has been shown to demonstrate good performance and has broad applicability.

An Improved Algorithm for Measuring Nitrate Concentrations in Seawater Based on Deep-Ultraviolet Spectrophotometry: A Case Study of the Aoshan Bay Seawater and Western Pacific Seawater.

Nowadays, it is still a challenge for commercial nitrate sensors to meet the requirement of high accuracy in a complex water. Based on deep-ultraviolet spectral analysis and a regression algorithm, a different measuring method for obtaining the concentration of nitrate in seawater is proposed in this paper. The system consists of a deuterium lamp, an optical fiber splitter module, a reflection probe, temperature and salinity sensors, and a deep-ultraviolet spectrometer. The regression model based on weighted average kernel partial least squares (WA-KPLS) algorithm together with corrections for temperature and salinity (TSC) is established. After that, the seawater samples from Western Pacific and Aoshan Bay in Qingdao, China with the addition of various nitrate concentrations are studied to verify the reliability and accuracy of the method. The results show that the TSC-WA-KPLS algorithm shows the best results when compared against the multiple linear regression (MLR) and ISUS (in situ ultraviolet spectrophotometer) algorithms in the temperatures range of 4-25 °C, with RMSEP of 0.67 µmol/L for Aoshan Bay seawater and 1.08 µmol/L for Western Pacific seawater. The method proposed in this paper is suitable for measuring the nitrate concentration in seawater with higher accuracy, which could find application in the development of in-situ and real-time nitrate sensors.

Launch Delay of New Drugs in China and Effect on Patients' Health.

PURPOSE: Although the launch delay of new drugs in China has been a deep concern during the past few years, research on this topic is scarce. The effect of recent regulatory efforts, such as initiating fast review channels to improve access to medical innovations, remains unclear. In this work, we measure the launch delay in China and study whether the fast channels contribute to shorter delays. We also offer an examination of the effect of launch delay on patients' health. METHODS: We examined the launch delays of 40 new drugs engaged in the 3 national price negotiations in China. Launch delay was defined as the differences between the approval dates of the United States or the European Union and that of China and was measured according to approved indications of every specific drug. Thirty-four health impact models comparing the new drugs and their corresponding comparator therapies were populated with open data from published studies to assess the loss of health attributable to launch delay. The time horizon for each model was the specified delay time. FINDINGS: A total of 40 new drugs with 54 approvals were studied. The median delay was 44.40 months (range, 7.30-196.24 months). For the 20 approvals granted with the fast channels, the median delay was 38.14 months, which was shorter than the 68.25 months of those 34 approvals on the track of standard procedure (P = 0.0276). Moreover, among the 34 health models for 27 new drugs, the largest loss of health was 5.76 life-years and 4.14 quality-adjusted life-years per potential patient, whereas the least loss was 0.006 life-years per head and 0.0035 quality-adjusted life-years per head, respectively. IMPLICATIONS: Access to new drugs is delayed significantly in China, which may undermine patient benefit by causing loss of life-years and quality of life. The fast review procedures in China have appeared to mitigate the launch delay.

Tunicamycin Mediated Inhibition of Wall Teichoic Acid Affects Staphylococcus aureus and Listeria monocytogenes Cell Morphology, Biofilm Formation and Virulence.

The emergence of bacterial resistance to therapeutic antibiotics limits options for treatment of common microbial diseases. Subinhibitory antibiotics dosing, often aid in the emergence of resistance, but its impact on pathogen's physiology and pathogenesis is not well understood. Here we investigated the effect of tunicamycin, a cell wall teichoic acid (WTA) biosynthesis inhibiting antibiotic at the subinhibitory dosage on Staphylococcus aureus and Listeria monocytogenes physiology, antibiotic cross-resistance, biofilm-formation, and virulence. Minimum inhibitory concentration (MIC) of tunicamycin to S. aureus and L. monocytogenes was 20-40 µg/ml and 2.5-5 µg/ml, respectively, and the subinhibitory concentration was 2.5-5 µg/ml and 0.31-0.62 µg/ml, respectively. Tunicamycin pre-exposure reduced cellular WTA levels by 18-20% and affected bacterial cell wall ultrastructure, cell membrane permeability, morphology, laser-induced colony scatter signature, and bacterial ability to form biofilms. It also induced a moderate level of cross-resistance to tetracycline, ampicillin, erythromycin, and meropenem for S. aureus, and ampicillin, erythromycin, vancomycin, and meropenem for L. monocytogenes. Pre-treatment of bacterial cells with subinhibitory concentrations of tunicamycin also significantly reduced bacterial adhesion to and invasion into an enterocyte-like Caco-2 cell line, which is supported by reduced expression of key virulence factors, Internalin B (InlB) and Listeria adhesion protein (LAP) in L. monocytogenes, and a S. aureus surface protein A (SasA) in S. aureus. Tunicamycin-treated bacteria or the bacterial WTA preparation suppressed NF-κB and inflammatory cytokine production (TNFα, and IL-6) from murine macrophage cell line (RAW 264.7) indicating the reduced WTA level possibly attenuates an inflammatory response. These results suggest that at the subinhibitory dosage, tunicamycin-mediated inhibition of WTA biosynthesis interferes with cell wall structure, pathogens infectivity and inflammatory response, and ability to form biofilms but promotes the development of antibiotic cross-resistance.

Rapid detection and differentiation of Staphylococcus colonies using an optical scattering technology.

Staphylococcus species are a major pathogen responsible for nosocomial infections and foodborne illnesses. We applied a laser-based BARDOT (bacterial rapid detection using optical scattering technology) for rapid colony screening and detection of Staphylococcus on an agar plate and differentiate these from non-Staphylococcus spp. Among the six growth media tested, phenol red mannitol agar (PRMA) was found most suitable for building the Staphylococcus species scatter image libraries. Scatter image library for Staphylococcus species gave a high positive predictive value (PPV 87.5-100%) when tested against known laboratory strains of Staphylococcus spp., while the PPV against non-Staphylococcus spp. was 0-38%. A total of nine naturally contaminated bovine raw milk and ready-to-eat chicken salad samples were tested, and BARDOT detected Staphylococcus including Staphylococcus aureus with 80-100% PPV. Forty-five BARDOT-identified bacterial isolates from naturally contaminated foods were further confirmed by tuf and nuc gene-specific PCR and 16S rRNA gene sequence. This label-free, non-invasive on-plate colony screening technology can be adopted by the food industries, biotechnology companies, and public health laboratories for Staphylococcus species detection including S. aureus from various samples for food safety and public health management. Graphical abstract.

Study on fluorescence spectra of chlorothalonil residues and the interaction between chlorothalonil and Chinese herbal medicines.

The fluorescence spectrum was studied for the chlorothalonil (0.2928 mg x mL(-1)) using spectrofluorophotometer. The experiment results showed that the characteristic peaks (352 and 366 nm) are found in the spectrum of chlorothalonil standard solution when the excitation wavelength is 320 nm. And it was found that the shoulder peak gradually disappeared at 366 nm, while the fluorescence peak is stable at 352 nm with the decline of the solution concentration The exponential functional relationship between the concentration of chlorothalonil and fluorescence intensity at 352 nm was obtained, and its correlation coefficient is 0.999. The experimental results are consistent with the theoretical formula about fluorescence intensity and concentration The prediction model functions were also obtained through the liner fitting to the chlorothalonil solution of low concentration, and the correlation coefficient is 0. 995. The limit of detection (LOD) is 0.0188 microg x mL(-1), the limit of quantification (LOQ) is 0.0627 microg x mL(-1), and the linear range is 0.0627-28.45 microg x mL(-1). And fluorescence spectra were studied for the mixed system of astragalus, medlar and chlorothalonil. It was found that the fluorescence intensity of chlorothalonil solution is all declined with the addition of two kinds of Chinese Herbal Medicines, which indicates that there is an interaction between them. The decay rate of fluorescence intensity was obtained which is 88.5% and 99.7%, respectively. Then the model functions were established between fluorescence intensity and the volume of addition, and the correlation coefficient is 0.994 and 0.997, respectively. This study provides the experimental foundation for the detection of chlorothalonil residues using fluorescence spectrum. It is shown that it is possible to detect pesticide residues of chlorothalonil using fluorescence spectra directly, and the relevant parameter value satisfied the requirement of testing standard. Therefore there is an important value for further detecting the pesticide residues in fruit juice using fluorescence spectrum. It was also found that the fluorescence intensity of chlorothalonil is decreased with the addition of astragalus or medlar, which provides the new research approach to studying the pesticide degradation using medicinal and edible Chinese Herbal Medicines.

[Study on experiment of absorption spectroscopy detection of pesticide residues of carbendazim in orange juice].

Absorption spectra were studied for the carbendazim, in the mixed solution of orange juice and carbendazim using spectrophotometer. The most intensive characteristic peak (285 nm) was found in the spectrum of carbendazim standard solution. Compared with the carbendazim drug solution, the peak position of absorption spectrum has the blue shift (285-280 nm) when carbendazim (0.28 mg x mL(-1))was added in the orange juice. So that we can conclude that interaction happened between the orange juice and carbendazim. Through the method of least squares fitting, the prediction models between the absorbance of orange juice and carbendazim content was obtained with a good linear relationship. The linear function model was: I = 2.41 + 9.26x, the correlation coefficient was 0.996, and the recovery was: 81%-102%. According to the regression model, we can obtain the amount of carbendazim pesticide residues in orange juice. It was verified that the method of using ultraviolet-visible absorption spectra was feasible to detect the carbendazim residues in orange juice. The result proved that it is possible to detect pesticide residues of carbendazim in orange juice, and it can meet the needs of rapid analysis. This study provides a new way for the detection of pesticide residues.